No. 71
1,l-Sichlorethylene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
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DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone 'scrutiny to
ensure its technical accuracy.
-------
1,1-DICHLOROETHYLENE
Summary .
Ambient levels of 1,1-dichloroethylene have not been determined. The
primary effect of acute and chronic occupational exposure to 1,1-dichloro-
ethylene is depression of the central nervous system. In experimental ani-
mals, both liver and kidney damage have been noted after exposure, regard-
less of the route of administration. 1,1-Oichloroethylene has been shown to
be a mutagen in bacterial systems and a carcinogen in mice. Both kidney
adenocarcinomas and mammary adenocarcinomas were 'produced after exposure to
1,1-dichloroethylene by inhalation. No teratogenic effects have been ob-
served.
For freshwater fish, the reported 96-hour LC5Q values range from
73,900 to 108,000 ug/1 1,1-dichloroethylene. Reported 48-hour EC5Q values
for Daphnia magna range from 11,600 to 79,GOO ug/1. 96-Hour LC,-n values
—• - - >u
of over 22^,000 ug/1 have been observed for saltwater fish and inverte-
brates. An embryo-level test with freshwater fish resulted in an adverse
effect occurring at 2,800 ug/1. Algae, both fresh and saltwater, apparently
are not affected by concentrations of 1,1-dichloroethylene as high as
716,000 ug/1.
7/-3
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1,1-OICHLOROETHYUENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Dichloroethylenes (U.S. EPA, 1979a).
1,1-Dichloroethylene (C2H2C12; molecular weight 96.95) is a clear
colorless liquid used as a chemical intermediate in the synthesis of methyl-
chloroform and in the production of polyvinylidene chloride copolymers
(PVCDs). Prior to 1976, annual production of 1,1-dichloroethylene was ap-
proximately 120,000 metric tons (Arthur 0. Little, Inc.t 1976). 1,1-Qi-
chloroethylene has the following physical/chemical properties: water solu-
bility of 2,500 ug/ml, vapor pressure 591 mm Hg, and a melting point of
-122.1°C. For more general information regarding the dichloroethyienes,
the reader is referred to the EPA/ECAO Hazard Profile on Dichioroethyler.es
(U.S. EPA, 1979b).
II. EXPOSURE
A. Water
The National Organic Monitoring Survey (U.-S. EPA, 1978a) reported
detecting 1,1-dichloroethylene in finished drinking waters; however, neither
the amount nor the occurrence was quantified.
8. Food
Pertinent data could not be located in the available literature on
the ingestion of 1,1-dichloroethylene in foods. The U.S. EPA (1979a) has
estimated the weighted, bioconcentration factor for 1,1-dichloroethylene- to
be 6.9 for the edible portions of fish and shellfish consumed by Americans.
*•
This estimate was based on the octanol/water partition coefficient of 1,1-
dichloroethylene. '
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C. Inhalation
The population at risk due to vinylidene chloride exposure is com-
posed primarily of workers in industrial or commercial operations manufac-
turing or using it. Airborne emissions of vinylidene chloride are not like-
ly to pose a significant risk to the general population. Emissions during
production, storage, and transport can be controlled by methods similar to
those planned for control of vinyl chloride (Hushon and Kornreich, 1978).
III. PHARMACOKINETICS
A. Absorption
Specific data en the absorption of dichloroethylenes are unavail-
able. However, a recent study by McKenna, et al. (1978b) suggests that in
rats most, if not all, of the orally administered dcss is absorbed at two
dose levels: 1 and 50 mg/kg.
3. Distribution
Distribution of 1,1-dichlorcethylene v;ss studied in rats follcv;ir.g
inhalation (Jaeger, et al. 1977). The largest concentrations were found in
kidney, followed by liver, spleen, heart, and brain, and fasting made no
difference in the distribution pattern. At the subcellular level 1,1-di-
chloroethylene or its metabolites appear to bind to rnacromolecules of the
iTiicrosomes and mitochondria (Jaeger, et al. 1977). There is also some asso-
ciation with the lipid fraction.
C. Metabolism
In the intact animal, a large portion of the systemically absorbed
1,1-dichloroethylene is metabolically converted, with 36 percent appearing
in the urine of rats within 26 hours (Jaeger, et ai. 1977). The essential
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feature of 1,1-dichloroethylene metabolism is the presence of epoxide inter-
mediates, which are reactive and may form covalent bonds with tissue macro-
molecules (Henschler, 1977). In rats and mice, covalently bound metabolites
ars found in the kidney and liver (McXenna, et al. 1978b). Interaction of
1,1- dichloroethylene with the microsomal mixed function oxidase system is
not clear, since both inhibitors (dithiocarbamate) and inducers (phenobarbi-
tal) decreased the toxic effects of the compound (Anderson and- Jenkins,
1977; Reynolds, et al. 1975; Jenkins, et al. 1972). However, Carlson and
Fuller (1972) reported increased mortality from 1,1-dichloroethylene in rats
following phenobarbital pretreatment. There is evidence that the 1,1-di-
chloroethylene metabolites are conjugated with glutathione, which presumably
represents a detoxification step (McXenna, et al. 197Sa).
0. Excretion
It is speculated that 1,1-dichloroethylene has a rapid rate of
elimination, sir.ce a substantial fraction of the total absorbed oose may be
recovered in the urine within 26 to 72 hours (Jaeger, et al. 1977; McKanna,
et al. 1978a). Also, disappearance of covalently bonded metabolites of 1,1-
dichloroethylene (measured as TCA-insoluble fractions) appears to be fairly
rapid, with a reported half-life of 2 to 3 hours (Jaeger, et al. 1977).
IV. EFFECTS
A. Carcinogenicity
1,1-Oichloroethylene has been shown to produce kidney adenocarci-
nomas in male mice and mammary adenocarcinomas in female mice upon inhala-
tion of 100 mg/m3 (Maltoni, 1977; Maltoni, et al. 1977). In similar ex-
periments with Sprague-Oawley rats exposed up to 800 mg/m , no significant
increase in tumor incidence was noted. Also, hamsters exposed to t'he same
71-6
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conditions as the mice failed to exhibit an increased tumor incidence (Mai-
toni, et al. 1977). In rats exposed to 1,1-dichloroethylene in their drink-
ing water (200 mg/1), there was no evidence of increased tumors (Rampy, et
al. 1977).' There was an increased incidence of mammary tumors in rats re-
ceiving 20 mg of 1,1-dichloroethylene by gavage 4 to 5 days a week for 52
weeks. The incidence was 42 percent in the treated animals and 34 percent
in the controls; however, the data was not analyzed statistically (Maltoni,
et al. 1977).
B. Mutagenicity
1,1-Dichloroethylene has been shown to be mutagenic in S^ typhimu-
rium (Bartsch, et al. 1975) and E^ coli K12 (Greim, et al. 1975). In both
systems, mutagenic activity required microsomal activation. In mammalian
systems, 1,1-dichloroethylene was negative in the dominant lethal assay
(Short, et al. 1977b; Andersen, et al. 1977).
C. Teratcgenicity
A study by Murrary, et al. (1979) failed to shcv/ tsratogenic af-
fects in rats or rabbits inhaling concentrations cf up to 160 ppm 1,1-di-
chloroethylene for 7 hours per day or in rats given drinking water contain-
ing 200 ppm 1,1-dichloroethylene.
0. Other Reproductive Effects
Pertinent data could not be located in the available literaure.
E. Chronic Toxicity
In animal studies, liver damage is associated with exposure, either
in the air or water, to 1,1-dichloroethylene (6 jdg/m or 0.79 pg/1) with
transitory damage appearing as vacuolization in liver cells. In both guinea
»
pigs and monkeys, continuous exposure to 1,1-dichloroethylene produced in-
creased mortality, while intermittent exposure to the same concentration in
-------
air produced no increase in mortality (U.S..EPA, 1979a). Less attention has
been paid to the renal toxicity of 1,1-dichloroethylene despite the occur-
rence of histologically demonstrated damage at exposures equal to or less
than those required for hepatotoxicity (Predergast, et al. 1967; Short, at
al. 1977a).
F. Other Relevant Information
Alterations in tissue glutathione concentrations affect the hepato-
toxicity of '1,1-dichloroethylene, with decreased tissue glutathione asso-
ciated with greater toxicity and elevated glutathione associated with de-
creased toxicity (Jaeger, et al. 1973,1977).
V. AQUATIC TOXICITY
A. Acute Toxicity
Dill, et al. calculated, for the fathead minnow, Pimephales prome-
las, 96-hour 1C--, values of 169,000 jug/1 using static tachnicues and
1CS,CCO ug/1 using flow-through tasts with measured concentrations. The re-
ported 96-hour LC--, value for the bluegill, Leoomis mactochirjs, is 73,900
ug/1 in a static test (U.S. EPA, 1978b). Two 48-hour tests with Daphnia
maona resulted in ECcg values of 11,600 and 79,000 jjg/1, respectively
(Dill, et al.; U.S. EPA, 1978b). The 96-hour LC5Q values for the sheeps-
heao minnow, Cyorinodon varieoatus, and the tidewater silversioe, Menidia
beryllina, are 249,000 and 250,000 ug/1, respectively (U.S. EPA, 1978b; Daw-
son, et al. 1977). The 96-hour LC^,, for the mysid shrimp, Mysidoosis
bahia, is reported to be 224,000 ug/1 (U.S. EPA, 1978b).
B. Chronic Toxicity
An embryo-larval test with the fathead minnow resulted in no ad-
•
verse effects occurring at 2,800 /jg/1, the highest test concentration (U.S.
EPA, 1978b).
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C. Plant Effects
The 96-hour EC-- value based on cell numbers of the freshwater
alga, Selenastrum capricornutum, is reported to be greater than 798,000 ug/1
(U.S. EPA,-1978b). The effective concentration of 1,1-dichloroethylene on
the saltwater alga, Skeletonema costatum, was observed to be 712,CGO ug/1
(U.S. EPA, 1978b).
D. Residues
Pertinent data could not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The American Conference of Governmental Industrial Hygienists
(ACGIH, 1977) threshold limit value (TLV) for 1,1-dichloroethylene is 40
mg/m , with calculated daily exposure limits of 286 mg/day. 1,1-Oichloro-
ethylene is suspected of being a human carcinogen; and using the "one-hit"
model, the U.S. EPA (1979a) has estimated levels of l,l-dichlcrcethyler:e in
ambient water which will result in soecified risk levels of human cancer:
Exposure Assumptions Risk Levels with Corresponding Draft Criteria
(per day)
10-7 ig-6 ig-5
2 liters of drinking water 0.013 ug/1 0.13-.ug/1 1.3 jjg/1
and consumption of 18.7
grams fish and shellfish.
Consumption of fish and 0.21 ug/1 2.1 ug/1 21 jug/1
shellfish only.
8. Aquatic
For 1,1-dichloroethylene, the drafted criterion to protect fresh-
water aquatic life is 530 ug/1 as a 24-hour average, not to exceed 1,200
»
/jg/1 at any time. No saltwater criterion has been proposed because of in-
sufficient data.
7'-?
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1,1-OICHLOROETHYLENE
REFERENCES
American Conference of Governmental Industrial Hygienists. 1977. Documen-
tation of the threshold limit values. 3rd ed.
Anderson, 0., et al. 1977. Dominant lethal studies with the halogenated
olefins vinyl chloride and vinylidene dichloride in male CD-I mice. Envi-
ron. Health Perspect. 21: 71.
Anderson, M.E. and L.J. Jenkins, Jr. 1977. Enhancement of 1,1-dichloro-
ethylene hepatotoxicity by pretreatment with low molecular weight epoxides.
Proc. Soc. Toxicol. 41.
Arthur D. Little, Inc. April, 1976. Vinylidene Chloride monomer emissions
from the monomer, polymer, and polymer processing industries, Arthur 0. Lit-
tle, Inc., for the U.S. Environ. Prot. Agency, Research Triangle Park, N.C.
Bartsch, H., et al. 1975. Tissue-mediated mutagenicity of vinyiidene
chloride and 2-chlorobutadiene in Salmonella tyohirnurium. Nature. 255: 641.
Carlson, G.P. and G.C. Fuller. 1972. Interactions of modifiers of hepatic
microscmal drug metabolism and the inhalation toxicity of 1,1-dichloroethyl-
ene. Res. Comm. Chem. Pathol. Pharmacoi. 4: 553.
Dawson, G.w., et al. 1977. The acute toxicity of 47 industrial chemicals
to fresh and saltwater fisn.es. Jour. Hazard Mater. 1: 303.
Oiil, O.C., at al. Toxicity of 1,1-dicnlcroethylene (vinylidene chloride)
to aquatic organisms. Dow Chemical Co. (Manuscript)
Greim, H., et al. 1975. Mutagenicity in vitro and potential carcinogeni-
city of chlorinated ethylenes as a function of metabolic oxirane formation.
Siochem. Pharmacoi. 24: 2013.
Henschlar, D. 1977. Metabolism and mutagenicity of halogenated olefins - A
comparison of structure and activity. Environ'. Health Perspect. 21: 61.
Hushon, J. and M. Kornreich. 1978. Air pollution assessment of vinylidene
chloride. EPA-450/3-78-015. U.S. Environ. Prot. Agency, Washington, O.C.
Jaeger, R.J., et al. 1973. Diurnal variation of hepatic glutathione con-
centration and its correlation with 1,1-dichloroethylene inhalation toxicity
in rats. Res. Comm. Chem. Pathol. Pharmacoi. 6: 465..
Jaeger, R.L., et al. 1977. 1,1-Oichloroethylene hepatotoxicity: Proposed
mechanism of action of distribution and binding of ^C-radioactivity^ f0j__
lowing inhalation exposure in rats. Environ. Health Perspect. 21: 113!
Jenkins, L.I., et al. 1972. Biochemical effects of 1,1-dichlorpethylene in
rats: Comparison with carbon tetrachloride and 1,2-dichloroethylene. Toxi-
col. Appl. Pharmacoi. 23: 501.
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Maltoni, C. 1977. Recent findings on the. carcinogenicity of chlorinated
olefins. Environ. Health Perspect. 21: 1.
Maltoni, C., et al. 1977. Carcinogenicity bioassays of vinylidene chlor-
ide. Research plan and early results. Med. Lav. 68: 241.
McKenna, M.J., et al. 1978a. The pharmacokinetics of (14C) vinylidene
chloride in rats following inhalation exposure. Toxicol. Appi. Pharmacol.
45: 599.
McKenna, M.J., et al. 1978b. Metabolism and pharmacokinetics profile of
vinylidene chloride in rats following oral administration. Toxicol. Appl.
Pharmacol. 45: 821.
Murray, F.J., et al. 1979. Embryotoxicity and fetotoxicity of inhaled or
ingested vinylidene chloride in rats and rabbits. Toxicol: Appl. Pharma-
col. 49: 189.
Prendergast, J.A., et al. 1967. Effects on experimental animals of long-
term inhalation of trichloroethylene, carbon tetrachloride, 1,1,1-trichloro-
ethane, dichlbrodifluoromethane, and 1,1-dichloroethylene. Toxicol. Appl.
Pharmacol. 10: 270.
Rampy, L.W., et al. 1977. Interim results of a two-year toxicological
study in rats of vinylidene chloride incorporated in the drinking water or
administered by repeated inhalation. Environ. Health Perspect. 21~: 33.
Reynolds, E.S., et al. 1975. Hepatoxicity of vinyl chloride and 1.1-di-
chioroethylene. Am. Jour. Pathol. 81: 219.
Short, R.D., et al. 1977a. Toxicity of vinylidene cnloride in mice and
rats and its alteration by various treatments. Jour. Toxicoi. Environ.
Health. 3: 913.
Short, R.D., et al. 1977b. A dominant lethal study in male rats after re-
peated exposures to vinyl chloride or vinylidene chloride. Jour. Toxicol.
Environ, health. 3: 965.
U.S. EPA. 1973a. Statement of basis and purpose for an amendment to cne
National interim primary drinking water regulations on a treatment technique
for synthetic organics. Off. Drinking Water. U.S. Environ. Prot. Agency,
Washington, D.C.
U.S. EPA. 1978b. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646, U.S. Environ. Prot.
Agency.
U.S. EPA. 1979a. Dichloroethylenes: Ambient Water Quality Criteria Docu-
ment. (Draft)
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Dichloro-
ethylenes: Hazard Profile. (Draft)
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No. 72
trana-l,2-Oichloroethylene
Health and environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracv.
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TRANS-1,2-DICHLQRETHYLENE
SUMMARY
There is little specific information available on trans-
1,2-dichloroethylene. This compound is quantitatively less
toxic than the 1,1-dichloroethylene isomer; however, the
toxicity appears qualitatively the same with depression
of the central nervous system as well as liver and kidney
damage. Trans-l,2-dichloroethylene has been shown to be
a mutagen in bacterial systems. The teratogenicity and
carcinogenicity of this compound have not been evaluated.
In the only aquatic study reported, the observed 96-
hour LCeg value for the bluegill is 135,000 pg/1 in a static
bioassay.
7*-}
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TRANS-1,2-DICHLORETHYLENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Dichloroethylenes (U.S. EPA, 1979).
Trans-1,2-dichloroethylene (traans 1,2-DCE; C-tUCl-;
molecular weight 96.95) is a clear colorless liquid. Since
the early 1960's trans-l,2-dichloroethylene has had no wide
industrial usage (Patty, 1963). Trans-l,2-dichloroethylene
has the following physical/chemical properties: water
solubility of 6,300 ug/ml, a vapor pressure of 324 mm Hg,
and a melting point of -50°C (Patty, 1963).
II. EXPOSURE
A. Water
Trans-l,2-dicnloroethylene was found at a concen-
tration of 1 ug/1 in Miami drinking water (U.S. EPA, 1975,
1978) .
B. Food
Pertinent data could not be located in the avail-
able literature on the ingestion of trans-1,2-dichloroethylene
in foods. The U.S. EPA (1979) has not estimated a biocon-
centration factor for trans-1,2-dichloroethylene.
C. Inhalation
Pertinent information could not be located in
the available literature.
7 a.-4/
- V/J*
"^5^7
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III. PHARMACOKINETICS
A. Absorption
Animal or human studies do not appear to exist
which specifically document the degree of systemic absorp-
tion of trans-l,2-dichloroethylene by any route.
B, Distribution
Pertinent data could not be located in the avail-
able literature.
C. Metabolism
Trans-l,2-dichloroethylene is metabolized through
an epoxide intermediate to either a dichloroacetaldehyde
or monochloroacetic acid (Liebman and Ortiz, 1977). The
epoxide intermediate which is reactive, may form covalent
bonds with tissue macromolecules (Henschler, 1977). Meta-
bolism of the cis-isomer relative to the amount tak'en up
by the liver was much greater than the trans-isomer (McKenr.a,
et al. 1977).
D. Excretion
Pertinent data could not be located in the avail-
able literature.
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not be located in the avail-
*
able literature.
B. Mutagenicity
»
Trans-l,2-dichloroethylene has been shown to be
negative in the E^ coli K12 and Salmonella mutagenicity
assays (Greim, et al. 1975; Cerna and Kypenova, 1977).
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C. Teratogenicity and Other Reproductive Effects
Pertinent information could not be located in
the available literature.
D. Chronic Toxicity
Although little data is available specifically
on trans-1,2-dichloroethylene, it appears that chronic expo-
sure results in kidney and liver damage similar to that
noted with 1,1-dichloroethylene (U.S. EPA, 1979). Jenkins,
et al. (J.972) found trans-l,2-dichloroethylene to be consider-
ably less potent than 1,1-dichloroethylene.
V. AQUATIC TOXICITY
A. Acute Toxicity
The reported 96-hour LC^Q value for the bluegill,
Lepomis macrochirus, exposed to 1,2-dichloroethylene is
135,000 ug/1 (U.S. EPA, 1979) in a static test procedure.
B. Chronic Toxicity, Plant Effects and Residues
Pertinent information could not be located in
the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The American Conference of Governmental Industrial
Hygienists (ACGIH, 1977) threshold limit value (TLV) for
1,2-dichloroethylene is 790 mg/m , with calculated daily
exposure limits of 5,643 mg/day. The U.S. EPA (1979) draft
Water Quality Criteria Document for Dichloroethylene stat.es
that human health criterion could not be derived due to
the lack of sufficient data on which to base a criterion.
74-6
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B. Aquatic
Guidelines do not exist for salt water species
because of insufficient data. The draft criterion to pro-
tect freshwater aquatic life is 530 ^g/1 as a 24-hour aver-
age and not to exceed 1200 pq/1 at any time (U.S. EPA, 1979).
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TRANS 1,2-DICHLOROETHYLENE
REFERENCES
American Conference of Governmental Industrial Hygienists.
1977. Documentation of the threshold limit value. 3rd. ed.
Cerna, M. , and H. Kypenova. 1977. Mutagenic activity of.
chloroethylenes analyzed by screening system tests. Mutat.
Res. 46: 214.
Greim, H., et al. 1975. Mutagenicity in vitro and potential
carcinogenicity of chlorinated ethylenes as a function of
metabolic oxirana formation. Biochem. Pharmacol. 24: 2013.
Henschler, D. 1977. Metabolism and mutagenicity of halo-
genated olefins - A comparison of structure and activity.
Environ. Health Perspect.' 21: 61.
Jenkins, L.J., et al. 1972. Biochemical effects of 1,1-di-
chloroethylene in rats: Comparisons with carbon tetrachloride
and 1,2-dichloroethylene. Toxicol. Appl. Pharmacol. 23: 501.
Leibman, K.C., and E. Ortiz. 1977. Metabolism of halogen-
ated ethylenes. Environ. Health Perspect. 21: 91.
McKenna, M.J., et al. 1977. The pharmacokinetiLcs of i^c]
vinylidene chloride in rats following inhalation exposure.
Toxicol. Appl. Pharmacol. 45: 599.
Patty. F.A. 1963. Aliphatic halogenated hydrocarbons. Ind.
Hyg. Tox. 2: 1307.
U.S. EPA. 1975. Preliminary assessment of suspected carcin-
ogens in drinking water. Rep. to Congress. Off. Toxic
Subst. U.S. Environ. Prot. Agency, Washington, D.C.
U.S. EPA. 1978. List of organic compounds identified in
U.S. drinking water. Health Effects Res. Lab. U.S. Environ.
Prot. Agency, Cincinnati, Ohio.
U.S. EPA. 1979. Dichloroethylenes: Ambient Water Quality
Criteria. (Draft).
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No. 73
Dlchloroethylanes
Health and Environmental Effaces
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
73-1
-------
DISCLAIMER
This report represents a survey of the.potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
73-3-
-------
DICHLOROETHYLENES
Summary
Of the three dichloroethylene isomers, cis 1,2-dichloroethylene,
trans 1,2-dichloroethylene, and 1,1-dichloroethylene, only the 1,1-dichloro-
ethylene isomer is produced in large quantities. Most of the health
effects information available is related to the 1,1-dichloroethylene
isomers; however, qualitatively the toxicity of the 1,2-dichloroethylene
isomers appears to be similar, with depression of the central nervous
system and liver and kidney damage. Of the three isomers, 1,1-dichloro-
ethylene is the most toxic. Both 1,1-dichloroethylene and trans 1,2-
dichloroethyler.e are autagenic in bacterial systems. Only 1,1-dichloro-
ethylene has been shown to be a carcinogen.
All of the available aquatic data, with one exception, are for 1,1-
dichlcroethyiene. Reported 96-hour [,€50 values for the bluegill are 73,900
and 135,500 ug/1, respectively, for 1 , 1-dicnlorcehtylene and 1,2-di-
chloroethylene. Two observed 46-hcur ^€50 values for Daphnia exposed to
1,1-dichloroethylene range were 11,600 and 79,000 ug/1. All saltwater
fish and invertebrates tasted with 1,1-dichioroethylene showed 96-hour
LC5Q values over 224,000 ug/1, and all algae tested both in fresh and
saltwater, had 96-hour EC^g values (based on cell numbers) of 716,000
and over. In the only reported chronic study, no adverse effects were
observed at the highest test concentration of 2,800 ug/1 for fathead
minnows exposed to 1,1-dichloroethylene.
73-3
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DICHLOROETHYLENES
I. INTRODUCTION
This profile is based on the draft Ambient Water Quality Criteria
Document for Dichloroethylenes (U.S. EPA, 1979).
The dichloroethylenes (^2^2^2'i molecular weight 96.95) consist of
the three isomers: 1,1-dichloroethylene, cis- 1,2-dichloroethylene, and
trans-l,2-dichloroethylene. Dichloroethylenes are clear colorless liquids
with water solubilities between 2,500 and 6,300 ug/1, vapor pressures
v
between 591 and 208 mm Hg, and melting points between -50°C and -122°C
(U.S. EPA, 1979). The 1,1-dichloroethylene isomer is the most extensively
used in industry, with annual production prior to 1976 of approximately
120,000 metric tons (Arthur D. Little, Inc., 1976). The 1,1-dichloroethylene
isomer is used as a chemical intermediate in the synthesis of methylchloroform
ana in the production of pclyvinylidene chloride copciymers (FVDCs).
II. EXPOSURE
I.
A. water
The National Organic Monitoring Survey (U.S. EPA, 1973a) reported
detecting 1,1-dichloroethylene in finished drinking waters; however,
neither the amount nor the occurrence was quantified. Both cis and trans-
1,2-dichlcroethylene were found at concentrations of 16 and 1 ug/1,
respectively, in Miami drinking water (U.S. EPA, 1975, 1978b).
B. Food
Pertinent data could not be located on the ingestion of dichloro-
ethylene in foods. The U.S. EPA (1979) has estimated the weighted bioconcen-
tration factor for 1,1-dichloroethylene to be 6.9 for the edible portions of
73-/
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fish and shellfish consumed by Americans. This estimate is based on the
octanol/water partition coefficients of 1,1-dichloroethylene. There is no
estimate for a bioconcentration factor for the other iscrners.
C. Inhalation
The population at risk due to vinylidene chloride exposure is composed
primarily of workers in industrial or commercial operations manufacturing or
using it. Airborne emissions of vinylidene chloride are not likely to pose a
significant risk to the general population. Emissions during production,
storage, and transport can be controlled by methods similar to those planned
for control of vinyl chloride (Hushon and Kornreich, 1978)
•
III. PHARMACOKINETICS
A. Absorption
Specific data on the absorption of dichloroethylenes are unavailable.
However, a recent study by McXenna, et al. (1973b) suggests that in rats most,
if not all, of the orally administered dose is absorbed at two dose levels: 1
and 50 35/kg.
B. Distribution
Distribution of 1,1-dichloroethylene was studied in rats following
inhalation (Jaeger, et al. 1977). The largest concentrations were found in
kidney, followed by livsr, spleen, heart, ar.d brain; and fasting made no
difference in the distribution pattern. At the subcellular level 1,1-dichloro-
ethylene or its metabolites appear to bind to macromolecules of the microsomes
and mitochondria (Jaeger, et al. 1977). There is also some association with
the lipid fraction. Distl,2-dichloroethylene isomers, are not available.
C. Metabolism
The essential feature of all dichloroethylene metabolism is the
presence of epoxide intermediates which are reactive and may form covalent
-------
bonds with tissue raacromolecules (Henschler, 1977). In rats and mice,
covalently bound metabolites of 1,1-dichloroethylene are found in the
kjdney and liver (McKenna, et al. 1978b). Interaction of dichloroethylenes
with the microsomal mixed function oxidase system is not clear,' since
both inhibitors (dithiocar'oamate) and inducers (phenobarbital) decreased
the toxic effects of 1,1-dichloroethylene (Anderson and Jenkins, 1977;
Reynolds, et al. 1975; Jenkins, et al. 1972). Carlson and Fuller (1972),
however, reported increased mortality from 1,1-dichloroethylene in rats
following phenobarbital pretreatment. There is evidence that the 1,1-
dichloroethylene metabolites are conjugated with gluthathione, which
presumably represents a detoxification step (McKenna, et al. 1978b).
B. Excretion
The only information available on elimination pertains to the
1,1-dichlorcethylene isc~er. It is postulated that the 1,1-dichloro-
ethylane isorner has a rapid rate of elimination since a substantial
fraction of the total absorbed dose may be recovered in urine within 26
to 72 hours (Jaeger, et al. 1977; McKenna, et al. 1978a). Also, dis-
appearance of covalently bonded metabolites of 1,1-dichloroethylene
(measured as TCA-insoluble fractions) appears to be fairly rapid, with a
reported half-life of 2 to 3 hours (Jaeger, et al. 1977).
IV. EFFECTS
A. Carcinogenicity
There is only data on the carcinogenicity of the 1,1-dichloro-
ethylene isomer. This isomer has been shown to produce kidney adeno-
carcinomas in male mice and mammary- adenocarcinomas in female mice upon
«
inhalation of 100 mg/m3 (Maltoni, et al. 1977; Maltoni, 1977). In
-------
similar experiments with Sprague-Dawley rats exposed as high as 800 mg/m^ f
no significant increase in tumor incidence was noted. Hamsters exposed
to the same conditions as the mice failed to exhibit an increased tumor
incidence-(Maltoni, et al. 1977). In rats exposed to 1,1-dichloroethylene
in their drinking water (200 mg/1) there was no evidence of increased
tumors (Rampy, et al. 1977). There was an increased incidence of mammary
tumors in rats receiving 20 mg of 1,T-dichloroethylene by gavage U to 5
days a week for 52 weeks. The incidence was 42 percent in the treated
animals and 31* percent in the controls; however, the data was not analyzed
statistically (Maltoni, et al. 1977).
B. Mutagenicity
1,1 -Dichloroethylene has been shown to be mutagenic in S_._ typhimuriuj
(Bartsch, et al. 1975) and Z^ coli K12 (Greim, et al. 1975); however,
both the cis and trans iscaers of 1,2-dichioroethylene were non-mucagenic
when assayed with £_._ coli K"2. In order to demonstrate mutagenic activity,
1,1-dichloroethylene needed microsomal activation. In addition, cis
1,2-dichloroethylene was tnutagenic in Salmonella tester strains, and
promoted chromosomal aberrations in cytogenic analysis of bone marrow
cells (Cerna and Kypenova, 1977). In mammalian systems, 1,1-dichloroethylene
was negative in the dominant lethal assay (Short, et ai. 1977b; Anderson,
et al. 1977).
C. Teratogenicity
A study by Murray, et al. (1979) failed to show teratogenic
,-
effects in rats or rabbits inhaling concentrations of up to 160 ppm 1,1-di-
chloroethylene for 7 hr/day or in rats given drinking water containing
»
200 ppm 1,1-dichloroethylene.
? 1-
-------
D. Other Reproductive Effects
Pertinent data could not be located in the available literature.
E. Chronic Toxicity
In- animal studies, liver damage is associated with exposure
either in the air or water, to dichloroethylenes (6 mg/m3 or 0.79 mg/1)
with transitory damage appearing as vacuolization in liver cells (U.S.
EPA, 1979). Jenkins, et al. (1972) found both cis and trans 1,2-dichloro-
ethylene to be considerably less potent than 1,1-dichloroethylene as a
hepatotoxin. Less attention has been paid to the renal toxicity of the
dichloroethylenes despite the occurrence of histologically demonstrated
damage at 1,1-dichloroethylene exposures equal to or less than those
required for hepatoxicity (Prendergast, et al. 1967; Short, et al. 1977a).
F. Other Relevant Information
Alterations in tissue glutathione concentrations affect the
hepatotoxicity of 1,1-dichloroethylene, with decreased tissue slutathicr.e
associated with greater toxicity and elevated gluthachione associated
with decreased toxicity (Jaeger, et al. 1973, 1977).
V. AQUATIC TOXICITY
A. Acute Toxicity
All of the available data for dichloroethyiene, with one exception,
are for 1,1-dichloroethylene. The data on acute static tests with bluegill,
Lepomis macrochirus, under similar conditions show a correlation between
the degree of chlorination and toxicity. The 96-hour LC5Q values for the
bluegill are 73,900 and 135,000 ug/1 for 1,1- and 1,2-dichloroethylene,
respectively. Additional data for other ethylene chlorides are as follows: 44,700
»
ug/1 for trichloroethylene, and 12,900 ug/1 for tetrachloroethylene (U.S.
EPA, 1978c). These results indicate an increase in the lethal effect on
bluegills with an increase in chlorine content.
73-?
-------
The 96-hour LC5Q value for the sheepshead minnow, Cypuimocen variegatus,
tidewater silverside, Menidia beryllina, and mysid shrimp, Mysidepsis
behia, following exposure to 1,1-dichloroethylenes are all over 224,000
ug/1 (U.S. EPA, 1978c).
B. Chronic Toxicity
In the only reported chronic study, an embryo-larval test in
fathead minnows, no adverse effects were observed at the highest test
concentration of 1,1-dichloroethylene, 2800 _ug/l (U.S. EPA, 1979).
C. Plant Effects
The 96-hour £050 values based on cell numbers of the freshwater
algae, Salenestr-un: capriecrr.utur. and the saltwater algae, Sksletcns-a
costatum, are 798,000 and 712,000 ug/1, respectively, for exposure to
1,1-dichloroethylsne (U.S. EPA, 1978c).
D. Residues
Pertinent information could not be located in the available
literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The American Conference of Governmental Industrial Hygienists
(ACGIH, 1977) threshold limit values (TLV) are 40 mg/m3 (1,1-dichloro-
ethylene) and 790 mg/ni3 (1,2-dichloroethylene). These values allow daily
exposures of 286 ag 1,1-dichloroethylene per day and 5,643 eg 1,2-di-
chloroethylene per day. The U.S. EPA (1979) draft water criteria document
f
for dichloroethylene states that no human health criterion could be derived
for cis- and trans-l,2-dichloroethylene due to the lack of sufficient
data on which to base a criterion. 1,1-dichloroethylene is suspected of
-------
being a human carcinogen, and using the "one-hit" model, the U.S. EPA
(1979) has estimated levels of 1,1-dichloroethylene in ambient water
which will result in specified risk levels of human cancer:
Exposure Assumptions
(per day)
2 liters of drinking water
and .consumption of 18.7
grams fish and shellfish
Consumption of fish and
shellfish only.
Risk levels and Corresoondine Draft Criteria
10'
10
-6
0.013 ug/1 0.13 ug/1
0.11 ug/1 2.1 ug/1
IP"3
•1.3 ug/1
21 ug/1
B. Aquatic
The -proposed draft criterion to protect freshwater species
from dichlcroethylene toxicity are as follows (U.S. EPA._ 1979):
Compound
1,1-dichloroethylene
1,2-dichloroethylene
For saltwater species:
1,1-dichioroethylene
1,2-dichloroethylene
2*4-hr. Average
530 us/I
620 ug/1
1,700 ug/1
Not available
Concentration not to be
exceeded at anytime
1,200 us/1
1,400 ug/1
3,900 ug/1
Not available
-------
DICHLOROETHYLENES
References
American Conference of Governmental Industrial Hygenists. 1977. Docu-
mentation of.the threshold limit values. 3rd ed.
Anderson, p., et al. 1977. Dominant lethal studies with the halogenatea
olefins vinyl chloride and vinylidene dichloride in male CO-i mice.
Environ. Health Perspect. 21: 71.
Anderson, M.E. and L.J. Jenkins, Jr. 1977. Enhancement of 1,1-dichloro-
ethylene hepatotoxicity by pretreatment with low molecular weight epoxides.
Proc. Soc. Toxicol. 41.
Arthur D. Little, Inc. April, 1976. Vinylidene chloride monomer emissions
from the monomer, polymer, and polymer processing industries, Arthus D.
Little, Inc., for the U.S. Environ. Prot. Agency, Research Triangle Park,
N.C.
Bartsch, H., 'et al., 1975. Tissue-mediated mutagenicity of vinylidene
chloride and 2-chiorobutadiene in Salmonella tv^himurii:". . Mature 255: 641.
Carlson, G.P. and G.C. Fuller. 1972. Interactions of modifiers of hepatic
microsomal drug metabolism and the inhalation toxicity of 1,1-dichloro-
ethylene. Res. Comm. Chem. Pathol. Pharmacol. 4: 553.
Carna, M., and H. Xypenova. 1977. The acute toxicity of 47 industrial
chemicals to fresn and saltwater fishes. Jour. Hazsrc. Mater, i: 3C3.
Dill, O.C., et al. Toxicity of 1,1-dichlcroethylene (vinylidene chloride)
to aquatic organisms. Dow Chemical Co. (Manuscript).
Greim, H., et al. 1975. Mutagenicity in vitro and potential carcino-
genicity of chlorinated ethylenes as a function of metabolic oxirane forma-
tion. Biochem. Pharmacal. 24: 2013.
Henschler, D. 1977. Metabolism and mutagenicity of halogenated ol'efins - a
comparison of structure ana activity. Environ. Health Fersoect. 21: 6i.
Hushon, J. and M. Kornreich. 1978. Air pollution assessment of vinylidene
chloride. EPA-480/3-78-015. U.S. Environ. Prot. Agency, Washington, D.C. "
Jaeger, R.J. 1973. Diurnal variation of hepatic glutathions concentration
and its correlation with 1,1-dichloroethylene inhalation toxicity in rats.
Res. Comm. Chem. Pathol. Pharmacol. 6: 465.
Jaeger, R.L., et al. 1977. 1,1-Dichloroethylene hepatotoxicity: Proposed
mechanism of action of distribution and binding of ^C radioactivity fol-
lowing inhalation exposure in rats. Environ. Health Perspect. 21: 113,
-------
Jenkins, L.J., et al. 1972. Biochemical effects of 1,1-dichloroethylene in
rats: Comparison with carbon tetrachloride and 1,2-dichloroethylene.
Toxicol. Appl. Fharmacol. 23: 501.
Maltoni, C. 1977. Recent findings on the carcinogenicity of chlorinated
olefins. Environ. Health Perspect. 21: 1.
Maltoni, C., et al. 1977. Carcinogenicity bioassays of vinylidene
chloride. Research plan and early results. Med. Law. 63: 241.
McKenna, M.J.. et al. 1978a. The pharmokinetics of [14C] vinylidene
chloride in rats following inhalation, exposure. Toxicol. Appl. Pharmacol.
45: 599.
McKenna, M.J., et al. 1978b. Metabolism and pharmokinetic profile of
vinylidene chloride in rats following oral administration. Toxicol. Appl.
Pharmacol. 45: 821.
Murray, F.J., et al. 1979. Embryotoxicity and fetotoxicity of inhaled or
ingested vinylidene chloride in rats and rabbits. Toxicol. Appl.
Pharmacol. 49: 139.
Prendergast, J.A., et al. 1967. Effects on experimental animals of long-
term inhalation of trichloroethylane, carbon tetrachloride, 1,1,1-trichioro-
ethans, dichlorodifluorcmethane, and 1,1-dichloroethylene. Toxicol. Appl.
Pharmacol. 10: 270.
Rsmpy, L.W., et =1. 1977. Interim results of a tv/o-yesr toxicologies!
study in rats of vir,yiidene chloride incorporated in the drinking water or
administered by repeated inhalation. Environ. Health Psrspect. 21: 33.
Reynolds. E.S., et al. 1975. Hepatoxicity of vinyl chloride and
1,1-dichloroethylene. Am. Jour. Pathol. 81: 219.
Short, R.D., et al. 1977a. Toxicity of vinylidene chloride in mice and
rats and its alteration by various treatments. Jour, Toxicol. Environ.
Health 3: 913.
Short, R.O., et al. 1977b. A dominant lethal study in male rats after
repeated exposure to vinyl chloride or vinylidene chloride. Jour. Toxicoi.
Environ. Health 3: 965.
U.S. EPA. 1975. Preliminary assessment of suspected carcinogens in
drinking water, Rep. to Congress. Off. Toxic Subst. U.S. Environ. Prot.
Agency, Washington, D.C.
U.S. EPA. 1978a. Statement of basis and purpose 'for an amendment to the
National interim primary drinking water regulations on a treatment technique
for synthetic organics. Off. Drinking Water. U.S. Environ. Prot. Agency,
Washington, O.C.
U.S. EPA. 1978b. List of organic compounds identified in U.S. drinking
water. Health Effects Res. Lab. U.S. Environ. Prot. Aoency, Cincinnati,
Ohio.
-------
U.S. EPA. 1978c. In-depth studies on health and environmental impacts of
selected water pollutants. Contract NO. 68-01-4646. U.S. Environ. Prot.
Agency.
U.S. EPA. 1979. Dichloroethylenes: Ambient Water Quality Criteria.
(Draft).
73-'?
-------
SJ-46-04
DRAFT
10-21-80
No. 74
Dichloromethane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C. 20460
October 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health and
environmental hazards from exposure to the subject chemical. The
information contained in the report is drawn chiefly from secondary
sources and available reference documents. Because of the limi-
tations of such sources this short profile may not reflect all
available information including all the adverse health and
environmental impacts presented by the subject chemical. This
document has undergone scrutiny to ensure its technical accuracy.
74-2
-------
DICHLOROMETHANE (DCM)
SUMMARY
In humans, DCM is a central nervous system depressant
resulting in narcosis at high concentrations, and impaired task
performance. Dichloromethane is metabolized to carbon monoxide
and causes an increase in carboxyhemoblogin, placing persons with
cardiovascular disease, and perhaps those-who are pregnant, at
increased risk of disease. On the basis of present evidence, DCM
cannot be firmly identified as an animal or human carcinogen.
DCM has been shown to be mutagenic to Salmonella, but not to
S. cerevisia and Drosophi'la, and causes cell transformation.
Aquatic organisms are fairly resistant to dichloro-
methane, with acute toxicity values ranging from 193,000 to 331,000
ug/1.
74-?
-------
DICHLOROMETHANE
I.< INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Ha'lomethanes (U.S. EPA, 1979a).
Dichloromethane (CH2C12, methylene chl'oride, methylene
dichloride, and methylene bichloride; molecular weight 84.93) is
a colorless liquid with a melting point of -95.18C, a boiling
point of 40°C, a. specific gravity of 1.327 g/ml at 20°C, a vapor
e
pressure of 362.4 mm Hg at 20*C, and a solubility in water of
13.2 g/1 at 25°C. Dichloromethane is a common industrial solvent
found in insecticides, metal cleaners, -paints, and paint and
varnish removers (Balmer, et al., 1976). In 1976, 244,129 metric
tons were imported (U.S. EPA, 1977). For additional information
regarding the halomethanes as a class, the reader is referred to
the Hazard Profile on Halomethanes (U.S. EPA, 1979b).
II. EXPOSURE
A. Water
The U.S. EPA (1975) has identified dichloromethane in
finished drinking waters in the U.S. in R of 83 sites, with a
maximum level of 0.007 mg/1 and a median of less than 0.001
mg/1. The dichloromethane in drinking water is not a product of
water chlorination (U.S. EPA, 1975; Morris and McKay, 1975). In
the national organics monitoring survey, dichloromethane was
detected in 15 of 109 sites, with a mean concentration (positive
results only) of 0.0061 mg/1 (U.S. EPA, 1978).
74-4
-------
B. Food
Pertinent information could not be located in the
available literature.
C. Inhalation
Reported background concentrations of dichloromethane
in both continental and saltwater atmospheres were about 0,0001?.
mg/m^, and urban air concentrations ranged from less than 0.00007
to 0.00005 mg/m^. Local indoor concentrations can be high due to
the use of aerosol sprays or solvents (Natl. Acad. Sci., 1978).
III. PHARMACOKINETICS
A. Absorption
Efficiences of absorption of dichloromethane by the
lungs are between 30 to 75 percent, depending on length of
exposure, concentration, and activity level (Natl. Acad. Sci.,
I
1978; Natl. Inst. Occup. Safety a.nd Health, 1976).
B. Distribution
Upon inhalation and absorption, dichloromethane levels
increase rapidly in the blood to equilibrium levels that depend
primarily upon atmosphere concentration (Natl. Acad. Sci., 1978).
Carlsson and Hultengren (1975) reported that dichloromethane
and its metabolites were in highest concentrations in white
adipose tissue, followed in descending order by levels in brain
and liver.
C. Metabolism
Dichloromethane is metabolized to carbon monoxide.
Some of this carbon monoxide is exhaled, but a significant amount
74-5
-------
is involved in the formation of carboxyhemoglobin (Natl. Inst.
Occup. .Safety and' Health, 1976). Cardiorespiratory stress from
elevated carboxyhemoglobin may be greater as a result of
dichloromethane exposure than from exposure to carbon monoxide
alone due to the continued formation of carbon monoxide following
cessation'of dichloromethane exposure (Stewart and Hake, 1976).
As shown by animal experiments, other possible human metabolites
of dichloromethane include carbon dioxide, formaldehyde, and
formic acid (Natl. Acad. Sci., 1978).
D. Excretion
A large proportion of absorbed dichloromethane is ex-
creted unchanged, primarily via the lungs, with some in the urine.
DiVincenzo, et al. (1972) have reported that about 40 percent of
absorbed dichloromethane undergoes some reaction and decomposition
process in the body.
IV. EFFECTS
A. Carcinogenicity
Friedlander et al. (1978) analyzed the mortality of
Eastman-Kodak male employees exposed to low levels of methylene
chloride. No significant neoplastic risk factors were identified.
Theiss and coworkers (1977) examined the tumorigenic activity
of dichloromethane in strain A mice. Dichloromethane at the low
dose (1:5 dilution of the maximum tolerated dose) produced
marginally significant increases in tumor response. Shimkin and
Stoner (1975) did not report a positive carcinogenic response for
the strain A mouse bioassay system.
74-6
-------
Although the data base is inadequate, there is a basis to
suspect' the potential carcinogenicity of DCM based on the (marginally
positive) pulmonary adenoma response in strain A mice, on positive
responses for mutagenicity in the Ames test, and on the ability
to transform rat embryo cells (see below).
B. Mutagenicity
Simmon, et al. (1977) reported that dichloromethane
tfas mutagenic to Salmonella typhimurium strain TA1QO when assayed
in a dessicator whose atmosphere contained the test compound.
Metabolic activation was not required, and the number of revertants
per plate was directly dose-related. A linear dose response curve
was observed. Dichloromethane did not increase mitoti.c recombination
in S_. cerevisia D3 (Simmon, et al., 1977), and it was reported
negative on testing for mutagenicity in Drosophila (Filippova, et
al., 1967). Positive results for dichloromethane in the Ames
assay were recently confirmed by Jongen, et al. (1978) with vapor
phase exposures (5,700 ppm) of strains TA98 and TA100.
C. Teratogenicity
4
Schwetz et al., (1975) showed that DCM can affect
embryonal and fetal development in rats and mice as evidenced by
the increased incidence of extra sternebrae. DCM also affects the
development of chick embryos, causing a 2 to 3-fold increase in mal-
formation frequencies (Elsavaara et al., 1979).
D. Other Reproductive Effects
Gynecologic problems in femal workers exposed for
74-7
-------
long period to gasoline and dichloromethane vapors were reported
by Vozovaya (1974). Also, inhalation exposures of rats and mice
to vapor levels of 4,342 mg/m^ for seven hours daily on gestation
days 6 to 15 produced evidence of feto- or embryotoxicity (Schwetz,
et al., r975; Natl. Inst. Occup. Safety and Health, 1976).
E. Chronic Toxicity
Acute exposures to dichloromethane produce central
nervous system disfunction, are irritating to mucous membranes,
and increase the level of carboxyhemoglobin (Natl. Acad. Sci.,
1978). Price, et al. (1978) reported that Fischer rat embryo
cells (F1706) were transformed by dichloromethane at high
concentrations (1.6 x 10"^M) in the growth medium. However,
Sivak (1978) indicated the presence of carcinogenic contaminants
in the dichloromethane and could not demonstrate transformation
in the BALB/C-3T3 assay system with highly purified food grade
dichloromethane.
V. AQUATIC TOXICITY
A. Acute Toxicity
Acute toxicity values have been obtained for two species
of freshwater fish and one species of freshwater invertebrates.
LC5Q values for the fathead minnow (Pimephales promelas) ranged
from 193,000 ug/1 in a flowthrough assay to 310,000 ug/1 in a
static assay. An LC^Q value of 224,000 ug/1 was obtained for the
bluegill (Lepomis Macrochirus) in a static assay. Daphnia magna
were reported as having an "LC^Q value of 224,0^0 ug/1 (U.S. EPA,
-------
1979a). For the marine fish, the sheepshead minnow (Cyprinodon
variegatus) , an 1650 of 331,000 ug/1 was obtained. The marine
mysid shrimp was reported as having an LC5Q value of 256,000
ug/1.
B. Chronic Toxicity
Chronic tests for freshwater or marine species could
not he located in the available literature.
C . Plant Effects
Both species of freshwater algae, Selenastrum capricor-
nortum and marine algae, Skeletonema cornutum, were equally
resistant to dichloromethane, with l>C$r\ values in excess of
662,000 ug/1.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by
the U.S. .EPA (1979a), which are summarized below, have gone
through the process of public review, therefore, there is a
possibility that these criteria will be changed.
A. Human
OSHA (1976) has established an eight-hour, time-weighted
average for dichloromethane of 1,737 mg/m^; however, NIOSH (1976)
has recommended a ten-hour, time-weighted average exposure limit
of 261 mg/m^. The U.S. EPA (1979a) draft water quality criterion
for dichloromethane is 2 ug/1. The reader is referred to the
Halomethanes Hazard Profile for discussion of criteria derivation
(U.S. EPA, 1979b).
74-9
-------
B.« Aquatic
The criterion for protecting freshwater aquatic life has
been drafted as 4,000 ug/1, not to exceed 9,000 ug/1, while the
marine criterion has been drafted as 1,900 ug/1, not to exceed
4,400 ug/1.
74-10
-------
DICHLOROMETHANE
References
Balmer, M. F . •, et al. 1976. Effects in the liver of
methylene chloride inhaled alone and with ethyl alcohol.
Am. Ind. Hyg. Assoc. Jour. 37:345.
Carlsson,.A., and M. Hultengren. 1975. Exposure to
methylene chloride, III. Metabolism of 14C-labeled
methylene dichloride _in rat. Scand. Jour. Work Environ.
Health 1:104.
DiVincenzo, G. D., et al. 1972. ^Hutnan and canine exposures
to methylene chloride vapor. Am. Ind. Hyg. Assoc. Jour.
33:125.
Elovaara, E., K. Hemminki, and H. Vaimio. 1979. Effects of
methylene chloride, trichloroethane, trichloroethylene and
tolerance on the development of chick embryos. Toxicology
2:111-119.
Filippova, L. M., et al. 1967. Chemical mutagens. IV.
Mutagenic activity of geminal system. Genetika 8:134.
Friedlander, B. R., T. Hearne and S. Hall. 1978. Epedemi-
ologic investigation of employees chronically exposed to
methylene chloride. J. Occup. Med. 20:657-666.
Jongen, W. M. F., et al. 1978. Mutagenic effect of di-
chloromethane on Salmonella typhimurium. Mutat. Res. 56:245.
Morris, J. C., and G. McKay. 1975. Formation of halogenated
organics by chlorination of water supplies. EPA 600/1-75-002.
PB 241-511. Natl. Tech. Inf. Serv., Springfield, Va.
National Academy of Sciences. 1978. Nonfluorinated halometh-
anes in the environment. Washington, B.C.
National Institute of Occupational Safety and Health. 1976a.
Criteria for a recommended standard: Occupational exposure
to methylene chloride. HEW Pub. NO. 76-138. U.S. Dep. Health
Educ. Welfare, Cincinnati, Ohio.
Occupational Safety and Health Administration. 1976. General
industry standards. OSHA 2206, revised January 1976. U.S.
Dep. Labor. Washington, D.C.
74-11
-------
Price, P. J., et al. 1978. Transforming activities of tri-
chloroethylene and proposed industrial alternatives. In Vitro
14:290*.
Schwetz, B. A., et al. 1975. The effect of maternally in-
haled trichloroethylene, perchloroethylene, methyl chloro-
form, and methylene chloride on embryonal and fetal develop-
ment in mice and rats. Toxicol. Appl. Pharmacol. 32:84-96.
Shimkin, M. B., and G. D. Stoner. 1975. Lung tumors in mice:
application to carcinogenesis bioassay. A'dv. Cancer Res. 21:1
Simmon, V. F. et al. 1977. Mutagenic activity of chemicals
identified in drinking water. In; S. Scott, et al., eds.
Progress in Genetic Toxicology.
Sivak, A. 1978. BALB/C-3T3 neoplastic transformation
assay with methylene chloride (food grade test specification).
Rep. Natl. Coffee Assoc., Inc.
Stewart, R. D., and C. L. Hake. 1976. Paint remover hazard.
Jour. Am. Med. Assoc. 235:398.
Theiss, J. C., et al. 1977. Test for carcinogenicity of
organic contaminants of United States drinking waters by
pulmonary tumor response in strain A mice. Cancer Res.
37:2717.
U.S. EPA. 1975. Preliminary assessment of suspected carcino-
gens in drinking water, and appendices. A report to Congress,
Washington, D.C.
U.S. EPA. 1977. Area 1. Task 2. Determination of sources
of selected chemicals in waters and amounts from these sources.
Draft final rep. Contract No. 68-01-3852. Washington, D.C.
U.S. EPA. 1978. The National Organic Monitoring Survey.
Rep. (unpubl.). Tech. Support Div., Off. Water Supple.
Washington, D.C.
U.S. EPA. 1979a. Halomethanes: Ambient Water Quality,
(Draft).
U.S. EPA. 1979b. Evironmental Criteria and Assessment
Office. Halomethanes: Hazard Profile. (Draft).
Vozovaya, M. A. 1974. Gynecological illnesses in workers
of major industrial rubber products plants occupations. Gig.
Tr. Sostoyanie Spetsificheskikh Funkts. Tab. Neftekhim. Khim.
Prom-sti. (Russian).56 (Abstract)
74-12
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LB-45-01
No. 75
2,4 - Dichlorophenol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C. 20460
October 1, 1980
-------
DISCLAIMER
This report represents a survey of the potential health and
environmental hazards from exposure to the subject chemical. The
information contained in the report is drawn chiefly from secondary
sources and available reference documents. Because of the
limitations of such sources, this short profile may reflect all
available information impacts presented by the subject chemical.
This document has undergone scrutiny to ecsure its technical accuracy
75-2
-------
2, 4-DICHLOROPHENOL
Summary
Insufficient data exist to indicate that 2,4-dichlorophenol
is a carcinogenic agent. 2 ,4-Dichlorophenol appears to act as a
nonspecific irritant in promoting tumors in skin painting studies.
No information on mutagenicity, teratogenicity, or chronic toxicity
is available. In a subacute study, the only adverse effect noted
in mice was microscopic nonspecific liver changes. 2, 4-
Dichlorophenol app.ears to be a weak uncoupler of oxidative
phosphorylation.
Acute and chronic toxic effects of 2,4-dichlorophenol have
been observed at a concentrations as low as 2,200 and 365 ug/1
respectively. Mortality to early life stages of one species of
fish occurs at 70 ug/1. Flavor impairment studies indicate'
that the highest concentrations of 2,4-dichlorophenol in water
which would not cause tainting of the edible portions of fish
range from 0.4 to 14 ug/1 depending on the species of fish
• consumed.
75-3
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2,4-DICHLOROHENOL (2,4 DCP)
I. INTRODUCTION
«
This profile is in large part based on the Ambient Water
Quality Criteria Document for 2,4-dichlorophenol (U.S. EPA,1980).
2,4-Dichlorophenol is a colorless, crystalline solid having
the empirical formula CgH^^O and a molecular weight of 163.0
(Weast, 1975). It has the following physical and chemical
properties (Sax, 1975; Aly and Faust, 1965; Weast, 1975; Kirk and
Othmer, 1964):
Melting Point: 45° C
Boiling Point: 210° C at 760 mm Hg
Vapor Pressure: : 1.0 mm Hg at 53.0° C
Solubility: slightly soluble in water
at neutral pH; dissolves
readily in ethanol and
benzene
2,4-DCP is a commercially produced, substituted phenol used
entirely as an intermediate in the manufacture of industrial and
agricultural products such as the herbicide 2,4-dichlorophenoxyacetic
acid (2,4-D), germicides, and miticides.
Little data exists regarding the persistence of 2,4-
dichlorophenol in the environment. It is a product resulting
from degradation of many commercial products by plants, micro-
organisms, and sunlight. Its low vapor pressure cause it to be
only slowly removed from surface water via volatilization (U.S.
EPA, 1980). Studies have indicated low absorption of 2,4-DCP
from natural surface waters by various clays (Aly and Faust,
1964). 2,4-DCP is photolabile in aqueous solutions (Aly and Faust,
1964; Crosby and Tutass, 1966) and can be degraded to succinic
75-4
-------
acid by microorganisms in soil and water (Alexander and Aleera,
1961; Ingols, et .al., 1966; Loos, et al., 1967). In lake water,
under laboratory conditions, the half life of 2,4-DCP is 8-9
days in aerated waters and 17 days under anaerobic conditions
(U.S. EPA 1980).
II. EXPOSURE
A. Water
Sources of 2,4-DCP in water are agricultural run-off (as a
contaminant' and metabolic breakdown product of biocides) and
manufacturing waste discharges (U.S. EPA, 1980). Recent
experiments under conditions simulating the natural environment
have not demonstrated that 2,4-dichlorophenol is a significant
product resulting from chlorination of phenol-containing wastes
(Glaze, et al. 1978; Jolley, et al. 1978). The worst-case exposure
to 2,4 DCP from drinking water, as calculated from 2,4-DCP level
in water downstreams from a 2,4-DCP manufacturing, facility,
has been estimated as 36 ug/kg body weight/day.
B. Food
Contamination of food with 2,4-DCP could be an indirect
result from use of the herbicide 2,4-D (U.S. EPA, 1980). The
worst use estimate for the degree of human exposure to 2,4-DCP from
consumption of contaminated meat is about 4 ug 2,4-DCP/kg body
weight.
The U.S. SPA (1980) has estimated the weighted average
bioconcentration factor for 2,4-dichlorophenol to be 41 for the
edible portions of fish and shellfish consumed by Americans.
This estimate is based on the octanol/water partition coefficient.
75-5
-------
C. Inhalation
Pertinent information regarding direct evidence indicating
*
that humans are exposed to significant amounts of 2,4-dichlorohenol
through inhalation has not been found in the available literature.
III. Absorption
Pertinent information regarding the Absorption of 2,4-
dichlorophenol in humans or animals was not found in the available
literature, although data on toxicity indicate that 2,4-
dichlorophenol is absorbed after oral administration (Deichmann, 1943;
Kobayashi, et al. 1972). Due, to its high lipid solubility and
low ionization at physiological pH, 2,4-dichlorophenol is expected
to be readily absorbed after oral administration (U.S. EPA, 1979).
B. Distribution
Pertinent information dealing directly with tissue distribution
after 2,4-dichlorophenol exposure was not found in the available
literature. Feeding of 2,4-D (300 - 2000 ug/g feed) to cattle
and sheep (Clark, et al. 1975) and Nemacide (50 - 800 ug/g feed)
to laying hens (Sherman, et al. 1972) did not produce detectible
residues of 2,4-dichlorophenol in muscle or fat. Cattle and
sheep had high levels of 2,4-dichlorophenol in kidney and liver;
hens had detectible levels of 2,4-dichlorophenol in liver and yolk.
C. Metabolism
Pertinent information dealing directly with metabolism of
administered 2,4-dichlorophenol was not found in the available
literature. In mice, urinary metabolites of ^C-labelled gamma
75-6
-------
or beta benzene hexachloride (hexachlorocylohexane) included 2,4-
dichorophenol and its glucuronide and sulfate conjugates (as 4-6
percent of total metabolites) (Kurihara,'1975) .
D. Excretion
Pertinent information dealing with excretion of administered
2,4-dichlorophenol was not found in the available literature.
After oral administration of 1.6 mg Nemacide to rats over a. 3-day
period, 67 percent of that compound appeared in urine as 2,4-
dichlorophenol within 3 days. With a dosage of 0.16 mg Nemacide,
70 percent of the compound appeared in urine as 2,4-dichlorophenol
within 24 hours (Shafik, et al. 1973).
IV. EFFECTS
A. Carcinogenicity
Existing data are not sufficient to indicate whether
2,4-dichlorophenol is a carcinogen. The only study performed
(Boutwell and Bosch, 1959) indicate that 2 ,4-dichlorophenol may
promote skin cancer in mice after initiation with dimethylbenz-
anthracene. An analysis of the data of Boutwell and Bosch using
the Fisher Exact Test indicated that the incidence of papillomas.
in 2,4-DCP-treated groups was significantly elevated over controls,
while the incidence of carcinomas was not (U.S. EPA, 1980) .
B. Mutagenicity, Teratogenicity and Other Reproductive
Effects
No studies addressing the mutagenicity, teratogenicity
or other reproductive effects of 2,4-DCP in mammaliam systems
were found in the available literature. However, genotoxic
effects of 2,4-DCP have been reported in plants. Exposure of
75-7
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flower buds or root cells of vetch (Vicla fabia) to solutions of
2,4-DCP, 01M and 62.5 mg/1, respectively, caused meiotic and
mitotic changes including alterations of chromosome stickiness,
lagging chromosome anaphase bridges and fragmentation (Amer and
Ali, 1968, 1969, 1974). The relationship of such changes in
plant cells .to potential changes in mammalian cells has not been
established (U.S. EPA, 1980).
C, Chronic Toxicity
One report (Bleiberg, et al. 1964) suggested that 2,4-
dichlorophenol was involved in the induction of chloracne and
porphyria cutanea tarda in workers manufacturing 2 ,4-dichlorophenol
and 2 , 4 , 5-trichlorophenol. Since various chlorinated dioxins
(powerful chloracnegens) have been implicated as contaminants of
2,4,5-trichlorophenol, the specific role of 2,4-dichlorophenol in
causing chloracne and porphyria is not conclusive (Huff and
Wassom, 1974).
In a study (Kobayaski, et al. 1972) in which male mice
were fed 2,4-dichlorophenol at estimated daily doses of 45, 100,
and 230 mg/kg body weight, no adverse effects were noted except
for some microscopic nonspecific- liver changes after the maximum
dose. Parameters evaluated included body and organ weights and
food consumption, as well as hematological and histological
changes•
D. Other Relevant Information
2,4-DCP is a weak uncoupler of oxidative phosphorylation
(Farquharson, et al. 1958; Mitsuda, et al. 1963). Values on odor
75-8
-------
threshold, for 2,4-DCP in water range from 0.65 to 6.5 ug/1,
depending on the temperature of water (Hoak, 1957).
V. AQUATIC TOXICITY
A. Acute Toxicity (U.S. EPA, 1980)
Two 96-hour assays have been performed examining the
acute effects of 2,4-dichlorophenol in freshwater fish. An LC^O
value of 2,020 ug/1 for the bluegill, Lepomis macrochirus, and an
LC5Q value of 3,230 ug/1 for the juvenile fathead minnow,
Pimpephales promelas, have been reported. Two studies on the
freshwater cladoceran, Daphnia magna, have produced 48-hour static
LC5Q values of 2,610 and 2,600 ug/1.
Only one marine fish or invertebrate species has been
tested for the acute effects of 2,4-DCP: the mountain bass, a
species endemic to Hawaii is poisoned at 20 mg 2,4-DCP/l.
B. Chronic Toxicity
Data for the chronic effects of 2,4-DCP for either
freshwater or marine organisms were not located in the available
literature .
C. Plant Effects
Concentrations of 2,4-DCP causing a 56 percent reduction
in photosynthetic oxygen production or a complete destruction of
chlorophyll were 50 or 100 mg/1, respectively, in algal assays
with Chlorella pyrenoidosa. An earlier study reported that 58.3
mg 2,4-D/l caused a 50 percent reduction in Chlorophyll in the
duckweed, Lemna minor. No marine plant species have been examined.
75-9
-------
D. Residues
A bioconcentration factor of 130 has been estimated from
*
the octanol-water partition coefficient of 2,4-dichlorophenol for
aquatic organisms having a lipid content of eight percent. The
estimated weighted average bioconcentraion factor for the edible
portion 'of aquatic organisms is 41.
E. Miscellaneous
Flavor impairment studies indicated that the highest
concentration of 2,4-DCP in the exposure water which would not
cause tainting of the edible portion of fish ranged from 0.4 ug/1
for the largemouth bass (Microbterus salmoides), to 14 ug/1 for
the bluegill (Lepomis marcrochirus). The value for the rainbow
trout (Salmo gairdneri) was 1 ug/1.
A. Human
Based upon the prevention of adverse organoleptic
effected, the criterior for 2,4-DCP in water recommended by the
U.S. EPA (1980) is 0.3 ug/1. This level is far below minimal no-
effect concentrations determined in laboratory animals (U.S. EPA,
19RO). 3.09 mg/1 is the criterion based on toxicity' data (U.S.
EPA, 1980).
B. Aquatic
The criterion for protecting freshwater organisms is
2020 ug/1 (acute) and 365 ug/1 as a chronic exposure value. No
criterion was derived for marine organisms (U.S. EPA, 1980).
75-10
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2,4-DICHLOROPHENOL
REFERENCES
Alexander, M. and M.I.H. Aleera. 1961. Effect of Chemical
structure on microbial decomposition of aromatic herbicides.
Jour. Agric.' Food Chera. 9;44.
Aly, O.M. and S.D. Faust. 1963. Studies on the fate of 2,4-D
and ester derivatives in natural surface waters. Jour. Agric.
Food Chem. 12:541.
Amer, S.M. and E.M. Ali. 1968. Cytological effects of pesticides.
II. Meiotic effects of some phenols. Cytologia 33:21.
Amer, S.M. and E.M. All. 1969. Cytological effects of pesticides.
IV. Meiotic effects of some phenols. Cytologia 34:533.
Amer, S.M. and E.M. Ali. 1^74. Cytological effects of pesticides.
V. Effect of some herbicides on Specia f aba. Cytologia 33:633.
Bleiberg, J.M., et al.. 1964. Industrially acquired prophyria.
Arch. Dermatol. 89:793.
Boutwell, R.K. and D.K. Bosch. 1959. The tumor-promoting action
of phenol and related compounds for mouse skin. Cancer Res.
19:413.
Clark, D.E., et al. 1975. Residues of chlorophenoxy acid herbicides
and their phenolic metabolites in tissues of sheep and cattle.
Jour. Agric. Food Chem. 23:573.
Crosby, D.G. and H.O. Tutass. 1966. Photodecomposition of 2,4-
dichlorophenoxyacetic acid. Jour. Agric. Food Chem. 14:596.
Deichmann, W.B. 1943. The toxicity of chlorophenols for rats.
Fed . Proc .2:76.
Farquharson, M.E., et al. 1958. The biological action of
chlorophenols. Br. Jour. Pharmacol. 13:2D.
Glaze, W.H., et al. 1978. Analysis of new chlorinated organic
compounds formed by chlorination of municipal wastewater. Page
139 In: R.L. Jolley, (ed.) Water chlorination - environmental
impact and health effects. Ann Arbor Science Publishers.
Hoak, R.D. 1957. The causes of tastes and odors in drinking
water. Water and Sew. Works. 104:243.
75-11
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Huff, J.E. and J.S. Wassom. 1974. Health hazards from chemical
impurities: chlorinated debenzodioxins and chlorinated dibenzofurans
Int. Jour. Environ. Studies 6:13.
»
Ingols, R.S., et al. 1966. Biological activity of halophenols.
Jour. Water Pollut. Control. Fed. 38:629.
Jolley, R.L., et al. 1978. Chlorination of organics in cooling
waters and process effluents. In Jolley, R.L., Water chlorination
environmental impact and health effects. 1:105. Ann Arbor Science
Publishers.
Kirk, R.E., and D.F. Othmer. 1964. Kirk-Othmer encyclopedia of
chemical technology. 2nd ed. Interscience Publishers, New York.
Kobayashi, S.,'et al. 1972. Chronic toxicity of 2,4-dichlorophenol
in mice. Jour. Med. Soc. Toho, Japan. 19:356.
Kurihara, N. 1975. Urinary metabolites fromjfand £-BHC in the
mouse: chlorophenolic conjugates. Environ. Qual. Saf. 4:56.
Loos, M.H., et al. 1967b. Phenoxyacetate herbicide detoxication
by bacterial enzymes. Jour. Agrlc. Food Chem. 15:858.
Mitsuda, W., et al. 1963. Effect of chlorophenol analogues on
the oxidative phosphorylation in rat liver mitochondria. Agric.
Biol. Chem. 27:366.
Sax, N.I. 1975. Dangerous properties of industrial materials.
4th ed. Van Nostrand Rheinhold Co., New York.
Shafik, T.M., et al. 1973. Multiresidue procedure for halo and
nitrophenols. Measurement of exposure to biodegradable pesticides
yielding these compounds as metabolites. Jour. Agric. Food Chem.
21:295.
•
Sherman, M., et al. 1972. Chronic toxicity and residues from
feeding Nemacide [o-(2,4-dichlorophenol)-o,o-diethylphosphoro-
thioate] to laying hens. Jour. Agric. Food Chem. 20:617.
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. Contract No. 68-01-4646.
U.S. Environ. Prot. Agency.
U.S. EPA. 1980. Ambient Water Quality Criteria for 2,4-dichloro-
pehnol: EPA 440/5-80-042.
Weast, R.C., ed. 1975. Handbook of chemistry and physics. 55th
ed. CRC Press, Cleveland, Ohio.
75-12
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No. 76
2,6-Dichlorophenol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C.
OCTOBER 30, 1980
76-1
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such so.urces , this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
76-2
-------
2,6-DICHLOROPHENOL
SUMMARY
There is 'no available information on the possible
carcinogenic, teratogenic, or adverse reproductive effects
of 2,6-dichlorophenol.
The compound did not show mutagenic activity in the Ames
assay. A single report has indicated that 2,6-dichlorophenol
produced chromosome aberrations in rat bone marrow cells;
details of this study were not available for evaluation.
Prolonged administration fo 2,6-dichlorophenol may
produce hepatoxic effects. Pertinent data on the toxicity of
2,6-dichlorophenol to aquatic organisms were not found in the
available literature. However, EPA/ECAO Hazard Profiles on
related compounds may be consulted, including metachlorophenol,
2,4,5-trichlorophenol, and 2,3,4,6-tetrachlorophenol.
76-3
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I. INTRODUCTION
2, 6-Dichlorophenol (2,6-DCP), CAS registry number 87-65-0,
exists' as white needles and has a strong penetrating odor
resembling o-chlorophenol . It has the following physical and
chemical constants (Weast, 1972; Hawley, 1971):
Formula:
•Molecular Weight: 163
Melting Point: 68AC - 69°C
Boiling Point: 219°C - 220°C (74n torr)
Vapor Pressure: 1 torr @ 59.5°C
pH: . 6.79
Production: unknown
2,6-DCP is produced as a by-product from the direct chlorination
of phenol. It is used primarily as a starting material for
the manufacture of trichlorophenols , tetrachlorophenols , and
pentachlorophenols (Doldens, 1964).
II. EXPOSURE
A. Water
Phenols occur naturally in the environment and
chlorophenols are associated with bad taste and odor in tap
water (Hoak, 1957). 2,6-DCP has a taste and odor threshold
•
of 0.002 mg/1 and 0.003 mg/1, respectively (McKee and Wolf,
1963). Piet and DeGrunt (1975) found unspecified dichlorophenols
in Dutch surface waters at 0.01 to 1.5 ug/1, and Burttschell,
et al. (1959) demonstrated that chlorination of phenol-
containing water produced, among other products, 2,6-DCP in a
25-percent yield after 18 hours of reaction.
76-4
-------
B. -Food
Pertinent data could not be located in the available
literature.
C. Inhalation
Olie, et al. (1977) reported finding dichlorophenols
in flue gas•condensates from municipal incinerators. The
levels were not quantified.
D. Dermal
Pertinent data could not be located in the available
literature; however, it is known that dichlorophenols are
less toxic by skin contact than mono-chlorophenols and less
likely to be absorbed through the skin (Doldens, 1964).
III. PHARMACOKINETICS
. A. Absorption
Pertinent data could not be located in the available
literature. By comparison with other chlorophenols, it is
expected that 2,6-DCP is absorbed through the skin and from
the gastrointestinal tract, and rapidly eliminated (U.S. EPA,
1980).
B. Distribution
Pertinent data could not be located in the available
literature. The high lipid solubility of the compound would
suggest that the unexcreted and unmetabolized compound distributes
to adipose tissues.
C. Metabolism and Excretion
Pertinent data could not be located in the available
literature. By comparison with other chlorophenols, it is
76-5
-------
expected that 2,6-DCP is rapidly eliminated from the body,
primarily as urirvary sulfate and glucuronide conjugates (U.S.
•
EPA, 1980).
IV. EFFECTS-
A. Carcinogencity
• Pertinent data could not be located in the available
literature.
B. Mutagenicity
2,6-DCP did not show mutagenic activity in the Ames
assay (Rasanen, et al. 1977). Chromosome aberrations in rat
bone marrow cells have been observed following compound
administration (route and dosage not indicated) (Chung, 1978).
C. Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the available
literature.
D. Chronic Tcxicity
Administration of 2,6-DCP to rats (route and dosage
not specified) has been reported to produce hepatic degeneration
(Chung, 1978).
E. Other Relevant Information
In vitro tests have indicated that 2,6-DCP inhibits
liver mitochondrial respiration (level not specified) (Chung,
1978). At relatively high concentrations 2,6-DCP affects the
nervous system (U.S. EPA, 1980).
76-6
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V. AQUATIC TOXICITY
A. Acute
*
McLeese., et al. (1979) reported a 52-hour lethal
threshold limit of 19,100 ug/1 for marine shrimp (Crangon
septemspinosa) exposed to 2,6-DCP.
B. Chronic Toxicity, Plant Effects and Residues
Pertinent data could not be located in the available
literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
Based on the organoleptic properties of 2,6-DCP, a
water quality criterion of 0.2 ug/1 has been recommended by
the U.S. EPA (1980).
B. Aquatic
No existing criteria to protect fresh and saltwater
organisms were found in the available literature.
76-7
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REFERENCES
Burttschell, R.H., et al. 1959. Chlorine derivatives of
phenol causin'g taste and odor. Jour. Amer. Water Works Assoc.
51:205.
Chung, Y. 1978. Studies on cytochemical toxicities of
chlorophenols to rat. Yakhak Hoe Chi 22:175.
Doldens, J.D. 1964. Chlorophenols. In; Kirk-Othmer Encyclopedia
of Chemical Technology. John Wiley and Sons, Inc., New York.
p. 325.
Hawley, G.G. (ed.) 1971. The Condensed Chemical Dictionary,
8th ed. Van Nostrand Reinhold Co., New York.
Hoak, R.D. 1957. The causes of tastes and odors in drinking
water. Purdue Eng. Exten. Service. 41:229.
McKee, J.E. and H.W. Wolf. 1963. Water quality criteria.
The Resources Agency of California, State Water Quality
Control Board.
McLeese, D.W., V. Zitko and M.R. Peterson. 1979. Structure-
lethality relationships for phenols, anilines, and other
aromatic compounds in shrimp and clams. Chemosphere 8:53.
Olie, K., et al. 1977. Chlorodibenzo-p-dioxins and
chlorodibenzofurans are trace components of fly ash and flue
gas of some municipal incinerators in the Netherlands.
Chemosphere 8:445.
Pfet, G.J. and F. DeGrunt. 1975. Organic chloro compounds
in surface and drinking water of the Netherlands in -problems
raised by the contamination of nan and his environment.
Comm. Eur. Communities, Luxembourg, p.81.
Rasanen, L., M.L. Hattula and A. Arstila. 1977. The
mutagenicity of MCPA and its soil metabolites, chlorinated
phenols, catechols and some widely used slimicides in Finland.
Bull. Environ. Contam. Toxiciol. 18:565.
U.S. EPA, 1980. Ambient Water Quality Criteria for Chlorinated
Phenols, EPA 440/5080-032.
Weast, R.C. 1972. Handbook of Chemistry and Physics, 53rd
ed. Chemical Rubber Co., Cleveland, Ohio.
76-8
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No. 77
2,4-Dlchlorophenoxy3cetic Acid (2,4-D}
Health and Environmental Streets
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
77-/
-------
DISCLAIMER
•
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
77-2.
-------
2 , 4-OICHLOROPHENOXYACETIC ACID
Summary
Oral administration of 2,4-Oichlorophenoxyacetic acid (2,4-0) failed to
produce carcinogenic effects in mice or dogs; however, feeding technical
grade 2,4-0 did produce tumors in a study with rats. Subcutaneous adminis-
tration of the isooctyl ester of 2,4-0 has been reported to produce reticu-
lum cell sarccmas in mice.
A single study has indicated that 2,4-0 produced mutagenic effects in
Saccharomyces. Other investigations have failed to show mutagenic effects
of the compound Salmonella, Drosoohila, Saccharomyces , or the dominant
lethal assay with mice.
2,4-0 and several of its esters failed to shew teratcgsnic effects in
mice; the propylene glycol butyl ether ester of the compound produced an in-
crease in cleft palates in this st'jdy. Studies in hamsters orally adminis-
tered 2,4-0 and derivatives showed teratogenic effects. Oral administration
of 2,4-0 to rats failed to indicate teratogenicity in one study; another in-
vestigation using oral administration of 2,4-0 to rats found teratogenic ef-
fects. A three-generation feeding study of 2,4-0 to rats indicated feto-
toxic effects at a dosage of 1,500 ppm.
Toxicity tests on a variety of aquatic organisms generally have demon-
strated that various esters of 2,4-0 are more toxic than the 2,4-0 acid, di-
methyl amine, or sodium salt. Freshwater trout and bluegill sunfish were
adversely affected by the propylene glycol butylether (PGSE) ester at con-
s
centrations of 900 to 2,000 ug/1. Daphnids and freshwater seed shrimp were
sensitive to the PGBE ester at concentrations of 100 to 300 ug/1. Chronic
exposure of several species of fish to concentrations up to 310 jug/1 has not
demonstrated any toxic effect.
77-3
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2,4-QICHLOROPHENOXYACETIC ACID
I. INTRODUCTION
2,4-Oichlorophenoxyacetic acid, CAS Registry number 94-75-7, commonly
known as 2,4-0, is a whits or slightly yellow crystalline compound which is
odorless when pure. 2,4-0 has the following physical and chemical proper-
ties (Herbicide Handbook, 1979}:
Density:
Vsc-or Pressure:
Solubility:
Formula: C^
Molecular Weight: 221.0
Msltina Point: 135°C-133°C (technical);
140°C-141°C (purs)
160 C S 0.4 torr
1.56530
0.4 torr 1 lc'GcC
Acetone alcohol, oioxane ether,
isopropyl alcohol; slightly
soluble in benzene, solubility in
water 0.09c/100g, H20
Production: Unknown
2,4-0 is used as an herbicide along with its various salts and esters,
which vary its solubility properties. It is used mainly to control broad-
leafed plants in pastures, and right-of-ways, and, and to keep lakes and
ponds free of unwanted submersed and emersed weeds.
II. EXPOSURE
A. Water
No estimates of average daily uptake of 2,4-0 from water are
available; however, after treatment for water milfoil in reservoirs in
/v » i
' J W
77-
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Alabama and Tennessee, the Tennessee Valley Authority found the concentra-
tion at downstream monitoring stations to be 2 ppb. 2,4-0 was not found in
the harvested beans of red Mexican bean plants after irrigation with contam-
inated water (Gangst, 1979).
B. Food
The Food and Drug Administration, in monitoring milk and meat for
residues of 2,4-0. from 1963 to 1969, found no trace of the herbicide in
13,000 samples of milk and 12,000 samples of meat (Day, et al. 1978).
Cattle and sheep which were fed 2,000 ppm of 2,4-0 for 28 days had less than
0.05 ppm 2,4-0 in the fat and muscle tissue and no detectable amount of
2,4-dichlorophenol. After seven days withdrawal from the 2,4-0 diet, these
tissue levels were drastically reduced (Clark, et al. 1975). Six species of
fish were monitored for three weeks after the water in a pcnd was treated
with a 2.4_o ester. The highest tissue concentration reached was 0.24 ppm
sight days sftsr application. Subssc'jently, ths herbicide cr its ^etacclite
•"as eliminated raoidlv. Clams and ovsters acc'.jrr"jiste more 2,4-Q than dc
fish and crabs. Residue peaks occur from 1 to 9 days after application and
then rapidly decline (Gangst, 1979).
C. Inhalation
Pertinent data were not found in the available literature; how-
ever, some 2,4-0 esters which are much more volatile than the parent com-
pound have been monitored in air up to 0.13 pg/nv5 (Farwell, et al. 1976;
Stanley, et al. 1971).
0. Dermal
Pertinent data were not found in the available literature.
77-J-
-------
III. PHARMACQKINETICS
A. Absorption
Human absorption of 2,4-0 following oral intake is extensive;
Kohli et al. (1974) have determined absorption of 75 to 90 percent of the
total dietary intake of the compound. Animal studies have indicated that
the gastrointestinal absorption of 2,4-0 esters may be less efficient than
that of the free acid or salt form of the compound (NRCC, 1978).
3. Distribution
The phenoxy herbicides are readily distributed throughout the body
tissues of mammals. Tissue levels of herbicide may be higher in the kidney
than in the blood; liver and muscle show levels lower than those determined
in the bleed (NRCC, 1973). withdrawal of dietary compound produced almost
complete tissue loss of residues in seven cays (Clark, at al. 1975).
Small amounts of phenoxy herbicides are passed to the young
through the mother's milk (Blerke. e^ al. ^972). Transolacsntal transfer of
2.4-0 has been renorted in mice (Lindquist and Ullberg, 1971).
C. Metabolism
Sauerhoff, et al. (1976) determined that following oral adminis-
tration of 2,4-0 to human volunteers, the major amount excreted in the urine
was free compound: a smaller amount was excreted as a conjugate. Tissue
analysis of sheep and cattle fed 2 4-0 have shown unchanged compound and
2,4-dichlorophenol to be present (Clark, et al. 1975).
D. Excretion
Elimination of orally administered 2,4-0 by humans is primarily
through the urine (95.1 percent of the initial dose); the half-life of the
compound in the body has been estimated as 17.7 hours (Sauerhoff, et.al.
1976). Clark, et al. (1964) have reported urinary elimination of 96 percent
-------
of an oral dose of labelled 2,4-0 within 72 hours by sheep; approximately
1.4 percent of the administered dose was eliminated in the feces.
The plasma half-life of 2,4-0 has been estimated to be- from 11.7
to 33 hours in' humans (NRCC, 1978).
IV. EFFECTS
A . Carcinogenicity
Innes, et al. (1969) reported no significant increase in tumors
following feeding of mice with 2,4-0 for 18 months. A two-year feeding
study in rats did indicate an increase in total tumors in females and malig-
nant tumors in males following feeding of -technical 2,4-0; a parallel study
with dogs fed technical compound did not show carcinogenic effects (Hansen,
et al. 1971).
Mice were administered maximum tolerated doses of 2,4-0 and its
butyl, isoprcoyl, and isooctyl esters in a long-terrr, carcir.ogenicity study.
Carcinogenic effects were seen after subcutaneous acministraticr, of the iso-
octyl ester (reticulum cell sarcomas) (NiCI, 1963).
3. Mutansnicity
No mutagenic effects of 2,4-0 in tests with Salmonella,
Saccharomvces, or Orosophila were observed (Fahrig, 1974). Siebert and
Lemperle (1974) have reported m.'jtaaenic effects following tr3=t~ert of
Saccharomvces csrevisiae strain 04 with aqueous 2,4-0 solution (1,000 mg/1).
Gavage or intraperitoneal administration of 2,4-0 to mice failed
to show mutagenic effects in the dominant lethal assay (Epstein, et al.
1972) .
t
C. Teratogenicity
Testing of 2,4-0 and its n-butyl, isopropyl, and isooctyl esters
in pregnant mice produced no significant teratogenic effects. There was a
77-7
-------
significant increase in cleft palate deformities after administration of the
propylene glycol butyl ether ester of 2,4-0 (Courtney, 1974).
Subcutaneous injection of the two isopropyl esters and the iso-
octyl ester of 2,4-0 in pregnant mice has been reported to produce terato-
genic effects (Caujells, et al. 1967), although the DMSC vehicle used is,
itself, a teratogen. Sage, et al. (1973) have also reported teratogenic ef-
fects in mice following injection of 2,4-0.
Oral administration of 2,4-D to hamsters resulted in the produc-
tion of some terata (Collins and Williams, 1971). Studies with rats report-
ed that oral administration of the parent compound or its isooctyl and butyl
esters, and butoxy ethanol and dimethylamine salts, produced teratogenic ef-
fects (Khera and McKinlay, 1972). However, Sclr.vetz, et al. (1971) were un-
able to show teratogenic effects in rats following the oral administration
of 2,4_o or its isoocytoi or propylene giycol butyl ether esters.
0. Other Ssorccuctivs Effects
Embryctoxic effects following subcutaneous administration of 2,4-0
to pregnant mice 'nave been reported (Caujolle, et al. 1967; Sage, et al.
1973).
Fetotoxic effects of the compound and its esters have been report-
ed after oral aciTiiniSursLiGn or rnaxii7iaij.y L0i=rauec doses vjcruvcuz, ec 5^.
1971; Khera and McKinely, 1972).
Results of a three-generation study of rats fed 2,4-0 indicate
that at dietary levels up to 500 ppm, no reproductive effects are produced;
at levels of 1,500 ppm, a decrease in survival and body weights of weanlings
was observed (Hansen, et al. 1971)-. Bjorklund and Erne (1965) reported no
adverse reproductive effects in rats fed 1,000 mg/1 2,4-0 in drinking water.
-------
E. Chronic Toxicity
Animal studies with prolonged oral administration of 2,4-0 or its
amine salt have indicated renal and hepatic effects (Bjorklund ana Erne,
1971; Sjorn and Northen, 1948); the chemical purity of the material adminis-
tered is not known. A feeding study in rats has reported histcpatholcgical
liver changes at dietary levels of 2,4-0 equivalent to 50 mg/kg (Oow Chem-
ical, 1962).
V. AQUATIC TOXICITY
A. Acute Toxicity
\
The National Research Council of Canada (1978) has reviewed the
toxic effects of 2,4-0 to fish. For the blusgill sunfish (Lescmis
macrcchirus), 2,4-0 acid and 2,4-0 dimethyl amine produced toxic affects at
concentrations greater than 100,000 ug/1. At 2,4-0 concentrations of 50,000
ug/1 or less, no increased mortalities were reported except in pink salmon.
The isoprcpyi, butyl, ethyl, butoxy etnanoi, and FG5E esters produced
48-hour LC5Q values of 900, 1,300, 1,400. 2,100, and from 1,000 to 2,100
ug/1, respectively.
For other fish species, the results follow a similar trend in that
the esters tend to be more toxic than other formulations. Meehan, st al.
(1974) ccnductac tssts of various formulations of 2,4-0 en echo salmon fry
and fingerlings (Oncorhycus Kitutch), chum salmon fry (0_. keta), pink salmon
fry (0_. gorbuscha), sockeye salmon smolts (0_. nerka), Dolly Varden
(Salvelinus malma), and rainbow trout (Salmo gairdneri). The butyl ester
was the most toxic ester tested, with concentrations of 1,000 ug/1 or
greater producing nearly 100 percent mortalities in all species tested. The
PGBE ester was similar in toxicity to the butyl ester. Rainbow trout were
reported to have shown a 48-hour LC5Q vaiue Of 1,100 /ug/i on exposure to
-------
the PG8E ester of 2,4-0. Harlequin fish (Rasbora heteromorpha) showed a
48-hour LC5Q value of 1,000 ug/1 on exposure to the butoxyethyl ester of
2,4-0 (National Research Council of Canada 1978). Rehwoldt, et al. (1977)
have observed 96-hour LC50 values of 26,700; 40,000; 70,100; 70,700;
94,600; 96,500; and 300,600 ug/1 for banded killifish (Fundulus diaphanus),
white perch (Roccus americanus), stripped bass (Morone sazatilis), guppies
(Libistes reticulatus), bumpkinseed sunfish (Lepomis gibbosus), carp
(Cyprinus carpio), and American eel (Anguilla rostrata), respectively,
exposed to commercial technical grade 2,4-0.
Sanders (1970) conducted a comparative study on the toxicities of
various formulations of 2,4-0 for six species of freshwater crustaceans.
The PG8E ester was generally most toxic, while the dimethylamine salt was
least toxic. The crayfish (Orconectes nails) was the most resistant species
tested, with 46-hour static 1C values areater than 100.COO uo/1 for all
^u - •• -
formulations tested. The water flea (Dap'nnia ~.acna) and seed shrimp
(Cypridopsis vidua) were most sensitive to the FGBE ester, with 43-hour
LC=g values of 100 and 320 jug/1, respectively. Scuds (Gammarus
fasciatus), scwbugs (Ascellus brevicaucus), and freshwater grass shrimp
(Palaemonetes kadiakensis) were also moderately sensitive, with 48-hour
LC5Q values ranging from 2,200 to 2,700 ,ug/l. Sanders and Cope (1968)
reported a 96-hour LC5Q value of 1,600 ug/1 for stonefly naiads
(Pteronarcv californica) exposed to the butoxyethanol ester of 2,4-0. Tech-
nical grade 2,4-0 produced a 96-hour LC5Q vaiue of 14,000 ug/1. Robertson
.•
and Bunting (1976) reported 96-hcur LC5Q values ranging from 5,320 to
11,570 /jg/1 for copepods (Cyclops vernalis) nauplli exposed to 2,4-0 as free
acid. The range of 96-hour LC5Q values for nauplli exposed to 2,4-0 alko-
nolamine salt was 120,000 to 167,000 Aig/1.
-------
Among marine invertebrates, those of commercial significance have
been examined for toxic effects on exposure to 2,4-0 formulations. Butler
(1965) determined the 96-hour median effective concentration based on shell
growth for oysters as 140 ug/1 for the PGEE ester of 2,4-0. The 2,4-0 acia
had no detectable effect at exposures of 2,000 jug/1 for 96-hours. Butler
(1963) observed paralysis of brown shrimp (Penaeus aztecus) exposed to 2,4-0
acid at a concentration of 2,000 (ug/l for 48-hours. Sudak and Claff (1960)
found a 96-hour LC5Q vaiue of 5,000,000 jug/1 for fiddler crabs (yea
pugmax) exposed to 2,4-0.
McKee and Wolf (1963) have reviewed the toxic effects of 2,4-0 to
aquatic organisms. Toxic concentrations as lev; as 1,000 ug/I produced -3. 40
percent mortality for fingerling bluegills exposed to 2,4-0 butyl ester. In
general, esters of 2,4-0 were reported to be more toxic than sodium salts of
2,4-0.
E. Chronic Tcxicity
Rehwoldt!, et al. (1970) exposed several species of fish to 100
jug/1 2,4-0 for ten months and observed no overt effects to any tasted
species. The percent reduction of brain acetylcolinestarase ranged from 16
percent in white perch to 35 oercent in American eels. In breeding exoeri-
ments with guppies, a 100 ug/1 concentration of 2,4-0 had no significant ef-
fect on the reproductive process of the species under experimental ccnc-i-
tions. Cope, et al. (1970) examined the chronic effects of FGEE ester of
2,4-0 to bluegill sunfish. Fish were exposed to the herbicide in one-eighth
.-
acre pcr.ds containing initial concentrations of up to 10,CCO pg/1. Altera-
tions in spawning activity, and the occurrence of pathological lesions of
the liver, brain, and vascular system were reported for a period of up to 84
-*»•
-------
days. Mount and Stsphan (1967) exposed 1-inch fathead minnows (Pimeohales
promelas) to a continuous series of concentrations of the butoxyethanol
ester of 2,4-0 ranging from 10 to 310 ug/1 for a 10-month period. No deaths
of deleterious effects, including abnormal spawning activity and reduced
survival of eggs from exposed fish, were observed.
In static-renewal tests, Sigmon (1979) reported that the percent
pupation and the percent emergence of Chironomus larvae were significantly
reduced by exposure to 1,000 or 3,000 ug/1 1,4-0 (acid equivalent in Wesdone
LV-4 formulation).
».
C. Plant Effects
The genera Microcystis, Scanedesmus, Chlorella, and Nitzschia
shewed no tcxic response when exposed to 2,OCO jug/1 2,4-0 Lawrence (1952).
Poorman (1973) treated cultures of Euglena gracilis with concentrations of
50,OCO .ug/1 2,4-0 for 24 hours and observed cecressed growth rates.
Valentine and Einc°?.m (1974) cemonstrateo that at 100,000 ug/1, 2,4-D re-
duced the ceil nurnoers of Scenecesmus to one percent of control levels,
Chlai7iydo~.or.3s to 43 percent of control levels, Chlorella to 66 percent of
control levels, and Euglena to 90 percent of control levels within 4 to 12
days. The bluegreen algae (Nostoc muscor.ji~1 displayed s. 68-percent reduc-
•^-.cpi — n grew ^i . n)icr< cxposec ^c -LWW ug/j. *_,-T— ^ ^w^.-w-^ o.iv- wav'ci«.j — •>— , — ^«^/.
Singh (1974) exposed Cylindrosoermum to 2,4-0 sodium salt at concentrations
ranging from 100,000 to 1,200,000 jjg/1 and reported that concentrations
above 800,000 ug/1 caused growth to cease completely. McKee and Wolf (1963)
reviewed the effectiveness of 2,4-0 in control of emergent aquatic plants
and reported that concentrations ranging from 6,000 to 100,000 jug/1 have
been effective in controlling a number of species.
• ? 7 ?~
^^^^^^^^7
-------
0. Residue
Cope, et al. (1970) examined residues of the PG3E ester of 2,4-0
in the freshwater vascular plant, Potamogeten nodosus, in a one-eighth acre
pond treated with single 100 to 10,000 ug/1 applications of the chemical. A
gradual depeletion of the herbicide to insignificant levels was•demonstrated
within three months.
Schultz and Gangstad (1976) reported that the flesh of fish ex-
posed to 2,4-0 dimethyl sodium salt in ponds treated with from 2.24 to 8.96
kg (as an acid equivalent) of the chemical did not attain the 100 ug/1 level
realized in the water two weeks after application.
The National Research Council of Canada (NRCC) (1978) has reviewed
the bioconcsntraticn data and associated residues of 2,4-0 in a number of
studies. NRCC indicated that a relatively short half-life of less than two
days is found for fish and oyster. At water concentrations of 100 to 2CQ
ug/1, the bicconcentration of 2,4-0 various aquatic invertebrates v/as one to
two orders of magnitude greater than lin the water. Oysters (Crassostica
viroinica) were reported to have a bioconcentration factor of 150 when ex-
oosed to the butoxyethanol ester of 2,4-0. The freshwater oluegill and mos-
quito fish (Garnbusia affinls) had bioccncsntration factors ranging from 7 to
55, respective to water concentrations.' fish fee; a diet containing 2,4-G
bicconcentrated the 2,4-0 acid by less than 0.2.
VI. EXISTING GUIDELINES
A. Human
The acceptable daily intake of 2,4-0 for humans has been estab-
lished at 0.3 mg/kg (FAO, 1969).
B. Aquatic
Pertinent data were not found in the available literature.
-------
2,4-OICHLOROPHENOXYACETIC ACID
References
Bage, at al. 1973. Teratogenic and embryotoxic effects of herbicides diand
trichlorophenoxyacetic acids (2,4-0 and 2,4,5-T). Acta Pharmacol. Toxicol.
32: 408.
Sjerke, E., et al. 1972. Residue studies of phenoxy herbicides in milk and
cream. Jour. Agric. Food Chem. 20: 963.
Bjorklund, N. and K. Erne. 1966. Toxicological studies of phenoxy acetic
herbicides in animals. Acta Vet. Scand. 7: 364.
Bjorklund, M. and K. Erne. 1971. Phenoxy-acid-induced renal changes in the
chicken. I. Ultra structure. Acta Vet. Scand. 12: 243.
Bjorn, M. and H. Northen. 1948. Effects of 2,4-dichlorophenoxyacetic acid
on chicks. Science 108: 479.
Butler, P.A. 1963 Commercial Flshary Investigations. U.S. Oept. Interior
U.S. Fish anc Wildlife Service Circ. 167: 11.
Butler, P.A. 1965. Effects of herbicides on estusrir.e fauna. Prcc.
Southern Weed Conference 18: 576.
Caujoile, F., et al. 1967. Limits cf toxic and tsratcgsnic tolerance of
ci~3thyl sulfc:
-------
Dow Chemical Company. 1962. Results of 90-day dietary feeding of the pro-
pylene glycol isobutyl ether ester of silvex (Dowco 171) to rats. Unpub-
lished Report. Oow Chemical Co., Midland, MI.
Epstein, S., et al. 1972. Detection of chemical mutagens by the dominant
lethal assay in the mouse. Toxicol. Appl. Fharmacol. 23: 283.
Food and Agriculture Organization of the United Nations (FAO). 1969. Work-
ing party of experts on pesticide residues. Evaluations at some pesticide
residues in food, the monographs. FAQ/WHO PL 1968/m/9/l.
Fahrig, R. 1974. Comparative mutagenicity studies with pesticides. Chem-
ical Carcinogenesis Assays. IARC Scientific Publication 10: 161. Lyoh.
Farwell, S.O. et al. 1976. Survey of airborne 2,4-0 in south central
Washington. Jour. Air Pollut. Control Assoc. 26: 224.
Gangst, E.O. 1979. Herbicide Residue of 2,4-0, Office of Chief of Engine-
ers, Washington, O.C. NTIS AD-67160.
Hansen, w. et al. 1971. Chronic toxicity of 2,4-dichlorophenoxyacetic acid
in rats and dogs. Toxicoi. Api. Fharmacoi. 20: 122.
Herbicide Handbook. 1979. 4th ed. Weed Science Society of America,
Champaign, IL. p. 129.
Innes, J. , et ai. 1969. Bicassay of pesticides and industrial chemicals
for tumorigencity in mice: A preliminary note. Jour. Nstl. Cancer Instit.
42: 1101.
p'nera, K. ana w. McKiniey. 1572. Pre and postnatal srjci^s en 2,4,5-tri-
chlorophenoxyacetic acid, 2,4-dichiorophenoxyacetic acid and their deriva-
tives in rats. lexical. Appl. Fharmacol. 22: 14.
Konli, J., et al. 1974. Absorption and excretion of 2,4-dichlorophenoxy-
acetic acid in man. Xenobiotica, 4: 97.
Lawrence, J.M. 1962. Aquatic Herbicide Data. U.S. Dept. of Agriculture,
p.
Lindquist, N. and S. Ullberg. 1971. Distribution of the herbicides 2,4,5-T
and 2,4-0 in pregnant mice. Accumulation in the yolk sac epithelium.
Experientia, 27: 1439.
McKee, J.E. and H.w. Wolf. 1963. Water Quality Criteria. Calif. State
water Quality Board Publication 3-A.
Meehan, W.R., et al. 1974. Toxicity of various formulations of 2,4-0 to
saimcnids in southeast Alaska. Jour. Fish Red. 3d. Canada 31: 480.
Mount, O.I. and C.E. Stephen. 1967. A method for establishing acceptable
toxicant limits for fish - malathion and the butoxy ethanol ester of 2,4-0.
Trans. Am. Fish Soc. 96: 185.
-------
National Research Council Canada (NRCC). 1978. Phenoxy Herbicides - Their
Effects on Environmental Quality. Associate Committee on Scientific
Criteria for Environmental Quality NRCC No. 16075, ISSN 0316-0114. Avail-
able: Publications NRCC/CNRC Ottawa K1A OR6.
National Cancer Institute. 1968. Evaluation of carcinogenic, teratogenic,
and mutaaenic. activities of selected pesticides and industrial chemicals.
National Cancer Institute, PB-223 159.
Poorman, A.E. 1973. Effects of pesticides on Euglena gracilis I growth
studies. Bull. Environ. Contain. Toxicol. 10: 25.
Rehwoldt, R.E., et al. 1977. Investigations into the acute toxicity and
some chronic effedts of selected herbicides and pesticides on several fish
species. Bull. Environ. Contam. Toxicol. 18: 361.
Robertson, E.B. and D.L. Bunting. 1976. The acute, toxicity of four herbi-
cides to 0-4 hour Nauplli of Cyclops vernalis fishes. Bull. Environ.
Contam. Toxicol. 16: 682.
Sanders, H.O. 1970. Toxicities of some herbicides to six species of fresh-
v/ater crustaceans. Int. Jcur. Water Pcllut. Ccntrcl Fed. 42: 1544.
Sanders, H.O. and O.B. Cope. 1963. The relative toxicities of several pes-
ticides to naiads of three species of stoneflies. Limnol and Oceanogr.
13: 112.
Sauerhcff, M.., et ai. 1976. The fate of 2,i-dichicrcpr,er,oxyacetic acia
(2,4-C) fallawina oral administration to rr,an. Toxicoi. Apcl. Fhsr~iacci.
37: 136.
Scnwetz, 3., et al. 1571. The effect of 2,4-tiichlorcphenoxyacetic acid
(2,4-0) and esters of 2,4-0 on rat srcbrycnal, foetal, sr.d necnatal growth
and development. Food Cosmet. Toxicol. 9: 301.
Schultz, D.P. and E.O. Gangstad. 1976. Dissipation of residues of 2,4-0 in
water, hydrosoil, and fish. Jour. Aquat. Plant Managa. 14: 43
Sisoer^". 0. and P. Lsn^c^rle, 1974. Genetic effects of herbicides: inc'jc—
ticn of mitotic gene conversion in Saccharcrnyres cerevisiae. Mut. Res.
22: 111.
Sigmon, C.F. 1979. Influence of 2,4-0 and 2,4,5-T on life history charac-
teristics of Chironomus (Diptera Chironomidae). Bull Environ. Contam.
Toxicol. 21: 596.
Singh, P.K. 1974. Algicidal effect of 2,4-dichlorophenoxyacetic acid on
blue-green algae. Cylindrosperum sp. Arch. Microbiol. ' 97: 69.
Stanley, C.W., et al. 1971. Measurement of atmospheric levels of pesti-
cides. Environ. Sci. Technol. 5: 430.
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Sudak, F.N. and C.L. Claff. 1960. Survival of Uca pugnax in sand, watsr,
and vegetation contaminated with 2,4-dichlorophenoxyacetic acid. Proc.
Northeast Weed Cont. Conf. 14: 5Q8.
Valentine, J.P. and S.'.v. Bingham. 1974. Influence of several algae on
2,4-0 residues in water. Weed Sci. 22: 358.
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No. 78
l,2-Dichloropco,pane
Health and Environmental Effects
U.S. ENVKOT.ENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical acc-uracy.
- ?~J cr~
-------
1,2-DICHLOROPROPANE
Summary
The major environmental source of dichloropropane is from the use of a
mixture of dichlorcpropanes and dichloropropenes as a soil fumigant. On
chronic exposure of rats to dichloropropanes the only observed effect was a
lack of normal weight gain. There is no evidence that dichloropropanes are
carcinogens or teratogens. Oichloropropanes have produced mutations in bac-
teria and caused chromosomal aberrations in rats. ••
Aquatic toxicity tests of 1,2-dichloropropane are limited to four acute
investigations. Two observed 96-hour LC--, values for the bluegill are
230,000 and 320,000 jjg/1 and the 43-hour LC50 value for Osphnia magna is
52,500 jug/1. A saltwater fish has a reported 96-hour LC5Q value of
240,000 Jjg/i.
-------
1.2-OICHLOROPRQPANE
' I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Dichloropropanes/Dichloropropenes (U.S. EPA, 1979).
1,2-Oichloropropane (1,2-rDC, molecular weight 112.99) is a liquid at
environmental temperatures. This isomer of dichloropropane has a boiling
point of 96.4°C, a density of 1.156 g/ml, a vapor pressure of 40 mm Hg at
19.4°C and a water solubility of 270 mg/100 at 20°C (U.S. EPA, 1979).
Mixtures of 1,2-dichloropropane and cis-trans-L, 3-dichloropropene are used
as soil fumigants. For the purposes of discussion in this hazard profile
document, dichloropropane refers to the 1,2-dichlorcpropane iscmer. When
heated to decomposition temperatures, l,2-dichioropropane emits highly toxic
fumes of phosgene (Sax, 1975).
II. EXPOSURE
A. ',','3 tar
Oichlorooropane can enter the aquatic environment as discharges
from industrial and manufacturing processes, as run-off frcm agricultural
land, and from municipal effluents. This compound was identified but not
quantified in New Orleans drinking water (Oowty, et al. 1975).
8. Food
Information was not found, concerning the concentration of dichloro-
propane in commerical foodstuffs; therefore, the amount of this compound in-
gested by humans through food is not known. The U.S. EPA (1979) has esti-
mated the bioconcentration factor (BCF) of dichloropropane to be 20. This
estimate is based on the octanol/water partition coefficients of dichloro-
9
propane. The weighted average BCF for edible portions of all aquatic organ-
isms consumed by Americans is calculated to be 5.3.
-------
C. Inhalation
Atmospheric levels of aichloropropane have not been positively
determined. However, it is known that 5-10 percent of the dichloropropane
which is applied to the soil as a fumigant is released to the air (Thc~as
and McXeury, 1973).
III. PHARMACOKINETICS
A. Absorption, Distribution and Metabolism
Pertinent data could not be located in available literature
searches regarding the absorption of dichloropropane.
B. Excretion
Pertinent data cculd not be located in available literature
searches regarding excretion of dichloropropane. in the rat, approximately
50 percent of an orally administered dose of dichloropropane was eliminated
in the urina in 24 hours (Hutson, et ai. 1971).
A. Carcinogenicity
Only one study is reported on the carcinogenicicy of dichloro-
propane. Heppel, et al. (1948) repeatedly exposed mice (37 exposure
periods) to 1.76 mg dichloropropane per liter of air. Of the 80 mice, only
three survived the exposure and subsequent observation period; however, the
three survivors had multiple hepatomas at the termination of the experiment
(13 months of age). Due to the high mortality, an evaluation based on' this
study cannot be made.
B. Mutagenicity
DeLorenzo, et al. (1977) and Bignami, et al. (1977) showed
»
dichloropropane to be mutagenic in S. typhimurium strains TA 1535 and TA
100. Dichloropropane has also been shown to cause mutations in A. nidulans
-------
(Bignami, et al. (1977), and to cause chromosomal aberrations in rat bone
marrow (Dragusanu and Goldstein, 1975).
C. Teratogenicity
Pertinent information ccuid not be located in available literature
searches regarding teratogenicity.
0. Other Reproductive Effects
Pertinent information could not be located regarding other repro-
ductive effects.
E. Chronic Toxicity
Pertinent information could not be located in available literature
searches regarding chronic tcxicity studies of dichloroprooane exposure in
humans. In one study by Heppel, et al. (1948) rats, guinea pigs, and dogs
were exposed to 400 ppm of dichloropropane for 128 to 140 daily seven hour
•period (given five aays per week). The only effect observed was a decreased
weight in rats.
V. AQUATIC TOXICITY
A. Acute Toxicity
Two observed 96-hour LC5Q values for the bluegill, Lepcmis
macrochirus, upon exposure to 1,2-dichloropropane were 280,000-and 320,000
ug/1 (Oawscn, et al. 1977; U.S. EPA, 1978). In the only freshwater inverte-
brate study reported, the 48-hour LCjQ for Daphnia macna is 52,500 ug/1
(U.S. EPA, 1979). Tidewater silverside, (Menidia bewllina), has an
observed 96- hour LC^ of 240,000/jg/l (Oawson, et al. 1977).
8. Chronic Toxicity
Chronic data are not available for any saltwater or freshwater
species.
-------
C. Plant Effects
The phytotoxicity of 1,2-dichloropropane has not been investigated.
0. Residues
No information available.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by the U.S.
EPA (1979), which are summarized below, have gone through the process of
public review; therefore, there is a possibility that these criteria will be
changed.
A. Human
The TLV for dichloropropane is 75 pom (350 mg/m ) (Am. Conf. Gcv.
Ind. Hyg., 1977). The draft water criteria for dichloropropane is 203 ug/i
(U.S. EPA, 1979).
;-cr i.2-dichlorcprcpane, the proposed draft criteria to protect
i
frsshv/ater aquatic life are 92C ug/1 a 24-hour average-and the concentration
should not exceed 2,ICO ug/1 at any time. Criteria are not available for
saltwater species (U.S. EPA, 1979).
ni'i
7 ' i *S4f
71-7
-------
1,2-DICHLOROPROPANE
REFERENCES
American Conference of Governmental Industrial Hygienists.
1977. Documentation of the threshold limit values. 3rd.
ed.
Bignami, M. , et al. 1977. Relationship between chemical
structure and mutagenic activity in some pesticides: The use
of Salmonella typhimurium and Aspergillus nidulans. Mutag.
Res. 46: 3. ~*"~~~~~~~~~
Dawson, G.W., et al. 1977. The acute toxicity of 47 indus-
trial chemicals to fresh and saltwater fishes. Jour. Hazard.
Mater. 1: 303.
DeLorenzo, F., et al. 1977. Mutagenicity of pesticides
containing 1,3-dichloropropene. Cancer Res. 37: 6.
Dowty, B., et al. 1975. Halogenated hydrocarbons in New
Orleans drinking water and blood plasma. Science 87: 75.
Dragusanu, S., and I. Goldstein. 1975. Structural and nu-
merical changes of chromosomes in experimental intoxication
with dichloropropane. Rev. Ig. Bacteriol. virusol. Parazi-
tol. Epidemiol. Pr.euir.cf itziol. Ig 24: 37.
Heppel, L.A., =t al. 1943-. Toxicology of 1,2-d ichloroprc-
pane (propylene dichloride) IV. Effect of repeated exposures
to a lev; concentration of the vapor. Jcur. Ind. Hyg. Tex i-
col. 30: 139
Hutson, D.H., et al. 1971. Excretion and retention of com-
ponents of the soil fumigant D-D^R^ and their metabolites
in the rat. Food Cosmet. Toxicol. 9: 677.
Leistra, M. 1970. Distribution of 1,3-Dichloropropene over
the phase in soil. Jour. Agric. Food Chem. 18: 1124.
Roberts, R.T., and G. Staydin. 1976. The degradation of (2)-
and (E)-l,3-dichloropropenes and 1,2-dichloropropanes in
soil. Pestic. Sci. 7: 325.
Sax, N.I. 1975. Dangerous properties of industrial mate-
rials. Reinhold Book Corp., New York.
Thomason, I.J., and M.V. McKenry. 1973. Movement and fate
as affected by various conditions in several soils. Part I.
Hallgardia 42: 393.
»
U.S. EPA. 1978. In-depth studies on health and environmen-
tal impacts of selected water pollutants. Contract No. 68-
01-4646.
7F-?
-------
U.S. EPA. 1979a. Dichloropropenes/Dichloropropanes: Ambient
Water Quality Criteria. (Draft).
U.S. EPA. 1979b. Dichloropropenes/Dichloropropanes: Hazard
Profile.
7*-?
'
-------
No. 79
«•
Dichloropropane/Dichloropropenes
Health and Rnvlrotnaental Effects
u.s. ENvmoNMEmL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
77-t
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
DICELGROPROPANES/DICHLOROPROPENES
SUMMARY
The major environmental source of dichloropropanes and
dichloropropenes is from the use of these compounds as soil fumi-
gants. Some mild kidney damage has been observed in rats chroni-
cally exposed to 1,3-dichlorpropene. Both dichloropropane and
dichloropropene have been shown to be mutgenic in the Ames assay
test. Data are not available to prove conclusively that these
compounds are chemical carcinogens.
Aquatic toxicity studies suggest that the acute toxicity
of the dichloropropanes decreases as the distance between the
chlorine atoms increases. As an example, the reported 96-hour
LCen values for the bluegill, Lepomis macrochirus, for 1,1-,
1,2-, and 1,3-dichloropropane are 97,900, 280,000, and greater
than 520,000 ug/1, respectively. For Daphnia itiagna, the corres-
ponding reported 48-i-iour LC-fl values are 23,000, 52,000, and
282,000 ug/1, respectively. Similar results have been obtained
with marine organisms.
The dichloropropenes ara considerably more toxic in acute
exposure than the dichloropropanes. For 1,'3-dichlorpropene,
the 96-hour LC-Q value for the bluegill is 6,060 pg/1 compared
to 520,000 ug/1 for 1,3-dichloropropane. For Daphnia magna,
the corresponding values are 6,150 and 282,000 pg/1, respectively.
The ECSQ, based on chlorophyll a for a freshwater alga, is 4,950
ug/1 for 1,3-dichloropropene, and 48,000 for 1,3-dichloropropane.
»
Data on measured residues could not be located in the available
literature for any saltwater or freshwater species.
-------
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Dichloropropanes/Dichloropropenes (U.S. EPA, 1979).
Dichloropropanes (molecular weight 112.99) and dichloropro-
penes (molecular weight 110.97) are liquids at environmental
temperatures. Their boiling points range from 76 to 120.4°C
depending on the compound and the isomer. They are slightly
denser than water, with densities ranging from 1.11 to 1:22.
The principal uses of dichloropropanes and dichloropropenes are
as soil fumigants for control of nematodes, in oil and fat sol-
vents, and in dry cleaning and degreasing processes (Windholz,
1976). When heated to decomposition temperatures, 1,2-dichloropro-
pane emits highly toxic fumes of phosgene, while 1,3-dichloropro-r
pane gives off toxic fumes of chlorides (Sax, 1975). Production
of mixtures of dichloropropanes/dichioropropenes approached 50
million pounds per year prior to 1975 (U.S. EPA, 1979).
II. EXPOSURE
A. Water
Dichlorcpropanes and dichloropropenes can enter the
aquatic environment in discharges from industrial and manufactur-
ing processes, as run-off from agricultural land, and from munici-
pal effluents. These compounds have been identified but not .
quantified in New Orleans drinking water (Dowty/ et al. 1975).
B. Food
Information was not found in the available literature
»
concerning the concentrations of dichloropropanes and dichloro-
propenes in commercial food stuffs. Therefore, the amount of
these compounds ingested by humans is not known. The U.S. EPA
7T-Y
-------
(1979) has estimated the weighted average bioconcentration fac-
tors (BCFs) of dichloropropanes and dichioropropenes to range
between 2.9 and 5.8 for the edible portions of fish and shellfish
consumed by Americans. This estimate is based on the octanol/
water partition coefficients of these compounds.
C. Inhalation
Atmospheric levels of dichloropropanes and dichioro-
propenes are not known. However, from information on loss of
these- compounds to the air after land application, it was esti-
mated that, in California alone, about 72 tons (8 percent of
the pesticide used) were released to the atmosphere in 1971 (Calif,
State Dept.'Agric. 1971).
Ill. PHARMACOKINETICS
A. Absorption, Distribution and Metabolism
?3rtinent information regarding tha absorption, dis-
tribution, and metabolism of the dichloroprcpanes and dichioropro-
penes could not be located in the available information.
B. Excretion
No human data are available on the excretion of dichlor-
cpropanes or dichloroprcpenes. In the rat, 30 to 90 percent '
of an orally administered dose of dichloropropane or dichloropro-
pene was eliminated by all routes within 24 hours (Hutson, et
al. 1971). Approximately 50 percent of the administered dose
was eliminated in the urine within 24 hours."'
IV. EFFECTS
A. Carcinogenicity
Information concerning the carcinogenicity of mixtures
of dichloropropanes and dichioropropenes could not be located
79-f
-------
in the available literature. However, cis-l,3-dichloropropane
has produced local sarcomas at the site of repeated subcutaneous
injections (Van Duuren, et al., in press). No remote treatment-
related tumors were observed.
B. Mutagenicity
Mixtures of 1,2-dichloropropane and 1,3-dichloropro-
pene are mutagenic to S^_ typhimurium strains TA 1535 and TA 100,
as are the individual compounds. The mixture, but not the in-
dividual compounds, is also mutagenic to TA 1978 (in the presence
of microsomal activation) indicating a frame-shift mutation not
capable of being produced by the individual compounds.
C. Teratogenicity and Other Reproductive Effects
Pertinent information could not be located in the
available literature.
D. Chronic Toxicity
Inhalation exposure of rats, guinea pigs, and decs
to 400 ppm of 1,2-dichloropropane for 128 to 140 daily 7-hour
periods (5 days per week) decreased normal weight gain in rats
(Keppel, et al., 1948). Inhalation exposures of rats to 3 ppm
of 1,3-dichloropropene, 4 hours a day, for 125 to 130 days pro-
duced cloudy swelling in renal tubular epithelium which disap-
peared by 3 months after exposures ended (Torkelson and Oyen,
1977) .
V. AQUATIC TOXICITY
A. Acute Toxicity
»
Exposures of bluegill, Lepomis macrochirus, to 1,1-,
1,2-, and 1,3-dichloropropane under similar conditions yielded
96-hour LC5Q values of 97,900, 280,000, and greater than 520,000
-------
rag/1, respectively (U.S. EPA, 1978). These data suggest that
toxicity decreases as the distance between the chlorine atoms
increases. A reported 96-hour LC-Q for 1,3-dichloropropene is
5,060 ug/1 for the bluegill, approximately two orders of magni-
tude lower than for 1,3-dichloropropane (U.S. EPA, 1979). Under
static test conditions, reported 48-hour LC5Q values for 1,1-,
1,2-, and 1,3-dichloropropanes are 23,000, 52,500 and 282,000
ug/1, respectively, (U.S. SPA, 1978) for the only freshwater
invertebrate species tested, Daphnia magna. The 48-hour LC-Q
value for 1,3-dichloropropene and Daphnia magna under static
conditions is 6,150 ug/1 (U.S. SPA, 1978).
The 96-hour -Ceg values for the saltwater sheepshead
minnow, Cyprinodon variegatus, exposed to 1,3-dichloropropane
and 1,3-cichioroprcpane ware 36,700 jjg/'l and 1,770 ug/1, respec-
tively (U.S. SPA, 1973). Dawson, et al. -(1977) obtained a 96-
hour LCSO of 240,000 ug/1 for the tidewater silvsrsida, Manidia
beryllina, for exposure to 1,2-dichloropropane.
For Mysidopsis sahia, the 96-hour LC^Q for 1,3-dichlcro-
propene was one-thirteenth thac for 1,3-dichloropropane, i.e.,
790 ug/1 and 10,300 ug/1, respectively (U.S. SPA, 1978)
B. Chronic Toxicity
Chronic studies are limited to one freshwater study
and one saltwater study. In an embryo-larval test, the chronic
value for fathead minnows, Pimephales promelas, exposed to 1,3-
dichloropropene was 122 ug/1 (U.S. EPA, 1978). The chronic value
»
for mysid shrimp, Mysidopsis bahia, was 3,040 ug/1 for 1,3-di-
chloropropane in a life cycle study (U.S. EPA, 1978)
77-7
-------
C. Plant Effects
For 1,3-dichloropropene, the 96-hour EC5Q values,
based on chlorophyll a concentrations and cell numbers of the
freshwater alga, Selenastrum capricornutum, were 4,950 ug/1 and
4,960 ug/1, respectively. The respective values obtained for
1,3-dichloropropane were 48,000 and 72,200 ug/1. Thus, the pro-
pene compound is much more toxic than the propane compound, as
is true for the bluegill and Daphnia magna.
0. Residues
Measured steady-state bioconcentration factors (BCF)
are not available for any dichloropropane or dichloropropene
in any fresh or saltwater species.. Based on octanol/water coef-
ficients of dichloropropanes and dichloropropenes, the U.S. EPA;
(1979) has estimated the bioconcentration factors for these com-
pounds to range between 10 and 35.
VI. Other Pertinent Information
In the non-aquatic environment, movement of 1,2-dichloro-
propane in the soil results from diffusion in the vapor phase,
as these compounds tend to establish an equilibrium between the
vapor phase, water and absorbing phases (Leistra, 1970). 1,2-
dichloropropane appears to undergo minimal degradation in soil
with the major route of dissipation appearing to be volatiliza-
tion (Roberts and Staydin, 1976).
Following field application, movement'of 1,3-dichloropro-
pene in soil results in vapor-phase diffusion (Leistra, 1970).
»
The distribution of 1,3-dichloropropene within soils depends
on soil conditions. For example, cis-l,3-dichlorobenzene is
chemically hydrolyzed in moist soils to the corresponding cis-
-------
3-chloroalkyl alcohol, which can be microbially degraded to car-
bon dioxide and water by Pseudomonas sp. (Van Dijk, 1974).
VII. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived
by U.S. EPA (1979), which are summarized below, have gone through
the process of public review; therefore, there is a possibility
that these criteria may be changed.
A. Human
The TLV for dichloropropane is 75 ppra (350 rag/m )
(Am. Conf. Gov. Ind. Hyg., 1977). The draft water criterion
(U.S. EPA, 1979) for dichloropropane is 203 ug/I. The draft
water criterion for dichloropropenes is 0.53 pg/1 (U.S. EPA,
1979) .
3. Aquatic
The dr'aft criteria for the dichioroprcpanes and gi-
chloropropsr.as to prctact frashwatar aquatic life are as follows
(U.S. EPA, 1979):
Concentration not
to be exceeded
Compound 24-Hour Average at any time
1,1-dichloropropane 410 pg/1 930 ug/1
1,2-dichloropropane 920 ^ug/1 2,100 ug/1
1,3-dichloropropane 4,800 ug/1 11,000 ug/1
1,3-dichloropropene L8 pg/1 250 ug/1
The draft criteria to protect saltwater species are as follows
#
(U.S. EPA, 1979):
-------
Concentration not
to be exceeded
Compound 24-Hour Average at any time
1,1-dichloropropane not derived not derived
1,2-dichloropropane 400 jig/1 910 ug/1
1,3-dichloropropane 79 pg/1 180 pg/1
1,3-dichloropropene 5.5 ng/1 14 pg/1
-------
DICHLOROPROPANES/DICHLOROPROPENE5
REFERENCES
American Conference of Governmental Industrial Hygienists. 1977. Documen-
tation of the threshold limit values. 3rd. ed.
California State Department of Agriculture. 1971. State pesticide use
report.
Oawson, G.W., et al. 1977. The acute toxicity of 47 industrial chemicals
to fresh and saltwater fishes. Jour. Hazard. Mater. 1: 303.
Oowty, 8., et al. 1975. Halogenated hydrocarbons in New Orleans drinking
water and blood plasma. Science 37: 75.
Heppel, L.A., et al. 1948. Toxicology of 1,2-dichloropropane (propylene
dichloride). IV. Effect of repeated exposures to a low concentration of the
vapor. Jour. Ind. Hyg. Toxicol. 30: 189.
Hutson, D.H., et al. 1971. Excretion and ratantion of comocnents of the
soil fumigant 0-OAR) and their metabolites in the rat. Food Cosrnet. Toxi-
col. 9: 677.
Leistra, M. 1970. Distribution of 1,3-dichloropropene over the pnase in
soil. Jour. Agric. Food Chem. 13: 1124.
Roberts, R.T. and G. Stoydin. 1975. The degradation of (2)- arc
(E)-l,3-di- chioropropenes and l,2-dichioroproper.5s in soil. Psstic. Sci.
7: 325.
Sax, N.I. 1975. Dangerous properties of industrial materials. Reinhoid
Book Corp., New York.
Torkelson, R.R. and F. Oyen. 1977. The toxicity of 1,3-dichloropropene as
determined by repeated exposure of laboratory animals. Jour. Am. Ind. Hyg.
Assoc. 38: 217.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-101-4646.
U.S. EPA. 1979. Dichloropropanes/Dichloropropenes: Ambient Water Quality
Criteria. (Draft).
Van Oijk, J. 1974. Degradation of 1,3-dichloropropenes in the soil.
Agro-Ecosystems. 1: 193.
Van Ouuren, 8.L., et al. 1979. Carcinogenicity of halogenated olefinic and
alipahtic hydrocarbons. (In press). •
Windholz, M., ed. 1976. The Merck Index. 9th ed. Merck and Co., Inc.,
Rahway, N.J.
77-//
-------
No. 80
Dichloropropanol
Health and Envirorraental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
DICHLOROPROPANOL
Summary
There was no evidence found in the available literature to indicate
that exposure to dichloropropanol produces carcinogenic effects. Conclusive
evidence of mutagenic, teratogenic, or chronic effects of dichloropropanol
was not found in the available literature. Acute exposure results in toxi-
city similar to that induced by carbon tetrachloride, including hepato- and
nephrotoxicity. Data concerning the effects of dichloropropanol to aquatic
•
organisms was not found in the available literature.
-------
I. INTRODUCTION
This profile is based on computerized searches of Toxline, Biosis, and
Chemical Abstracts, and review of other appropriate information sources as
available. Oichloropropanol (molecular weight 128.9), a colorless, viscous
liquid with a chloroform-like odor, refers to four iscmers with the mole-
cular formula C-3H6OC12. The physical properties of each isomer are
given below.
Boiling Point Density Solubility (Weast. 1976)
Water Alcohol Ether
2,3-Oichloro-l-propanol 182QC 1.368 slight miscible miscible
l,3-Oichloro-2-propanol 1740c 1.367 very very miscible
3 , 3-Oichloro-l-pfooanol 32-33°C 1.316 not listed
1 , l-Oichioro-2-prcpanol 146-1 AO^C 1.3334 slight very very
Additional physical data and synonyms of the above isomers are avail-
able in Heilbron (1965), Fairchild (1979)-, Sax (1979), Windholz (1976), ana
Verscnueren (1977).
Oichioropropanol is prepared from glycerol, acetic acicj, and hydrogen
chloride. It is used as a solvent for hard resins and nitrocellulose, in
the manufacture of photographic and Zapon lacquer, as a cement for cellu-
loid, and as a binder for water colors (Windholz, 1976). The compound is
considered to ba a moderate firs hazard when exposed to neat, flame, or oxi-
dizers, and a disaster hazard in that it may decompose at high temperatures
to phosgene gas (Sax, 1979).
II. EXPOSURE
Dichloropropanol was detectable in the air of a glycerol manufacturing
plant in the U.S.S.R. (Lipina and Selyakov, 1975). Unreacted dichloropro-
panol was also found in the wastewater effluent of a halohydrin manufactur-
ing plant (Aoki and Katsube, 1975). No monitoring data are available to
indicate ambient air or water levels of the compound.
-------
Human exposure to dichloropropanol from foods cannot be assessed, due
to a lack of monitoring data.
Bioaccumulation data on dichloropropanol was not found in the available
literature.
III. PHARMACOKINETICS
Pertinent data could not be located in the available literature on the
metabolism, distribution, absorption, or excretion of dichloropropanol.
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not be located in the available literature.
8. Mutagenicity
2,3-OichloropropanoI and 1,3-dichloroprcpanol were evaluated for
mutagenicity by a modified Ames assay using S_._ typhimurium strains. Some
evidence of rnutagenic activity was seen, but the authors fait that further
evidence and clarification of the metabolic activation pathway to mutagens
I
via halcalkanols were r.ecessary (Nskamura, et al. 1579).
C. Teratogenicity, Other Reproductive Effects and Chronic Toxicity
Pertinent data could not be located in the available literature.
0. Acute Toxicity
2,3-Dichlcropropanol was found to have an oral LD^ j_n the rat
of 90 mg/kg. The lowest published lethal concentration (LCLQ) in rats is
500 ppm by inhalation for 4 hours. A dose of 6,800 ug in the eye of the
rabbit caused severe irritation (Fairchild, 1979). 1,3-Dichloropropanol was
found to have an oral LD5Q in the rat of 490 mg/kg'and lowest published
lethal concentration for inhalation exposure in rats of 125 ppm/4 hrs. Ten
»
mg applied to the skin of the rabbit for 24 hours produced mild irritation,
and 800 mg/kg was the LD50 for the same route and species (Fairchild,
1979).
-------
Several references report the clinical indications of acute di-
chloropropanol intoxication as being similar to carbon tetrachloride poison-
ing, i.e., central nervous depression; hepatotoxicity, including" hepatic
cell necrosis and fatty infiltration; and rsnal toxicity, including fatty
degeneration and necrosis of the renal tubular epithelium (Sax, 1979; Gos-
selin, et al. 1976).
V. AQUATIC TOXICITY
Data concerning the effects of dichloropropanol to aquatic organisms
were not fou.nd in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The maximum allowable concentration of dichloropropanol in the
working environment air in the U.S.S.R. is 5 mg/m3 (lipina and Belyakov,
1975).
The maximum allowable ccncar.tration in Class I waters for the pro-
duction of drinking water is 1 mg/1 (verschueren, 1577).
B. Aquatic
The organoleptic limit in water set in the U.S.S.R. (1970) is 1.0
. mg/1 (Verschueren, 1977).
-------
REFERENCES
Aoki, S. and E. Katsube. 1975. Treatment of waste waters from haiohydrin
manufacture. Chem. Abs. CA/083/15875D.
Fairchild, E. (ed.) 1979. Registry of Toxic Effects of Chemical Sub-
stances. U.S. Department of Health, Education and Welfare, National Insti-
tute for Occupational Safety and Health, Cincinnati, Ohio.
Gosselin, et al. 1976. Clinical Toxicology of Commercial Products. Wil-
liam and wilkins Publishing Co., Baltimore, Maryland.
Heilbron, I. (ed.) 1965. Dictionary of Organic Compounds. 4th edition.
University Press, Oxford.
Lipina, T.G. and A.A. Belyakov. 1975.- Determination of allyl alcohol, al-
lyl chloride, epichlorohydrin and dichlorohydrin in the air. Gig. Tr. Prof.
Zabol. 5: 49.
Nakamura. A., et al. 1979. The mutagenicity of halogenated alkanols and
their phosphoric acid esters for Salmonella tyohimurium. Mutat. Res.
66: 373.
Sax, N.I. 1979. Dangerous Properties of Industrial Materials. Van Nos-
trand Reinhold Co., New York.
Verschueren, !<. 1977. Handtcc-k of Environmental Data on Organic Chemicals.
Van Ncstrand Reinhold Co., New York, p. 659.
i
V/east, R.C. (ed-.) 1976. Handbook of Chemistry and Physics. CRC Press,
Cleveland, Ohio, p. c-^54.
Windholz, M. (ed.) 1976. The Merck Index. 9th ed. Merck and Co., Rahway,
New Jersey.
Sro-7
-------
No. 81
1,3-Dichloropropene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
1.3-OICHLOROPROPENE
SUMMARY
The major environmental source of dichlorcpropenes is from the use of a
mixture of dichloropropenes and dichloropropanes as a soil funigant. On
chronic exposure of rats to dichloropropene mild kidney damage was observed.
Dichloropropene has produced subcutaneous tumors at the site of injection,
and has been shown to be mutagenic in bacteria. However, not enough infor-
mation is available to classify this compound as a carcinogen.
o
The bluegill (Leoomis macrochirus) has a reported 96-hr LC5Q value of
oCoG uc/1; Saohnia magna has a reported 43-hr LC5Q of 5130 ug/i. ^or the
saltwater invertebrate, Mysidoosis bahia, a reported 96-hr LC-- value is
790 /jg/1. In the only long-term study available, the value obtained for
1,3-dichloropropene toxicity to fathead minnows (Pimeohales oromeles) in an
embryo-larval test is 122 jug/1. Based en chlorophyll a concentrations and
cell numbers, the 96-hr EC-- values for the frsshwazar alga Selsnastrun
caorieornutum are 4,950 and 4,960 ug/1, respectively: for the' marine alga
Skeletonema costatum, the respective values are- 1,000 and 1,040 ;jg/l.
-------
1,3-DICHLOROPROPENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Dichloropropanes/Dichloropropenes (U.S. EPA, 1979a).
1,3-dichloropropene (molecular weight 110.97) is a liquid at environ-
mental temperatures. The isomers of 1,3-dichloropropene have boiling points
of 104.3°C for the trans-isomer and 112°C for the cis-isomer, and the
densities are 1.217 and 1.224 g/ml, respectively. The water solubility for
the two isomers is approximately 0.275 percent. When heated to
decomposition temperatures, 1,3-dichloropropene gives off toxic fumes of
chlorides (Sax, 1975). Mixtures of cis- and trans- 1,3-dichloropropene and
1,2-dichloropropane are used as soil fumigants. In this document,
dichloropropene will refer to either cis- or trans-1,3-dichloropropene. For
more information regarding the dic'nloroprcoanss, tha reader is rsfsrrsd to
the EPA/ECAC Hazard Profile on Dichlorcpropanes/Dichloropropenes (U.S. EFA,
1979b).
II. EXPOSURE
A. Water
Dichloropropene can enter the aquatic environment in the discharges
from industrial and manufacturing processes, in run-off from agricultural
land, or from municipal effluents. This compound has been identified but
not quantified in New Orleans drinking water (Dowty, et al. 1975).
B. Food
Information was found in the available literature concerning the
concentration of dichloropropene in commercial foodstuffs. Thus, the amount
»
of this compound ingested by humans is not known. The U.S. EPA (1979a) has
estimated the weighted average bioconcentration factor (BCF) of dichloropro-
pene to be 2.9 for the edible portions of fish and shellfish consumed by
-------
Americans. This estimate is based on the dctanol/water partition coeffi-
cient of dichloropropene.
C. Inhalation
Atmospheric levels of dichlcrcprcpene have not been measured. How-
ever, it is estimated that about 8 percent of the dichloropropene which is
applied to the soil as a fumigant is released to the atmosphere (U.S. EPA,
1979a).
III. PHARMACOKINETICS
^.
A. Absorption
Data on the absorption, distribution and metabolism of dichloropro-
pene could not be located in the available literature.
Data on the excretion of dichloropropene by humans could not be
located in the available literature. In the rat, however, approximately 80
percent of an orally aoninistered dose of dicnioropropene was eliminated in
the urine within 24 hcurs (Hutson, et al. 1971).
IV. EFrECTS
A. Carcinogenicity
Van Ouuren, et al. (1979) investigated the ability of dichloropro-
pene to act as a tumor initiator or promoter in mouse skin, or to cause
tumors after subcutaneous injection. Dichloropropene showed no initiation
or promotion activity, and only local sarcomas developed in mice following
subcutaneous administration. In none of the studies were treatment-related
remote tumors observed.
^
8. Mutagenicity
DeLorenzo, et al. (1977) and Neudecker, et al. (1977) reported tjhat
dichloropropene was mutagenic in S. typhimurium strains TA1535 and TA100 but
not in TA1978, TA1537, or TA98. Results did not differ with or without the
-------
addition of liver microsomal fraction. Neudecker, et al. (1977) found the
cis-isomer to be twice as reactive as the trans-isomer.
C. Teratogenicity and Other Reproductive Effects
No pertinent information regarding the teratogenicity and other
reproductive effects could not be located in the available literature.
D. Chronic Toxicity
On exposure of rats to 3 ppm dichloropropene for period of 0.5, 1,
2 or 4 hours/day, 5 days a week for 6 months (Torkelson and Oyen, 1977), or
rats, guinea pigs, and rabbits to 1 or 3 ppm of dichloropropene, 7 hours per
day for 125-130 days over a 180-day period, only rats exposed 4 hours/day at
3.0 ppm showed an effect (U.S. EPA, 1979a). The only effect observed was a
cloudy swelling of the renal tubular epithelium which disappeared by 3
months after exposures ended.
V. AQUATIC TOXICITY
A. Acute Toxicity
Tests on the bluegill, Legcmis .Tiacrochirus, yielded a 96-hr LC5Q
value of 6060 )jg/l for 1,3-dichloroprcpene exposure. For Daphnia maona, the
48-hr LC5Q value is 6,150 jug/1 (U.S. EPA, 1978). The observed 96-hr
LC5Q for the saltwater my rid shrimp, Mysidopsis bania, is 790 jjg/1 (U.S.
EPA, 1973).
B. Chronic Toxicity
An embryo-larval test has been conducted with the fathead minnow
(Pimephales promeles) and 1,3-dichloropropene. The. observed chronic value
was 122 jjg/1 (U.S. EPA, 1979a).
C. Plant Effects
»
Based on chlorophyll a concentrations and cell numbers, the 96-hr
EC5Q values for the freshwater alga, Selenestrum caoricornutum, are 4,950
-------
and 4,960 pg/1, respectively (U.S. EPA, 1978). The respective values for
the saltwater alga Skeletonema ccstatum were 1,000 and 1,040 jug/1 (U.S. EPA,
1978).
0. Residues
Measured steady-state bioconcentration factors (8CF) are not avail-
able for 1,3-dichloropropene. A BCF of 19 has been estimated based on the
octonol/water coefficient for 1,3-dichloropropene (U.S. EPA, 1979a).
E. Other Relevant Information
Following field application, movementsof 1,3-dichloropropene in
soil results in vapor-phase diffusion (Leistra, 1970). The distribution of
1,3-dichloropropene within soils depends on soil conditions. For example,
cis-l,3-dichlcroprcpane is chemically hydroiyzed in moist soils to the cor-
responding cis-3-chloroalkyl alcohol, which can be microbially degraded to
carbon dioxide and water by Pseudomonas so. (Van Dijk 1974).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979a), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed.
A. Human
The draft water criterion for 1,3-dichloropropene is 0.63 /jg/1
(U.S. EPA, 1979a).
B. Aquatic
The draft criterion to protect freshwater'species is 18 /jg/1 as a
24-hr average not to exceed 250 jug/1 at any time. For marine species, the
»
value is 5.5-jug/l as a 24-hr average not to exceed 14 ;jg/l at any time (U.S.
EPA, 1979).
-------
1,3-DICHLOROPROPENE
REFERENCES
OeLorenzo, p., et al. 1977. Mutagenicity of pesticides containing 1,3-di-
chloropropene. Cancer Res. 37: 6
Dowty, 8., et al. 1975. Halogenated hydrocarbons in New Orleans drinking
water and blood plasma. Science 87: 75.
Hutson, O.H., et al. 1971. Excretion and retention of components of the
soil, fumigant QrQ^> and their metabolites in the rat. Food Cosmet.
Toxicol. 9: 677.
Lsistra, M. .197,0. Distribution of 1,3-dichloropropene over the phase in
soil. Jour. Agric. Food Chem. 18: 1124.
Neudecker, T.-, et al. 1977. In vitro mutagenicity of the soil nematocide,
1,3-dichloropropene. Experientia 33: 8.
Sax, M.I. 1975. Dangerous Properties of Industrial Materials. Reinhold
Book Corp., New York.
Torkelson, R.R. and F. Oyen. 1977. The toxicity of 1,3—dichloroprcpene as
determined by repeated exposure of laboratory animals. Hour. Am. Ind. Hyg.
Asscc.. 38: 217. .
U.S. EPA. 1978. In-depth studies on health, and environmental impacts of
selected water pollutants. Contract No. 63-01-4646.
U.S. EPA. 1979a. Oichloropropanes/Oichloropropenes: Ambient Water Quality
Criteria (Draft)
U.S. EPA. 1979b. Dichloropropanes/Dichloropropenes: EPA/ECAO Hazard Pro-
file.
Van Dijk, J. 1974. Degradation of 1,3-dichloropropenes in the soil. Agro-
Ecosystems. 1: 193.
Van Duuren, et al. 1979. Carcinogenicity at halogenated olefinic and
aliphatic hydrocarbons. (In press).
-------
No. 82
Dieldrin
Health and EirrLroTaaental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA1s Carcinogen Assessment Group (CAG) has evaluated
dieldrin and has found sufficient evidence to indicate that
this compound is carcinogenic.
-------
DIELDRIN
SUMMARY
Dieldrin is a compound belonging to the group of cyclodiene
insecticides. The chronic toxicity of low doses of dieldrin
includes shortened life span, liver changes ana teratogenic effects.
The induction of hepatocellular carcinoma in mice by dieldrin
leaas to the conclusion that it Is lively to" be a human carcinogen.
Dieldrin has been found to be non-mutagenic in several test sys-
tems. The WHO'S acceptable daily intake for dieldrin is 0.0001
mg/kg/day.
The toxicity of disidrin to aquatic organisms has been
investigated in numerous studies. The 96-hour i->Ccn values for
the common freshwater fish range from 1.1 to 360 ug/1. The acute
toxicity is considerably more varied for ft.esnwacer invertebrates,
with 96-hcur I^Q values ranging frcrr, 0.5 ug/1 for the stonefiy
to- 7^0 ,ug/l for the crayfish. Acute i-Ccn values for eight salt-
water fish species range from 0.66 to 24.0 ug/1 in flow-through
tests; LC,-Q values for estuarine invertebrates range from 0.70
to *:40 ug/1. The only reported chronic values are 0.11 jug/I
for steel head trout (Salmo guirdnes) in an emoryolarval study
ana 0.4 ug/1 for the guppy (Poecilia reticulata) in a life-cycle
test. Both fresh and salt water algae are less sensitive to
dieldrin toxicity than the corresponding fish ana inverteorates.
Bioconcentration factors were 128 for a freshwater alga, 1395
for Daphnia magna, 2993 for the channel catfish, ana 8000 for
— - #
the edible tissues of the Eastern oyster.
-------
DI2LDRIN
I. INTRODUCTION
This profile is based on the draft Ambient Water Quality
Criteria Document for Aldrin and Dieldrin (U.S. EPA, 1979).
Dieldrin is a white crystalline substance with a melting point
of 176-177°C and is soluble in organic solvents (U.S. EPA, 1979).
The chemical name for dieldrin is 1,2,3,4,10,10-hexachlor-6,7-
epoxy-1,4,4a,5,6,7,8,8a-octohydro-endo, exo-1,4:5,3-dimethanonaph-
thalene. v
Dieldrin is extremely stable and persistant in the environ-
ment. Its pe'rsistance is due to its extremely low volatility
(1.78 x 10"7 mm Hg at 20°C) and low solubility in water (186
ug/1 at 25-29°C). The time required for 95 percent of the dieldrin
to disappear from soil has been estimated to vary from 5 to 25
years depending on the microbial flora of the soil (Edwards..
1966). Patil, et al. (1972) reported that dieldrin was not de-
graded or metabolized in sea water or polluted water.
Dieldrin was primarily used as a broad spectrum insecticide
until 1974, when the U.S. EPA restricted its use to termite con-
trol by direct soil injection, ana non-food seed and plant treat-
ment (U.S. EPA, 1979). From 1966 to 1970, the amount of dieldrin
used in the United States decreased from 500 to approximately
335,000 tons (U.S. EPA, 1979). This decrease in use has been
attributed primarily to increased insect resistance to dieldrin
and to development of substitute materials. Although the produc-
»
tion of dieldrin is restricted in the United States, formulated
products containing dieldrin are imported from Europe (U.S.
EPA, 1979).
-------
II. EXPOSURE
A. Water
Dieldrin has been applied to vast areas of agricul-
tural land and aquatic areas in the United States, and in most
parts of the world. As a result, this pesticide is found in
most fresh and marine waters. Dieldrin has been measured in
many freshwaters of the United States, with mean concentrations
ranging from 5 to 395 ng/1 in surface water and from 1 to 7 ng/1
in drinking water (Epstein, 1976) . Levels as high as 50 ng/1
have been found in drinking water (Karris, et al. 1977). The
half-life of dieldrin in water, 1 meter in depth, has been esti-
mated to be 723 days (i-iacKay and Wolkoff, 1373).
B. Food
Dieldrin is one of the most stable and persistant
organcchiorine pesticides (Nash and Woolson, 1957} , and because
it is lipophilic, it accumulates in the food chain (Wurster,.
1971). Its persistence in soil varies with the type of soil.
(Matsumura and Boush, 1967).
The U.S. EPA (1971) estimated that 99.5 percent of
all human beings have dieldrin residues in their tissue. These
residues are primarily due to contamination of foods of animal
origin. The overall concentration of dieldrin in the diet in
the United States has been calculated to be approximately 43
ng/g of food consumed (Epstein, 1976). The U.S. EPA has estimated
the weighted average bioconcentration factor for dieldrin to
»
be 4,50.0 in the edible portion of fish and shellfish consumed
by Americans (U.S. EPA, 1979). This estimate is based on measured
-------
steady-state bioconcentration studies in several species of fish
and shellfish.
C. Inhalation
Dieldrin enters the air through various mechanisms,
such as spraying, wind action, water evaporation, and adhesion
to particulates. The U.S. EPA detected dieldrin in more than
85 percent of the air samples tested between 1970-1972, with
the mean levels ranging from 1 to 2.8 ng/m (Epstein, 1976).
From these levels, the average daily intake of dieldrin by respi-
ration was calculated to be 0.035 to 0.098 ug.
Although dieldrin is no longer used in the United
States, there is still the possibility of airborne contamination
from ocher parts of the world.
D. Cerraai
Dermal .exposure to dieldrin is limited to those in-
volved in its manufacture or application as a pesticide. Wolfe,
et al. (1972) rapcrtad that exposure in workers was mainly through
dermal absorption rather than inhalation. The ban on the manufac-
ture of dieldrin in the United States has greatly reduced the
cis'< of e:-:pc:s_re.
III. PHARMACOKINETICS
A. Absorption
The absorption of dieldrin by the upper gastrointes-
tinal tract begins almost immediately after oral administration
in rats and has been found to vary with the amount of solvent
used (Heath and Vandekar, 1954). These authors also demonstrated
that absorption takes place via the portal vein, and that dieldrin
-------
could be recovered from the stomach, small intestine, large intes-
tine and feces one hour after oral administration.
B. Distribution
The distribution of dieldrin has been studied in numer-
ous feeding experiments. Dieldrin has an affinity for fat, but
high concentrations are also reported in the liver and kidney,
with moderate concentrations in the brain one and two hours after
administration in rats (Heath and Vandekar, 1964). Deichman,
et al. (1968) fed dieldrin to rats for a- period of 183 days.
The mean concentration in the fat was 474 times that in the blood,
while the concentration in the liver was approximately 29 times
the blood concentration.
Additional animal studies on the distribution of diel-
drin have shown that concentrations in tissues are dose related
and IT.ay vary with the sex cf the animal ("yalk-=r:; et al. 136^).
Matthews, et al. (1971) found that female rats administered oral
doses of dieldrin had higher tissue levels of the compound than
male rats. The females stored the compound predomir.atly as diel-
drin. In males, other metabolites, identified as keto-dieidrin
trans-hydro-aidrin and a polar metabolite, were detected.
The concentrations of dieldrin in human body fat were
found to be 0.15 + 0.02 ^ag/g for the general population and 0.36
ug/g in one individual exposed to aldrin (aldrin is metabolized
to dieldrin) (Dale and Quinby, 1963). The tnean concentrations
of dieldrin in the fat, urine, and plasma of pesticide workers
»
were 5.67, 0.242 and 0.0185 mg/g, respectively (Hayes and Curley,
1963). Correlations between, the dose and length of exposure
to dieldrin and the concentration of dieldrin in the blood and
-------
other tissues have been reported (Hunter, et al. 1969). Dieldrin
residues in the blood plasma of workers averaged approximately
four times higher than that in the erythrocytes (Mick, et al.
1971).
C. Metabolism
The epoxidation of aldrin to dieldrin has been reported
in many organisms, including man (U.S. EPA, 1979). The reaction
is NADPH-dependent, and the enzymes have been found to be heat
labile (Wong and Terriere, 1965).
The metabolism of dieldrin has been studied in several
species, including mice, rats, rabbits, and sheep. Dieldrin
metabolites have been identified in the urine and faces in the
form of several compounds more polar than the parent compound
(u.S. E?A, 1979). Bedford and Hutscr. (1975) summarized the four
.
-------
as in the feces. Robinson, et al. (1969) found that 99 percent
of the dieldrin fed to rats for 8 weeks was excreted during a
subsequent 90-day observation period. The half-life of dieldrin
in the liver and blood was 1.3 days for the period of rapid elimi-
nation and 10.2 days for a later, slower period. The half-life
of dieldrin in adipose tissue and brain were 10.3 and 3.0 days,
respectively.
The concentration of dieldrin in the urine of the
general human population is 0.3 mg/1 for man and 1.3 mg/1 for
women as compared to 5.3, 13.8, or 51.4 mg/1 for men with low,
medium, or high exposure (Ceuto and Biros, 1967). Tha half-life
for dieidrin in the blood of humans ranges from 141-592 days
with a mean of 369 days (Hunter, et al. 1969). Jager (1970)
reported the half-iifa tc be 265 days. Because there is a rela-
tionship between the concentration of dieidrin in che blood and
that in adipose and other tissues, it seems likely that che half-
life in the blood may reflect the over-all half-life in other
tissues (U.S. EPA, 1979).
IV EFFECTS
.-.. Care i nog en ic i ty
Dieldrin has produced liver tumors in several strains
of mice according to six reports of chronic feeding studies (NCI,
1976 (43 FR 2450); Davis and Fitzhugh, 1962; Davis, 1965; Song
and Harville, 1964; Walker, et al. 1972; Thorpe, and Walker, 1973).
In rats, dieldrin has failed to induce a statistically significant
excess of tumors at any site in three strains during six chronic
feeding studies (Treon and Cleveland, 1965; Cleveland, 1966;
-------
Fitzhugh, et' al. 1964; Deichman, et al. 1967; Walker, et al.
1969; Deichmann, et al. 1970).
The only information concerning the carcinogenic poten-
tial of dieldrin in man is an occupational study by Versteeg
and Jager (1972) . The workers had been employed in a plant pro-
ducing aldrin and dieldrin with a mean exposure time of 6.6 years.
An average of 7.4 years had elapsed since the end of exposure.
No permanent adverse effects, including cancer, were observed.
B. Mutagenicity
• .
Microbial assays concerning the mutagenicity of aldrin
and dieldrin have yielded negative results even when some type
of activation system was added (Fahrig, 1S73; Bidwell, et al.
1575; Marshall, et al. 1976) . A host-mediated assay and a domi-
nant lethal test, also yielded negative results (Bidwell, et
ai. 1975). L-iajumdar, et al. (1977), however, fcund dial-rin
to be mutagenic in S. typ.h iph imur i urn, although these positive
results wera questioned because several differences existed be-
tween their procedures and those recommended (U.S. EPA, 1979).
A decrease in the mitotic index was observed in vivo
v;itli .T.CUSS bone marrow cells and _in y i erg wicn human iung cells
treated with 1 mg/kg and 1 ^ig/ml dieldrin, respectively (Majumdar,
et al. 1976).
D. Teratogenicity
14
In 1967, Hathaway, et al. established that C-diel-
drin could cross the placenta in rabbits. Dieldrin caused signifi-
»
cant increases in fetal death in hamsters, and increased fetal
anomalies (i.e. open eye, webbed foot, cleft palate, and others)
-------
in hamsters and mice when administered. in single oral doses dur-
ing gestation (hamsters 50, 30, 5 mg/kg and mice 25, 15, 2.5
mg/kg) (Ottolenghi, et al. 1974).
However, in subsequent studies no evidence has been
found that dieldrin causes teracogenic effects in mice and rats
(Chernoff, et al. 1975) or mice (Dix, et al. 1977).
D. Other Reproductive Effects
Deichmann (1972) reported that aldrin and dieldrin
(25 mg/kg/diet) fed to mice for six generations affected ferti-
lity , gestation, viability, lactation, and survival of the young.
However, no changes in weight or survival of fetuses were found
in mice administered dieldrin for day 5 through 14 of gestation
at doses already mentioned in this report (Ottolenghi, et al.
1374).
E. Chronic Toxicity
The other effects produced by chronic administr -sticr.
of dieldrin to mice, rats, and dogs include shortened life span,
increased liver to body weight ratio, various changes in liver
histology, and the induction of hepatic enzymes (U.S. EPA, 1979).
F. Gch=r Relevanc Information
Since aldrin and dieldrin are metabolized by way of
the mixed function oxidase (MFC) system and dieldrin has been
found to induce the production of these enzymes, any inducer
or inhibitor of the MFO enzymes should affect the metabolism
of dieldrin (U.S. EPA, 1979). Dieldrin fed in low dose9-^i£_ior
»
to an acute dose of dieldrin alters its metabolism (Baldwin,
et al. 1972). Dieldrin can effect the storage of DDT (U.S. EPA,
-------
1979) and induce a. greater number of tumors in mice when admini-
stered with DDT as compared to DDT alone (Walker, at al. 1372).
V. AQUATIC TOXICITY
A. Acute Toxicity
The acute toxicity of dieldrin has been investigated
in numerous studies. Reported 96-hour LC5Q values for freshwater
fish are 1.1 to 9.9 ug/1 for rainbow trout, Salmo gairdneri (Katz,
1961; Macek, et al. 1969); 16 to 36 ug/1 for fathead minnows,
Pimephales promelas (Henderson, et al. 1959; Tarzwell and Henderson,
1957) ; and 8 to 32 pg/1 for the bluegill, Lepomis macrochirus
(Henderson, et al. 1959; Macek, et al. 1969; Tarzwell and Henderson,
1957) . Freshwater invertebrates appear to be more variable in
their sensitivity to acute dieldrin toxicity. The 96-hour LC
values range from 0.5 ug/1 for the stone fly (Sanders and Cope,
i:>66) to 740 ug/1 for the crayfish (Sanders, 1372) .
The acute LCr« values for eight saltwater fish species
-* u
range from 0..55 to 24.0 ug/1 in flow-through tests (Butler, 1963;
Earnest and Benville, 1972; Korn and Earnest, 1974; Parrish,
et al. 1973; Schoettcer, 1970; and Lowe, undated). LC5Q values
ranging from 0.7 to 240.0 ug/1 have oeen reported for estuarian
invertebrates species, with the 'most sensitive species tested
being the commercially important pink shrimp, Penaeus duorarum
(U.S. EPA, 1978).
B. Chronic Toxicity
Chronic toxicity has been studied in two species of
»
freshwater fish. The chronic value for steelhead trout (Salmo
gairdneri) from an embro-larval study is 0.11 ug/1 (Chadwick
-------
and Shumway, 1969). For the guppy, Poecilia reticulata, in a
life-cycle test, the chronic value is 0.4 pg/1 (Roelofs, 1971).
C. Plant Effects
Freshwater plants are less sensitive to dieldrin than
freshwater fish or invertebrates. For example, a concentration
of 100 ^ig/1 caused a 22 percent reduction in the biomass of the
alga Scenedlesmus quadricaudata (Stadnyk and Campbell, 1971) ,
and 12,800 ug/1 reduced growth by 50 percent in the diatom, Navi-
cula seminulum after 5 days of exposure (Gairns, 1968). In a
saltwater plant species growth rate was reduced at concentrations
of approximately 950 ug/1 (Batterton, et al. 1971).
D. Residues
Bioconcentration factors (BCF) have been determined
for 9 freshwater species (U.S. EPA, 1976). Representative BCF
values are 128 for the alga, Sc_ence=_smus_ gbl^guus (Reinert, 1972,
1395 for p_a£hn_i_a mag_na (Reinert, 1972) , 2385-2993 for the channel
catfish, Ictjilurus pu_nctatus_ (Shannon, 1977a; i»77b) and 63,268
for the yearling lake trout, Salvelinus namaycush (Reinert, et
al. 1974). The edible tissue of the Eastern oyster, Crassostrea
vjLrgj^nica, had a 3CF value of 3000 after 392 days of exposure
(Parrish, 1974). Spot, Leiostomus xanthurus, had a BCF of 2,300
after 35 days exposure to dieldrin (Parrish, et al. 1973).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived
by U.S. EPA (1979), which are summarized below, have gone through
»
the process of public review; therefore, there is a possibility
that these criteria will be changed.
-------
A. Human
The current exposure level for dieldrin set by OSKA
is an air time-weighted average of 250 ug/m for skin absorption
(37 FR 22139). In 1959, the U.S. Public Health Service Advisory
Committee recommended that the drinking water standard for diel-
drin be 17 ug/1 (Mrak, 1969) . The U.N. Food and Agricultural
Organization/World Health Organization's acceptable daily intake
for dieldrin is 0.0001 rag/kg/day (Mrak, 1969).
The carcinogenicity data of Walker, et al. (1972)
were used to calculate the draft ambient water quality criterion
for dieldrin of 4.4 x 10~2 ng/1 (U.S. EPA, 1979). This level
keeps the lifetime cancer risk for humans below iO'3.
B. Aquatic
The draft criterion to protect freshwater life L=
0.0019 ug/1 as a 24-hcur average; the concentration should noc
exceed 1.2 ug at any time. To protect saltwater acu?.cic life..
she draft criterion is 0.0069 ^ug/1 as a 24-hour average; the
concentration should not exceed 0.16 ug/1 at any time.
-------
DIELDRIN
REFERENCES
Baldwin, M..K. , et al. 1972. A comparison of the metabolism
of HEOD (dieldrin) in the CFT mouse with that in the CFE rat.
Food Cosmet. Toxicol. 10: 333.
Batterton, J.C., et al. 1971. Growth response of bluegreen
algae to aldrin, dieldrin, endrin and their metabolites.
Bull. Environ. Contam. Toxicol. 6: 589.
Bedford, C.T., and D.H. Hutson. 1976. The comparative me-
tabolism in rodents of the isomeric insecticides dieldrin and
endrin. Chem. Ind. 10: 440.
Bidwell, K., et al. 1975. Comprehensive evaluation for mu-
tagenic activity of dieldrin. Mutat. Res'; 31: 314.
Butler, P.A. 1963. Commercial fisheries investigations. I_n
Pesticide and wildlife studies: A review of Fish and Wildlife
Service investigations during 1961 and 1962. U.S. Fish
V;ilcl. Serv. Ci~c. 167: ''I.
Cairns, J., et al. 1968. Ths effects of dieldrin on dia-
toms. Mosquito News 28: 177.
Chadwick, G.G., and D.L. Shumway. 1969. Effects of dieldrin
on the growth and development of steelhead trout. Page 9.0 _in
The Biological impact of pesticides in the environment. En-
viron. Health Sci. Ser. No. 1 Oregon State University.
Chernoff, N., et al. 1975. Prenatal effects of dieldrin and
photodieldrin in mice and rats. Toxicol. Appl. Pharmacol.
31: 302.
Cleveland, F.P. 1966. A summary of work on aldrin and diel-
drin toxicity at the Kettering Laboratory. Arch. Environ.
Health 13: 195.
Cole, J.F., et al. 1970. Endrin and dieldrin: A comparison
of hepatic excretion in the rats. Toxicol. Appl. Pharmacol.
16: 547.
Cueto, C., Jr., and F.J. Biros. 1967. Chlorinated insecti-
cides and related materials in human urine. Toxicol. Appl.
Pjharmacol. 10: 261.
Dale, W.E., and G.E. Quinby. 1963. Chlorinated insecticides
in the body fat of peoole in the United States, Science 142:
593.
-------
Davis, K.J. 1965. Pathology report on mice for aldrin,
dieldrin, heptachlor, or heptachlor epoxide for two years.
Int. Food and Drug Admin.
Davis, K.J., and O.G. Fitzhugh. 1962. Tumorigenic potential
of aldrin and dieldrin for mice. Toxicol. Appl. Pharmacol.
4: 187.
Deichmann, W.B. 1972. Toxicology of DDT and related chlor-
inated hydrocarbon pesticides. Jour. Occup. Med. 14: 285.
Deichmann, W.B., et al. 1967. Synergism among oral carcino-
ge-ns in the simultaneous feeding of four tumorigens to rats.
Toxicol. Appl. Pharmacol. 11: 88.
Deichmann, W.B., et al. 1968. Retention of dieldrin in
blood, liver, and fat of rats fed dieldrin for six months.
Ind. Med. Surg. 37: 837.
Deichmann, W.B., et al. 1970. Tumor igenicity of aldrin,
dieldrin and endrin in the albino rat. Ind. Med. Surg. 39:
Dix, K.H., et al. 1977. Toxicity studies with dieldrin:
Teratoiog ical studies in mice dosed orally with HEOD. Tera-
tology . 16 : 57 .
Earnest, R.D., and P.E. Benviile, Jr. 1972. Acute toxicity
of four qrganochior ine insecticides to two species or surf
perch. Calif. Fish Game. 58:
Edwards, C.A. 1966. Insecticide residues in soils. Residue
Epstein, S.S. 1976. Case study 5: Aldrin and dieldrin sus-
pension based on experimental evidence and evaluation and so
cietal need. Ann. N.Y. Acad. Sci. 271: 187.
,
1972. Comparative -utagenicity studies with pes-
ticides. Chera. Carcinogenesis Essays 10: 161.
Fitzhugh, O.G., et al. 1964. Chronic oral toxicity of al-
drin and dieldrin in rats and dogs. Food Cosmet. Toxicol.
2: 551.
Harris, R.H., et al. 1977. Carcinogenic hazards of organic
chemicals in drinking water. Page 309 in H.H. Hiath, et al .
eds. Origins of human cancer. Cold Sp"rTngs Harbor Lab. Mew
York .
Hathaway, D.E., et al. 1967. Transport of dieldrin from
mother to blastocyst and from mother to foetus in pregnant
rabbits. Eur. Jour. Pharmacol. 1: 167.
-------
Hayes, W.J., and A. Curley. 1968. Storage and excretion of
dieldrin and related compounds: Effect oif occupational expo-
sure. Arch. Environ. Health 16: 155.
Heath, D.F., and M. Vandekar. 1964. Toxicity and metabolism
of dieldrin in rats. Br. Jour. Ind. Med. 21: 269.
Henderson, C., at al. 1959. Relative toxicity of ten chlor-
inated hydrocarbon insecticides to four species of fish.
Trans. Am. Fish. Soc. 88: 23.
Hunter, C.G., et al. 1969. Pharmacodynamics of dieldrin
(HEOD). Arch. Environ. Health 18: 12.
Jager, K.W. 1970. Aldrin, dieldrin, endrin and telodrin: An
epidemiological and toxicological study of long-term occupa-
tional exposure. Elsevier Publishing Co., Amsterdam.
Katz, M. 1961. Acute toxicity of some organic insecticides
to three species of salmonids and to the threespine sticle-
back. Trans. Am. Fish. Soc. 90: 264.
Korn, 5., and R. Earnest. 1974. Acute toxicity of twenty
insecticides to striped bass, Morone saxatilis. Calif. Fish
Game. 60: 128.
Lowe, J.I. Results of toxicity tes-ts with fishes and macro
i^*r3v*tebrcit':ic. D^ts sbeets —T?.~ "' ^ s'c 13 frcrr. 'T. S. E^v^^cr.
O *~o i~ LI rj a rvo * 7 ^r> TT i y-/^n Oac ^".^•^ ("I'iT^ O >- p o -7 a ^ 1 a
Macek, K.J., et al. 1969. The effects of temperature on the
encr*o»^***^^ 1 i*-t» r\£ V-.1 «•• o *"• ^ T 1 ^ ^r\ A v- -3 i ^ l-> *•>». T *-•*-.-> i •»*- *-<•> r^o^i'^1-^^
— UOw^.j—'— — -^—-i.~s_)- ^_ -^ *-/j_— ^-^— — — J C* * . \_* i. w — - . *- ^-^ •' w.v^v. w — O— -.^.^.w — ^*
pesticides. Bull. Environ. Contam. Toxicol. 4: 174.
HacKay, D., and A.W. Wolkoff. 1973. Rate of evaporation of
low-solubility contaminants from water bodies to atmosphere.
Environ. Sci. Technol. 7: 611.
Majuir.dar, S.K., et al. 1976. Dieldrir,- induced chromosome
damage in mouse bone-marrow and WI-38 human lung cells.
Jour. Hered. 67: 303.
Majumdar, S.K., et al. 1977. Mutagenicity of dieldrin in
the Salmonella-microsome test. Jour. Herd. 68: 194.
Marshall, T.C., et al. 1976. Screening of pesticides for
mutagenic potential using Salmonella typhimurium mutants.
Jour. Agric. Food Chem. 24: 560.
Matsumura, F., and G.M. Bousch. 1967. Dieldrin: Degradation
by soil microorganisms. Science 156: 959. •
_ A ft —
-------
Matthews, H.B., et al. 1971. Dieldrin metabolism, excre-
tion, and storage in male and female rats. Jour. Agric.
Food Chem. 19: 1244.
Mick, D.L., et al. 1971. Aldrin and dieldrin in human blood
components. Arch. Environ. Health 23: 177.
Mrak, E.M. 1969. Chairman 1969 report on the secretary's
commission on pesticides and their relationship to environ-
ment health. U.S. Dept. Health Edu. Welfare, Washington,
D.C.
Nash, R.G., and E.A. Woolson. 1967. Persistence of chlori-
nated hydrocarbon insecticides in soils. Science 157: 924.
Ottolenghi, A.D., et al. 1974. Teratogenic effects of al-
drin, dieldrin and endrin in hamsters and mice. Teratology
9: 11.
Parrish, P.R. 1974. Arochlor 1254, DDT and DDD, and diel-
drin: accumulation and loss by American oysters, Crassostrea
virginica exposed continuously for 56 weeks. ?roc. Naci.
Shellfish Assoc. 64.
Parrish, P.R., et al. 1973. Dieldrin: Effects en several
estaurine organisms. Pages 427-434 in Proc. 27th Annu. Conf.
S.E. Assoc. Game Fish Comn.
Patil, K.C., et al. 1972. -Metabolic trar.sfsrnaticn of DITT,
dieldrin, aldrin, ar.d endrin by -.r.arine microorganisms. Envi-
ron. Sc'i. Technol. 5: 631.
Reinert, R.E. 1972. Accumulation of dieldrin in an alga
Scenedesrnus obi iqus, Daphnia magna and the guppy, Poecilia
reticulata. Jour. Fish Res. Board Can. 29: 1413.
Reinert, R.E., et al. 1974. Dieldrin and DDT: Accumulation
from water and food by lake trout, Salvelinus namaycush, in
the laboratory. Proc. 17th Conf. Gr^=t Lakes Res. 52.
Robinson, J., et al. 1969. The pharmacokinetics of HEOD
(dieldrin) in the rat. Food Cosmet. Toxicol. 7: 317.
Roelofs, T.D. 1971. Effects of dieldrin on the intrinsic
rate of increase of the guppy, Peocilia reticulata Peters.
Thesis. Oregon State University, Corvallis.
Sanders, H.O. 1972. Toxicity of some insecticides to four.
species of malacostracan crustaceans. Bur. Sport Fish. Wild.
Tech. Pap. No. 66.
-------
Sanders, H.O., and O.B. Cope. 1968. The relative toxicities
of several pesticides to naiads of three species of stone-
flies. Limnol. Oceanogr. 13: 112.
Schoettger, R.A. 1970. Progress in sport fishery research.
Fish-Pestic. Res. Lab. U.S. Dep. Inter. Bur. Sport Fish Wild.
Resour. Publ. 106.
Shannon, L.R. 1977a. Accumulation and elimination of diel-
drin in muscle tissue of channel catfish. Bull. Environ.
Contam. Toxicol. 17: 637.
Shannon, L.R. 1977b. Equilibrium between uptake and elimi-
nation of dieldrin by channel catfish, Ictalurus punctatus.
Bull. Environ. Contam. Toxicol. 17: 278.
Song, J., and W.E. Harville. 1964. The carcinogenicity of
aldrin and dieldrin on mouse and rat liver. Fed. Proc. 23:
336.
Stadynyk, L., and R.S. Campbell. 1971. Pesticide effect on
growth and C assimilation irs a freshv;ater alga. Bull.
Environ. Contam. Toxicol. 6: 1.
Tarzwell, C.M., and C. .Henderson. 1957. Toxicity of diel-
drin to fish. Trans. Am. Fish. Soc. 86: 245.
Thorpe, E., and A.I.T. Walker. 1973. The toxicology of
dieicrin (HECD). Part II. Comparative long-term oral toxic-
icy studies in mice with dieidrin, DDT, phenobarbitone, beta-
3HC and garrjr.a-BHC. Food Cosrr.at. Toxicol. 11: 433.
Treon, J., and F.D. Cleveland. 1955. Toxicity of certain
chlorinated hydrocarbon insecticides for laboratory animals
with special reference to aldrin and dieldrin. Agric. Food
Chem. Jour. 3: 402.
U.S. EPA. 1971. Reasons underlying the registration deci-
sion, concerning products containir.g DDT, 2,4,5-T, ai'Jrin and
dieldrin.
U.S. EPA. 1979. Aldrin/Dieldrin: Ambient Water Quality Cri-
teria (Draft).
Versteeg, J.P.J., and K.W. Jager. 1973. Long-term occupa-
tional exposure to the insecticides aldrin and dieldrin, en-
drin, and telodrin. Br. Jour. Ind. Med. 30: 201.
Walker, A.I.T., et al. 1969. The toxicology and pharmacody-
namics of dieldrin (HEOD): Two-year oral exposures of rats
and dogs. Toxicol. Appl. Pharmacol. 15: 345.
-W-
y
-------
Walker, A.I.T., et al. 1972. The toxicology of dieldrin
(HEOD). Long-term oral toxicity studies in mice. Food Cos-
met. Toxicol. 11: 415.
Winteringham, F.P.W., and J.M. Barnes. 1955. Comparative
response of insects and mammals to certain halogenated hydro-
carbons used as pesticides. Physiol. Rev. 35: 701.
Wolfe, H.R., et al. 1972. Exposure of spraymen to pesti-
cides. Arch. Environ. Health 25: 29.
Wong, D.T., and L.C. Terriere. 1965. Epoxidation of aldrin,
isodrin, and heptachlor by rat liver microsomes. Biochem.
Pharmacol. 14: 375.
Wurster, C.F. 1971. Aldrin and dieldrin. Environment 13:
33.
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No. 83
o,o-Dlethyl Dithiophosphoric Acid
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
•/
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
£3-3-
-------
0,0-DIETHYL DITHIOPHOSPORIC ACID
Summary
There is no available information to indicate that o,o-diethyl dithio-
phosphoric acid produces carcinogenic, mutagenic, teratogenic, or adverse
reproductive effects.
A possible metabolite of the compound, o,o-diethyl dithiophosphoric
acid, did not show mutagenic activity in Drosophila, E. coli, or Saccha-
romyces.
The pesticide phorate, which may release o,o-diethyl dithiophosphoric
«,
acid as a metabolite, has shown some teratogenic effects in developing chick
embryos and adverse reproductive effects in mice.
An acute value of 47.2 /jg/1 has been reported for rainbow trout exposed
to a diethyl dithiophosphoric acid analogue, dioxathion. A synergistic
toxic effect with the latter chemical and malathicn is suaaested.
-------
I. INTRODUCTION
o,o-0iethyl hydrogen dithiophosphate, CAS registry number 298-06-6, al-
so called o,o-diethyl phosphorodithioic acid or o,o-diethyl dithiophosphoric
acid, is used primarily as an intermediate in the synthesis of several pest-
icides: azinphcsmethyl, carbcphenothion, dialifor, dioxathion, disulfoton,
ethion, phorate, phosalone and terbufos. It is made from phosphorus penta-
sulfide (SRI, 1976).
II. EXPOSURE
A. Water v
Pertinent data were not found in the available literature; how-
ever, if found in water, its presence would most likely be due to microbial
action on phorate or disulfoton (Daughton, et al. 1575), or as a contaminant
of any of the above pesticides for which it is a starting compound.
8. Food
Pertinent data were net found in t.u;2 available literature; how-
ever, if present in food, the compound would probably originate from the
same sources discussed above. Organcphosphorus pesticide residues have been
found in feed (Vettorazzi, 1975).
C. Inhalation
Pertinent data were not found in the available literature; how-
ever, major exposure could come from fugitive emissions in manufacturing
facilities.
0. Dermal
Pertinent data were not found in the available literature.
-------
III. PHARMACOKINETICS
A. Absorption
Information relating specifically to the absorption of o,o-diethyl
dithophosphoic acid was not found in the available literature. Acute toxi-
city studies with the pesticides disulfoton and phorate indicate that these
related organophosophorous compounds are absorbed following oral or dermal
administration (Gaines, 1969).
B. Distribution
Pertinent data were not found in the available literature. Oral
administration of labelled phorate, the S-(ethyl thio)methyl derivative of
o,o-diethyl dithiophosphoric acid, to cows accumulated in liver, kidney,
lung, alimentary tract, and glandular tissues; fat samples showed very low
residues (Bowman and Casida, 1553).
C. Metabolism
Pertinent data were net found in the available literature. Metab-
olism studies with disulfoton (3ull, 1965) and phorate (Sc.vman and Casida,
1958} indicate that both compounds are converted to diethyl phosphorodithic-
ate, diethyl phorphorcthicate, and diethyl phosphate.
0. Excretion
Pertinent data were net round in the available literature, c^sed
on animal studies with related organophosphorous compounds, the parent com-
pound and its oxidative metabolites may be expected to eliminated primarily
in the urine (Matsumura, 1975).
IV. EFFECTS
.-
A. Carcinogenesis
The dioxane s-s diester with o,o-diethyl dithiophosphoric acid,
dioxathion, has been tested for carcinogenicity in mice and rats by
-------
long-term feeding. No carcinogenic effects were noted in either species
(NCI, 1978).
Q. Mutagenicity
Diethyl phosphorothioate, a possible metabolite of the parent com-
pound, did not show mutagenic activity in Orosophila, £. coli, or Saccha-
romyces (Fahrig, 1974).
C. Teratogenicity
Pertinent data were not found in the available literature. In-
jection of phorate into developing chick embryos, has been reported to
produce malformations (Richert and Prahlad, 1972).
0. Other Reproductive Effects
Pertinent data were not found in the available literature. An
oral feeding study conducted in mice with pnorate (0.6 to 3.0 ppm) indicated
that the hicrest level of compound did produce sc^e adverse rsprcd'jctive
effects (American Cyanaaiid, 1966}. Chronic feeding of mics with technical
dicxatnion at levels of 430 to 6CG ppm produced seme testiscular atrophy
(NCI, 1978).
E. Chronic Toxicity
Chronic feeding of technical dioxathicn produced hyperplastic
nodules "'^ ^iv°rs of ^s1? mice, o c-Oisthyl dit~iocncsrhc!ric scid like
other organophosphates, is expected to produce cholinesterase inhibition
(MAS, 1977).
V. AQUATIC TOXICITY
A. Acute
Marking (1977) reports on LC5Q value of 47>2 jug/i f0r rainbow
trout (Salmo gairdneri) exposed to the dithiodioxane analogue • of
bis(o,o-diethyl dithiophosphoric acid), dioxathion, and an LC5Q value of
-------
3.44 pg/1 when this latter compound is applied in combination with mal-
athion. The synergistic action with malathion suggests that the combination
is more than eight times as toxic as either of the individual chemicals.
B. Chronic, Plant Effects, and Residues.
Pertinent data were not found in the available literature.
VI. EXISTING GUIDELINES
Existing guidelines or standards were not found in the available lit-
erature.
-------
REFERENCES
American Cyanamid 1966. Toxicity data on 15 percent Thimet granules.
Unpublished report. In: Initial Scientific and Minieconomic Review of
Phorate (Thimet) Office of Pesticide Programs, Washington.
Bowman, J. and J. Casida 1958. Further studies on the metabolism of Thimet
by plants, insects, and mammals. J. Econ. Entomol. 51: 338.
Bull, 0. 1965. Metabolism of di-systox by insects, isolated cotton leaves,
and rats. J. Econ. Entcmol. 58: 249.
Daughton, C.G., A.M. Cook, M. Alexander 1979. Phosphate and soil binding
factors limiting bacterial degradation of ionic phosphorus-containing
pesticide metabolites. App. Environ. Micrcbio. 37: 605.
«.
Fahrig, R. 1974. Comparative mutagenicity studies with pesticides.
Chemical Carcinogsnesis Assays, IARC Scientific Publication #10, p. 161.
Gaines, T. 1969. Acute toxicity of pesticides. Toxicol. A.ppl. Pharmacol.
14: 515.
Marking, L.I. 1977. Method for asssessing additive toxicity of chemical
mixtures. In: Aquatic Toxicology and Hazard Evaluation. STP 634 ASTM
Special Technical Publication. p. 99.
Matsumura, F. 1975. Toxicolocy of Insecticides. Mew York: Plenum Press,
o. 223. ' " • •
National Academy of Sciences 1977. Drinking Water and Health. National
Sesearcn Council, wasnington, p. 615.
National Cancer Institute 1973. 3icassay of Oioxathion for Possible
Carcinogenicity. U.S. OHEW, NCI Carcinogenesis Technical Report Series
0125, 44 pp.
Richert, E. and '<. Prahlad 1972. Effect of the organophcsohate o,o-diethvl
s-t(ecnylthio)metnyij pnospnoroaitnioate on tne cnick. Pouit. Sci. 51: 513.
SRI 1976. Chemical Economics Handbook. Stanford Research Institute.
Pesticides, July 1976.
vettorazzi, G. 1975. State of the art on the tcxicolcgical evaluation
carried out by the joint FAO/WHO meeting on pesticide residues. II.
Carbamate and organophosphorus pesticides used in agriculture and public
health. Res. Rev. 63: 1.
PT(9—
- / / v
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No. 84
3
o,o-Diethy1-4-methyl Phosphorodithioate
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documen-ts.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
o,o-OIETHYL-S-METHYL PHOSPHORODITHIOATE
Summary
There is no available information on the possible carcinogenic, muta-
genic, teratogenic or adverse reproductive effects of o,o-diethyl-S-methyl
phosphorodithioate. Pesticides containing the o,o-diethyl phosphoro-
dithioate moiety did not show carcinogenic effects in rodents (dioxathion)
or teratogenic effects in chick embryos (phorate). The possible metabolite
of this compound, o,o-diethyl phosphorothioate, did not show mutagenic
activity in Drosophila, E. coli, or Saccharomyces. o,o-Oiethyl-S-methyl
phosphorodithioate, like other organophosphate compounds, is expected to
produce chclinesterase inhibition in humans.
There is no available data on the aquatic toxicity of this compound.
-------
0,0-0IETHYL-S-METHYL PHOSPHORODITHIOATE
I. INTRODUCTION
o,o-Oiethyl-S-methyl .phosphorodithioate (CAS registry number 3288-58-2)
is described in German patents 1,768,141 (CA 77:151461s) and 1,233,390 (CA
66:115324p). The latter states the compound has "partly insecticidal,
acaricidal and fungicidal activity" and is useful as an intermediate for
organic synthesis. It has the following physical and chemical properties:
Formula: C5H13
Molecular Weight: 200
Boiling Point: ICCOQ to 102°C (4 torr)
(CA 55:8335h)
Density: 1.192420
(CA 55:S335n)
Pertinent data were not found in the available literature with respect
tc production, consumption or the current use of this ccmcound.
II. EXPOSURE
Pertinent data were not found in the available literature.
III. PHARMACGKINETICS
A. Absorption
Information relating specifically to the absorption of c,o-di-
ethyl-S-methyl phosphcrcdithioats was not found in the available liter-
ature. Oral administration of the S-ethylthio derivative of this ccmpcund,
the insecticide phorate, indicates that this derivative is absorbed from the
gastrointestinal tract (Bowman and Casida, 1958).
«•
3. Distribution
Pertinent data were not found in the available literature.
Studies with 22p radiolabelled phorate in the cow indicated that following
oral administration, residues were found in the liver, kidney, lung,
-------
alimentary tract, and glandular tissues; fat samples showed very low
residues (Bowman and Casida, 1958).
C. Metabolism
Pertinent data were not found in the available literature. Based
on metabolism studies with various crganophosphatss in mammals, o,o-diethyl-
S-methyl phosphorodithioate may be expected to undergo hydrolysis to diethyl
phosphorodithioic acid, diethyl phosphorothioic acid, and diethyl phosphoric
acid (Matsumura, 1975).
0. Excretion
Pertinent data were not found in the available literature.
Related metabolites (o,o-diethyl phosphorodithioic, phosphorothioic, and
phosphoric acids) have been identified in the urine of rats fed phcrate
(Bowman and Casida, 1958).
IV. EFFECTS
A. Carci.noqenicity
Pertinent data were not found in the available literature. The
dioxane-S-S-diester with o,o-diethyl phosphorodithioate, dioxathion, has
been tested for carcinogenicity in mice and rats by long-term feeding. No
carcinogenic effects wers noted in either species (NCI, 1978).
3. Mutagenicity
Pertinent data were not found in the available literature.
Diethyl phosphorothioate, a possible metabolite of the parent compound, did
not show mutagenic activity in Orosphila, E_. coli, or Saccharomyces (Fahrig,
1974).
-------
C. Teratogenicity
Pertinent data were not found in the available literature. In- •
jection of phorate into developing chick embryos has been reported to pro-
duce malformations (Richert and Prahlad, 1972).
0. Other Reproductive Effects
Pertinent data were not found in the available- literature. An
oral feeding study conducted in mice with phorate (0.6 to 3.0 ppm) indicated
that the highest level of compound did produce some adverse reproductive ef-
fects (American Cyanamid, 1966). Chronic feeding of rats with technical
dioxathion at levels from 450 to 600 ppm produced some testicular atrophy
(NCI, 1978).
E. Chronic Toxicity
Pertinent data were not found in the available literature.
Chronic feeding of technical dioxathion produced hyperplastic nodules in the
livers of ,7,aie mice. o,o-Oietnyi-S-methyI onospnoroaichioats, like other
organophosphates, is expected to produce choiinesterase inhibition (NAS,
1977).
V. AOJATIC TOXICITY
Pertinent data were not found in the available literature.
VI. EXISTING GUIDELINES AND STANCAF.CS
Existing guidelines and standards were not found in the available
literature.
-------
0,0-OIETHYL-S-METHYL PHOSPHORODITHIOATE
References
American Cyanamid. 1966. Toxicity data on 15 percent Thimet granules. Un-
published report. In: Initial Scientific and Minieconomic Review of
Phorate (Thimet) Washington, DC: Office of Pesticide Programs.
Bowman, J. and J. Casida. 1958. Further studies on the metabolism of
Thimet by plants, insects, and mammals. Jour. Econ. Entom. 51: 838.
Fahrig, R. 1974. Comparative mutagenicity studies with pesticides. Chem-
ical Carcinogenesis Assays, IARC Scientific. Publication No. 10. p. 161. •
Matsumura, F. 1975. Toxicology of Insecticides. Plenum Press, New York
p. 223.
National Academy of Sciences. 1977. Drinking Water and Health. National
Research Council, Washington, DC. p. 615.
National Cancer Institute. 1578. 3ioassay of Dioxathion for Possible Car-
cinogenicity. QHEW. National Cancer Institute. Carcinogenesis Tecnnical
Report Series No. 125: 44.
Richert, E.P. and K.V. Prahlad. 1972. Effect cf the crganophcspnate
o,o-dirthyl-5-C(sthyithio)methyi] phospnorocithiste on the chick. Fault.
Sci. 31: 513.
-------
No. 85
Dlethyl Phchalate
Health and Eavironnental Effaces
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources ana available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
_ L^^"r .
') I/ U ) ""
-------
DIET3YL PHTHALATE
SUMMARY"
Diethyl phthalate has been shown to produce rautagenic
effects in the Ames Salmonella assay.
Teratogenic effects were reported foJ .owing i.p. admin-
istration of diethyl phthalate to pregnan rats. This same
study has also indicated fetal toxicity aa increased resorp-
tions after i.p. administration of DEP.
Evidence that diethyl phthalate prc .uces carcinogenic
effects has not been found.
A single clinical report indicates t. at the development
of hepatitis in several hemodialysis pati nts may have been
related to leaching of diethyl phthalate from the plastic
tubings utilized.
Diethyl phthalate appears to be mor toxic for marine
species acutely tested, with a concentra :on of 7,590 ug./l
being reported as the LC-n in marine i vertebrates. The
data base for the toxic effects of die lyl phthalates to
aquatic organisms is insufficient to d ift criterion for
their protection.
* "/!?l/ Cr"
-------
DIETHYL PHTHALATE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Phthalate Esters (U.S. EPA, 1979a).
Diethyl phthalate (DEP) is a diester of the ortho form
of benzene dicarboxylic acid. The compound has a molecular
weight of 222.23, specific gravity of 1.123, boiling point
of 296.1°C", and is insoluble in water (U.S. EPA, 1979a) .
DEP is used as a plasticizer for cellulose ester plas-
tics and as a carrier for perfumes.
The 1977 current production of diethyi phthalate was:
3.75 x 10 tons/year (U.S. EPA, 1979a).
Phthalates have been detected in soil, air, and water
samples; in animal and human tissues; and in certain vegeta-
tion. Evidence from in vitro studies indicate that certain
bacterial flora may be capable of metabolizing phthalates
to the monoester form (Engelhardt, et al. 1975).
II. EXPOSURE
Phthalate esters appear in all areas of the environ-
ment. Environmental release of the phthalates may occur
through leaching of plasticizers from plastics, volatiliza-
tion of phthalates from plastics, and the incineration of
plastic items. Human exposure to phthalates includes contami-
nated foods and fish, dermal application -'in cosmetics, and
parenteral administration by use of plastic blood bags,
»
tubings, and infusion devices (mainly DEHP release) (U.S.
EPA, 1979a).
-------
Monitoring studies have indicated that most water phthal-
ate concentrations are in the ppra range, or 1-2 pg/1 (U.S.
EPA, 1979a). Industrial air monitoring studies have mea-
sured air levels of phthalates from 1.7 to 66 mg/m (Milkov,
ec al. 1975) . Information on levels of DEP in foods is
not available. The-U.S. EPA (1979a) has estimated the weighted
average bioconcentration factor for DEP to be 270 for the
edible portions of fish and shellfish consumed by Americans.
This estimate is based on measured steady-state bioconcen-
tration studies in bluegills.
III. PKARMACOKINETICS
Specific information is not available on the absorp-
tion, metabolism, distribution, or excretion of DEP. The
reader is referred to a general coverage of onthalate metabo-
lism in the phthalate ester hazard profile {"J.5. SPA, 137Sb) .
IV. EFFECTS
A. Carcinocenicity
Pertinent information could not be located in.
the available literature.
3. Mutagenici*:y
Diethyl phthalate has been shown to produce muta-
genic effects in the Ames Salmonella assay (Rubin, et al.
1979) .
C. Teratogenicity
Administration of DEP to pregnant rats by i.p.
»
injection has been reported to produce teratogenic effects
(Singh, et al. 1972).
A
-i /> / * -
u i J
-------
D. Other Reproductive Effects
Fetal toxicity and increased resorptions were
produced following i.p. injection of pregnant rats with
DEP (Singh, et al. 1972).
E. Chronic Toxicity
A single clinical report has been cited by the
U.S. EPA (1979a) which correlated leaching of DEP from hemo-
dialysis tubing in several patients with hepatitis. Char-
acterization of all compounds present in the hemodialysis
fluids was not done.
V. AQUATIC TOXICITY
A. Acute Toxicity
Among aquatic organisms, the bluegill sunfish, ;
Lepomis macroc'nirus, has beer, shown to be acutely sensitive
to diethyl phthalate; a 96-hour static LCCQ of 98,200 pg/i
is reported (U.S. EPA. 1978). For the freshwater inverte-
brate, Daphnia magna, a 48-hour static LC,-Q of 51,100 pg/1
was obtained. Marine organisms proved to be more sensitive,
with the sheepshead minnow, Cyprinodon variegatus, showing
a 96-hour static LC5Q of 29,600 jjg/1, while the mysid shrimp,
Mysidopsis bahia, showed an 96-hour static LC of 7,590
ug/1 (U.S. EPA, 1978).
B. Chronic Toxicity
Pertinent information could' not be located in
the available literature.
C. Plant Effects
Effective concentrations based on chlorophyl a
content and cell number for the freshwater alga, Selena-
-------
strum capcicornutum, ranged from 35,600 to 90,300 ug/1,
while the marine alga, Skeletonema costatum, was more sensi-
tive, with effective concentrations ranging from 65,500
to 35,000 ug/1.
D. Residues
A bioconcentration of 117 was obtained for the
freshwater invertebrate, Daphnia magna.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria de-
rived by U.S. EPA (1979a) , which are summarized below, have
gone through the process of review; therefore, there is
a possibility that these criteria will be changed.
A. Human
Based on "no effect" levels observed in chror.ic
feeding studies with rats or dogs, the U.S. E?A has calcu-
lated an acceotable daily intake (ADI) level of 438 me/day
for DEP.
The recommended water quality criterion level
for protection of human health is 50 mg/1 for DE? (U.S.
EPA, 1979a).
B. Aquatic
Data are insufficient to draft criterion for the
protection of either freshwater or marine organisms (U.S.
EPA, 1979a).
-------
DIETHYL PHTHALATES
REFERENCES
Engelhardt, G. et al. 1975. The raicrobial metabolism of
di-n-butyl phthalate and related dialkyl phthalates. Bull.
Environ. Contain. Toxicol. 13: 32.
Milkov, L.E., et al. 1975. Health status of workers ex-
posed to phthalate plasticizers in the manufacture of artifi-
cial leather and films based on PVC resins. Environ. Health
Perspect. Jan. 1975.
Rubin, R.J., et al. 1979. Ames mutagenic assay of a series
of phthalic acid esters: Positive response of the dimethyl
and diethyl esters in TA 100. Abstract. Soc. Toxicol. Annu.
Meet. March 11, 1979, New Orleans.
Singh, A. et al. 1972. Teratogenicity of phthalate esters
in rats. Jour. Pharm. Sin. Gl, 51.
U.S. EPA. 1978. In-depth studies on health and environ-
mental impacts of selected water pollutants. U.S. Environ.
Prot. Agency, Contract No. 68-01-4646.
U.S. EPA. 1979a. Phthalate Esters: Ambient Water Quality
Criteria (Draft).
U.S. EPA. I979b. Environmental Criteria and Assessment
Office. Hazard Profile: Phthalate Esters (Draft).
-------
No. 36
DimethyInitrosamine
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
¥<-
-------
DIMETHYLNITROSAMINE
SUMMARY
Dimethylnitrosamine produces liver and kidney tumors
in rats. It is mutagenic in several assay systems. No
information specifically dealing with the teratogenicity,
chronic toxicity or other standard toxicity tests of dimethyl-
nitrosamine was available for review.
Hepatocellular carcinoma has been induced in rainbow
trout administered 200 to 800 fig dimethylnitrosamine in
their diet.
-j &/ 3 "
-------
DIMETHYLNITROSAMINE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Nitrosamines (U.S. EPA, 1979a).
Specific information on the properties, production,
and use of dimethylnitrosamine was not available. For general
information on dimethylnitrosamine, refer to the ECAO/EPA
Hazard Profile for Nitrosamines (U.S. EPA, 1979b).
Dimethylnitrosamine can exist for extended periods
of time in the aquatic environment (Tate and Alexander,
1975; Fine, et al., 1977a).
II. EXPOSURE
A. Water
Dimethylnitrosamine has beer, detected at a concen-
tration cf 2 to 4 ug/1 ir. wastawatar samples from waste
treatment plants adjacent to, or receiving effluent from,
industries using nitrosamines or secondary amines in produc-
tion operations (Fine, et al., 1977b).
3. Feed
Dimethyinitrosamine was found to oe present in
Na variety of foods (including smoked, dried or salted fish,
^
chees£v<3alaiai, frankfurters, and cured meats) in the 1
to 10 u/kg "tfange and occasionally at levels up to 100 ug/kg
(Montesano anc>Bartsch, 1976).
The U.\S. SPA (1979a) has estimated the weighted
average bioconce.ntrati°r; factor for dimethylnitrosamine
for the edible pc?rtions of fish and shellfish consumed by
-------
Americans to be 0.06. This estimate is based on the n-octanol/
water 'partition coefficient of dimethylnitrosamine.
C. Inhalation
Dimethylnitrosamine has been detected in ambient
air samples collected near two chemical plants, one using
the amine as a raw material and the other discharging it
as an unwanted byproduct (Fine, et al., 1977a).
Tobacco smoke contains dimethylnitrosamine. The
intake of dimethylnitrosamine from smoking 20 cigarettes
per day has been estimated at approximately 2 ug/day (U.S.
EPA, 1979a).
III. JHA3MACCKINETICS
A. Absorption
Pertinent data could not be located in the avail-
able literature.
3. Distribution
Following intravenous injection into rats, dimetnyi-
nitrosamine is rapidly and rather uniformly distributed
throughout the body (Mages, 1972).
C. i-ietaboiism and Excretion
In vitro studies have demonstrated that the organs
in the rat with the major capacity for metabolism ct dimethyl-
nitrosamine are the liver and kidney (Montesanc and Magee,
1974). After administration of 14C-labeled-- "imethylnitro-
samine to rats oc mice, about 60 percent o: fc^e isotope
appears as I4C02 within 12 hours, while 4 tarcent is axcretaa"
.„ / a ^*"
-------
in the urine (Magee, et al., 1976). Dimethylnitrosamine
is excreted in the milk of female rats (Schoental, et al.,
1974}.
IV. EFFECTS
A. Carcinogenicity
Chronic feeding of dimethylnitrosamine at doses
of 50 mg/kg induces liver tumors in rats (Magee and Barnes,
1956; Rajewski, et al., 1966). Shorter, more acute expo-
sures to dimethylnitrosamine ranging from 100 to 200 mg/kg
produce kidney tumors in rats and liver tumors in hamsters
(Magee and Barnes, 1959; Tomatis and Cafis, 1967). A single
unspecified intraperitoneal dose given to newborn mice in-
duced hepatocellular carcinomas (Toth, et al., 1964).
3. Mutacenicity
Dimethylnitrosamine and diethylnitrosamine have
been reported to induce forward and reverse mutations in
3_. typhimurium, E. coli, iMeurospora crassa and other organisms;
gene recombination and conversion in Saccharomyces cerevisiae;
"recessive lethal mutation" in Drosophila; and chromosome
aoerracions in mammalian cells (Montesano and Bartsch, 1976).
Nitrosamines must be metabolically activated to be mutagenic
in microbial assays (U.S. EPA, 1979a). Negative results
were obtained in the mouse dominant lethal test (U.S. EPA,
1979a).
C. Teratogenicity and Other Reproductive Effects
*
Pertinent information could not be located in
the available literature on the teratogenicity and other
reproductive effects of dimethylnitrosamine.
-------
D. Chronic Toxicity
Pertinent information could not be located in
the available literature on the chronic activity of dimethyl-
nitrosamines.
E. Other Relevant Information
Aminoacetonitrile, which inhibits the metabolism
of dimethylnitrosamine, prevented the toxic and carcinogenic
effects of dimethylnitrosamine in rat livers (Magee, et
al., 1976).
Ferric oxide, cigarette smoke, volatile acids,
aldehydes, methyl nitrite, and benzo(a)pyrene have been
suggested to act in a cocarcinogenic manner with dimechyl-
nitro-samine (Stenback, et al., 1973; Magee, et al., 1976).
V. AQUATIC TOXICITY
Pertinent information about acute and chronic aquatic
toxicity was not found in the available literature. Addition-
ally, -c mention was made in any reports ariout plane effects
or residues.
One study reported that Shasta strain rainbow trout
(Salmo gaircneri), fed dimethylnitrosamine in their diet
for 52 weeks, developed a dose-response incidence of hepato-
cellular carcinoma during a range of exposures from 200
to 300 mg dimethylnitrosamine per kg body weight 52 to 78
weeks after dosing (Grieco, 1978).
VI. EXISTING GUIDELINES AND STANDARDS
»
Neither the human health nor aquatic criteria derived
by U.S. EPA (1979a), which are summarized below, have gone
-------
through the process of public review; therefore, there is
a possibility that these criteria may be changed.
A. Human
The U.S. EPA (1979a) has estimated that the water
concentrations of dimethylnitrosamine corresponding to life-
time cancer risks for humans of 10~ , 10 , or 10 are
0.026 ug/1, 0.0026 ug/1, and 0.00026 pg/1, respectively.
3. Aquatic
Data are insufficient to draft freshwater marine
criteria for dimethylnitrosamine.
/
-------
DIMETHYLNITROSAMINE
REFERENCES
Fine, D.H., et al. 1977a. Human exposure to N-nitroso com-
pounds in the environment. In: H.H. Hiatt, et al., eds.
Origins of human cancer. CoTd Spring Harbor Lab., Cold
Spring Harbor, New York.
Fine, D.H., et al. 1977b. Determination of dimethylnitrosa-
mine in air, water and soil by thermal energy analysis: mea-
surements in Baltimore, Md. Environ. Sci. Technol. 11:
581.
Grieco, M.P., et al. 1978. Carcinogenicity and acute toxic-
ity of dimethylnitrosamine in rainbow trout (Salmo gaird-
neri). Jour. Natl. Cancer Inst. 60: 1127.
Magee, P.N. 1972. Possible mechanisms of carcinogenesis and
mutagenesis by nitrosamines. Inr W. Nakahara, et al., eds.
Topics in chemical carcinogenesTs. University of Tokyo
Press, Tokyo.
Magee, P.N., and J.M. Barnes. t956. The producrion of ma-
lignant primary hepatic tumors in the rat by feeding dimethyl-
nitrosamine. Br. Jour. Cancer 10: 114.
Magee, P.N., and J.M. Barnes. 1959. The experimental pro-
duction of tumors in the rat by dirnechylnitrosamine (N-nitro-
sodimethyiamine). Acta. CJn. Int. Cancer 15: 137.
Magee, P.N1., ac al. 1976. N-Nitroso compounds and related
carcinogens. In; C.S. Searie, ed. Chemical Carcir.ccens.
ACS Monograph No. 173. Am. Chem. Soc., Washington, D.C.
Mcntesano, R., and H. Sartsch. 1976. Mutagenic and carcino-
genic N-nitroso compounds: possible environmental hazards.
Mutat. Res. 32: 179.
Montesano, R., and P.N. Magee. 1974. Comparative metacoiism
_in vitro of nitrosamines in various animal species including
man. In: R. Montesano, et al. , eds. Chemical carcinogenesis
essays. IARC Sci. Pub. No. 10. Int.. Agency Res. Cancer,
Lyon, France.
Rajewsky, M.F., et al. 1966. Liver carcinogenesis by di-
ethylnitrosamine in the rat. Science 152c 83.
Schcental, R., et al. 1974. Carcinogens in milk: transfer
of ingested diethylnitrosamine into milk lactating rats. Br.
Jour. Cancer 30: 238.
-------
Stenback,, P., et al. 1973. Synergistic effect of ferric
oxide on dimethylnitrosamine carcinogenesis in the Syrian
golden hamster. Z. Krebsforsch. 79: 31.
Tate, R.L., and M. Alexander. 1976. Resistance of
nitrosamines to microbial attack. Jour. Environ. Qual. 5:
131.
Tomatis, L., and F. Cefis. 1967. The effects of multiple
and single administration of dimethylnitrosamine to hamsters,
Tumori 53: 447.
Toth, B.f et al. 1964. Carcinogenesis study with dimethyl-
nitrosamine administered orally to adult and subcutaneously
to newborn BALBC mice. Cancer Res. 24: 2712.
U.S. EPA. 1979a. Nitrosamines: Ambient Water Quality Cri-
teria. (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment Of-
fice. Nitrosamines: Hazard Profile.
-SO
-------
No. 37
2,4-Dlmethylphenol
Health and Environmental iffacts
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-103.1-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
niay not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
2.4-OIMETtiYLPhENOL
Summary
2,4-Oimethylphenol (2,4-OMP) is an intermediate in a number of indus-
trial and agricultural products. The main route of exposure for humans is
dermal with 2,4-OMP being readily absorbed through the skin.
Little data is available on the mammalian effects of 2,4-OMP. Tests on
mice conclude that the compound may be a promoting agent in carcinogenesis.
2,4-OMP inhibits vasoconstriction in isolated rat lungs; this ability may
cause adverse health effects in chronically exposed humans.
A reported 96-hour LC-j-, value for fathead minnows is 16,750 jug/1;
chronic value using embryo-larval stages of the same species is 1,100 ug/1.
Oacnnia magna has an observed 48-hour LC-Q value of 2,120 ,ug/l. In
limited testing, one aquatic alga ana auckweed are over 100 times less
•«
sensitive than the Caonnia in acute exposures. The bioconcsntration factor
for 2,4- diiTietnyiphehoi is 150 for the bluegili. rrom half-life stuoies,
residues of the chemical are noc a potential hazard for aquatic species.
-------
I. INTRODUCTION
This profile is based primarily on the Ambient Water Quality Criteria
Document for 2,4-Oimethylphenol (U.S. EPA, 1979).
2,4-Oimethylphenol (2,MM5) is derived from coal and petroleum sources
and occurs naturally in some plants. 2,4-DMP (C-H,gO) is usually found
with the five other dimethylphenol and three methylphenol isomers. It has a
molecular weight of 122.17 and normally exists as a colorless crystalline
solid. 2,4-OMP has a melting point of 27 to 28°C, a boiling point of
210°C (at 760 mm Hg), a vapor pressure of 1 mm Hg at 52.8°Cr and a dens-
ity of 0.0965 g/ml at 20°C (U.S. EPA, 1979).
2,4-QMP is a weak acid (pk_-10.6) and is soluble in alkaline solu-
tions. It readily dissolves in organic -solvents and is slightly soluble in
water (Weast, 1976). •
2,4-OM? is a chemical intermediate in the manufacture of a number of
industrial and agricultural products, including phenolic antioxidants, dis-
infectants, solvents, Pharmaceuticals, insecticides, fungicides, plasti-
cizers, rubber chemicals, polyphenylene oxide, wetting agents, and dye-
stuffs. It is also found in lubricants, gasolines, and cresylic acid (U.S.
EPA, 1979).
Very little information exists on the environmental persistence of 2,4-
DMP. Complete biodegradation of 2,4-OMP occurs in approximately two months
(U.S. EPA, 1979); however, no environmental conditions were described.
II. EXPOSURE
A. Water
U.S. EPA (1979) reported that no specific data are available on the
•
amounts of 2,4-OMP in drinking water. The concentrations of 2,4-OMP present
in drinking water vary depending on the amounts present in untreated water
-------
and on the efficiency of water treatment systems in removing phenolic com-
pounds. In the U.S., the gross annual discharge of 2,4-OMP into waters was
estimated to be 100 tons in 1975 (Versar, 1975). Manufacturing was the lar-
gest source of the discharge. Leachates from municipal and industrial
wastes also contain the compound (U.S. EPA, 1979).
Hoak (1957) determined that, at 30°C, the odor threshold for 2,4-
OMP was 55.5>jg/l.
8. Food
DMP's occur naturally in tea (Kaiser, 1967)T tobacco (Baggett and
Marie, 1973; Spears, 1963), marijuana (Hoffmann, et al. 1975), and a conifer
(Gcrncstasva, et al. 1977). There is no evidence to suggest that
dimethylphenols occur in many plants used for food; however, it may be
assumed that trace amounts are ingested (U.S. EPA, 1979). ;
The U-S. E?A (1979) has estimated the weighted average biocon-
centraticn factor for 2,4-QMP to be 340 for tna edible portions of fish ana
shellfish consumed by Americans. This estimate is based on the measured
steady-state bioconcentration studies in the bluegill.
C. Inhalation
2,4-Oimethylphenol has been found in commercial degreasing agents
(NIQSH, 1978), cresol vapors (Corcos, 1935), cigarette smoke condensatss
(Baggett and Morie, 1973; Hoffmann and Wynder, 1963; Smith and Sullivan,
1964), marijuana cigarette smoke (Hoffmann, et al. 1975) and vapors from the
combustion and pyrolysis of building materials (Tsuchiya and Sumi, 1975).
Concentrations in smoke condensates from six different brands of American
cigarettes ranged from 12.7 to 20.3 mg/cigarette without filters and 4.4 to
»
9.1 mg/cigarette with filters (Hoffman and Wynder, 1963).
-------
There is no evidence in the available literature indicating that
humans are exposed to 2,4-DMP other than as components of complex mixtures.
Adverse health effects have been found in workers exposed to mixtures con-
taining amounts of 2,4-DMP; however, the effects were not attributed to
dimethylphencl exposure per se (NIOSH, 1978).
0. Dermal
Absorption through the skin is thought to be the primary route of
human exposure to complex mixtures containing 2,4-OMP (U.S. EPA, 1979).
III. PHARMACOKINETICS
A. Absorption
2,4-DMP is readily absorbed through the skin (U.S. E?A, 1979). The
dermal LD^g for molten 2,4-OMP is 1,040 mg/kg in the rat (Uzhdovini, et
al. 1974).
8. Distribution
U.S. EPA (1979) found no pertinent data on the distribution of 2,4-
OMP in humans or animals in the available literature. 2,6- or 3,4-CMP given
orally to rats for eight months caused damage to the liver, spleen, kidneys,
and heart (Maazik, 1963).
C. Metabolism
Urinary metabolites, resulting from oral administration of 350 mg
of 2,4-OMP to rabbits, were primarily ether-soluble acid and ether glucuro-
nide, with lesser amounts of ethereal sulfate, ester glucuronide and free
non-acidic phenol (Bray, et al. 1950). Similar metabolism of the other
dimethylphenol positional isomers was reported.
0. Excretion
»
A study done on rabbits by Bray, et al. (1950) indicates rapid
metabolism and excretion of 2,4-OMP.
-------
IV. EFFECTS
A. Carcinogenicity
Epidemiologic studies of workers exposed to 2,4-OMP were not loca-
ted in the available literature.
In a Carcinogenicity bioassay, 26 female Sutter mice were dermally
exposed to 25 jul of 20 percent 2,4-OMP in benzene twice weeekly for 24
weeks. Twelve percent of the exposed mice developed carcinomas; however,
benzene was not evaluated by itself in this study Ooutwell and Bosch,
1959). In a related study, Boutwell and Bosch (1959) applied 25 ul of 20
percent 2,4-OMP in benzene to the skin of female Sutter mice twice a week
for 23 weeks following a single acclication of a sub-carcinogenic dose (75
ug) of CMBA. Papillomas or carcinomas developed in 18 percent of the mice,
indicating that 2,4-OMP may be a promoting agent for carcinogenesis.
Fractions of cigarette smoke condensate containing phenol, methyl-
phenols and 2,4-OMP have been snown to promote carcinogenesis in mouse skin
bioassays (Lazar, et al. 1566; Sock, et al. 1971; Roe, et al. 1559).
B. Mutagenicity, Teratogenicity and Other Reproductive Effects
Pertinent data could not be. located in the available literature
regarding mutagenicity, teratogenicity and other reproductive effects.
C. Chronic Toxicity
Pertinent information concerning the chronic effects of 2,4- OMP
was not located in the available literatureHU.S. EPA, 1979); however, data
was available on other positional isomers. Examination of rats treated
orally with 6 mg/kg of 2,6-dimethylphenol or 14 mg/kg of 3,4-dircethylphencl
for eight months revealed fatty dystrophy and atrophy of the hepatic ceJ^ls,
-------
hyaline-droplet dystrophy in the kidneys, proliferation of mycloid and
reticular cells, atrophy of the lymphoid follicles of the spleen, and paren-
chymatous dystrophy of the heart cells (Maazik, 1968).
0. Other Relevant Information
Tests on isolated rat lungs indicate that 2,4-OMP may inhibit vaso-
constriction, most likely due to its ability to block ATP (Lunde, et al.
1968). Because of 2,4-OMP's physiological activity, U.S. EPA (1979) reports
that chronic exposure to the compound may cause adverse health effects in
humans.
V. AQUATIC TOXICITY
Pertinent data cculd net be located in the available literature re-
garding any saltwater species.
A. Acute Toxicity
A reported 96-hour LC-g value for juvenile fathead minnows is
16,750 ,ug/l (U.S. EPA, 1979). For the freshwater invertebrate Dacnnia
maqna, the observed 48-hour LC5Q is 2,120 jjg/1 (U.S. EPA, 1579).
3. Chronic Toxicity
3ased on an embryo-larval test with the fathead minnow, Pimeohales
oromelas, the derived chronic value is 1,100 pg/1 (U.S. .EPA, 1978). NO
chronic values are available for invertebrate species.
C. Plant Effects
Based on chlorosis effects, the reported LC,-Q for duckweed, Lemna
minor, is 292,800 jjg/1 for 2,4-dimethylphenol exposure (Blackman, et al.
1955).
D. Residues
»
A bioconcentration factor of 150 was obtained for the bluegill.
The biological half-life in the bluegill is less than one day, indicating
-j^r\ iLr
17'?
-------
that 2,4-dimethylphenol residues are probably not a potential hazard for
aquatic organisms (U.S. EPA, 1978).
VI. EXISTING GUIDELINES AND STANDARDS
Standards have not been promulgated for 2,4-CMP for any sector of the
environment or workplace.
A. Human
The draft criterion for 2,4-dimethylphenol in water recommended by
the U.S. EPA (1979) is 15.5 jug/1 based upon the prevention of adverse
effects attributable to the organoleptic properties of 2,4-OMP.
8. Aquatic
For 2,4-dimethylphenol, the draft criterion to protect freshwater
aquatic life is 38 ug/1 as a 24-hour average; the concentration should not
exceed 86 jug/1 at any time. No criterion exists for saltwater species (U.S.
EPA, 1575).
-------
2.4-OIMETHYLPHENOL
Referencss
Baggett, M.S., and G.P. Morie. 1973. Quantitative determination of phenol
and alkylpnenols in cioarette smoke and their removal by various filters.
Tob. Sci.' 17: 30.
Blackman, E.G., et al. 1955. The physiological activity of substituted
phenols. I. Relationships between chemical structure and physiological
activity. Arch. Biochem. Biophys. 54: 45.
Bock, F.G., et al. 1971. Composition studies on tobacco. XLIV. Tumor-
promoting activity of subfractions of the weak acid fraction of cigarette
smoke condensate. Jour. Natl. Cancer Inst. 47: 427.
Boutwell, R.K., and O.K. Bosch. 1959. The tumor-producing action of phenol
and related compounds for mouse skin. Cancer Res. 19: 413.
Bray, H.G.. et al. 1950. Metabolism of derivatives of toluene. 5. The
fate of the xylenois in the rabbit with further observations on the metab-
olism of the xyienes. Biochem. Jour. _ 47: 395.
Corcos, A. 1939. Contribution to the study of occupational poisoning ;by
cresols. Dissertation. Vigot Freres Editeurs. (Fre).
Gornostaeva, L.I., et al. 1977. Phenols from abies sibirica sssentaial
oil. Khim. Pirir. Soedin: ISS 3, 417-413.
Hcak, R.D. 1957. The causes of tastes and odors in drinking water. Proc.
llth Ind. Waste Conf. Purdue Univ. Eng. Bull. 41: 229.
Hoffmann, 0., et al. 1975. On the carcinogenicity of marijuana smoke.
Recent Adv. Phytochem. 9: 63.
Hoffmann, 0., and E.L. Wyncer. 1963. Filtration of phenols from cigarette
smoke. Jour. Natl. Cancer Inst. 30: 67.
Kaiser, H.E. 1967. Cancer-promoting effects of phenols in tea. Cancer
20: 614.
Lazar, P., et al. 1966. 8enzo(a)pyrene, content and carcinogenicity of
cigarette smoke condensate - results of short-term and long-term tests.
Jour. Natl. Cancer Inst. 37: 573.
Lunde, P.K., et al. 1968. The inhibitory effect of various phenols on
ATF-induced vasoconstricticn in isolated perfused rabbit lungs. Acta.
Physiol. Scand. 72: 331.
»
Maazik, I.K. 1963. Oimethylphenol (xylenoi) isomers and their standard
contents in water bodies. Gig. Sanit. 9: 18.
-------
National Institute of Occupational Safety and Health. 1978. Occupational
exposure to cresol. OHEW (NIOSH) Publ. No. 78-133. U.S. Dep. Health Edu.
Welfare, Pub. Health Ser., Center for Dis. Control.
Roe, r.j.c., et al. 1959. Incomplete carcinogens in cigarette smoke con-
densate: tumor-production by a phenolic fraction. Br. Jour. Cancer
13: 623.
Smith, G.A., and P.2. Sullivan. 1964. Determination of the steam-volatile
phenols present in cigarette-smoke condensate. Analyst 89: 312.
Spears, A.W. 1963. Quantitative determination of phenol in cigarette
smoke. Anal. Chem. 35: 320.
Tsuchiya, Y., and K. Sumi. 1975. Toxicity of decomposition products -
phenolic resin. Build. Res. Note-Natl. Res. Counc. Can., Oiv. Build. Res.
106.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract NO. 68-01-4646. U.S. Environ. Prot.
Agency, Washington, O.C.
U.S. EPA. 1979. 2,4-Oimethylphenol: Ambient Water Quality Criteris
(Draft).
Uzhdovini, E.R., et al. 1974. Acute toxicity of lower phenols. Gig. fr.
Prof. Zaboi. (2): 58.
Versar, Inc. 1975. Identification of organic compounds in effluents frcm
industrial sources. EPA-560/3-75-002. U.S. Environ. Prat. Agency.
Weast, R.C. 1576. Handbook of chemistry and physics. 57th ed. CRC Press,
Cleveland, Ohio.
-------
No. 88
Dimethyl Phthalate
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical acc-uracv.
-------
DIMETHYL PHTHALATE
SUMMARY
Dimethyl phthalate has been shown to produce mutagenic
effects in the Ames Salmonella assay.
Administration of dimethyl phthalate to pregnant rats
by i.p. injection has been reported to produce teratogenic
effects in a single study. Other reproductive effects pro-
duced by dimethyl phthalate included impaired implantation
and parturition in rats following i.p. administration.
Chronic feeding studies in female rats have indicated
an effect of dimethyl phthalace on the kidneys. There is
no evidence to indicate that dimethyl phthalate has carcino-
genic effects.
Among the four aquatic species examined, freshwater
fish and invertebrates appeared to be more sensitive than
their marine counterparts. Acute toxicity values at concen-
trations of 49,500 pg/1 were obtained for freshwater fish.
Criterion could not be drafted because of insufficient daca
concerning the toxic effects of dimethyl phthalates to aquatic
organisms.
**/$ 3 7
-------
DIMETHYL PHTHALATE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Phthalate Esters (U.S. EPA, 1979a).
Dimethyl phthalate (DM?) is a diester of the ortho
form of benzene dicarboxylic acid. The compound has a mole-
cular weight of 194.18, specific gravity of 1.189, boiling
point of 282°C, and a solubility of 0.5 gms in 100 ml of
water (U.S. EPA, 1979a).
DMP is used as a plasticizer for cellulose ester plas-
tics and as an insect repellant.
Current Production: 4.9 x _10" tons/year in 1977 (U.S.
EPA, 1979a).
Phthalates have been detected in soil, air, and water
samples; in animal and human tissues; and in certain vegeta-
tion. Evidence from _in_ vitro studies indicates that certain
i
bacterial flora may be capable of metabolizing DMP to the
monoester form (Englehardt, et al. 1975).
For additional information regarding the phthaiate
escers in general, the reader is referred to the EPA/SCAO
Hazard Profile on Phthalate Esters (U.S. EPA, 1979b).
II. EXPOSURE
Phthalate esters appear in all areas of the environ-
ment. Environmental release of phalates may occur through
leaching of the compound from plastics, volatilization from
»
plastics, or the incineration of plastic items. Sources
of human exposure to phthalates include contaminated foods
and fish, dermal application, and parenteral administration
-------
by use of plastic blood bags, tubing, and infusion devices
(mainly DEHP release). Relevant factors in the migration
of phthalate esters from packaging materials to food and
beverages are: temperature, surface area contact, lipoidial
nature of the food, and length of contact (U.S. EPA, 1979a).
Monitoring studies have indicated that most water phtha-
late concentrations are in the ppm range, or 1-2 pg/liter
(U.S. EPA, 1979a). Industrial air monitoring studies have
measured air levels of phthalates from 1.7 to 66 mg/m (Mil-
kov, et al. 1973) . Information on levels of DMP in foods
is not available.
The U.S. SPA (1979a) has estimated the weighted average
bioconcentration factor for BMP to be 130 for the edible .
portions of fish and shellfish consumed by Americans. This
estimate is based on the measured steady-state bioconcen-
tra^ion studies in bluegills.
III. PHARMACGKINETICS
Specific information is not available on the absorp-
tion, distribution, metabolism, or excretion of DMP. The
reader is referred to a general coverage of phthalate metabo-
lism in the phthalate ester hazard profile (U.S. EPA, 1979b).
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not be located in the avail-
able literature.
B. Mutagenicity
Dimethyl phthalate has been shown to produce muta-
genic effects in the Ames Salmonella assay (Rubin, et ai.
1979) .
-------
C. Teratogenicity
Administration of DMP to pregnant rats by i.p.
injection has been reported to produce teratogenic effects
(Singh, et al. 1972). Intraperitoneal administration of
DMP to pregnant rats in another study did not result in
teratogenic effects (Peters and Cook, 1973).
D. D. Other Reproductive Effects
Adverse effects by DMP on implantation and parturi-
tion were reported by Peters and Cook (1973) following i.p.
administration of the compound to rats.
E. Chronic Toxicity
Two-year feeding studies with dietary DMP have
produced some kidney effects in female rats and minor growth
effects (Draize, et al. 1943).
7. . AQUATIC TOXICITY
A. Acute Toxicity
Two freshwater species were examined for acute
toxicity from dimethyl phthalate exposure. The 48-hour
static "C_Q for the Cladcceran, Daphnia rnagna, was 33,000
ug/1 (U.S. EPA, 1978). The 96-hour static LC-Q value for
the bluegill, Lepomis macrochirus, was 49,500 pg/1. For
marine species, 96-hour static kC^Q values for the sheeps-
head minnow, Cyprinodon variegatus, and mysid shrimp, Mysid-
opsis bahia, were 58,000 and 73,700 pg/1, respectively.
B. Chronic Toxicity
»
Pertinent information could not be located in
the available literature.
-------
C.. Plant Effects
Effective concentrations based on chlorophyl a
content and cell number for the freshwater algae Selena-
.strum capricornutum and the marine algae Skeletonema costa-
tum ranged from 39,800 to 42,700 pg/1 and 26,100 to 29,800
ug/1, respectively.
D. Residues
A bioconcentration factor of 57 was obtained for
the freshwater bluegill, Lepomis macrochirus.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived
by U.S. SPA (1979a), which are summarized below, have gone
through the process of public review; therefore, there is
a possibility that these criteria will be changed.
A. Human
Based on "no effect" levels ooserved in chronic
^do^ * -~ e*-i-J-a= i— >- = -c 3->r* [•'r«e= h h P fl ^ ^T^A MQ7Qa\ U-^
^.c^C^xii^ OUM^*^.G>^ ^.^. j.
-------
DIMETHYL PHTHALATES
REFERENCES
Draize, J.K., et al. 1948. Toxicological investigations
of compounds proposed for use as insect repellents. Jour.
Pharmacol. Exp. Ther. 93: 26.
Engelhardt, G., et al. 1975. The raicrobial metabolism
of di-n-butyl phthalate and related dialkyl phthalates.
Bull. Environ. Contain. Toxicol. 13: 342.
Milkov, L.2., et al. 1973. Health status of workers exposed
to phthalate plasticizers in the manufacture of artificial
leather and films based on PVC resins. Environ. Health
Perspect. Jan. 175.
Peters, J.W., and R.M. Cook. 1973. Effects of phthalate
esters on reproduction of rats. Environ. Health Perspect.
Jan. 91.
Rubin, R.J., et al. 1979. Ames rautagenic assay of a series
of phthalic acid esters: positive response of the dimethyl
and diethyl esters in TA 100. Abstract. Sec. Toxicoi. Annu.
Meet. Naw'orleans, March 11.
Singh, A., at al.- 1972. Terat:cgenicity of phthalate esters
in ra^s. Jour. Pharin. Sci. 61: 51.
U.S. EPA. 1978. In-depth studies on health and environ-
mental impacts of selected water pollutants. "J.5. Environ.
Prot. Agency, Contract No. 68-01-4646.
U.S. SPA. 1979a. Phthalate Esters: Ambient Water Quality
Criteria (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment
Office. Hazard Profile: Phthalate Esters (Draft).
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
No. 89
Dinitrobenzenes
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DINITROBENZENE5
Summary
Due to ths lack of available information no sssessmsnt of ths °ctsn—
tial of dinitrobenzenes to produce carcinogenic effects, mutagenic effects,
teratogenic effects, or adverse reproductive effects can be made.
Oinitrobenzene is the most potent methemoglobin-forming agent of the
nitroaromatics and rapidly produces cyanosis in exposed populations.
x
Fish have been acutely affected by exposure to non-specified isomers of
dinitrobenzene at concentrations ranging from 2,000 to 12,000 ug/1.
-------
OINITR08ENZENE-
I. INTRODUCTION
This profile is based on the Investigation of Selected Potential
Environmental Contaminants: Nitroaromatics (U.S. EPA, 1976).
The dinitrobenzenes exist as the ortho, meta, or para isomers, depend-
ing on the position of the nitro group substitutents. Ortho-dinitrobenzene
(1,2-dinitrobenzene, M.W. 168.1) is a white, crystalline solid with a boil-
ing point of 319°C, a melting point, of 118°C, and a specific gravity of
1.57. Meta-dinitrobenzene (1,3-dinitrobenzene) is a yellow, crystalline
solid that melts at 89-90°C, boils at 300-303°C, and has a density of
1.55. Para-dinitrobenzene (1,4-dinitrobenzene) is a white, crystalline
solid with a coiling point of 299°C, a melting point of 173-174°C, and a
density of 1.63 (windholz, 1976). The dinitrobenzenes have low aqueous
sclubiiitv =nd z~° soluble in alcohol.
The dinitrcbenzanes are used in organic synthesis-, the orccuc'ion of
ayes, and as a camphor substitute in celluloid prediction.
The ccmestic production volume of meta-dinitrcbenzsne in 1572 was
aporoximately 6 x Id^ tons (U.S. EPA, 1976).
Oinitrobenzenes are generally stable in neutral aqueous solutions; as
tne medium oecomes more alkaline they may undergo hydrolysis (Murto, 1966).
Para-dinitrobenzene will undergo photochemical reduction in isoproparol
under nitrogen, but this reaction is quenched when the solvent is aerated
(Hashimoto and Kano, 1972).
Biodegradation of dinitrobenzenes has been reported for acclimated
microorganisms (Chambers, et al. 1963; Bringmann and Kuehn, 1959).
»
Based on the octanol/water partition coefficient, Neely et al. (1974)
have estimated a low bioconcentration potential for the dinitrobenzenes.
-------
II. EXPOSURE
Industrial dinitrobenzene poisoning reports have- shown that workers
will develop intense cyanosis with only slight exposure (U.S. EPA, 1976).
Exposure to sunlight or ingestion of alcohol may exacerbate the toxic
effects of dinitrobenzene exposure (U.S. EPA, 1976).
Monitoring data on levels of dinitrobenzenes in water, air, or food
were not found in the available literature; human exposure from these
sources cannot be evaluated.
III. PHARMACOKINETICS
A. Absorption
Metherccglobin formation in workers exposed to dinitrobenzene indi-
cates that absorption of the compound by inhalation/dermal routes occurs.
Animal studies demonstrate that .dinitrobenzene is absorbed following oral
„ ,j_ .• _ .• _ j— i. .• - „
awl—i lj.iv-.Lac-i.ui i.
3. Distribution
Pertinent information on districution of dinicrcbenzenes \vas not
found in the available literature.
C. Metabolism
Dinitrobenzene undergoes both metabolic reduction and cxidaticn.
.-.nri2_ s^ucies indicate ... .sti •„.
-------
0. Excretion
Oral administration of radiolabelled meta-dinitrobenzene to
rabbits was followed by elimination of 65-93% of the dose within two days.
Excretion was almost entirely via the urine; 1-5% of the administered label
was determined in the feces (Parks, 1961).
IV. EFFECTS
A. Carcinogenicity
Information on the Carcinogenicity of the dinitrobenzenes was not
found in the available literature.
B. Mutagenicity
Information on the mutagenicity of the dinitrobenzenes was not
found in the available literature. The possible dinitrobenzene metabolite,
dinitropnenoi (U.S. EPA, 1979), has been reported to induce chromatid breaks
in bone ."arrow cells of injected mice (Micra ana Manna, 1971).
C. Teratogenicity
Information on the ceratogenicity of the oinitrobenzenes was not
fc-jrd in the available literature. The possible dinitrcbenzene metacoiite,
dinitropnenoi (U.S. EPA, 1979), has produced developmental abnormalities in
the sea urchin (Hagstrom and Lonning, 1966). No effects were seen follcv.-i.-g
injection cr era! administration of dinitropnenol to mice (Gioson, 1973).
0. Other Reproductive Effects
Pertinent information was not found in the available literature.
E. Chronic Toxicity
Oinitrobenzene is the most potent methemoglobin-forming agent of
the nitroaromatics. Poisoning symptoms in humans may be potentiated by
»
exposure to sunlight or ingestion of alcohol (U.S. EPA. 1976).
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
McKee and Wolf (1963) have presented a brief synopsis of the
toxic effects of dinitrobenzenes to aquatic life. A study by LeClsrc (1960)
reported lethal doses of non-specific isomers of dinitrobenzene for minnows
(unspecified) at concentrations of 10,000 to 12,000 ug/1 in distilled water
or 8,000 to 10,000 ug/1 in hard water. Meinck et al. (1956) reported lethal
concentration of 2,000 pg/1 for unspecified dinitrobenzenes for an unspeci-
fied fish species.
8. Chronic Toxicity
Pertinent data could not be found in the 2vail3ble litsrsturs
regarding aquatic toxicity.
C. Plant Effects
Howard et al. (1975) rsport that the algae Chlorella sp. dispiayec
inhibited photosynthetic activity upon exposure to n-dinitrobenzene at a
concentration of 10~4 M.
VI. EXISTING GUIDELINES
The 8-hour time-weighted-averace (TWA) occupational exoosure limit for
dinitrobenzenes is 0.15 ppm(ACGIH, 1974).
-------
DINITR08ENZENES
References
ACGIH. 1974. Committee on threshold limit values: Documentation of the
threshold limit values for substances in the workroom air. Cincinnati, Ohio.
3ringmann, G. and R. Kuehn. 1959. Water toxicity studies with protozoans
as test organisms. Gesundh.-Ing. 80: 239.
Chambers, C.W., et al. 1963. Degradation of aromatic compounds by pheno-
ladopted bacteria. Jour. Water Pollut. Contr. Fedr. 35: 1517.
Gibson, J.£. 1973. Teratology studies in mice with 2-sec-Butyl-4,- 6-dini-
trophenol (Dinoseb). Fd. Cosmet. Toxicol. 11: 31.,.
Hagstrom, 8.E. and S. Lcnning. 1966. Analysis of the effect of -Qinitro-
phenol on cleavage and development of the sea urchin embryo. Protoplasms.
42(2-3): 246. •
Hashimoto, 5. and K. Xano. 1572. Fhotocnsmical reduction of nitrobenzene
and reduction intermediates. X. Photochemical reduction of the mono-
substitutsc1 nitrcbenzanes in 2-propanol. Bull. Chem. Soc. Jap. 45(2): 549.
Howard, P.M., et al. 1975. Investigation of selected potential environ-
mental contaminants: Nicrcaromatico. Syracuse, N.Y.: Syracuse Research
Corccration, T° 76-573.
LeClerc, E. 1960. Self purification .of streams and the relationship ce-
tv/een chemical arc1 biological tests. 2nd Symposium on the Treatment of
Waste Waters. Pergamon Press, p. 282.
McKee, J.E. and H.w. Wolf. 1963. Water quality criteria. The Resource
Agency of California State Water Quality Control Board Publication NO. 3-A.
Meinck, ,-., et al. 1956. Industrial waste water. 2nd ed. Gustav Fisher
Verlag Stutosrt, o. 536.
Micra, A.3. and G.K. Manna. 1971. Effect of some phenolic compounds on
chromosomes of bone marrow cells on mice. Indian J. Med. Res. 59(9): 1442.
Murto, J. 1966. Nucleophilic reactivity. Part 9. Kinetics of the reac-
tions of hydroxide ion and water with picrylic compounds. Acta Chem.
Scand. 20: 310.
s
Neely, W.B., et al. 1974. Partition coefficient to measure bicconcan-
tration potential of organic chemicals in fish. Environ. Sci. Technoi.
3: 1113.
«
Parke, O.W. 1961. Detoxication. LXXXV. The metabolism of m-dinitro-
benzene-C^ in the rabbit. Biochem. Jour. 78: 262.
-------
U.S. EPA. 1976. Investigation of selected potential environmental contam-
inants: Nitroaromatics.
U.S. EPA. 1979. Environmental Criteria and Assessment Office. 2,4-Dini-
trophenol: Hazard Profile (Draft).
Windholz, M. (ed.) 1975. The Merck Index. 9th ed. Merck and Co., Inc.,
Rahway, N.J. p. 3269.
-------
No. 90
4,6-Dinitro-o-cresol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCt
WASHINGTON, D.C. 20460
APRIL 30, 1980
Jo-/
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical acc-aracy.
-------
4,6-DINITRO-O-CRESOL
SUMMARY
There is no available evidence to indicate that 4,6-
dinitro-ortho-cresol (DNOC) is carcinogenic.
This compound has produced some DNA damage in Proteus
mirabilis but failed to show mutagenic effects in the Ames
assay or in E. coli. Available information does not
indicate that DNOC produces teratogenic or adverse
reproductive effects.
Human exposure incidents have shown that DNOC produces
an increase in cataract formation.
-------
4 ,6-DINITRO-O-CRESOL
I. INTRODUCTION
This profile is based on the Ambient Water Quality Cri-
teria Document for Nitrophenols (U.S. EPA, 1979a).
Dinitrocresols are compounds closely related to the di-
nitrophenols; they bear an additional 2-position methyl
group. The physical properties of 4,6-dinitro-ortho-cresol
(DNOC, M.W. 198.13) include a melting point of 85.8°C and a
solubility of 100 mg/1 in water at 20°C (U.S. EPA, 1979a).
Dinitro-ortho-cresol is used primarily as a blossom
thinning agent on fruit trees and as a fungicide, insecticide
and miticide on the fruit trees during the dormant season.
There is no record of current domestic manufacture of DNOC
(U.S. EPA, 1979a). For additional information regarding the
nitrophenols in general, the reader is referred to the Hazard
Profile on Nitrophenols (U.S. EPA, 1979b).
II. EXPOSURE
The lack of monitoring data makes it difficult to assess
exposure from water, inhalation, and foods. DNOC has been
detected at 13 mg/1 in effluents from chemical plants (U.S.
EPA, 1979a).
Exposure to DNOC appears to be primarily through occupa-
tional contact (chemical manufacture, pesticide application).
Contaminated water may result in isolated poisoning inci-
dents.
The U.S. EPA (1979a) has estimated a weighted average
bioconcentration factor for DNOC to be 7.5 for the edible
portions of fish and shellfish consumed by Americans. This
estimate is based on the octanol/water partition coefficient.
X
-------
III. PHARMACOKINETICS
A. Absorption
WOC is readily absorbed through the skin, the res-
piratory tract, and the gastrointestinal tract (NIOSH,
1978).
B. Distribution
DNOC has been found in several body tissues; how-
ever, the compound may be bound to serum proteins, thus pro-
ducing non-specific organ distribution (U.S. EPA, 1979a).
C. Metabolism
Animal studies on the metabolism of DNOC indicate
that like the nitrophenois, both conjugation of the compound
and reduction of the nitro groups to amino groups occurs.
The metabolism of DNOC to 4-amino-4-nitro-c-crescl is a de-
toxification mechanism that is effective only when toxic
doses of DNOC are administered (U.S. EPA, 19T9a). The
metabolism of DNOC Ls very slow in man as compared to that
observed in animal studies (King and Harvey, 1953).
D. Excretion
The experiments of Parker and coworkers (1951) in
several animal species indicates that DNOC is rapidly ex-
creted following injection; however, Harvey, et al. (1951)
have shown slow excretion of DNOC in volunteers given the
compound orally. As in metabolism, there is a substantial
difference in excretion patterns of humans vs. experimental
animals.
-------
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not located in the available
1iterature.
B. Mutagenicity
Adler, et al. (1976) have reported that DNOC shows
some evidence of producing DNA damage in Proteus mirabilis.
Testing of this compound in the Ames Salmonella system
(Anderson, et al., 1972) or in JB. coli (Nagy, et al., 1975)
failed to show any mutagenic effects.
C. Teratogenicity and Other Reproductive Effects
Pertinent data could n.ot be located in the
available literature regarding teratogenicity and other
reproductive effects.
D. Chronic Tcxicity
Human use of DNOC as a dieting aid has produced
poisoning cases at accepted thereputic dose levels, as well
as some cases of cataract development resulting from
overdoses (HIOSH, 1978).
E. Other Relevant Information
DNOC is an uncoupler of oxidative phosphorylation,
an effect which accounts for its high acute toxicity in
mammals.
V. AQUATIC TOXICITY
Pertinent information could not be located in the
available literature.
-------
VI. EXISTING GUIDELINES AND STANDARDS
A. An eight-hour TLV exposure limit of 0.2 mg/m^ has
been recommended for DNOC by the ACGIH (1971).
A preliminary draft water criterion for DNOC has
been established at 12.8 ug/1 by the U.S. EPA (1979a). This
draft criterion has not gone through the process of public
review; therefore, there is a possibility that the criterion
may be changed.
B. Aquatic
Criteria for the protection of freshwater and
marine aquatic organisms were not drafted due to lack of
tcxicoiogical evidence (U.S. SPA, 1979a) .
-------
VI. EXISTING GUIDELINES AND STANDARDS
A. An eight-hour TLV exposure limit of 0.2 mg/m-3 has
been recommended for DNOC by the ACGIH (1971).
A preliminary draft water criterion for DNOC has
been established at 12.3 ug/1 by the U.S. SPA (197Sa). This
draft criterion has not gone through the process of public
review; therefore, there is a possibility that the criterion
may be changed.
B.. Aquatic
Criteria for the protection of freshwater and
marine aquatic organisms were not drafted due to lack of
toxlcological evidence (U.S. EPA, 1979a).
-------
No. 91
2,4-Dlnitrophenol
Health and Environmental Effects
CJ.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
_^^*^--A.
) U U ^
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
2,4-DINITROPHENOL
Summary
There is no evidence to indicate that 2,4-dinitrophenol pos-
sesses carcinogenic activity.
Genetic toxicity testing has shown positive effects in mouse
bone marrow cells and in E_._ coli. In_ vitro cell culture assays
failed to show the potential for mutagenic activity of 2,4-dinitro-
phenol as measured by unscheduled ONA synthesis.
Teratogenic effects have been observed in the chick embryo
following administration of 2,4-dinitrophenol. Studies in mammals
failed to show that the compound produced any taratocenic effacts.
At the levels of compound used in these mammalian studies, embryo-
*
toxic effecrs were observed.
Human use of 2,4-dinitrophenol as a 'dieting aid has produced
seme cases cf agranulccytosis, neuritis, functional heart da.~age,
and cataract development.
For aquatic organisms LC^g values ranged from 620 ug/1 for
the biuegill tc 15,700 j:g/l for the fathead minnow.
-------
2,4-DINITROPHENOL
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Nitrophenols (U.S. EPA, 1979a).
The dinitrophenols are a family of compounds composed of the
isomers resulting from nitro-group substitution of phenol at vari-
ous positions. 2,4-Dinitrophenol has a molecular weight of 184.11,
a melting point of 114-115°C, a density of 1.683 g/ml and is sol-
uble in water at 0.79 g/1 (U.S. EPA, 1979a).
The dinitrophenols are used as chemical intermediates for
sulfur dyes, azo dyes, photochemicais, pest control agents, wood
preservatives, and explosives (U.S. EPA, 1979a). The 1963 pro-
duction of 2,4-dinitroohenol was 4.3 x 10^ tons/yr. (U.S. EPA^
*" *
1979a).
For additional ir.fcrniaticn regarding the nitrochenols as
a class, the' reader is referred to the Hazard Profile on Nitro-
phenols (1979b).
II. EXPOSURE
The lack of monitoring data for the nitrophenols makes it
difficult co assess exposure from water, inhalation, and foods.
Nitrophenols have been detected in effluents from chemical plants
(U.S. SPA, 1979a) . Dermal absorption of the dinitrcphenols has
been reported (U.S. EPA, 1979a).
Exposure to nitrophenols appears to be primarily through
occupational contact (chemical plants, pesticide application) .
»
Contaminated water may contribute to isolated poisoning incidents.
The U.S. EPA (1979a) has estimated the weighted average biocon-
centration factor for 2,4-dinitrophenol to be 2.4 for the edible
-------
portions of fish and shellfish consumed by Americans. This esti-
mate was based en the. cctanol/water partition coefficients of
2,4-dinitrophenol.
III. PHARMOCOKINETICS
A. Absorption
The dinitrophenols are readily absorbed following oral,
inhalation, or dermal administration (U.S. EPA, 1979a).
3. Distribution
Dinitrophenol blood concentrations rise rapidly after
absorption, with little subsequent distribution or storage at tis-
sue sites (U.S. EPA, 1979a).
C. Metabolism
Metabolism of the nitrophenols occurs through conjuga-
tion and reduction of nitro-grcups to amino—groups, or oxidation to
dihydric-nitropher.Qls (U.S. EPA, 1979a) .
D. Excretion
Experiments .with several animal species indicate that
urinary clearance of dinitrophenols is rapid (Harvey, 1959).
"TT r~--n r^T">/-*fT*r^
>/l. ixriCTS •**
A. Carcinogenicity-
2,4-Dinitrophenol has been found not to promote skin
tumor formation in mice following DMBA initiation (Bautwell and
Sosch, 1959) „
B. Mutagenicity
Testing of 2,4-dinitrophenol has indicated mutagenic
»
effects in E. coli (Demerec, et al.. 1951) . In vitro assays of
unscheduled DNA synthesis (Friedman and Staub, 1976) and DNA
-------
damage induced during cell culture (Swenberg, et al. 1976) failed
to show the potential for mutagenic activity of this compound.
C. Teratogenicity
2,4-Dinitrophenol has been shown to produce development-
al abnormalities in the chick embryo (Bowman, 1967; Miyatmoto, et
al. 1975) . No teratogenic effects were seen following intragastric
administration to rats (Wulff, et al. 1935) or intraperitoneal ad-
ministration to mice (Gibson, 1973).
D. Other Reproductive Effects
Feeding of 2,4-dinitrophenol to pregnant rats produced
an increase mortality in offspring (Wulff, et al. , 1935); simi-
larly, intraperitoneal administration of the compound to mice
induced embryotoxicity (Gibson, 1973). The influence of this
compound or. maternal health may have contributed to these effects.
S. Chronic Toxicity
Use of 2,4— dir.itroohenol as a human distinc aid has pro-
duced some cases of agranulocytosis, neuritis, functional heart
damage, and a large number of patients suffering from cataracts
(Horner, 1342).
?. Other Relevant Information
2,4-Dinitrophenol is a classical uncoupler of oxidative
phosphorylation, an effect which accounts for its high acute
toxicity in mammals.
A synergistic action in producing ' teratogenic effects
in the developing chick embryo has been reported with a combina-
»
tion of 2,4-dinitrophenol and insulin (Landauer and Clark, 1964).
-------
V. AQUATIC TOXICITY
A. Acute
The bluegill (Lepomis macrochirus) was the most sensi-
tive aquatic organism tested, with an LC^Q of 620 pg/1 in a static,
96-hour assay (U.S. EPA, 1978). Juvenile fathead minnows (Pime-
phales promelas) were more resistant in flow through tests, with
an I*CCQ of 16,720 pg/1 (Phipps, et al. manuscript). The fresh-
water cladoceran (Daphnia magna) displayed a range of observed
LC5Q values of 4,090 to 4,710 pg/1 (U.S. EPA, 1979a) . Acute
values for the marine sheepshead minnow (Cyprinodon variegatus)
are LC--, values ranging from 5,500 to 29,400 pg/1 (Rosenthal
and Stelzer, 1970). The marine mysid shrimp (Mysidopsis bahia)
had an LC5Q of 4,350 ug/1 (U.S. EPA, 1978). j.
3. Chronic Toxicity
Pertinent data could not be located in the available
literature.
C. Plant Effects
Effective concentrations for freshwater plants ranged
from 1,472 pg/1 for duckweed (Lemna minor) to 50,000 /ag/1 for
the alga (Chlorella pyranoidosa) (U.S. EPA, 1979a). The marine
alga (Skeletonema costatum) was more resistant with a reported
96-hour SC-Q value based on cell numbers of 98,700 pg/1.
D. Residues
Based on the octanol/water partition coefficient, a bio-
concentration factor of 8.1 has been estimated for 2,4-dinitro-
»
phenol for aquatic organisms with a lipid content of 8 percent.
?f-7
-------
V. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived by U.S.
EPA (1979a) which are summarized below have undergone the process of
public review; therefore, there is a possibility that these criter-
ia will be changed.
A. Human
The draft water, criterion for dinitrophenols, based
on data describing adverse effects, has been estimated by the
U.S. EPA (1979a) as 68.6 ug/1.
B. Aquatic
For protecting freshwater aquatic life, the draft cri-
terion is 79 ug/1 as a 24-hour avetage concentration not to exceed
180 ug/1. The marine criterion has been proposed as 37 ug/1
as a 24-hour average not to exceed 84 ug/1 at any time (U.S.
EPA, 1979aj .
To protect saltwater life, the draft criterion is 37
ug/1 as a 24-hour average not to exceed 84 ug/1 at any time (U.S.
EPA, 1979a).
-------
2,4-DINITROPHENOL
REFERENCES
Bautwell, R., and D. Bosch. 1959. The tumor-promoting action
of phenol and related compounds for mouse skin. Cancer Res.
19: 413.
Bowman, P. 1967. The effect of 2,4-dinitrophenol on the develop-
ment of early chick embryos. Jour. Embryol. Exp. Morphol. 17: 425.
Demerec, M., et al. 1951. A survey of chemicals for rautagenic ac-
tion on E. coli. Am. Natur. 85: 119.
Friedman, M.A., and J. Staub. 1976. Inhibition of mouse testicular
DNA synthesis by mutagens and carcinogens as a potential simple
mammalian assay for mutagenesis. Mutat. Res. 37: 67.
Gibson, J.E. 1973. Teratology studies in mice with 2-secbutyl-4,
5-dinitrcphenol (dinoseb). Food Cosmet. Toxicol. 11: 31.
Harvey, D.G. 1959. On the metabolism of some aromatic nitro com-
pounds by different species of animal. Part III. The toxicity of
the dinitrophenols, with a note on the effects of high environment^
al temperatures. Jour. Pharm. Pharmacoi. II: 462.
Homer, W.D. 1942. Dinitroohenol and ics relation to formation of
cataracts. Arch. Ophthal. 27: 1097.
Landauer, W., and E. Clark. 1964. uncoupiers of oxidative phos-
phorylation and teratogenic activity of insulin. Nature 204: 235.
Miyamoto, K., ec al. 1975. Deficient myelination by 2, 4-dinicro-
phencl administration in early stage of development. Teratology
12: 204.
.-nu,A -. *^ . . ^ — <_—.,,,_,;_.. ,— — -> « — — -s ' -. „ -i — ,-*.— i. : »«
J. ** ^ AW M <_ w wOA.iO.fcwy <*J A. ^llCliw^ dli**J d U«^ M *- X W
phenols to the fathead minnow. (Manuscript).
Rosenthal, H., and R. Stelzer. 1970. Wirkungen von 2,4-und 2,5-
dinitrophenol auf die Embryonalentwicklung des Herings Clupea
harengus. Mar. Biol. 5: 325. "
Swenberg, J.A., et al. 1976. In vitro DNA damage/akaline elution
assay for predicting carcinogenic potential., Biochem. Biophys.
Res. Commun. 72: 732.
U.S. EPA. 1979a. Nitrophenols: Ambient water quality criteria.
(Draft).
U.S. EPA. I979b. Nitrophenols: Hazard Profile. Environmental
Criteria and Assessment Office (Draft).
* LJ. '&-
* i D i) ^
-------
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. Contract No. 68-01-4646.
Wulff, L.M.B., et al. 1935. Some effects of alpha- dinitrophenol
on pregnancy in the white rat. Proc. Soc. Exp. Biol. Med. 32: 678.
9/-/0
-------
No. 92
Dinitrotoluene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
,„{,{} ^7 /
* I V ) ''"
7
-------
DINITROTOLUENE
SUMMARY
Most of the information on the effects of dinitrotoluene
deals with 2,4-dinitrotoluene. 2,4-Dinitrotoluene induces
liver cancer and mammary tumors in mice and is mutagenic
in some assay systems. Information on teratogenicity was
not located in the available literature. Chronic exposure
to 2.,4-dinitrotoluene induces liver damage, jaundice, raethemo-
globinemia and anemia in humans and animals.
Acute studies in freshwater fish and invertebrates
suggest that 2,3-dinitrotoiuene is much more toxic than
2,4-dinitrotoluene.
-------
DINITROTOLUENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Dinitrotoluene (U.S. EPA, 1979).
There are six isomers of dinitrotoluene (CH-,CgH3 (N02)2;
molecular weight 182.14), with the 2,4-isomer being the
most important commercially. 2,4-Dinitrotoluene has a melt-
ing point of 71°C, a boiling point of 300°C with decomposi-
tion, and a solubility in water of 270 mg/1 at 22°C. It
is readily soluble in ether, ethanol, and carbon disulfide
(U.S. EPA, 1979). 2,6-Dinitrotoluene has a melting point
of 66°C and is soluble in alcohol. Production in 1975 was
273 x 10 tons per year for the 2,4- and 2,6- isomers com-
bined (U.S. S?A, 1979) .
Dinitrotcluene is an ingredient of explosives for commer-
cial anc military use, a chemical stabilizer in the manufac-
ture of smokeless powder, an intermediate in the manufacture
of toluene diisocyanates used in the production of urethane
polymers, and a raw material for the manufacture of dyestuffs.
Dinitrotoluenes are relatively stable at ambient tempera-
tures (U.S. EPA, 1979).
II. EXPOSURE
A. Water
Data on concentration levels for dinitrotoluene
were not available. Dinitrotoluene waste products are dumped
into surface water or sewage by industries that manufacture
dyes, isocyanates, polyurethanes and munitions (U.S. SPA,
1979) .
-------
B . Food
According to the U.S. EPA (1979), the likelihood
of dinitrotoluene existing in food is minimal since it is
not used as a pesticide or herbicide.
The U.S. EPA (1979) has estimated the weighted
average bioconcentration factor for 2,4-dinitrotoluene to
be 5.5 for the edible portions of fish and shellfish consumed
by Americans. This estimate is based on the octanol/water
partition coefficient.
C. Inhalation
Exposure to dinitrotoluene by inhalation is most
likely to occur occupationally (U.S. EPA, 1979). However,
pertinent data could not be located in the available litera-
ture en atmospheric concentrations of dinitrctcius-2 and,
thus, ocssible human •=.v<'oosure canr.ct be sstimatac.
A. Absorption
14
The absorption of "C-labeled iscmers of dinitrctol
uene after oral administration to rats was essentially com-
plete within 24 hours, with 60 to 90 percent of the dose
being absorbed. The 2,4- and 3,4-isomers were absorbed
to a greater extent than the 3,5- and 2,5- isomers, which
in turn were absorbed to a greater extent than the 2,3-
and 2,5-isomers (Hodgson, et al. 1977) . 2/4-Dinitrotoluene
is known to be absorbed through the respiratory tract and
skin (U.S. EPA, 1979) .
-------
B. Distribution .
Tissue/plasma ratios of radioactivity after adminis-
14
tration of C-labeled dinitrotoluene to rats indicated
14
retention of C DMT in both the liver and kidneys but not
in other tissues (Hodgson, et al./ 1977). A similar experi-
ment with tritium-labeled 2,4-dinitrotoluene ( H-2,4-DNT)
in the rat showed relatively high amounts of radioactivity
remaining in adipose tissue, skin, and liver seven days
after administration (Mori, et al., 1977).
C. Metabolism
No studies characterizing the metabolism of dinitro-
toluene in mammals are available. However, on the basis
of a comparison of the metabolism of 2,4-dinitrotoluene
and 2,4,5-trinitrotoluene in microbial sys-ems, and the
known metabolism of 2,4,5-trinitrotoluene in mammals, the
U.S. Z?A (1379) speculated that tiie metabolites of 2,4-di-
nitrotoluene in mammals would be either tcxic and/or car-
cinogenic .
D. Excretion
T |
In studies involving oral administration of ~"C-
dinitrotoluene or H-2,4-dinitrotoluene to rats (Hodgson,
et al., 1977; Mori, et al., 1977), elimination of radioactiv-
ity occurred mainly in urine and feces. No radioactivity
.•
was recovered in the expired air. About 46 percent of the
administered dose in the latter study was excreted in the
feces and urine during the seven days following administration.
-------
IV. EFFECTS
A. Carcinogenicity
2,4-Dinitrotoluene fed to rats and mice for two
years produced dose-related increases in fibromas of the
skin in male rats and fibroadenomas of the mammary gland
in female rats. All of these were benign tumors. No statis-
tically significant increase in tumor incidence was noted
in mice (Natl. Cancer Inst., 1978).
In a second bioassay of rats and mice fed 2,4-
dinitrotoluene for two years, the findings in rats included
a significant increase of hepatccailuiar carcinomas and
neoplastic nodules in the livers.of females, a significant
increase of mammary gland tumors in females, and a suspicious
ir.craase of hepaeocellular carcincrr.as of che liver in males.
Male mice had a highly signi'f icar.c ir.craase of kidney tumors
(Lee, et ai., 1975; .
2. Mutagenicicy
2,4-Dinitrotoluene was mutagenic in the dominant
lethal assay and in Salmonella typhimurium strain TA1535
(Hodgson, et al. 1976). Cultures of lymphocytes and Kidney
cells derived from rats fed 2,4-dinitrotoluene had signifi-
cant increases in the frequency of chromatid gaps but not
in translocations or chroraatid breaks (Hodgson, et al.,
1976).
The mutagenic effects of products from ozonation
»
or chlorination of 2,4-dinitrotoluene and other dinitrotoluenes
7*1-7
-------
were negative in one study (Simmon, et al., 1977), and,
for products of ozonation alone, were ambiguous in another
study (Cotruvo, et al., 1977).
C. Teratogenicity and other Reproductive Effects
Pertinent data could not be located in the avail-
able literature.
D. Chronic Toxicity
Chronic exposure to 2,4-dinitrotoluene may produce
liver damage, jaundice, methemoglobineraia and reversible
anemia with reticulocytosis in humans and animals (Linch,
1974; Key, et al. 1977; Proctor and Hughes, 1978; Kovalenko,
1973).
E. Other Relevant Information N
Animals were more resistant, to the toxic effects
of 2,4-dinitrotoluene administered in the diet when given
diets high in fat or protein (Clayton and Baumann, 1944,
1948; Shils and Goldwater, 1953) or protein (Shils and Gold-
water, 1953) .
Alcohol has a synergistic effect on the toxicity
of 2,4-dinitrotoluene (Friedlander, 1900; McGee, et al.,
1942).
In subacute studies (13 weeks), 2,4- and 2,6-dini-
trotoluene caused methemoglobinemia, anemia with reticulocyto-
sis, gliosis and demyelination in the brain', and atrophy
with aspermatogenesis of the testes in several species (Ellis,
*
et al., 1976).
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
Static assays with the freshwater bluegill (Lepomis
macrochirus) produced a 96-hour LCen value of 330 ug/1 for
2,3-dinitrotoluene (U.S. EPA, 1978), while the same assay
with the fathead minnow (Pimephales promelas) produced a
96-hour LC5Q value of 31,000 pg/1 for 2,4-dinitrotoluene
(U.S. Army, 1976). The greater toxicity of 2,3-dinitrotoluene
when compared to that of 2,4-dinitrotoluene, was demonstrated
in 48-hour static assays with the freshwater cladoceran,
Daphnia magna, with I*CCQ values of 660 jjg/l(U.S. EPA, 1978)
and 35,000 ug/1 (U.S. Army, 1976) being reported. A single-
marine fish, sheepshead minnow (Cyprinodon variegatus),
has been tested for adverse acute effects of 2,3-dinitro-
toluene. A 96-hour static assay LC5Q- value of 2,280 ug/1
was reported (U.S. EPA, 1978). For marine invertebrates
a 96-hour static LC5Q value of 590 jig/1 was obtained for
the mysid shrimp (Mysidopsis bahia) with 2,3-dinitrotoluene.
3. Chronic Toxicity
The sole chronic study examining the effects of
2,3-dinitrotoluene in an embryo-larval assay on the fathead
minnow produced a chronic value of 116 ug/1 based on reduced
survival of these stages. No marine chronic data were pre-
sented (U.S. EPA, 1979).
C. Plant Effects
Concentrations of 2,3-dinitrotoluene that caused
50 percent adverse effects in cell numbers or chlorophyll
^^^^^2OL-_
lu ) i!!"*
-------
a in the freshwater algae, Selenastrum capricornutum, were
1,370 or 1,620 ug/1, respectively. These same effects mea-
sured in the marine algae, Skeletonema costatum, showed
it to be more sensitive. ECco values were 370 or 400 ug/1,
respectively.
D. Residues
A bioconcentration factor of 19 was obtained for
aquatic organisms having a lipid content of 8 percent (U.S.
EPA, 1979).
VI. EXISTING STANDARDS AND GUIDELINES
Neither, the human health nor aquatic criteria derived
by U.S. EPA (1979), which are summarized below, have gone
through the process of public review; therefore, there is
a possibility that these criteria may be changed.
A. Human
Based on the induction of fibroadenomas of the
mammary gland in female rats (Lee, et al., 1978), and using
the "one-hit" model, the U.S. EPA (1979) has estimated levels
of 2,4-dinitrotoluene in ambient water which will result
in specified risk levels of human cancer:
Exposure Assumptions Risk Levels and Corresponding Draft Criteric
(Per day) £ ^7 ^-6^o '
2 liters of drinking water and 7.4 ng/1 74.0 mg/1 740 ng/1 ;
consumption of 18.7 grams fish •
and shellfish.
Consumption of fish and shell- .156 ^ug/1 1.56 pg/1 15.6
fish only. '
-------
The American Conference of Governmental Industrial
Hygienists (1978) recommends a TLV-time weighted average
for 2,4-dinitrotoluene of 1.5 mg/m with a short term expo-
sure limit of 5 mg/m .
3. Aquatic
A criterion to protect freshwater life has been
drafted as 620 ug/1 for a 24-hour average not to exceed
1,400 pg/1 for 2.4-dinitrotoluene and 12 ug/1 not to exceed
27 pg/1 for 2,3-dinitrotoluene. For marine environments
a criterion has been drafted for 2,3-dinitrotoluene as a
4.4 pg/1 as a 24-hour average not to exceed 10 pg/1. Data
was insufficient to draft a criterion for 2,4-dinitrotoluene
for marine environments.
ft ' ~ r> *
' I U v **
72-11
-------
DINITROTOLUENE
REFERENCES
American Conference of Governmental Industrial Hygienists. 1978. TLV's:
Threshold limit values for chemical substances and physical agents in the
workroom environment with intended changes for 1978.
Clayton, C.C. and C.A. Baumann. 1944. Some effects of diet on the resis-
tance of mice toward 2,4-dinitrotoluene. Arch. Biochem. 5: 115.
Clayton, C.C. and C.A. Baumann. 1948. Effect of fat and calories on the
resistance of mice to 2,4-dinitrotoluene. Arch. Biochem. 16: 415.
Cotruvo, J.A., et al. 1977. Investigation of mutagenic effects of products
of ozonation reactions in water. Ann. N.Y. Acad. Sci. 298: 124.
Ellis, H.V., III, et al. 1976. Subacute toxicity of 2,4-dinitrotoluene and
2,6-dinitrotoluene. Toxicol. Appl. Pharmacol. 37: 116. (Abstract from
15th Ann. Meet. Soc. Toxicol., March 14-18.)
Friedlander, A. 1900. On the clinical picture of poisoning with benzene
and toluene derivatives with special reference to the so-called anilinism.
Neurol. Centrlbl. 19: 155.
Hodgson, J.R., et al. 1976. Mutation studies on 2,4-dinitrotoluene.
Mutat. Res. 38: 387. (Abstract from the 7th Ann. Meet. Am. Environ. Muta-
gen. Soc., Atlanta, March 12-15.)
Key, M.M., et al. (eds.) 1977. Pages 278-279 In; Occupational diseases: A
guide to their recognition. U.S. Dept. Health Edu. Welfare. U.S. Govern-
ment Printing Office, Washington, O.C.
Kovalenko, I.I. 1973. Hemotoxicity of nitrotoluenes in relation to number
and positioning of nitro groups. Farmakol. Toxicol. (Kiev.) 8: 137.
Lee, C.C., et al. 1978. Mammalian toxicity of munition compounds. Phase
III: Effects of lifetime exposure. Part I: 2,4-dinitrotoluene. U.S. Army
Med. Res. Dev. Command. Contract No. OAMO-17-74-C-4073. Rep. No. 7, Sep-
tember.
Linch, A.L. 1974. Biological monitoring for industrial exposure to cyano-
genic aromatic nitro and amino compounds. Am. Ind. Hyg. Assoc. Jour.
35: 426.
McGee, L.C., et al. 1942. Metabolic distrubances in workers exposed to
dinitrotoluene. Am. Jour. Dig. Ois. 9: 329.
»
Mori, M., et al. 1977. Studies on the metabolism and toxicity of dinitro-
toluenes — on excretion and distribution of tritium-labeled 2,4-dinitroto-
luene (^H^^-ONT) in the rat. Radioisotopes 26: 780.
-------
National Cancer Institute. ' 1978. Bioassay of 2,4-dinitrotoluene for possi-
ble carcinogenicity. Carcinogenesis Tech. Rep. Ser. No. 54. USOHEW (NIH)
Publ. No. 78-1360. U.S. Government Printing Office, Washington, O.C.
Proctor, N.H. and J.P. Hughes. 1978. Chemical hazards of the workplace.
J.8. Lippincott Co., Philadelphia/Toronto.
Shils, M.S. and L.J. Goldwater. 1953. Effect of diet on the susceptibility
of the rat to poisoning by 2,4-dinitrotoluene. Am. med. Assoc. Arch. Ind.
Hyg. Occup. Med. 8: 262.
Simmon, V.F., et al. 1977. Munitions wastewater treatments: does chlorina-
tion or ozonation of individual components produce microbial mutagens?
Toxicol. Appl. Pharmacol. 41: 197. (Abstract from the 16th Ann. Meet. Soc.
Toxicol., Toronto, Can., March 27-30.)
U.S. Army Research and Development Command. 1976. Toxicity of TNT waste-
water (pink water) to aquatic organisms. Final report, Contract DAM017-75-
C-5056. Washington, D.C.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646.
U.S. EPA. 1979. Oinitrotoluene: Ambient Water Quality Criteria. (Draft) ^
-------
No. 93
2,4-Dinitrotoluene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
93-2-
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
2,4-dinitrotoluene and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
2.4-OINITROTOLUENE
Summary
2,4-Qinitrotoluene induces liver cancer and mammary tumors in mice and
is mutagenic in some assay systems. Information on teratogenicity was not
located in the available literature. Chronic exposure to 2,4-dinitrotoluene
induces liver damage, jaundice, methemoglobinemia and anemia in humans and
animals.
Two acute studies, one on freshwater fish and the other on freshwater
invertebrates, provide the only data of 2,4-dinitrotoluene's adverse effects
on aquatic organisms. Acute LC5Q values were reported as 17,000 and
30,000 jug/I. No marine data are available.
•*f D
-------
2,4-OINITROTOLUENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Dinitrotoluene (U.S. EPA, I979a).
2,4-Oinitrotoluene (2,4-ONT) has a melting point of 71°C, a boiling
point of 300°C with decomposition, and a solubility in water of 270 mg/1
at 22°C. It is readily soluble in ether, ethanol, and carbon disulfide
(U.S. EPA, 1979a).
Production in 1975 was 273 x 10 tons/year for the 2,4- and
2,6-isomers combined (U.S. EPA, 1979a). 2,4-Oinitrotoluene is an ingredient
in explosives for commercial and military use, a chemical stabilizer in the
manufacture of smokeless powder, an intermediate in the manufacture of tol-
uene diisocyanates used in the production of urethane polymers, and a raw
material for the manufacture of dye-stuffs. Dinitrotoluenes are relatively
stable at ambient temperatures (U.S. EPA, I979a). For additional infor-
mation regarding the dinitrotoluenes in general, the reader is referred to
the EPA/ECAO Hazard Profile on Oinitrotoluenes (U.S. EPA, 1979b).
II. EXPOSURE
A. Water
Data on concentration levels of 2,4-ONT in water were not avail-
able. Dinitrotoluene waste products are dumped into surface water or sewage
by industries that manufacture dyes, isocyanates, polyurethanes and muni-
tions (U.S. EPA, 1979a).
8. Food
According to the U.S. EPA (1979a), the likelihood of 2,4-dinitro-
•
toluene existing in food is minimal since it is not used as a pesticide or
herbicide.
,n/ ~f
-------
The U.S. EPA (1979a) has estimated the weighted average biocon-
centration factor for 2,4-dinitrotoluene to be 5.5 for edible portions of
fish and shellfish consumed by Americans. This estimate was based on the
octanol/water partition coefficient.
C. Inhalation
Exposure to dinitrotoluene by inhalation is most Likely to occur
occupationally (U.S. EPA, 1979a). However, pertinent data could not be
located in the available literature on atmospheric concentrations of dini-
trotoluene; thus, possible human exposure cannot be estimated.
III. PHARMPCOKINETICS
A. Absorption
The absorption of u-labeled isomers of dinitrotoluene after
oral administration to rats was essentially complete within 24 hours, with
60 to 90 percent of the dose being absorbed. The 2,4-and 3,4-isomers were
absorbed to a greater extent than the 3,5- and 2,5-isomers, which in turn
were absorbed_to a greater extent than the 2,3- and 2,6-isomers (Hodgson, et
al. 1977). From toxicity studies, 2,4-Oinitrotoluene is known to be ab-
sorbed through the respiratory tract and skin (U.S. EPA, I979a).
B. Distribution
Tissue/plasma ratios of radioactivity after administration of
C-labeled dinitrotoluene (DNT) to rats indicated retention of C
2,4-QNT in both liver and kidneys but not in other tissues (Hodgson, et al.
1977). A similar experiment with tritium-labeled 2,4-dinitrotoluene
(rl-2,4-QNT) in the rat showed relatively high amounts of radioactivity
remaining in adipose tissue, skin, and liver seven days after administration
(Mori, et al. 1977).
17* 3 0"u "
-------
C. Metabolism
No studies characterizing the metabolism of 2,4-dinitrotoluene in
mammals are available. However, on the basis of a comparison of the metab-
olism of 2,4-dinitrotoluene and 2,4,6-trinitrotoluene in microbial systems,
and the metabolism of 2,4,6-trinitrotoluene in mammals, the U.S. EPA (1979a)
speculated that the metabolites of 2,4-dinitrotoluene in mammals would be
either toxic and/or carcinogenic.
D. Excretion
14
In studies involving oral administration of C-dinitrotoluene or
H-2,4-dinitrotoluene to rats (Hodgson, et al. 1977; Mori, et al, 1977),
elimination of radioactivity occurred mainly in urine and feces. No radio-
activity was recovered in the expired air. About 46 percent of the admin-
istered dose in the latter study was excreted in the feces and urine during
the seven days following administration.
IV. EFFECTS
A. Carcinogenic!ty
2,4-Dinitrotoluene fed to rats and mice for two years produced
dose-related increases in fibromas of the skin in male rats and fibro-
adenomas of the mammary gland in female rats. These tumors were benign. No
statistically significant reponse was noted in mice (Natl. Cancer Inst.,
1978).
In a second bioassay of rats and mice fed 2,4-dinitrotoluene for
two years, the findings in rats included a significant increase of hepato-
*
cellular carcinomas and neoplastic nodules in the livers of females, a sig-
nificant increase of mammary gland tumors in females, and a suspicipus in-
crease of hepatocellular carcinomas of the liver in males. Mice had a
highly significant increase of kidney tumors in males (Lee, et al. 1978).
93-7
-------
8. Mutagenicity
2,4-Oinitrotoluene was mutagenic in the dominant lethal assay and
in Salmonella typhimurium strain TA 1535 (Hodgson, et al. 1976). Cultures
of lymphocytes and kidney cells derived from rats fed 2,4-dinitrotoluene had
significant increases in the frequency of chromatid gaps but not in trans-
locations or chromatid breaks (Hodgson, et al. 1976).
The mutagenic effects of products from ozonation or chlorination of
2,4-dinitrotoluene and other dinitrotoluenes were negative in one study
(Simmon, et al. 1977) and, of products from ozonation alone, were ambiguous
in another study (Cotruvo, et al. 1977).
C. Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the available literature.
0. Chronic Toxicity
Chronic exposure to 2,4-dinitrotoluene may produce liver damage,
jaundice, methemoglobinemia and reversible anemia with reticulocytosis in
humans and animals (Linen, 1974; Key, et al. 1977; Proctor and Hughes, 1978;
Kovalenko., 1973).
E. Other Relevant Information
Animals were more resistant to the. toxic effects of 2,4-dinitro-
toluene administered in the diet when given diets high in fat (Clayton and
Baumann, 1944, 1948; Shils and Goldwater, 1953) or protein (Shils and
Goldwater, 1953).
Alcohol has a synergistic effect on the toxicity of 2,4-dinitrotoluene
(Friedlander, 1900; McGee, et al. 1942).
73 -8
-------
In subacute studies (13 weeks) of several species, 1,2,4-dinitrotoluene
caused methemoglobinemia, anemia with reliculocytasis, gliosis, and demyeli-
nation in the brain, and atrophy with aspermatogenesis of the testes (Ellis
et al., 1976).
V. AQUATIC TOXICITY
A. Acute Toxicity
The only toxicity data available for the effects of 2,4-dinitro-
toluene in aquatic animals are from a single freshwater fish and inverte-
brate species (U.S. Army, 1976). A 96-hour static LCcn value for the fat-
j\j
head minnow (Pimephales promelas) was reported as 31,000 pg/1 and a 48-hour
static LC5Q value for the cladoceran, Daohnia magna, was reported as
35,000 ;jg/l.
8. Chronic Toxicity and Plant Effects
Pertinent data could not be located in the available literature.
C. Residues
A bioconcentration factor of 19 was obtained for 2,4-dinitrotoluene.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived by U.S. EPA
(1979a), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria may be changed.
A. Human
Based on the induction of fibroadenomas of the mammary gland in
female rats (Lee, et al. 1978), and using the "one-hit" model, the U.S. EPA
s
(1979a) has estimated levels of 2,4-dinitrotoluene in ambient water which
will result in specified risk levels of human cancer:
, ~| O> -
fV ) l
73-?
-------
Exposure Assumptions Risk Levels and Corresponding Criteria
(per day)
0 1C.-7 10-* 10-5
Consumption of 2 liters of drink- 7.4 ng/1 74.0 ng/1 740 ng/1
ing water and 18.7 grams fish and
shellfish.
Consumption of fish and shellfish .156 jjg/1 1.56 jjg/1 15.6/jg/l
only.
The American Conference of Governmental Industrial Hygienists
(1978) recommends a TLV-time-weighted average for 2,4-dinitrotoluene of 1.5
mg/m with a short term exposure limit of 5 mg/m .
8. Aquatic
A criterion has been drafted for protecting freshwater life from
the toxic effects of 2,4-dinitrotoluene. A 24-hour average concentration of
620 jug/1, • not to exceed 1,400 ;jg/l, has been proposed. Data are insuffi-
cient for drafting a marine criterion.
-------
2,4-DINITROTOLUENE
REFERENCES
American Conference of Governmental Industrial Hygienists.
1978. TLV'sR: Threshold limit values for chemical
substances and physical agents in the workroom environment
with intended changes for 1978.
Clayton, C.C., and C.A. Baumann. 1944. Some effects of diet
on the resistance of mice toward 2,4-dinitrotoluene. Arch.
Biochem. 5: 115.
Clayton, C.C., and C.A. Baumann. 1948. Effect of--fa-fe-and
calories on the resistance of mice to 2,4-dinitrotoluene.
Arch. Biochem. 16: 415.
Cotruvo,, J.A., et al. 1977. Investigation of mutagenic
effects of products of ozonation reactions in water. Ann.
N.Y. Acad. Sci. 298: 124.
Friedlander, A. 1900. On the clinical picture of poisoning
with benzene and toluene derivatives with special reference
to the so-called anilinism. Neurol. Centrlbl. 19: 155.
Hodgson, J.R., et al. 1976. Mutation studies on 2,4-dini-
trotoluene. Mutat. Res. 38: 387. (Abstract from the 7th
Annu. Meet. Am. Environ. Mutagen Soc., Atlanta, March 12-15).
Hodgson, J.R., et al. 1977. Comparative absorption, distri-
bution, excretion, and metabolism of 2,4,6-trinitroluene
(TNT) and isomers of dinitrotoluene (DNT) in rats. Fed.
Proc. 36: 996.
Key, M.M., et al. (eds.) 1977. Pages 278-279 Ijn:
Occupational diseases: A guide to their recognition. U.S.
Dept. Health, Edu. Welfare. U.S. Government Printing Office,
Washington, D.C.
Kovalenko, I.I. 1973. Hemotoxicity of nitrotoluene in rela-
tion to number and positioning of nitro groups. Farmakol.
Toxicol. (Kiev.) 8: 137.
Lee, C.C., et al. 1978. Mammalian toxicity of munition com-
pounds. Phase III: Effects of life-time exposure. Part I:
2,4-Dinitrotolune. U.S. Army Med. Res. Dev. Command. Con-
tract No. DAMD-17-74-C-4073. Rep. No. 7, September.
-------
Linch, A.L. 1974. Biological monitoring for industrial ex-
posure to cyanogenic aromatic nitro and amino compounds. Am.
Ind. Hyg. Assoc. Jour. 35: 426.
McGee, L.C., et al. 1942. Metabolic disturbances in workers
exposed to dinitrotoluene. Am. Jour. Dig. Dis. 9: 329.
Mori, M., et al. 1977. Studies on the metabolism and tox ic-
ity of dinitrotoluenes — on excretion and distribution of
tritium-labelled 2,4-dinitrotoluene (3H-2,4-DNT) in the
rat. Radioisotopes 26: 780.
National Cancer Institute. 1978. Bioassay of 2,4-dinitro-
toluene for possible carcinogenicity. Carcinogenesis Tech.
Rep- Ser. No. 54. U.S. DHEW (NIH) Pufal. No. 78-1360. U.S.
Government Printing Office, Washington, D.C.
Proctor, N.H., and J.P. Hughes. 1978. Chemical hazards of
the workplace. J.B. Lippincott Co., Philadelphia/Toronto.
Shils, M.E., and L.J. Goldwater. 1953. Effect of diet on
the susceptibility of the rat to poisoning by 2,4-dinitro-
toluene. Am. Med. Assoc. Arch. Ind. Hyg. Occup. Med. 8:
262..
Simmon, V.F., et al. 1977. Munitions wastewater treatments:
dose chlorination or ozonation of individual components pro-
duce microbial mutagens? Toxicol. Appl. Pharmacol. 41: 197.
(Abstract from the 16th Annu. Meet. Soc. Toxicol., Toronto,
Can., March 27-30) .
U.S. Army Research and Development Command. 1976. Toxicity
of TNT wastewater (pink water) to aquatic organisms. Final
Report, Contract DAMD 17-75-C-5056. Washington, D.C.
Q.S. EPA. 1979a. Dinitrotoluene: Ambient Water Quality Cri-
teria. (Draft).
U.S. EPA. 1979b. Dinitrotoluene: Hazard Profile. Environ-
mental Criteria and Assessment Offica.
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No. 94
2,6-Dinitrotoluene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
9Y-.
-------
Ill
2,6-Dinitrotoluene
SUMMARY
2,6-Dinitrotoluene is known to cause methemoglobinemia in
cats, dogs, rats, and mice. When administered orally to these
animals for a maximum of thirteen weeks, the major effects seen
in addition to the blood effects were depressed spermatogenesis,
degeneration of the liver, bile duct hyperplasia, incoordination
and rigid paralysis of the hind legs, and kidney degeneration.
Positive results were obtained with mutagenicity testing in
a number of Salmonella typhimurium strains.
2,6-DNT has been found in tap water in the United States.
The nitro groups on the aromatic ring retard degeneration so
there is a potential for it to accumulate in the aquatic environ-
ment.
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Dinitrotoluene (U.S. EPA, 1979b) and a U.S. EPA
report entitled "Investigation of Selected Potential Environ-
mental Contaminants: Nitroaromatics" (1976).
2,6-Dinitrotoluene (2,6-DNT; CyHgNjO^; molecular weight
182.14) is a solid at room temperature. It is in the shape of
rhombic needles and is soluble in ethanol. Its melting point is
»
66°C and its density is 1.28 at lll'C (Weast, 1975).
A review of the production range (includes importation)
statistics for 2,6-dinitrotoluene (CAS. No. 606-20-2) which is
-------
listed in the initial TSCA Inventory (1979a) has shown that
between 50,000,000 and 100,000,000 pounds of this chemical were
produced/imported in 1977._/
Mixtures of the dinitrotoluene isomers are intermediates in
the manufacture of toluene diisocyanates, toluene diamines and
trinitrotoluene (Wiseman, 1972). Dinitrotoluene (both 2,4- and
2,6-) is an ingredient in explosives for commercial and military
use and is also used as a chemical stabilizer in the manufacture
of smokeless powder (U.S. EPA, 1979b).
II. EXPOSURE
A. Environmental Fate
Based on the photodecomposition of trinitrotoluene (TNT)
described by Burlinson et al. (1973), 2,6-dinitrotoluene would be
expected to react photochemically. Decomposition of 65% of the
TNT had occurred when the decomposition products were examined.
2,6-Dinitrotoluene would be expected to biodegrade to a
limited extent. The nitro groups retard biodegradation and
studies with soil microflora have shown that mono- and di-
substituted nitrobenzenes persist for more than 64 days
(Alexander and Lustigmann, 1966). McCormick _et_ _al_. (1976) and
Bringmann and Kuehn (1971) reported microbial degradation of
2,6-DNT by anaerobic and aerobic bacteria, respectively.
—/ This production range information does not include any ,
production/importation data claimed as confidential by the
person(s) reporting for the TSCA inventory, nor does it
include any information which would compromise Confidential
Business Information. The data submitted for the TSCA
Inventory, including production range information, are subject
to the limitations contained'in the Inventory Reporting
-------
B. Bioconcentration
In general nitroaromatic compounds do not have high biocon-
centration potential based on calculations using their octanol-
water partition coefficients. They are not expected to
biomagnify based on their water solubility (U.S. EPA, 1976).
C. Environmental Occurrence
2,6-Dinitrotoluene has been identified in tap water in the
United States (Kopfler and Melton, 1975). Its environmental con-
tamination would come almost exclusively from the chemical plants
where it is produced. It was detected in the water effluent from
a TNT plant in Radford, Virginia at concentrations of 3.39 to
56.3 ppm. It was also found in the raw waste of a DNT plant at
150 ppm. The raw effluent contained 0.68 ppm and the pond efflu-
ent 0.02 ppm (U.S. EPA, 1976).
III. PHARMACOKINETICS
2,6-Dinitrotoluene can enter the body through inhalation of
vapors or dust particles, ingestion of contaminated food, and
absorption through the skin (EPA, 1979b) . Hodgson _et_ _al_. (1977)
traced the pathway of * C labeled di- and tri-substituted nitro-
toluenes after oral administration of the compounds to rats. All
of the compounds were well absorbed with 60 to 90% absorption
after 24 hours. The radiolabel was found in the liver, kidneys
and blood but not in other organs; none was found in the expired
air indicating that the aromatic ring was not broken down through
metabolism of the compounds. Most of the labeled compounds were
Regulations (40 CFR 710).
W-5
-------
eliminated in the urine as metabolites; biliary excretion was
also an important elimination pathway.
IV. HEALTH EFFECTS
A. Carcinogenicity
No carcinogenicity testing of 2,6-DNT has been reported in
the literature. The National Cancer Institute conducted a bio-
assay to determine the carcinogenicity of 2,4-DNT by administer-
ing it to rats and mice in their diet. 2,4-DNT induced benign
tumors in male and female rats, however, the benign tumors were
not considered a sufficient basis for establishing carcinogen-
icity. The assay produced no evidence of carcinogenicity of the
compound in mice (NCI, 1978).
B. Mutagenicity
Simmon _et^ _al_. (1977) tested 2,6-dinitrotoluene for
mutagenicity in Salmonella typhimurium. Positive results were
obtained with strains TA1537, TA1538, TA98, and TA100, but not
TA1535. These results were obtained without metabolic activa-
tion.
C. Other Toxicity
1. Chronic
The subchronic toxicity of 2,6-dinitrotoluene was determined
by oral administration to dogs, rats, and mice for about 13
weeks. The primary effects were on red blood cells, the nervous
system, and the testes. Both dogs and rats had decreased mu^cu-
lar coordination primarily in the hind legs, rigidity in exten-
sion of the hind legs, decreased appetite, and weight loss. The
-------
mice experienced only the decreased appetite and weight loss.
All of the animals had methemoglobinemia, and anemia with reticu-
locytosis. The tissue lesions seen were extramedullary hemato-
poeisis in the spleen and liver, gliosis and demyelination in the
brain, and atrophy with aspermatogenesis in the testes (Ellis et
al., 1976>. Methemoglobinemia was also found in cats adminis-
tered 2,6-DNT (U.S. EPA, 1979b).
2. Acute
Oral LDSO's have'been reported for rats and mice. They are
180 mg/kg and 1,000 mg/kg respectively (Vernot et al., 1977). A
mixture of 2,4-DNT and 2,6-DNT was applied to the skin of rabbits
in a series of 10 doses over a two week period and no cumulative
toxicity was found (U.S. EPA, 1976).
VI. EXISTING GUIDELINES
The OSHA standard for 2,6-DNT in air is a time-weighted
average of 1.5 mg/m3 (39 PR 23540).
-------
BIBLIOGRAPHY
Alexander, M. and B.K. Lustigmann. Effect of chemical structure
on microbial degradation of substituted benzenes. J. Aor. Food.
Chem. 14(4), 410-41, 1966. (As cited in U.S. EPA, 1976).
Bringmann, G. and R. Kuehn. Biological decomposition of nitro-
toluenes and nitrobenzenes by Azotobacter Agilis. Gesundh.-Ing.,
92(9), 273-276, 1971. (As cited in U.S. EPA, 1976).
Burlinson, N.E. _et_ jal^. Photochemistry of TNT: investigation of
the "pink water" problem. U.S. NTIS AD 769-670, 1973. (As cited
in U.S. EPA, 1976).
Ellis, H.V., III j|t_ ^1^. Subacute toxicity of 2,4-dinitrotoluene
and 2,6-dinitrotoluene. Toxicol. Appl. Pharm. 37," 116, -1976.
Hodgson, J.R. et al. Comparative absorption, distribution,
excretion, and metabolism of 2,4,6-trinitrotoluene (TNT) and
isomers of dinitrotoluene (DNT) in rats. Fed. Proc. 36, 996,
1977.
Kopfler, F.C. and R.G. Melton. 1977. Human exposure to water
pollutants. In Advances in Environmental Science and Technology,
Vol. 3. Fate of Pollutants in the Air and Water Environments.
Part 2. Chemical and Biological Fate of Pollutants in the
Environment. Symposium at the 165th National American Chemical .
Society Meeting in the Environmental Chemistry Division. Phila-
delphia, PA. April 1975. John Wiley and Sons, Inc., New York.
McCormick, N.G. _et_ _al_. Microbial transformation of 2,4,6-trini-
trotoluene and other nitroaromatic compounds. Appl. Environ.
Microbiol. 31(6), 949-958, 1976.
National Cancer Institute. Bioassay of 2,4-dinitrotoluene for
possible carcinogenicity. PB-280-990, 1978.
National Institute of Occupational Safety and Health. Registry
of Toxic Effects of Chemical Substances, 1978.
Simmon, V.F. et al. Mutagenic activity of chemicals identified
in drinking water. Dev. Toxicol. Environ. Sci. 2, 249-258, 1977.
U.S. EPA. Investigation of Selected Potential Environmental
Contaminants: Nitroaromatics. PB-275-078, 1-976.
U.S. EPA. Toxic Substances Control Act Chemical Substance
Inventory, Production Statistics for Chemicals on the Non-Confi-
dential Initial TSCA Inventory, 1979a.
U.S. EPA. Ambient Water Quality Criteria: Dinitrotoluene.
PB-296-794, 1979b.
-------
Vernot, E.H. et_ _al^. Acute toxicity and' skin corrosion data for
some organic and inorganic compounds and aqueous solutions.
Toxicoi. Appl. Pharmacol. 42(2), 417-424, 1977.
Weast, R.C., ed. 1978. CRC Handbook of Chemistry and Physics.
CRC Press, Inc., Cleveland, Ohio.
Wiseman, P. 1972. An Introduction to Industrial Organic
Chemistry. Interscience Publishers, John-Wiley and Sons, Inc.,
New York.
y
-11 * 3-
*f r o J
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No. 95
Di-n-octyl Phthalate
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C, 20460
APRIL 30, 1980
^^^-j±M-
-yyw
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
DI-n-OCTYL PHTHALATE
' • Summary
Di-n-octyl phthalate has produced teratogenic effects following
i.p. injection, of pregnant rats. This same study has also indicated
some increased resorptions and fetal toxicity.
Evidence is not available indicating mutagenic or carcinogenic
effects of 'di-n-octyl phthalate.
Data pertaining to the aquatic toxicity of di-n-octyl phthalate
is not available.
. / /> z.—
) )w v
-------
DI-n-OCTYL PHTHALATE
I. INTRODUCTION
. This profile is based on the Ambient Water Quality Criteria Document
for Phthalate Esters (U.S. EPA, 1979a).
Di-n-octyl phthalate (OOP) is a diester of the ortho form of
benzene dicarboxylic acid. The compound has a molecular weight of
391.0, specific gravity of 0.978, boiling point of 220°C at 5 mm Hg,
and is insoluble in water.
DOP is used as a plasticizer in the production of certain plastics.
Current Production: 5.8 x 103 tons/year in 1977 (U.S. EPA, 1979a).
Phthalates have been detected in soil, air, and water samples; in
animal and human tissues, and in certain vegetation. Evidence from in
vitro studies indicates that certain bacterial flora may be capable of
metabolizing DOP to the monoester form (Engelhardt, et al» 1975). For
additional information regarding the phthalate esters in general, the
reader is referred to the EPA/ECAO Hazard Profile on Phthalate Esters
'(U.S. EPA 1979b).
II. EXPOSURE
Phthalate esters appear in all areas of the environment. Environmental
release of phthalates may occur through leaching of the compound from
plastics, volatilization from plastics, or the incineration of plastic
items. Sources of human exposure to phthalates include contaminated
foods and fish, dermal application, and parenteral administration by
use of plastic blood bags, tubings, and infusion devices (mainly DEHP
release). Relevant factors in the migration of phthalate esters from
packaging materials to food and beverages are: temperature, surface
area contact, lipoidal nature of the food, and length of contact (U.S.
EPA, I979a).
/ / fl s
^7
-------
Monitoring studies have indicated that most water phthalate concentrations
are in the ppm range, or 1-2 jug/liter (U.S. EPA, I979a). Industrial
air monitoring studies have measured air levels of phthalates from 1.7
to 66 mg/m3-(Milkov, at al. 1973).
Information on levels of OOP in foods is not available. Bio-
concentration factor is not available for OOP.
III. PHARMACOKINETICS
Specific information could not be located on the absorption.,
distribution, metabolism, or excretion of DOP. The reader is referred
to a general coverage of phthalate metabolism (U.S. EPA, 1979b).
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not be located in the available literature.
B. Mutagenicity
Pertinent data could not be located in the available literature.
C. Teratogenicity
Administration of DOP to pregnant rats by i.p. injection has
been reported to produce some teratogenic effects, although less so
than several other phthalates tested (Singh, et al. 1972).
D. Other Reproductive Effects
An increased incidence of resorption and fetal toxicity was
produced following i.p. injection of pregnant rats with.DOP (Singh, et
al. 1972).
E. Chronic Toxicity
Pertinent data could not be located in the available literature.
-------
V. AQUATIC TOXICITY
Pertinent data could not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S.
EPA (1979a), which are summarized below, have gone through the process
of public review; therefore, there is a possibility that these criteria
will be changed.
A. Human
Pertinent data concerning the acceptable daily intake
(ADI) level in humans of DOP could not be located in the available
literature.
Recommended water quality criterion level for protection
of human health is not available for DOP.
B. Aquatic
Pertinent data is not available pertaining to the aquatic
toxicity of di-n-octyl phthalate; therefore, no criterion could be
drafted.
-------
DI-N-OCTYL PHTHALATE
Engelhardtj • G., at al. 1975, The microbial rnetabolism of di-n-butyl phtha-
late. and related dialkyl phthalates. Bull. Environ. Contam. Toxicol.
13: 342.
Milkov, L.E., at al. 1973. Health status of workers exposed to phthalata
plasticizers in the manufacture of artificial leather and films based on PVC
resins. Environ. Health Perspect. (Jan.): 175.
Singh, A.R., st al. 1972. Teratogenicity of phthalate esters in rats.
Jour. Pharm. Sci. 61: 51.
U.S. EPA. 1979a. Phthalate Esters: Ambient Water Quality Criteria. (Draft)
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Phthalate
Esters: Hazard Profile. (Draft)
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No. 96
1,2-Dlphenylhydrazine
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
1,2-diphenylhydrazine and has found sufficient evidence to
indicate that this compound is carcinogenic.
16-3
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1, 2-DIPHENYLHYDRAZINE
Summary
The adverse effects of exposure to 1,2-diphenylhydrazine in-
clude damage to both the kidney and liver. Acute LD5Q values have
ranged from 300 to 960 rag/kg in experimentally dosed rats. No data
concerning the absorption, distribution, or excretion of the 1,2-
diphenylhydrazine have been generated. Benzidine has been identi-
fied as a metabolite in urine of rats exposed to the chemical.
Diphenylhydrazine is carcinogenic in both sexes of rats and in fe-
male mice.
The only aquatic toxicity data for diphenylhydrazine are for
freshwater organisms. Acute toxicity levels of 270 and 4,100 ug/3,'
were reported for bluegill and Daphnia magna, respectively, and a
single chronic value of 251 jag/1 was reported for Daphnia magna.
-------
1,2-DIPHENYLHYDRAZINE
I. INTRODUCTION
This profile is based primarily on the Ambient Water Quality
Criteria Document for Diphenylhydrazine.
Diphenylhydrazine (DPH) has a molecular weight of 184.24, a
melting point of 131°C and a boiling point of 220°C. DPH is slight-
ly soluble in water and is very soluble in benzene, ether and
alcohol.
The symmetrical isomer of diphenylhydrazine, 1,2-diphenyl-
hydrazine is used ia the synthesis of benzidine for use in dyes,
and in the synthesis of phenylbutazone, an anti-arthritic drug.
The reported commercial production of more than 1000 pounds
annually, as of 1977, is most lively an underestimation of the
total amount of diphenylhydrazine available. Diphenylhydrazine is
produced .in several synthetic processes as an intermediate and a
contaminant, but there is no way of estimating these substantial
quantities.
II. EXPOSURE
A.. Water
The highest reported concentration of 1,2-diphenylhydra-
zine in drinking water is one ug/1 (U.S. EPA, 1975).
B. Food
The U.S. EPA (1979) has estimated the weighted average
bioconcentration factor for diphenylhydrazine to be 29 for the
,-
edible portions of fish and shellfish consumed by Americans. This
estimate is based on the octanol/water partition coefficient of
diphenylhydrazine.
-------
C. Inhalation
Pertinent data could not be located in the available
literature.
III. PHARMACOKINETICS
Pertinent information could not be located in the available
literature regarding absorption, distribution and excretion.
A. Metabolism
- Various metabolites, including the known carcinogen ben-
zidine, -have been identified in the urine of rats. 1,2-Diphenylhy-
drazine was administered orally (200,400 mg/kg), intraperitoneally
(200 mg/kg), intratracheally (5r10 mg/kg) and intravenously (4,8
mg/kg). The metabolites detected were not dependent upon the base
or route of administration (Williams, 1959). 4
IV. EFFECTS
A. Carcinogenicity
Diphenylhydrazine has been identified as producing
significant increases in hepatocellular carcinoma at 5 ug/kg/day
and 18.3 ug/kg/day in both sexes of rats; Zymbal's gland squamous-
cell tumors in male rats at 13.8 ug/kg/day; neoplastic liver
nodules in female rates at 7.5 ug/kg/day; and hepatocellular
carcinomas in female mice at 3.75 ug/kg/day (NCI, 1978). Diphenyl-
hydrazine was not carcinogenic in male mice.
B. Mutagenicity
No microbial mutagenetic assays witir'or without metabolic
activation have been conducted on diphenylhydrazine. An intraperi-
toneal dose of 100 mg/kg had an inhibitory effect on the incorpora-
tion of ( H)-thymidine into testicular DNA of experimental mice
(Sieler, 1977).
76-7
-------
C. Teratogenicity
Pertinent information could not be located in the avail-
able literature.
D. Toxicity
One study reported an LDcg of 959 mg/kg for male rats ad-
ministered DPH as a five percent solution. In the Registry of
Toxic Effects of Chemical Substances, the oral LD5Q is listed as
301 mg/kg. Neoplasms resulted in rats after 52 weeks with a total
dose of 16- g/kg DPH administered subcutaneously. In 2 mice
studies, neoplasms resulted after 25 weeks with topical application
of 5280 mg/kg and after 38 weeks with subcutaneous injection of
8400 mg/kg DPH. Liver and kidney damage have been implicated in
the adverse effects of diphenylhydrazine chronically administered.
to rats. No experimental or epidemiological studies have been con-
ducted on the effects of diphenylhydrazine in humans.
V. AQUATIC TOXICITY
A. Acute
Ninety-six-hour LCen values for freshwater organisms
have been reported as 270 pg/1 for the bluegill, Lepomis macro-
chirus, and the 48-hour LCcg for the cladoceran, Daphnia magna,
is 4,100 ug/1 (U.S. EPA, 1978). No toxicity data for marine
animals could be located in the available literature.
B. Chronic
A chronic value of 251 ^ag/1 has been obtained for the
freshwater cladoceran, Daphnia Magna (U.S. EPA, 1978). No chronic
»
tests of diphenylhydrazine ace available for marine organisms.
-------
C. Plants
Pertinent data could not be located in the available
literature.
0. Residues
Based on the octanol/water partition coefficient of 870
for 1,2-diphenylhydrazine, a bioconcentration factor of 100 has
been estimated for aquatic organisms with a lipid content of 8 per-
cent.
VI. EXISTING GUIDELINES AND STANDARDS
Neither .the human health nor aquatic criteria derived by
U.S. EPA (1979), which are summarized below have gone through
the process of public review; the'refore, there is a possibility
that these criteria may be changed.
A. Humans
*
No standards were found for humans exposed to diphenylhy-
drazine in occupational or ambient settings.
Recommended draft criteria for the protection of human
health are as follows:
Exposure Assumptions Risk Levels and Corresponding Criteria
0 10f7 lOf6 10_~5
2 liters of drinking water 0 4 ng/1 40 ng/1 400 ng/1
and consumption of 18.7
grams fish and shellfish (2)
Consumption of fish and 0 .019 ug/1 0/19 ug 1.9
shellfish only.
~*} / t V "
-------
B. Aquatic
Criterion to protect freshwater aquatic life from toxic
effects of diphenylhydrazine have been drafted as a 24-hour aver-
age concentration of 17 ug/1 and not to exceed 38 ug/1 at any
time.
./ / ft
*i) I • /*"
-------
DIPHENYLHYDRAZINE
REFERENCES
NCI Publication NO. (NIH) 78-1342. 1978. Bioassay of hydrazoben-
zene for possible carcinogenicity.
Sieler, J.P. 1977. Inhibition of testicular DNA synthesis by
chemical rautagens and carcinogens.. Preliminary results in the
validation of a novel short term test. Mutat. Res. 46: 305.
U.S. EPA. 1375. Primary assessment of suspected carcinogens
in drinking water. Report to Congress.
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. Contract No. 68-01-4646.
U.S. EPA. 1979. Diphenylhydrazine: Ambient Water Quality Cri-
teria. (Draft).
Williams, R. 1959. Detoxication Mechanisms. New York: John
Wiley and Sons. p. 480.
-------
No. 97
Disulfoton
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
Disclaimer Notice
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.
-------
DISULFOTON
Summary
Oisulfotcn is a highly toxic organophosphorous insecticide used on many
agricultural crops, the human oral LDLQ is estimated at 5 'mg/kg body
weight. Exposure results in central nervous system toxicity. The LD5Q
for several animal species ranges from 3.2 to 6 mg/kg. Carcinogenic, muta-
genic, and teratogenic studies were not found in the available literature.
The occupational threshold limit value for disulfoton is 10 ug/m5. Allow-
able residue tolerances for agricultural commodities range from 0.3 to 11.0
ppm.
Although disulfoton is considered toxic to aquatic organisms, specific
studies on aquatic toxicity were not located in the available literature.
I I *] //
') I A. * •
77-y
-------
I. INTRODUCTION
Disulfoton is a highly toxic organophosphorous insecticide used in
agriculture to control mainly sucking insects such as aphids and plantfeed-
ing mites. Small amounts are used on home plants and gardens in the form of
dry granules with low content of active ingredient (U.S. EPA, 1974). Disul-
foton was introduced in 1956 by Bayer Leverkusen (Martin and Worthing,
1974), and today it is produced by only one U.S. manufacturer, Mobay Chemi-
cal Corporation, at its Chemogro Agricultural Division in Kansas City, Misr
souri (Stanford Research Institute (SRI), 1977). An estimated 4500 tonnes
were • produced in 1974 (SRI, 1977). Disulfoton is made by interaction of
0,0-diethyl hydrogen phosphorodithioate and 2-(2-ethylthio)ethylchloride
*
(Martin and Worthing, 1974). Disulfoton is slightly soluble in water and
readily soluble in most organics. Its overall degradation constant is
0.02/day. Disulfoton has a bioconcentration factor of 1.91 and an octanol/
water partition coefficient of 1.0 (see Table 1).
II. EXPOSURE
A. Water
Disulfoton concentrations are highest during the production pro-
cess. Concentrated liquid wastes are barged to sea (150-200 mi; 240-320
km), and sludge wastes are disposed in landfills.
Agricultural application rates normally range from 0.25 to 1.0
Ib/acre (0.28-1.1 kg/ha); to a maximum of 5.0 Ib/acre (5.5 kg/ha) for some
uses. Target crops include small grains, sorgum, corn, cotton, other field
crops; some vegetable, fruit and nut crops; ornamentals (Fairchild, 1977).
Disulfoton is considered stable in groundwater. Less than 10 per-
cent is estimated to decompose in five days (equivalent to 50-250 mi; 80-400
tjn IT t
* It X -!»'
-------
TABLE 1. PHYSICAL AND CHEMICAL PROPERTIES OF OISULFQTON
Synonyms: 0,0-Qiethyl S-(2-(ethylthio)ethyl) phosphorodithioate;
0,0-Oiethyl S-(2-(ethylthio)ethyl) dithiophosphate; Thiodemeton;
Frumin; Glebofos; Ethylthiometon B; VUAgT 1964; Di-Syston G;
Disipton; ENT-23437; Ethyl thiometon; VUAgT 1-4; Bay 19639; M 74
[pesticide]; Ekatin TO; CAS Reg. No. 298-Q4-4; M 74 (VAN); Bayer
19639; Oi-Syston; Dithiodemeton; Oithiosystox; Solvirex; Frumin
AL; Frumin G
Structural Formula:
Molecular Weight: 274.4
Description: Colorless oil; technical product is a dark yellowish oil;
readily soluble in most organics
2Q
Specific Gravity and/or Density:, d, = 1.144
Melting and/or Boiling Points: bp 620Q at 0.01 mm Hg
Stability: Relatively stable to hydrolysis at pH below 8
Overall degradation rate constant (0.02/day)
Solubility (water): 25 ppm at room temp.
sediment . .5
H20 ' 1
Vapor Pressure: 1.8 x 10-4 mm Hg at 2QQC
Bioconcentration Factor (BCF) and/or
Octanol/water partition coefficient (Kow): • KQW = 1.91
BCF =1.0
Source: Martin and Worthing, 1974; Fairchild, 1977; Windholz, 1976;
U.S. EPA, 1980; Berg, et al. 1977.
,' | ~\ f
T^&*^
-------
km) in a river environment. Decomposition in a lake environment is estimat-
ed to be near 90 percent in one year (U.S. EPA 1980). —- ""• -" ~~r -' -
B. Food
In a study by Van Dyk and Krause (1978), disulfoton was applied as
a granular formulation at 2 g/m length in rows during cabbage planting (5
percent active ingredients, rows one meter apart, plants 0.5 meters apart).
The disulfoton sulphone concentration reached a maximum in 18 to 32 days and
decreased to between 0.3 and 6.4 mg/kg 52 riays after application. The cab-
bage residue of disulfoton at harvest time was below the maximum limit of
0.5 mg/kg.
Disulfoton applied at about 1.5 kg/10 cm-ha (hectare slice) per-
•
sisted for the first week, and residue levels declined slowly the following
week. After one month, only 20 percent of the amount applied was found.
Disulfoton was not found to translocate into edible parts of lettuce,
onions, and carrots (less than 5 ppb), but was present at about 20 ppb in
the root system of lettuce (Belanger and Hamilton, 1979).
C. Inhalation and Dermal
Data are not available indicating the number of people subject to
inhalation or dermal exposure to disulfoton. The primary human exposure
would appear to occur during production and application. The U.S. EPA
(1976) listed the frequency of illness, by occupational groups caused by
exposure to organophosphorous pesticides. In 1157 reported cases, most ill-
nesses occurred among ground applicators (229) and mixer/loaders (142); the
lack of or refusal to use safety equipment, was a major factor of this con-
tamination. Other groups affected were gardeners (101), field workers ex-
posed to pesticide residues (117),-nursery and greenhouse workers (75), soil
fumigators in agriculture (29), equipment cleaners and mechanics (28), trac-
? 7-7
-------
tor drivers and irrigators (23), workers exposed to pesticide drift (22),
.pilots (crop dusters) (17), and flaggers for aerial application (6). Most
illnesses were a result of carelessness, lack of knowledge of the hazards,
and/or lack of safety equipment, under dry, hot conditions, workers tended
not to wear protective clothing. Such conditions also tended to increase
pesticide levels and dust on the crops.
III. PHARMACOKINETICS
A. Absorption, Distribution, and Excretion
Pertinent data could not be located in the available literature.
B. Metabolism
•
Oisulfoton is metabolized in plants to sulfoxide and sulfone and
the corresponding derivatives of the phosphorothioate and demeton-S. This
is also the probable route in animals (Martin and Worthing, 1974; Menzie
1974; Fairchild, 1977).
IV. EFFECTS
A. Carcinogenic!ty, Mutagenicity and Teratogenicity
Pertinent data could not be located in the available literature.
8. Chronic Toxicity and Other Relevant Information
Oisulfoton is highly toxic to all terrestrial and aquatic fauna.
Human oral LD^ is estimated to be 5 mg disulfoton per kilogram body
weight (5 mg/kg). The symptoms produced by sublethal doses are typical of
central and peripheral nervous-system toxicity (Gleason, et al. 1969). The
reported LD^Q concentrations for other species are summarized below (Fair-
child, 1977).
-*f) Si 2 "•
-------
Species Exposure Route LD5Q (mg/kg)
rat oral 5
rat dermal 6
rat intraperitoneal 5.4
rat intravenous 5.5
mouse oral 5.5
mouse intraperitoneal 7
bird . oral 3.2
Rats survived for 60 days at 0.5 mg/kg/day (Martin and Worthing 1974). The
no-effect level in the diet was 2 ppm for rats and 1 ppm for dogs (Fair-
child, 1977).
In rats, single injections of 1.2 mg disulfoton per kg body weight
caused 14 percent reductions of hippocampal norepinephrine within 3 hours of
exposure. Norepinephrine returned to control levels within 5 days (Holt and
Hawkins, 1978). In female chicks administered with disulfoton intraperito-
neally (single dose 8.6 mg/kg), the total lipid content of the sciatic
nerve, kidney and skeletal muscles increased whereas that of the brain and
spinal cord remained the same or decreased. When female chicks were orally
administered with disulfoton (0.29 mg/kg daily for 71 days), the total lipid
content in all the organs except the liver and sciatic nerves decreased.
Although degenerative changes were indicated in both exposure studies, no
adverse, effect on the growth of chicks was noted (Gopel and Ahuja, 1979).
Disulfoton applied at 1 to 1.5 kg/ha very markedly decreased the
populations of soil bacteria (Tiwari, et al. 1977). "
V. AQUATIC TOXICITY
The 96-hour Tl_m (equivalent to a 96-hour 1X50) for fathead
minnows was found to be 2.6 mg/1 in hard water and 3.7 mg/1 in soft water.
77-?
-------
Both tests were conducted at 25°C. The corresponding value for bluegilis
is estimated to be Q.07 mg/1 (McKee and Wolf, 1963).
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The occupational threshold limit value for air has been estab-
lished as 100 Ajg/m'. Established residue tolerance for crops range from
0.3 to 12.0 ppm; 0.75 ppm for most (Fairchild, 1977).
B. Aquatic
Pertinent data could not be located in the available literature.
-------
REFERENCES
Belanger, A. and H.A. Hamilton. 1979. Determination of disulfpton and per-
methrin residues in an organic soil and their translocation into lettuce,
onion and carrot. Jour. Environ. Sci. Health. 814: 213.
Berg, G.L., et al. (ed.) 1977. Farm Chemicals Handbook. Meister Publish-
ing Company, Willoughby, Ohio.
Fairchild, E.J., (ed.) 1977. Agricultural chemicals and pesticides: A
subfile of the NIOSH registry of toxic effects of chemical substances., U.S.
Dept. of HEW, July.
Gleason, M.N., et al. 1969. Clinical Toxicology of Commercial Products.
Acute Poisoning, 3rd ed.
Gopal, P.K. .and S.P. Ahuja. 1979. LLpid and growth changes in organs of
chicks Gallus domesticus during acute and chronic toxicity with disyston and
folithion.
Holt, T.M. and R.K. Hawkins. 1978. Rat hippocompel norepinephrine response
to cholinesterase inhibition. Res. Commun. Chem.. Pathol. Pharmacol 20: 239.
Martin and Worthing, (ed.) 1974. Pesticide Manual, 4th ed. p. 225
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria. 2nd ed. Cali-
fornia State Water Quality Control Board. Publication 3-A.
Menzie, C.M. 1974. Metabolism of Pesticides: An Update. U.S. Dept. of the
Interior Special Scientific Report — Wildlife No. 184, Washington, D.C.
Stanford Research Institute. 1977. Directory of Chemical Producers. Menlo
Park, California.
Tiwari, J.K., et al. 1977. Effects of insecticides on microbial flora of
groundnut field soil. Ind. Jour. Micro. 17: 208.
U.S. EPA. 1974. Production, Distribution, Use, and Environmental Impact
Potential of Selected Pesticides. Report No. EPA 540/1-74-001. U.S. Envi-
ronmental Protection Agency, Office of Water and Hazardous Materials, Office
of Pesticide Programs.
U.S. EPA. 1976. Organophosphate Exposure from Agricultural Usage, EPA 600/
1-76-025.
U.S. EPA. 1980. Aquatic Fate and Transport Estimates for Hazardous Chemi-
cal Exposure Assessments. Environmental Research Laboratory, Athens^ Geor-
gia.
Van Dyk, L.P. and M. Krause 1978. Persistence and efficacy of disulfoton
on Cabbages. Phytophylactica 10: 53.
Windholz, M., (ed.) 1976. The Merck Index, 9th ed. Merck and Co., Inc.,
Rahway, New Jersey.
-------
No. 98
Endosulfan
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
L^^^^^,
• 4) J->
-------
ENOOSULFAN
Summary
Endosulfan is an insecticide and is a member of the organochlorocyclo-
diene insecticides. Endosulfan does not appear to be carcinogenic, mutagen-
ic or teratogenic. In humansr chronic toxic effects have not been observed
when endosulfan has been properly handled occupationally. Chronic feeding
of endosulfan to rats and mice produced kidney damage, parathyroid hyperpla-
sia, testicular atrophy, hydropic change of the liver, and lowered survival.
Oral administration of endosulfan to pregnant rats increased fetal mortality
and resorptions. Sterility can be induced in embryos in sprayed bird eggs.
At very high levels of acute exposure, endosulfan is toxic to the central
nervous system. The U.S. EPA has calculated an ADI of 0.28 mg based on s
NOAEL of 0.4 mg/kg for mice in a chronic feeding study. The ADI established ;
by the food and Agricultural Organization (1975) and World Health Organiza-
tion is 0.0075 mg/kg.
Ninety-six hour LC5Q values ranged from 0.3 to 11.0 ug/1 for five
freshwater fish; from 0.09 to 0.6 ug/1 for five saltwater fish in 48- or 96-
hour tests; from 0.04 to 380 ug/1 (EC50 and t-C5Q) for seven saltwater
invertebrate species; and from 62 to 166 pg/1 for Daphnia maqna (48-hour
LC3Q). In the only chronic aquatic study involving endosulfan, no adverse
effects on fathead minnows were observed at 0.20 jug/1.
-------
I. INTRODUCTION
Endosulfan (6,7,8,9,10,10-hexachloro-l,5,5a,6,9,9a-hexahydro-6,9-
methano-2,4,3-benzodioxathiepin-3-oxide; CgClgHgO,S; molecular
weight 406.95) is a light to dark brown crystalline solid with a terpene-
like odor. Endosulfan is a broad spectrum insecticide of the group of poly-
cyclic chlorinated hydrocarbons called cyclodiene insecticides. It also has
uses as an acaricite. It has a vapor pressure of 9 x 10" mm Hg at 80
degrees centigrade. It exhibits a solubility in water of 60 to 150 pg/1 and
is readily soluble in organic solvents (U..S. EPA, 1979). The trade names of
endosulfan include Beosit, Chlorithiepin, Cyclodan, Insectophene, Kop-Thio-
dan, Malix, Thifor, Thisnuml, Thioden, and. Thionex (Berg, 1976).
Technical grade endosulfan has a purity of 95 percent and is composed
of a mixture of two stereoisomers. referred to as alpha-endosulfan and beta- 4
endosulfan or I and II. These isomers are present in- a ratio of 70 parts
alpha-endosulfan to 30 parts beta-endosulfan. Impurities consist mainly of
the degradation products and may not exceed 2 percent endosulfandiol and 1
percent endosulfan ether (U.S. EPA, 1979).
Production: three million pounds in 1974 (U.S~ EPA, 1979).
Endosulfan is presently on the Environmental Protection Agency's re-
stricted list. However, significant commercial use for insect control on
vegetables, fruits, and tobacco continues (U.S. EPA, 1979).
Endosulfan is stable to sunlight but is susceptible to oxidation and
the formation of endosulfan sulfate in the presence of growing vegetation
(Cassil and Drummond, 1965). Endosulfan is readily adsorbed and absorbed by
sediments (U.S. EPA, 1979). It is metabolically converted by microorgan-
isms, plants, and animals to endosulfan sulfate, endosulfandiol, endosulfan
ether, endosulfan hydroxyether and endosulfan lactone (Martens, 1976; Chopra
-------
and Mahfouz, 1977; Gorbach, et al. 1968; Miles and May, 1979).. The end-pro-
duct, endosulfan lactone, disappears quickly once formed. Accumulation of
endosulfan sulfate may be favored in acidic soils (Miles and Moy, 1979).
II. EXPOSURE '
A. Water
Endosulfan has been detected in water samples from some of the
streams, rivers, and lakes in the United States and Canada and in Ontario
municipal water supplies. The maximum concentration of endosulfan monitored
"in'municipal water was 0.083 jug/1,, which was found in Ontario- municipal
water samples but 68 jjg/1 has been measured in irrigation run-off (U.S. EPA,
1979). Endosulfan contamination of water results from agricultural runoff,
industrial effluents, and spills. One serious accidental industrial dis-
charge in Germany in 1969 caused a massive fishkill in the Rhine River.
Most of the river water samples contained less than 500 ng/1 endosulfan.
Residues in run-off water from sprayed fields can be as high as 220 jug/1
(U.S. EPA, 1979).
B. Food
An average daily intake (ADI) less than or equal to 0.001 mg of
endosulfan and endosulfan sulfate was estimated for 1965-1970 from the mar-
ket basket study of the FDA (Duggan and Comeliussen, 1972). The U.S. EPA
(1979) has estimated the weighted average bioconcentration factor for sndo-
sulfan to be 28 for the edible portions of fish and shellfish consumed .by
Americans. This estimate is based on measured steady-state- bioconcentration
studies with mussels. The processing of leafy vegetables causes endosulfan
residues to decline from 11 jug/kg to 6 pg/kg (Comeliussen, 1970).
7
-------
C. Inhalation
In 1970, air samples from 16 states showed an average level of 13.0
ng/m alpha-endosulfan and 0.2 ng/m beta-endosulfan. None of the air
samples collected in 1971 or 1972 contained detectable levels of either iso-
mer (Lee, 1976). Endosulfan residues (endosulfan and endosulfan sulfate)
have been detected in most types of U.S. tobacco products in recent years
(U.S. EPA, 1979). Average residue levels range from 0.12 mg/kg to 0.83
mg/kg for 1971-1973 (Domanski, et al. 1973,1974; Oorough and Gibson, 1972)..
The extent to which endosulfan residues in tobacco products contribute to
human exposure is not known. Spray operators can be exposed up to 50
jug/hour of endosulfan from a usual application of a 0.08 percent spray
(Wolfe, et al. 1972). Non-target deposition on untreated plants after-
spraying may lead to residues of up to 679 ug/kg (Keil, 1972).
0. Dermal
Wolfe, et al. (1972) estimated that sprayers applying a 0.08 per-
cent aqueous solution are exposed dermally -to 0.6 to 98.3 mg/hour. Endosul-
fan can persist on the hands for 1 to 112 days after exposure (Kazen, et al.
1974).
III. PHARMACOKINETICS
A. Absorption
Undiluted endosulfan is slowly and incompletely absorbed from the
mammalian gastointestinal tract, whereas endosulfan dissolved in cottonseed.
oil is readily though not completely absorbed (Boyd and Dobo.s, 1969; Maier-
Bode, 1968). The beta-isomer is more readily absorbed than the alphaisomer.
Alcohols, oils, and emulsifiers accelerate the absorption of endosulfan by
the skin (Maier-Bode, 1968). Inhalation is not considered to be an impor-
tant route of absorption for endosulfan except in spray operators (U.S. EPA,
1979).
-------
8. Distribution
After ingestion by experimental animals, sndosulfan is first dis-
tributed to the liver and then to the other organs of the body and the re-
mainder of the gastrointestinal tract (Boyd and Oobos, 1969; Maier-Sode,
1968). In cats, endosulfan levels peaked in brain, liver, spinal cord and
plasma, with the brain and liver retaining the highest concentrations after
administration of a 3 mg/kg dose (Khanna, et al. 1979).
In mice, 24 hours after oral administration of C-endosulfan,
residues were detected in fat, liver, kidney, brain, and blood (Deema, et
al. 1966).
Data from autopsies of three suicides show levels of endosulfan in
brain which were much lower than those in liver and kidney, which in turn,
were lower than levels in blood (Coutselinis, et al. 1978). Data from an-
other suicide indicate higher levels of endosulfan in liver and kidneys than
in blood (Demeter, et al. 1977).
C. Metabolism
Endosulfan sulfate is the metabolite most commonly present in tis-
sues, feces, and milk of mammals after administration of endosulfan (Whit-
acre, 1970; Oemma, et al. 1966;. FMC, 1963). The largest amounts of endosul-
fan sulfate are found in small intestine and visceral fat with only traces
in skeletal muscle and kidney (Deema, et al. 1966). Endosulfan sulfate has
been detected in the brains of two humans who committed suicide by ingesting
endosulfan (Demeter and Heyndrickx, 1978), but not--in the-brains of mice
,•
given nonfatal doses of endosulfan. However,, it has been detected in liver,
visceral fat and small intestines of mice (Deema, et al. 1966). Other meta-
bolites of endosulfan are endosulfan lactone, endosulfandiol, andosulfan hy-
droxyether, and endosulfan ether (Knowles, 1974; Menzie, 1974). These meta-
bolites have also been found in microorganisms and plants (U.S. EPA, 1979).
-------
D. Excretion
The principal route of excretion for endosulfan and endosulfan sul-
fate is in the feces (U.S. EPA, 1979). Other metabolites are also excreted
in the feces 'and to a'small extent in the urine, the metabolites in the lat-
ter being mainly in the form of endosulfan alcohol (U.S. EPA, 1979). In
studies with sheep receiving a single oral dose of radiolabeled endosulfan,
92 percent of the dose was eliminated in 22 days. The organ with the high-
est concentration of radiolabeled endosulfan after 40 days was the liver.
Major metabolites did not persist in the fat or in the organs (GorbachT et
al. 1968). After a single oral dose, the half-life of radiolabeled endosul-
fan in the feces and urine of sheep was approximately two days (Kloss, et
al. 1966). Following 14 days of dietary exposure of female rats, the half-
life of endosulfan residues was approximately seven days (Dorough, et al.«
1978).
IV. EFFECTS
A. Carcinogenicity
In bioassays on both mice and rats, orally administered endosulfan
was not carcinogenic even though doses were high enough to produce symptoms
of toxicity (Kotin, et al. 1968; Innes, et al.. 1969; Weisburger, et al.
1978).
B. Mutagenicity
Data from assays with Salmonella typhimurium (with and without mi-
crosomal activation) (Dorough, et al. 1978), Sacchaxomyces. cerevisiae, Esch-
ericia coli, and Serratia marcescens (Fahrig, 1974) indicate that endosulfan
is not mutagenic.
-------
C. Teratogenicity
Endosulfan did not produce teratogenic effects in rats (Gupta,
1978).
0. Other Reproductive Effects
In rats, endosulfan produced dose-related increases in maternal
toxicity and caused increases in fetal mortality and. resorptions (Gupta,
1978). Doses of 100 mg/kg' reduce hatchability of fertile, white leghorn
chicken eggs by 54 percent, but this was dependent on carrier (Ounachie and
Fletcher, 1969). Alterations in the gonads of the embryos within sprayed
hens' _eggs were noted and the progeny of hens and quails, Cotumix Cotumix
japonica, were sterile (U.S. EPA, 1979).
E. Chronic Toxicity
In the NCI bioassays (Xotin, et al. 1968; Weisberger, et al. 1978)
endosulfan was toxic to the kidneys of rats of both sexes, and to the kid-
neys of male mice. Other signs of toxicity were parathyroid hyperplasia,
testicular atrophy in male rats, and high early death rates in male mice.
In a two-year feeding study with rats (Hazelton 'Laboratories,
1959), endosulfan at 10 mg/kg diet reduced testis weight in males and low-
ered survival in females; at 100 mg/kg diet, renal tubular damage and some
hydropic changes in the liver were induced.
In humans, there has been an absence of toxic effects with proper
handling of endosulfan in the occupational setting (Hoechst, 1966).
F. Other Relevant Information "
The acute toxicity of endosulfan sulfate is about the same as that
of endosulfan. The LD50 for technical endosulfan in rats is *— 22 to &6
mg/kg and 6.9 to 7.5 mg/kg in mice (Gupta, 1976). Reagent grade a- and £-
endosulfan are less toxic to rats (76 and 240 mg/kg, respectively; Hoechst,
. I . I A_
- I I 7<>
/,
-------
1967). The inhalation 4-hour LC5Q values for rats have been reported as
350 and 80 ug/1 for males and females, respectively (Ely, et al. 1967).
Acute toxicities of other metabolites (endosulfan lactone, endosulfandiol,
endosulfan hydroxyether and endosulfan ether) are less than that of the
parent compound (Dorough, et al. 1978).
At very high levels of acute exposure, endosulfan is toxic to the
central nervous system (U.S. EPA, 1979). Endosulfan is a convulsant and
causes fainting, tremors, mental confusion, irritability, difficulty in uri-
nation, loss of memory and impairment of visual-motor coordination. Acute
intoxification can be relieved by diazepam but chronic effects are manifest-
ed in central nervous system disorders (Aleksandrowicz, 1979).
There appear to be sex differences (see previous Chronic Toxicity
section) and species differences in sensitivity to endosulfan. Of the spe-
cies tested with endosulfan, cattle are the most sensitive to the neurotoxic
effects of endosulfan and appear to be closer in sensitivity to humans.
Dermal toxicity of endosulfan-sprayed cattle is also high. Typical symptoms
'are listlessness, blind staggers, restlessness, hyperexcitability, muscular
spasms, goose-stepping and convulsions (U.S. EPA, 1979).
Endosulfan is a nonspecific inducer of drug metabolizing enzymes
(Agarwal, et al. 1978). Protein deficient rats are somewhat more suscepti-
ble to the toxic effects of endosulfan than controls (Boyd and Oobos, 1969;
Boyd, et al. 1970).
V. AQUATIC TOXICITY
A. Acute Toxicity
Ninety-six hour LC5g values, using technical grade endosulfan,
for five species of freshwater fish range from 0.3 jjg/1 for the rainbow
trout, Salmo qairdneri, (Macek, et al. 1969) to 11.0 ;jg/l for carp finger-
- I [ >/..{—
' j ) I >
f
-------
lings, Cyprinus caraio (Macek, et al. 1969; Schoettger, 1970; Ludemann acid-
Neumann, 1960; Pickering and Henderson, 1966). Among freshwater inverte-
brates, Oaohnia magna is reported to have 48-hour LC5Q values ranging, from-
62 to 166 ug/r (Macek, et al. 1976; Schoettger, 1970), with three other in-
vertebrates yielding 96-hour LC5Q values of 2.3 (Sanders and Cope, 1968)
to 107 jjg/1 (Sanders, 1969; Schoettger, 1970). Levels of 400 and 800 ng/1
of technical endosulfan damaged the kidney, liver, stomach and intestine of
Gvmonocorymbus ternetzi. The 96-hour LCep value was 1.6 ug/L- (Amminikutty—
and Rege, 1977,1978).
Of the five saltwater fish species tested, the reported 48- or 96-
hour LCeg values ranged from 0.09 (Schimmel, et al. 1977) to 0.6" ^g/1
(Butler, 1963,1964; Korn and Earnest, 1974; Schimmel, et al. 1977). The
most sensitive species was the spot (Leiostomus xanthurus).
The seven saltwater invertebrate species tested showed a wide range
of sensitivity to endosulfan. The range of EC5Q and LC5Q values is from
0.04 (Schimmel, et al. 1977) to 380 jug/1 with the most sensitive species be-
ing the pink shrimp (Penaeus duorarum).
3. Chronic Toxicity
Macek, et al. (1976) provided the only aquatic chronic study in-
volving endosulfan. No adverse effects on fathead minnow, Pimephales orome-
las, parents or offspring were observed at 0.20 jug/1. Gvmonocorvmbus ter-
netzi chronically exposed to 400 and 530 ng/1 for 16 weeks evinced necrosis
of intestinal mucosa cells, ruptured hepatic cells "and destruction of pan-
creatic islet cells (Amminikutty and Rege, 1977,1978).
C. Plant Effects
Little data is available concerning the effects of endosulfan on
aquatic micro/macrophytes. Growth of Chlorella vuloaris was inhibited
>2000ug/l (Knauf and Schulze, 1973).
4
?*•//
-------
0. Residues
Schimmel, et al. (1977) studied the uptake, depuration, and metabo-
lism of endosulfan by the striped mullet, Mugil cephalus. When the-eoncen--
trations of endosulfans I and II and endosulfan sulfate were combined to
determine the bioconcentration factor (BCF), an average whole-body BCF of
1,597 was obtained. Nearly all the endosulfan was in the form of the sul-
fate. Even though the duration of the study was 28 days, this investigator
questioned whether- a steady-state condition was reached. Complete-- depura-- -
tion occurred in just two days in an endosulfan-free environment. Residues
in pond sediments may be as high as 50 pg/kg B-endosulfan and 70 pg/kg of
endosulfan sulfate 280 days after insecticidal endosulfan application (FMC,
1971).
Dislodgable residues on cotton foliage in Arizona declined to 10
percent and one-third for the low-melting, and high-melting isomers, respec-
tively, 24 hours after application of 1.1 kg/ha endosulfan. However, though
residues had declined to 4 percent and 11 percent respectively, 4 days after
application endosulfan sulfate residues on the leaves increased markedly to
0.14 jug/cm2 (Estesen, 1979).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria, derived by U.S. EPA
(1979), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed.
j
A. Human
The U.S. EPA (1979) has recommended a draft criterion for endosul-
»
fan in ambient water of 0.1 mg/1 based on an ADI of 0.28 mg/day. This ADI
was calculated from a NOAEL of 0.4 mg/kg obtained for mice in a chronic
feeding study (Weisburger, et al. 1978) and an uncertainty factor of 100.
• ••it
^}) I J
-------
The American Conference of Governmental Industrial Hygienists
(ACGIH, 1977) TLV time weighted average for endosulfan is 0.1 mg/m . The
tentative value for the TLV short-term exposure limit (15 minutes) is 0.3
mg/m .
The ADI for endosulfan established by the Food and Agricultural
Organization and the World Health Organization is 7.5 ug/kg (FAO, 1975).
B. Aquatic
For endosulfan, the draft criterion to protect freshwater aquatic
life is 0.042 ug/1 in a 24-hour average and not to exceed 0.49 ug/1 at any
time. Saltwater criteria cannot be developed because of insufficient data
(U.S. EPA, 1979).
-------
ENDOSULFAN
REFERENCES
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agents in the workroom environment with intended changes for 1977. 1977 TLV
Ariborne Contaminants Committee, American Conference of Government Indus-
trial Hygienists, Cincinnati, Ohio.
Agarwal, O.K., et al. 1978. Effect of endosulfan on drug metabolizing en-
zymes and lipid peroxidation in rat. Jour. Environ. Sci. Health C13: 49.
Aleksandrowicz, O.R. 1979. Endosulfan poisoning and chronic brain syn-
drome. Arch. Toxicol. 43: 65.
Amminikutty, C.K. and M.S. Rege. 1977. Effects of acute and chronic ex-
posure to pesticides, Thioden-35 E.C. and Aoallol "3" on the liver of widow
tetra (Gymonocorymbus ternetzi). Boulenger-Indiana Jour. Exp. Biol. 15: 97.
Amminikutty, C.K. and M.S. Rege. 1978. Acute and chronic effect of Thioden
35 E.C. and Aoallol "3" on kidney, stomach and intestine of the widow- tetra
(Gymonocorymbus temetzi). Boulenger-IndiaRa Jour. Exp. Biol. 16: 202.
Berg, H. 1976. Farm chemicals handbook. Meister Publishing Co.,
Willoughby, Ohio.
Boyd, E.M. and I. Dobos. 1969. Protein deficiency and tolerated oral doses
of endosulfan. Arch. Int. Pharmacodyn. 178: 152.
Boyd, E.M., et al. 1970. Endosulfan toxicity and dietary protein. Arch.
Environ. Health 21: 15.
Butler, P.A. 1963. Commercial fisheries investigations, pesticide-wildlife
studies. A review of Fish and Wildlife Service Investigations during 1961
and 1962. U.S. Oept. Inter. Fish Wildl. Circ. 167: 11.
Butler, P.A. 1964. Pesticide-wildlife studies, 1963. A review of Fish and
Wildlife Service Investigations during the calendar year. U.S. Oept. Inter.
Fish Wildl. Circ. 199: 5.
Cassil, C.C. and P.E. Orummond. 1965. A plant surface oxidation product of
endosulfan. Jour. Econ. Entomol. 58: 356.
Chopra, N. and A. Mahfouz. 1977. Metabolism of eridosulfa'h I, endosulfan
II, and endosulfan sulfate in tobacco leaf. Jour. Agric^ Food Chem. 25: 32.
Comeliussen, P.E. 1970. Residues in food and feed: pesticide residues in
total diet samples (V). Pestic. Monit. Jour. 4: 89.
Coutselinis, A., et al. 1978. Concentration levels of endosulfan in bio-
logical material (report of three cases). Forensic Sci. 11: 75.
-------
Oeema, P., et al. 1966. Metabolism, storage, and excretion of i4C-endo-
sulfan in the mouse. Jour. Econ. Entomol. 59: 546.
Oemeter, 3. and A. Heyndrickx. 1978. Two lethal endosulfan poisonings in
man. Jour. Anal. Toxicol. 2: 68.
Oemeter, J., et al. 1977. Toxicological analysis in a case of endosulfan
suicide. Bull. Environ. Contain. Toxicol. 18: 110.
Ocmanski, J.J., et al. 1973. Insecticide residues on 1971 U.S. tobacco
products. Tobacco Sci. 17: 80.
Oomanski, J.J., et al. 1974. Insecticide residues on 1973 U.S. tobacco
products. Tobacco Sci. 13: 111.
Oorough, H.w. and J.R. Givson. 1972. Chlorinated insecticide residues in
cigarettes purchases in 1970-72. Environ. Entomol. 1: 739.
Dorough, H.W., et- al. 1978. Fate of endosulfan in rats and toxicological
considerations of apolar metabolites. Pestic. Biochem. Physiol. 8: 241.
Ouggan, R.E, and P.E. Comeliussen. 1972. Dietary intake of pesticide
chemicals in. the United States (III), Jutfe 1968 to April 1970. Pestic.
Monit. Jour. 5: 331.
Ounachie, J.F. and w.w. Fletcher. 1966. Effect of some insecticides on the
hatching rate of hens' eggs. Nature 212: 1062.
Ely, T.S., et al. 1967. Convulsions in Thiodan workers: a preliminary
report. Jour. Qccup. Med. 9: 36..
Estesen, B.J., et al. 1979. Oislodgable insecticide residues on cotton
foliage: Permethrin, Curocron, Fenvalarate, Sulprotos, Oecis and Endosulfan-
Bull. Environ. Contain. Toxicol. 22: 245.
Fahrig, R. 1974. comparative mutagenicity studies with pesticides. Int.
Agency Res. Cancer Sci. Publ. 10: 161.
FAQ. 1975. Pesticide residues in food: report of the 1974 Joint Meeting of
the FAQ Working Party of Experts on Pesticide Residues and the WHO Expert
Committee on Pesticide Residues. Agricultural Studies NO. 97, Food and
Agriculture Organization of the United States, Rome.
FMC Corp. 1963. Unpublished laboratory report of. Niagara Chemical Divi-
sion, FMC Corporation, Middleport, New York. In: Maie"r-8ode,'' 1968'..
^™" ,/
FMC Corp. 1971. Project 015: Determination of endosulfan I, endosulfan II
and endosulfan sulfate residues in soil, pond, mud and water. Unpublished
report. Niagara Chemical Division, FMC Corp., Richmond, Cal. In: Nati.
Res. Council, Canada, 1975.
Gorbach, S.G., et al. 1968. Metabolism of endosulfan in milk sheep. Jour.
Agric. Food Chem. 16: 950.
-------
Gupta, P.K. 1976. Endosulfan-induced neurotoxicity in rats and mice.
Bull. Environ. Contain. Toxicol. 15: 708.
Gupta, P.K. 1978. Distribution of endosulfan in plasma and brain after re-
peated oral administration to rats. Toxicology 9: 371.
Hazleton Laboratories. 1959. Unpublished report, May 22. Falls Church,
Virginia. In: ACGIH, 1971.
Hoechst. 1966. Unpublished report of Farbwerke Hoechst A.G., Frankfurt,
West Germany. In: Maier-Bode, 1968.
Hoechst. 1967. Oral 1050 values for white rats. Unpublished report of
Farbwerke Hoechst A.G., Frankfurtr, West Germany. Cited in Demeter and
Heyndrickx, 1978. Jour. Anal. Toxicol. 2: 68.
Innes, J.R.M., et al. 1969. bioassay of pesticides and industrial chem-
icals for tumorigenicity in mice: a preliminary .note. Jour. Natl. Cancer
Inst. 42: 1101.
Kazen, C., et al. 1976. Persistence of pesticides on the hands of some.
occupationally exposed people. Arch. Environ, health 29: 315.
Keil, J.E., et al. 1972. Decay of parathion and endosulfan residues on
field-treated tobacco, South Carolina, 1971. Pestic. Monit. Jour. 6: 73.
Khanna, R.N., et al. 1979. Distribution of endosulfan in cat brain.. Bull.
Environ. Contam. Toxicol. 22: 72.
Kloss, G., et al. 1966. Versuche an Schaffen mit C^-markierten Thiodan.
Unpublished. In: Maier-8ode, 1968.
Knaut, W. and C.F. Schulze. 1973. New findings on the toxicity of endo-
sulfan and its metabolites to aquatic organisms. Meded. Fac. Landlouwwey.
Kijksuniv. Gent. 38: 717.
Knowles, C.O. 1974. Detoxification of acaricides by animals. Pages 155-
176 In: M.A. Kahn and J.P. Bederka, Jr., eds. Survival in toxic environ-
ments. Academic Press, New York.
Korn, S., and R. Earnest. 1974. Acute toxicity of 20 insecticides to
striped bass Morone saxatilis. Calif. Fish Game 69: 128.
Kotin, P., et al. 1968. Evaluation of carcinogenic, teratogenic and muta-
genic activites of selected pesticides and industrial' chemicals. Pages 64,
69 In: Vol. 1: carcinogenic study. Bionetics Research .Laboratories report
to Natl. Cancer Inst. NTIS-PB-223-159.
Lee, R.L., Jr. 1976. Air pollution from pesticides and agricultural pro-
cess. CRC Press, Inc., Cleveland, Ohio.
Ludemann, D. and H. Neumann. 1960. Versuche uber die akute toxische
Wirkung neuzeitlicher Kontaktinsektizide auf einsommerige Karfen (Cyprinum
carpio L.) Z. Angew. Zool. 47: 11.
-------
Macek, K.J., et al. 1969. The effects of temperature on the susceptibility
of bluegills and rainbow trout to selected pesticides. Bull.. Environ.
Contam. Toxicol. 4: 174.
Macsk, K.J., et 'al. 1976. Toxicity of four pesticides to water fleas and
fathead minnows. EPA-600/3-76-G99. U.S. Environ. Prot. Agency.
Maier-Sode, H. 1968. Properties, effect, residues and analytics of the
insecticide endosulfan (review). Residue Rev. 22: 2.
Martens, R. 1976. Degradation of (8,9,-C-14) endosulfan by soil micro-
organisms. Appl. Environ. Microbiol. 31: 853.
Menzie, C.M. 1974. Metabolism of pesticides: an update. Special scien-
tific report. Fish and Wildlife Service, Wildlife 184. U.S. Department of
Interior, Washington, D.C.
Miles, J.R.W. and P. Moy. 1979. Degradation of endosulfan and its metab-
olites by a mixed" culture of soil microorganisms. Bull~ Environ. Contam..
Toxicol. 23: 13.
Pickering, Q.H. and C. Henderson. 1966. The acute toxicity of some pesti-
cides to fish. Ohio Jour. Sci. 66: 508.
Sanders, H.O. 1969. Toxicity of pesticides to the crustacean Gammarus
lacustris. U.S. Bur. Sport,Fish Wildl. Tech. Pap. 25.
Sanders, H.O. and- O.B. Cope. 1968. The relative toxicities of several
pesticides to naiads of three species of stoneflies. Limnol. Oceanogr.
13: 112.
Schimmel, S.C., et al. 1977. Acute toxicity to and bioconcentration of
endosulfan by estuarine animals. Aquatic toxicology and hazard evaluation.
ASTM STP 634, AM. Sac. Test. Mat.
Schoettger, R.A. 1970. Fish-pesticide research laboratory, progress in
sport fishery research. U.S. Dept. Inter. Bur. sport Fish Wildl. Resour.
Publ. 106.
U.S. EPA. 1979. Endrin: Ambient Water Quality Criteria. (Draft)
Weisburger, J.H., et al. 1978. Bioassay of endosulfan for possible car-
cinogenicity. National Cancer Institute Division of Cancer Cause and
Prevention, National Institutes of Health, Public "Health" Service, U.S.
Department of Health, Education and Welfare, Bethesda, Maryland, Pub.
78-1312. Report by Hazleton Laboratories to NCI, NCI-CG-TR-62. 54 pp.
Whitacre, O.M. 1970. Endosulfan metabolism in temperature-stressed rats.
Diss. Abstr. Int. 30: 44358.
Wolfe, H.R., et al. 1972. Exposure of spraymen to pesticides. Arch.
Environ. Health 25: 29.
-------
No. 99
Endrin
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
,-i ./ r>~
11 ) 7 -*
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
EN DRIM
SUMMARY
Endrin does not appear to be carcinogenic. Endrin is
teratogenic and embroytoxic in high doses and produces gross
chromosomal abnormalities when administered intratesticu-
larly. Chronic administration of endrin causes damage to the
liver, lung, kidney, and heart of experimental animals. No
information about chronic effects in humans is available.
The ADI established by the Food and Agricultural Organization
and World Health Organization is 0.002 mg/kg.
Endrin has proven to be extremely toxic to aquatic orga-
nisms. In general, marine fish are more sensitive to endrin
with an arithmetic mean LC^Q value of 0.73 ug/1, than
freshwater fish with an arithmetic mean LC^Q value of
4.42 ug/1. Invertebrate species tend to be more resistant
than fish with arithmetic mean LC^Q values of 3.80 and
58.91 ug/1 for marine and freshwater invertebrates, respec-
tively.
-------
ENDRIN
I. INTRODUCTION
Endrin (molecular weight 374) is a broad spectrum insec-
ticide of- the group of polycyclic chlorinated cyclodiene hy-
drocarbons of which the insecticides aldrin and dieldrin are
also members. Endrin is isomeric with dieldrin and is used
as a rodenticide and ovicide. The endrin sold in the U.S. is
a technical grade product containing not less than 95 percent
active ingred'ient. The solubility of endrin in water at 25 °C
is about 200 ug/1 (U.S. EPA, 1979). Its vapor pressure is 2
x 10"7 mm Hg at 25°C (Martin, 1971).
Endrin is used primarily as an insecticide and also as a
rodenticide and avicide. Over the past several years, endrin
utilization has been increasingly restricted (U.S. EPA, 1979.
Endrin production in 1978 was approximately 400,000 ..pounds
(U.S. EPA, 1978). Endrin persists in the soil (U.S. EPA,
1979) .
II. EXPOSURE
A. Water
Occasionally, groundwater may contain more than 0.1
ug/1. Levels as high as 3 ug/1 have been correlated with
precipitation and run off following endrin applications (U.S.
EPA, 1978).
Concentrations of endrin in finished drinking water
have been decreasing. In a study of ten municipal water
treatment plants on the Mississippi or Missouri Rivers, the*
number of finished water samples containing concentrations of
endrin exceeding 0.1 ug/1 decreased from ten percent in 1964-
99-f
-------
1965 to zero Ln 1966-1967 (Schafer, et al., 1969).. The high-
est concentration of endrin in drinking water in New Orleans,
Louisiana measured by the U.S. EPA in 1974 was 4 ng/1 (U.S.
EPA, 1974).
B. Food
The general population is rarely exposed to endrin
through the diet. In the market basket study by the FDA, the
total average daily intake from food ranged from approximate-
ly 0.009 ug/kg body weight in 1965 to 0.0005 ugAg body
weight in 1970 (Duggan and Lipscomb, 1969; Duggan and Corne-
liussen, 1972).
The U.S. EPA (1979) has estimated the weighted av-
erage bioconcentration factor of endrin at 1,900 for the edi-
ble portions of fish and shellfish consumed by Americans.
This estimate is based on measured steady-state bioconcentra-
tion studies in six species (both freshwater and saltwater).
C. Inhalation
Exposure of the general population to endrin via
the air decreased from a maximum level of 25.6 ug/ra3 in
1971 to a maximum level of 0.5 ug/m3 in 1975 (U.S. EPA,
1979).
Tobacco products are contaminated with endrin cesir-
dues. Average endrin residues for various types of tobacco
products have been reported in the range of'0.05 ug/g to 0.2
ug/<3 (Bowery, et al., 1959; Domanski and Guthrie, 1974).
•
Inhalation exposure of users and manufacturers of
endrin sprays may be around 10 ug/hour (Wolfe, et al. 1967)
but use of dusts can produce levels as high as 0.41 mg/hour
(Wolfe, et al. 1963).
-------
D. Dermal
Dermal exposure of spray operators .can range up to
3 mg/body/hour even for operators wearing standard protective
clothing (Wolfe, et al. 1963, 1967). The spraying of dusts
can lead to exposures of up to 19 mg/hour (Wolfe, et al.
1963).
III. PHARMACOKINETICS
A. Absorption
Endrin is known to be absorbed through the skin,
lungs, and gut, but data on the rates of absorption are not
available (U.S. EPA, 1979).
B. Distribution
Endrin is not stored in human tissues in signifi-
cant quantities. Residues were not detected in plasma, adi-
pose tissue, or urine of workers exposed to endrin (Hayes and
Curley, 1968). Measurable levels of endrin have not been de-
tected in human subcutaneous fat or blood, even in persons
living in areas where endrin is used extensively (U.S. EPA,
1979). Endrin residues have been detected in the body tis-
sues of humans only immediately after an acute exposure (U.S.
EPA, 1979; Coble, et al. 1967).
In a 128 day study, dogs were fed 0.1 mg/endrin/kg..
body weight/day. Concentrations of endrin, in the tissues at
the end of the experiment were as follows: adipose tissue,
0.3 to 0.8 ug/g; heart, pancreas, and muscle, 0.3 ug/1;
•
liver, kidney and lungs, 0.077 to 0.085 ug/g; blood, 0.002 to
0.008 ug/g (Richardson, et al., 1967). In a six month feed-
ing study with dogs at endrin levels of 4 to 8 ppm in the
-------
diet, concentrations of endrin were 1 ug/g in fat, 1 ug/g in
liver, and 0.5 ug/g in kidney (Treon, et al.,. 1955).
C. Metabolism
In rats, endrin is readily metabolized in the liver
and excreted as hydrophilic metabolites including hydroxyen-
drins, and 12-ketoendrin (also known as 9-ketoendrin). Hy-
droxyendrins and especially 12-ketoendrin have been reported
to be more acutely tox ic to mammals than the parent compound
(Bedford, et al., 1975; Hutson, et al., 19.75). The 12-keto-
endrin is also more persistent in tissues. Female rats me-
tabolize endrin more slowly than males (Jager, 1970).
D. Excretion
Endrin is one of the least persistent chlorinated
hydrocarbon pesticides (U.S.. EPA, 1979). Body content of en-
drin declines fairly rapidly after a single dose or when a
continuous feeding experiment is terminated (Brooks, 1969).
In rats, endrin and its metabolites are primarily excreted
with the feces (Cole, et al., 1968; Jager, 1970). The major
metabolite in rats is anti-12-hydroxyendrin which is excreted
in bile as the glucuronide. 12-Ketoendrin was observed as a
urinary metabolite in male rats; the major urinary metabolite
in female rats is anti-12-hydroxyendrin-O-sulfate (Hutson, et
al., 1975).
In rabbits, excretion is primarily urinary. In fe-
males, endrin excretion also occurs through the milk. Al-
»
though endrin is rapidly eliminated from the body, some of
!
its metabolites nay persist for longer periods of time (U.S.
EPA, 1979).
-------
IV. EFFECTS
A. Carcinogenicity
In lifetime feeding studies with Osborne-tMendel
rats, endrin was neither tumorigenic nor carcinogenic (Deich-
mann, et al., 1970; Deichmann and MacDonald, 1971; Deichmann,
1972). A recent MCI bioassay concluded that endrin was not
carcinogenic for Qsborne-Mendel rats or for B6C3F1 mice
(DHEW, 1979). However, a different conclusion has been
•
reached by Reuber (1979) based only on one study (National
Cancer Institute, 1977), compared with eight other inconclu-
sive or unsatisfactory studies.
B. Mutagenicity
Endrin (1 mgAg) administered intratesticularly
caused chromosomal aberrations in germinal tissues of rats,
including stickiness, bizarre configurations, and abnormal
disjunction (Dikshith and Datta, 1972, 19731) .
C. Teratogenicity
An increased incidence of club foot was found in
fetuses of mice that had been treated with endrin (0.58 mg/
kg) before becoming pregnant (Nodu, et al., 1972).
Treatment of pregnant hamsters with endrin (5 mg/
kg) produced the following congenital abnormalities: open
eye, webbed foot, cleft palate, fused ribs, and. meningoen-
cephalocele (Ottolenghi, et al., 1974; Chernoff, et al.,
1979). Treatment of pregnant mice with endrin (2-5 mg/kg)
»
produced open eye and cleft palate in the offspring (Otto-
lenghi, et al., 1974). Single doses which produced terato-
-------
genie effects in hamsters and mice were one-half the LD^g
in each species (Ottolenghi, et al., 1974).
D. Other Reproductive Effects
•Endrin given to hamsters during gestation produced
behavioral effects in both dams and offspring (Gray, et al.,
1979). In another study endrin produced a high incidence of
fetal death and growth retardation (Ottolenghi, et al.,
1974).
E- Chronic Toxicity
Mammals appeared to be sensitive to the toxic ef-
fects of endrin at low levels in their diet. Significant
mortality occurred in deer mice fed endrin at 2 mg/kg/day in
the diet (Morris, 1968). The mice exhibited symptoms of CNS
toxicity including convulsions. Lifetime feeding of endrin
to rats at 12 mg/kg/day in the diet decreased viability and
produced moderate increases in congestion and focal hemor-
rhages of the lung; slight enlargment, congestion and mott-
ling of the liver, and slight enlargement, discoloration or
congestion of the kidneys (Deichmann, et al., 1970). After
19 months on diets containing 3 mg/kg/day endrin, dogs had
significantly enlarged kidneys and hearts (Treon, et al.,
1955).
Chronic administration of relatively small doses of
endrin to monkeys produced a characteristic .change in the
electroencephalogram (EEC); at higher doses, electrographic
seizures developed. EEC and behavior were still abnormal
three weeks after termination of endrin administration; sei-
-------
zures recurred under stress conditions months after termina-
tion of endrin administration (Kevin, 1968).
P. Other Relevant Information
Endrin is more toxic, in both acute and chronic
studies, than other cyclediene insecticides (U.S. EPA,
1979).
Female rats metabolize and eliminate endrin more
slowly than males (Jager, 1970) and are more sensitive to en-
drin toxicity (U.S. EPA, 1979). Dogs and ..monkeys are more
susceptible to endrin toxicity than other species (U.S. EPA,
1979).
Endrin, given in equitoxic doses with delnav, DDT,
or parathion gave lower than expected LD5Q values, sug-
gestive of antagonism. Endrin given in equitoxic doses with
aldrin (a closely related compound) or chlordarie gave higher
than expected LD50 values suggestive of synergism (Kep-
linger and Deichmann, 1967). Humans poisoned acutely exhibit
convulsions, vomiting, abdominal pain, nausea, dizziness,
mental confusion, muscle twitching and headache. Such symp-
toms have been elicited by doses as low as 0.2 mg/kg body
weight. Any deaths have usually occurred through respiratory
failure (Brooks, 1974).
V. AQUATIC TOXICITY
A. Acute
The toxic effects of endrin have been extensively
studied in freshwater fish. LCgQ values for static
bioassays ranged from 0.046 ug/1 £or carp fry (Cyprinus
carpio) fry to 140.00 ug/1 for adult carp (lyatomi, et al.,
y
Co-//)
-------
1958). Excluding the results of age factor differences for
this species, adjusted static LCjQ values ranged from
0.27 ug/1 for large mouth bass (Microptecus salmoides)
(Fabacler, 1976) to 8.25 ug/1 for the bluegill (Lepomis
macrochirus) (Katz and Chadwick, 1961). The LC50 values
for flow-through assays were 0.27 ug/1 for the bluntnose
minnow (Pimeplales notatus) to 2.00 ug/1 for the bluegill
(U.S. EPA, 1979). Twenty-five LC5Q values for 17 species
of freshwater invertebrates were reported', and ranged from
0.25 ug/1 for stoneflies (Pteronarcys californica) to 500.0
ug/1 for the snail, (Physa gyrina) (U.S. EPA, 1979).
For marine fish, LCgQ values ranged from 0.005
ug/1 for the Atlantic silversides (Menidia menidia) (Eisler,
1970) to 3.1 ug/1 for the northern puffer (Sphaeroides macu-
latus). A total of 17 species were tested in 33 bioassays.
The most sensitive marine invertebrate tested was the pink
shrimp, (Penaeus duordrum) with an LC50 value of 0.037
ug/1, while the blue crab (Callinectes sapidus) was the most
resistant, with an LC50 of 25 ug/1.
B. Chronic
Freshwater fish chronic values of 0.187 ug/1 and
0.257 ug/1 were reported for fathead minnows (Pimephales
promelas) (Jarvinen and Tyo, 1978) and flagf ish.. (Jordanella
floridae) Hermanutz, 1978), respectively, in life cycle
toxicity tests. No freshwater invertebrate species have been
•
chronically examined. The marine fish, the sheepshead minnow
(Cyprinodon variegatus) has provided a chronic value of 0.19
ug/1 from embryolarval tests (Hansen, et al., 1977). The
-------
grass shrimp (Palaemonetes pugio) must be exposed to less
than a chronic concentration of 0.038 ug/1 for reproductive
success of this marine invertebrate species (TylerShroeder,
in press)
C. Plants
Toxic effects were elicited at concentrations for
freshwater algae ranging from 475 ug/1 for Anacystis nidu-
laras (Batterton, 1971) to >20,000 ug/1 for Scenedesmus quad-
ricauda and Oedogonium sp. Marine algae appeared. more_ sensi-
tive with effective concentration ranging from 0.2 ug/1 for
the algae, Agmenellum quadruplicaturn (Batterton, 1978), to
1,000 ug/1 for the algae Dunaliella tertiotecta (U.S. EPA,
1979).
D. Residues
Bioconcentration factors ranged from 140 to 222 in
four species of freshwater algae. Bioconcentration factors
ranging from 1,640 for the channel catfish Ictalurus puncta-
tus (Argyle, et al. 1973) to 13,000 for the flagfish Jordan-
ella floridae (Hermanutz, 1978) have been obtained. Among
four marine species, bioconcentration factors ranging from
1,000 to 2,780 were observed for invertebrates and from 1,450
to 6,400 for marine fish. Residues as high as 0.5 ppm have
been found in the mosquito fish, Gambusia-.affinjls (Finley, et
al. 1970) and fish frequently have contained' levels above 0.3
ppm (Jackson, 1976).
»
VI. EXISTING GUIDELINES AND STANDARDS
Both the human health and aquatic criteria derived by
U.S. EPA (1979), which are summarized below, have not gone
-------
through the process of public review;, therefore, there is a
possibility that these criteria may be changed.
A. Human
The U.S. EPA (1979) has calculated an ADI for en-
drin of 70 ug from a NOAEL of 0.1 mg/kg for dogs in a 128 day
feeding study and an uncertainity factor of 100. The U.S.
EPA (1979) draft criterion of 1 ug/1 for endrin in ambient
water is based on the 1 ug/1 maximum allowable concentration
for endrin in drinking water, proposed by the Public Health
Service in 1965 (Schafer, et al., 1969) and on the calcula-
tions by EPA. Human exposure is assumed to come from drink-
ing water and fish products only.
A maximum acceptable level of 0.002 mg/kg body
weight/day (ADI) was established by the Food and Agricultural
Organization (1973) and the World Health Organization.
A time weighted average TLV for endrin of 100
ug/m3 has been established by OSHA (U.S. Code of Federal
Regulations, 1972) and ACGIH (Yobs, et al., 1972).
The U.S. EPA (40 CFR Part 129.102) has promulgated
a toxic pollutant effluent standard for endrin of 1.5 ug/1
per average working day calculated over a period of one
month, not to exceed 7.5 ug/1 in any sample representing one.
working-day's effluent. In addition, d iseharge.. is not to ex-
ceed 0.0006 kg per 1,000 kg of production.
-------
B. Aquatic
The draft criterion for the protection of fresh-
water aquatic life is 0.0020 ug/1 as a 24 hour average con-
centration not to exceed 0.10 ug/1. For marine organisms,
the draft criterion is 0.0047 ug/1 as a 24 hour average not
to exceed 0.031 ug/1.
-------
ENDRIN
REFERENCES
Argyle, R.L., et al. 1973. Endrin uptake and release by
fingerling channel catfish, Ictaluras punctatus. Jour.
Fish Res. Board Can. 30: 1743.
Batterton, J.C., et al. 1971. Growth response of bluegreen
algae to aldrin, dieldrin, endrin and their metabolites.
Bull. Environ. Contam. Toxicol. 6: 589.
Bedford, C.T., et al. 1975. The acute toxicity of endrin
and its metabolites to rats. Toxicol. Appl. Pharmacol.
33: 115.
Bowery, T.G., et al. 1959. Insecticide residues on tobacco.
Jour. Agric. Food Chem. 7: 693.
Brooks, G.T. 1969. The metabolism of diene-organochlorine
(cyclodiene) insecticides. Residue Rev. 28: 81.
Brooks, G.T. 1974. Chlorinatedlnsecticides. Vol. II.
Biological and environmental aspects. CRC Press, Cleveland,
Ohio.
Chernoff, N., et al. 1979. Perinatal toxicity of endrin
in rodents. I. Fetotoxic effects of prenatal exposure in
hamsters. Manuscript submitted to Toxicol. Appl. Pharmacol.
and the U.S. Environ. Prot. Agency.
Colde, Y., et al. 1967. Acute endrin poisoning. Jour.
Amer. Med. Assoc. 203.: 489.
Cole, J.F., et al. 1968. Endrin and dieldrin: A comparison
of hepatic excretion rates in the rat. (Abstr.) Toxicol.
Appl. Pharmacol. 12: 298.
Deichmann, W.B. 1972. Toxicology of DDT and related chlorin-
ated hydrocarbon pesticides. Jour. Occup. Med. 14: 285.
Deichmann, W.B., and W.E. MacDonald. 1971. Organochlorine
pesticides and human health. Food Cosmet. Toxicol. 9:
91.
Deichmann, W.B., et al. 1970. Tumorigenfcity of aldrin,
dieldrin, and endrin in the albino rat. Indt Med. Srug.
39: 37.
Dikshith, T.S.S., and K.K. Datta. 1972. Effect of intra- .
testicular injection of lindane and endrine on the testes
of rats. Acta Pharmacol. Toxicol. 31: 1.
-------
Dikshith, T.S.S., and K.K. Datta. 1973. Endrin induced
cytological changes in albino rats. Bull. Environ. Cotam.
Toxicol. 9: 65.
Domanski, J.J., and F.E. Guthrie. 1974. Pesticide residues
in 1972 cigars. Bull. Environ. Contain. Toxicol. 11: 312.
Duggan, R.E., and G.Q. Lipscomb. 1969. Dietary intake
of pesticide chemicals in the United States (II), June 1966-
April 1968. Pestic. Monitor. Jour. 2: 153.
Duggan, R.E., and P.E. Corneliussen. 1972. Dietary intake
of pesticide chemicals in the United States (III) , June
1968-April 1970. Pestic. Monitor. Jour. 5: 331.
Eisler, R. 1970. Acute toxicities of organochlorine and.
organophosphorous insecticides to estuarirve fishes. Tech.
Pap. 46. Bur. Sport Fish. Wildl. U.S. Dep. Inter.
Fabacher, D.L. 1976. ' Toxicity of endrin and an endrinmethyl
parathion formulation to largemouth bass fingerlings. Bull.
Environ. Contain. Toxicol. 16: 376.
Finley, M.T., et al. 1970. Possible selective mechanisms
in the development of insecticide resistant fish. Pest.
Monit. Jour. 3: 212.
Gray, L.E., et al. 1979. The effects of endrin administra-
tion during gestation on the behavior of the golden hamster.
Abstracts from the 18th Ann. Meet. Soc. of Tox. New Orleans
p. A-200.
Hansen, D.J., et al. 1977. Endrin: Effects on the entire
lifecycle of saltwater fish, Cyprinodon variegatus. Jour.
Toxicol. Environ. Health 3: TZT~.
Hayes, W.J., and A. Curley. 1968. Storage and excretion
of dieldrin and related compounds. Arch. Environ. Health
16: 155.
Hermanutz, R.O. 1978. Endrin and malathion toxicity to
flagfish (Jordanella floridae). Arch. Enviorn. Contam.
Toxicol. 1: 159.
Hutson, D.H., et al. 1975.. Detoxification and bioactiva-
tion of endrin in the rat. Xenobiotica Ii: 69-7-.
lyatomi, K.T., et al. 1958. Toxicity of endrin to fish.
Prog. Fish.-Cult. 20: 155.
»
Jackson, G.A. 1976. Biologic half-life of endrin in chan-
nel catfish tissues. Bull. Environ. Contam. Toxicol. 16:
505.
-------
Jager, K.W. 1970. Aldrin, dieldrin, endrin, and telodrin.
Elsevier Publishing Co., Amsterdam.
Jarvinen, A.W., and R.M. Tyo. 1978. Toxicity to fathead
minnows of endrin in food and water. Arch. Environ. Contain.
Toxicol. 7: 409.
Katz, M., and G.G. Chadwick. 1961. Toxicity of endrin
to some Pacific Northwest fishes. Trans. Am. Fish. Soc.
90: 394.
Keplinger., M.L., and W.B. Deichmann. 1967. Acute toxicity
of combinations of pesticides. Toxicol. Appl. Pharmacol.
10: 586.
Martin, H. 1971. Pesticide manual, 2nd ed. Brit. Crop
Prot. Council.
Morris, R.D. 1968. Effects of endrin feeding on survival
and reproduction in the deer mouse, Peromyscus maniculatus.
Can. Jour. Zool. 46: 951.
National Cancer Institute. 1977. Bioassay of endrin for
possible carcinogenicity. NCI Technical Report Series,
No. 25.
National Cancer Institute. 1979. Bioassay of endrin for
possible carcinogenicity. HEW Pub. No. (NIH) 79-812. U.S..
Dept. of Health, Education and Welfare, Bethesda, Md.
Nodu, et. al. 1972. Influence of pesticides on embryos.
On the influence of organochloric pesticides (in Japanese)
Oyo Yakuri 6: 673.
Ottolenghi, A.D., et al. 1974. Teratogenic effects of
aldrin, dieldrin, and endrin in hamsters and mice. Terato-
logy 9: 11.
Reuber, M.D. 1979. . Carcinogenicity of endrin. Sci. Tot.
Environ. 12: 101.
Revin, A.M. 1968. Effects of chronic endrin administration
on brain electrical activity in the squirrel monkey. Fed.
Prac. 27: 597.
Richardson, L.A., et al. 1967. Relationship of dietary
intake to concentration of dieldrin and endrin in dogs.
Bull. Environ. Contam. Toxicol. 2: 207.
Schafer, M.L., et al. 1969. Pesticides in drinking water
- waters from the Mississippi and Missouri Rivers. Environ*.
Sci. Technol. 3: 1261.
-------
Treon, J.F., et al. 1955. Toxicity of endrin for labora-
tory animals. Agric. Food Chem. 3: 842.
Tyler-Schroeder, D.B. Use of grass shrimp, Palaemonetes
pugio, in a life-cycle toxicity test. In Proceedings of
Symposium on Aquatic Toxicology and Hazard Evaluation.
L.L. Marking and R.A. Kimerle, eds. Am. Soc. Testing and
Materials (ASTM), October 31-November 1, 1977. (In press).
U.S. EPA. 1974. Draft analytical report—New Orleans area
water supply study. Lower Mississippi River facility, Sur-
veillance and Analysis Division, Revion VI, Dallas. Texas.
U.S. EPA. 1978. Endrin-Position Document 2/3. Special
Pesticide Review Division. Office of Pesticide Programs,
Washington, D.C.
U.S. EPA. 1979. Endrin: Ambient Water Quality Criteria.
(Draft). ' •
Wolfe, H.R., et al. 1963. Health hazards of the pesticides
endrin and dieldrin. Arch. Enviorn. Health 6: 458.
Wolfe, H.R., et al. 1967. Exposure of workers to pesti-
cides. Arch. Environ. Health 14: 622.
Yobs, A.R., et al. 1972. Levels of selected pesticides
in ambient air of the United States. Presented at the National
American Chemical Society—Symposium of Pesticides in Air.
Boston, Maine.
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No. 100
Epichlorohydrin (l-chloro-2,3-epoxypropane)
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
100"/
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DISCLAIMER
This report represents a survey of the potential' health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA1s Carcinogen Assessment Group (CAG) has evaluated
epichlorohydrin and has found sufficient evidence to in-
dicate that this compound is carcinogenic.
-------
l-CHLDRO-2,3-EPOXYPROPANE
(Epichlorohydrin)
Summary
The adverse health effects associated with exposure to epichlorohydrin
are extreme irritation to the eyes, skin, and respiratory tract. Inhalation
of vapor and percutaneous absorption of the liquid are the normal human
routes of entry. Exposure to epichlorohydrin usually results from occupa-
tional contact with the chemical, especially in glycerol and epoxy resin op-
erations. Pulmonary effects have been well documented. Recent studies have
demonstrated epichlorohydrin to be a potent carcinogen to nasal tissue in
experimental animals. Cytogenic studies both in vitro and in vivo in humans
and experimental animals have indicated epichlorohydrin to be an active
clastogenic agent. NO data on the concentration of epichlorohydrin in drink-
ing water or foods have been reported. Studies on the effects of epichloro-
hydrin to aquatic organisms could not be located in the available literature.
100-V
-------
I. INTRODUCTION
This profile is based primarily on a comprehensive review compiled by
Santodonato, et al. (1979). The health hazards of epichlorohydrin have also
been reviewed, by the National Institute for Occupational Safety and Health
(NIOSH, 1976) and the Syracuse Research Corporation (SRC, 1979).
Epichlorohydrin (OLOCHOLCl; molecular weight 92.53) is a color-
less liquid at room temperature with a distinctive chloroform-type odor.
The boiling point of epichlorohydrin is 116.4°C, and its vapor pressure is
•
20 mm Hg at 29°C. These factors contribute to the rapid evaporation of
the chemical upon release into the environment.
Epichlorohydrin is a reactive molecule forming covalent bonds with bio-
logical macromolecules. It tends to react more readily with polarized
groups, such as sulfhydryl groups.
The total U.S. production for epichlorohydrin was estimated at 345 mil-
• lion pounds in 1973 (Oesterhof, 1975), with 160 million pounds used as feed-
stock for the manufacture of glycerine and 180 million pounds used in the
production of epoxy resins. Production levels for the year 1977 have been
estimated at 400 million pounds.
II. EXPOSURE
A. Water
No ambient monitoring data on epichlorohydrin are available from
which reliable conclusions on the potential exposure from drinking water may
be made. However, if a major release of epichlorohydrin were realized, the
chemical is stable enough to be transported significant distances. The rate
of evaporative loss would give an estimated half-life of about two days for
»
epichlorohydrin in surface waters (to a depth of 1m). The only reported
contamination of a public water supply resulted from a tank car derailment
-------
and subsequent spillage of 20,000 gallons (197,000 pounds) of epichlorohy-
drin at Point Pleasant, West Virginia on January 23, 1978. Wells at the
depth of 25 feet were heavily contaminated. More specific information is
not yet available.
B. Food
Epichlorohydrin is used as a cross-link in molecular sieve resins,
which are, in turn, used in the treatment of foods (21 CFR 173.40). Food
starch may be etherified with epichlorohydrin, not to exceed 0
alone or in combination with propylene oxide, acetic anhyd cc
anhydride (21 CFR 172.892). No data concerning concentrations of epichloro-
hydrin in foodstuffs has been generated.
C. Inhalation
Numerous environmental sources of epichlorohydrin have been identi-
fied (SRC, 1979). Epichlorohydrin is released into the atmosphere through
waste ventilation processes from a number of industrial operations which re-
sult in volatilization .of the chemical. ' No quantitative monitoring informa-
tion is available on ambient epichlorohydrin concentrations. High concen-
trations have been observed in the immediate vicinity of a factory discharg-
ing epichlorohydrin into the atmosphere, but these were quickly despersed,
with no detection of the chemical at distances greater than 600 M (Fomin,
1966).
III. PHARMACOKINETICS
A. Absorption . . . .
Absorption of epichlorohydrin in man and animals occurs via the
respiratory and gastointestinal tracts, and by percutaneous absorption (U.S.
EPA, 1979). Blood samples obtained from rats after 6 hours exposure" to
(1Z;C)epichlorohydrin at doses of 1 and 100 ppm in air revealed 0.46+0.19
and 27.8+4.7 ;jg epichlorohydrin per ml of plasma, respectively. The rates
-------
epichlorohydrin per ml of plasma, respectively. The rates of uptake at
these exposure levels were determined as 15.48 and 1394 ug per hour, and the
dose received was 0.37 and 33.0 mg/kg (Smith, et al. 1979).
B. Distribution
The distribution of radioactivity in various tissues of rats fed
(1ZlC)-epichlorohydrin has been examined (Weigel, et al. 1978). The chemi-
cal was rapidly absorbed with tissue saturation occurring within two hours
in males and four hours in females. The kidney and liver accumulated the
greatest amounts of radioactivity. Major routes of excretion were in the
urine (38 to 40 percent), expired air (18 to 20 percent), and the feces (4
percent). The appearance of large amounts of 14C02 in expired air sug-
gests a rapid and extensive metabolism of (^C)-epichlorohydrin in rats.
C. Metabolism
Limited data concerning mammalian metabolism of epichlorohydrin
suggest in_ vivo hydrolysis of the compound, yielding alpha-chlorohydrin
(Jones, et al. 1969). Upon exposure to radioactively-labeled epichlorohy-
drin a small percentage of the radioactivity was expired as intact epi-
chlorohydrin, while a large percentage of the radioactivity was excreted as
C02> indicating a rapid and extensive metabolism of the ( C)epi-
chlorohydrin. Metabolites in the urine have been obtained by these re-
searchers , but the final analysis as to the identity of the compounds is not
yet complete. Van Ouuren (1977) has suggested a metabolite pathway of epi-
chlorohydrin to include glycidol, glycidaldehyde and epoxy-propionic acid.
0. Excretion
The percentages of total radioactivity recovered in the urine and
expired air as 14C02 were 46 percent and 33 percent in the 1 ppm group,
and 54 percent and 25 percent in the 100 ppm group, respectively. Rats
-------
orally treated with 100 mg/kg excreted 51 percent of the administered epi-
chlorohydrin in the urine and 38 percent in expired air, while 7 to 10 per-
cent remained in the body 72 hours after exposure. Tissue accumulation of
radioactivity was highest in kidneys and liver.
IV. EFFECTS
A. Carcinogenicity
Epichlorohydrin appears to have low carcinogenic activity following
dermal application. In two studies, epichlorohydrin applied topically to
shaved backs of rats or mice did not induce any significant occurrence of
skin tumors (Weil, 1964; Van Ouuren, et al. 1974). However, subcutaneous
injection of epichlorohydrin at levels as low as 0.5 mg have resulted in the
induction of tumors at the injection site.
Extensive inhalation studies have recently identified epichlorohy-
drin as a potent nasal carcinogen in rats. At concentrations of 100 ppm,
significant increases in the occurrence of squamous cell carcinomas of the
nasal turbinatss have been observed. Such tumors have been reported in
lifetime exposure studies at 30 ppm but not at 10 ppm (Nelson, 1977, 1978).
Several recent epidemiological studies have suggested the risk of
cancer as a result of occupational epichlorohydrin exposure. Both respira-
tory cancers and leukemia are in excess among some exposed worker popula-
tions, but this increase was not shown to be statistically significant
(Enterline and Henderson, 1978; Enterline, 1979). The data suggest a laten-
cy period of roughly 15 years before the onset of- carcinogenic symptoms. A
second survey has failed to substantiate these findings (Shellenberger, et
al. 1979), However, this survey used a younger study population with less
»
exposure to epichlorohydrin.
-------
B. Mutagenicity
Epichlorohydrin has been shown to cause reverse mutations in sev-
eral organisms (SRC, 1979).
Cytogenetic studies with experimental animals have revealed in-
creased aberrations in animals treated with epichlorohydrin. Both mice and
rats have displayed dose-dependent increases in abnormal chromosome morpho-
logy at exposure levels ranging from 1 to 50 mg/kg (Santodonato, et al.
1979) .
•
In humans, the clastogenic properties of epichlorohydrin have been
reported in workers occupationally exposed to the chemical and in cultured
"normal" lymphocytes exposed to epichlorohydrin (SRC, 1979). Cytogenetic
i
evaluation of 'exposed workers has shown an increase of somatic cell chromo-
some aberrations associated with concentrations ranging from 0.5 to 5.0 ppm
(2.0 to 20 mg/m3) (SRC, 1979). Such chromosomal damage appears to be re-
versible once exposure to the chemical ceases.
C. Teratogenicity
Pregnant rats and rabbits exposed to 2.5 to 25 ppm epichlorohydrin
during days 6 to 15 or days 6 to 18 of -gestation showed a mild teratogenic
response (John, et al. 1979). However examinations of all fetal tissue have
not been completed. The incidence of resorbed fetuses was not altered by
exposure to epichlorohydrin at the doses employed.
D. Other Reproductive Effects
The antifertility properties of epichlorohydrin have been examined
by several investigators. Administration of 15 mg/kg/day of epichlorohydrin
for 12 days resulted in reduced fertility of male rats (Halen, 1970) . Five
»
repeated doses of 20 mg/kg were more effective in rendering male rats infer-
tile than was one 100 mg/kg dose or five 50 mg/kg doses (Cooper, et al.
-------
1974). The suggested mode of action of epichlorohydrin is via the in^ vivo
hydrolysis of the compound which produces alpha-chlorohydrin. Altered re-
productive function has been reported for workers occupationally exposed to
epichlorohydrin at concentrations less than 5 ppm.
E. Chronic Effects
Two species of rats and one specie of mice (both sexes) were ex-
posed to 5 to 50 ppm epichlorohydrin for six hours per day, five days per
week for a total of 65 exposures. All species and sexes displayed inflamma-
tory and degenerative changes in nasal tissue, moderate to severe tubular
nephrosis, and gross liver pathology at 50 ppm exposure (Quast, et al.
1979a). The same research group has also examined the effect of 100 ppm
exposure for 12 consecutive days. The toxicity to nasal tissues was similar
(Quast, et al. 1979b).
Altered blood parameters (e.g. increased neutrophilic megamyelo-
cytes, decreased hemoglobin, hematocrit, and erythrocytes) have been ob-
i
served in rats exposed to 0.00955 to 0.04774 ml epichlorohydrin per kg body
weight administered intraperitoneally (Lawrence, et al. 1972). Lesions of
the lungs and reduced weight gains were also observed.
Toxicity studies with various animal species have established that epi-
chlorohydrin is moderately toxic by systemic absorption (Lawrence, et al.
1972). Acute oral LDjg values in experimental animals have ranged frcm
155 to 238 mg/kg for the mouse and from 90 to 260 mg/kg in the rat. Inhala-
tion LC5Q values range from 360 to 635 ppm in rats, to- 800 ppm in mice
(SRC, 1979). Single subcutaneous injections of epich-lorohydrin in rats at
doses of 150 or 180 mg/kg have resulted in severe injury to the kidney
•
(Rotara and Pallade, 1966).
- ) /....>•» / ^
^^^^7
-------
Accidental human exposures have been .reviewed (NIOSH, 1976; Santo-
donato, et al. 1979). Direct exposure to epichlorohydrin vapor results in
severe irritation of the eyes and respiratory membranes, followed by nausea,
vomiting, headache, dyspnea, and altered liver function. A significant de-
crease was reported in pulmonary function among workers exposed to epichlor-
ohydrin in an epoxy-resin manufacturing process. Workers were simultaneous-
ly exposed to dimethyl amino propylamine.
V. AQUATIC TOXICITY
Pertinent data could not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS-
Existing occupational standards for exposure to epichlorohydrin are re-
viewed in the NIOSH (1976) criteria document. The NIOSH recommended envi-
ronmental exposure limit is a 2 mg/m3 10-hour time-weighted average and a
19 mg/m3 15-minute ceiling concentration. The current Occupational Safety
and Health Administration standard is an 8-hour time-weighted average con-
centration of 5 ppm (20 mg/m-5).
I oo-
-------
l-CHLORO-2,3-EPOXYPROPANE(EPICHLOROHYDRIN )
REFERENCES '
Cooper, E.R.A., et al. 1974. Effects of alhpa-chlorohydrin
and related compounds on the reproduction and fertility of
the male rat. Jour. Reprod. Pert. 38: 379.
Enterline, P.E. 1979. Mortality experience of workers ex-
posed to epichlorohydrin. In press: Jour. Occup. Med.
Enterline, P.E., and V.L. Henderson. 1978. Communication to
Medical Director of the Shell Oil Company: Preliminary find-
ing of the updated mortality study among workers exposed to •
epichlorohydrin. Letter dated July 31, 1978. Distributed to
Document Control Office, Office of Toxic Substances (WH-557)
U.S. Environ. Prot. Agency.
Fomin, A.P. '1966. Biological effects of epichlorohydrin and
its hygienic significance as an atmospheric pollutant. Gig.
Sanit. 31: 7.
Halen, J.D. 1970. Post-testicular antifertility effects of
epichlorohydrin and 2,3-epoxypropanol. Nature 226: 87.
John, J.A., et al. 1979. Epichlorohydrin-subchronic
studies. IV. Interim results of a study of the effects of
maternally inhaled epichlorohydrin on rats', and rabbits' em-
bryonal and fetal development. Jan. 12, 1979. Unpublished
report from Dow Chemical Co. Freeport, TX.
Jones, A.R., et al. 1969. Anti-fertility effects and metab-
olism of of alpha- and epichlorohydrin in the rat. Nature
24: 83.
Lawrence, W.H., et al. 1972. Toxicity profile of epichloro-
hydrin. Jour. Pharm. Sci. 61: 1712.
Nelson, N. 1977. Communication to the regulatory agencies
of preliminary findings of a carcinogenic effect in the nasal
cavity of rats exposed to epichlorohydrin. New York Univer-
sity Medical Center. Letter dated March 28, 1977.
Nelson, N. 1978. Updated communication to the regulatory
agencies of preliminary findings of a -carcinogenic effect in
the nasal cavity of rats exposed to epickloroh-ydrin. New
York University Medical Center. Letter dated June 23, 1978.
*•
NIOSH. 1976. NIOSH criteria for a recommended standard:
Occupational exposure to epichlorohydrin. U.S. DHEW. Na-
tional Institute for Occupational Safety and Health.
^T-U^^J^^^—
}) / &
-------
Oesterhof, D. 1975. Epichlorohydrin-. Chemical Economics
Handbook. 642.302/A-642.3022. Stanford Research Corp.,
Menlo Park, Calif.
Quast, J.F., et al. 1979a. Epichlorohydrin - subchronic
studies.. I. A 90-day inhalation study in laboratory rodents.
Jan. 12, 1979. Unpublished report from Dow Chemical Co.
(Freeport, TX).
Quast, J.F., et al. 1979b. Epichlorohydrin - subchronic
studies. II. A 12-day study in laboratory rodents. Jan. 12,
1979. Unpublished report from Dow Chemical Co. Freeport,
TX.
Rotara, G., and S. Pallade. 1966. Experimental studies of
histopathological features in acute epichlorohydrin
(l-chloro-2,3-epoxypropane) toxicity. Mortal Norm. Patol.
11: 155.
SantodonatOj J., et al. 1979. Investigation of selected
potential environmental contaminants: Epichlorohydrin and
epibromohydrin. Syracuse Research Corp. Prepared for Office
of Toxic Substances, U.S. EPA.
Shellenberger, R.J., et al. 1979. An evaluation of the
mortality experience of employees with potential exposure to
epichlorohydrin. Departments of Industrial Medicine, Health
and Environmental Research and Environmental Health. Dow
Chemical Co. Freeport, TX.
Smith, F.A., et al. 1979. Pharmacokinetics of epichlorohy-
drin (EPI) administered to rats by gavage or inhalation.
Toxicology Research Laboratory, Health and Environmental
Science. Dow Chemical Co., Midland, MI. Sponsored by the
Manufacturing Chemists Association. First Report.
Syracuse Research Corporation. 1979. Review and evaluation
of recent scientific literature relevant to an occupational
standard for epichlorohydrin: Report prepared by Syracuse
Research Corporation for NIOSH..
Van Duuren, B.L. 1977. Chemical structure, reactivity, and
carcinogenicity of halohydrocarbons. Environ. Health Persp..
21: 17.
Van Duuren, B.L., et al. 1974. Carcinogenic action of alky-
lating agents. Jour. Natl. Cancer Inst. 53: 695.
Weigel, W.W., et al. 1978. Tissue distribution and excre-
tion of (-^c)-epichlorohydrin in male and female rats. *
Res. Comm. Chem. Pathol. Pharmacol. 20: 275.
/06-/J
-------
Weil, C.S. 1964. Experimental carcinogenicity and acute
toxicity of representative epoxides. Amer. Ind. Hyg. Jour.
24: 305.
too-ff
-------
No. 101
Ethyl Methacrylate
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
ETHYL METHACRYLATE
Summary
Information on the carcinogenic and mutagenic effects of ethyl methac-
rylate was not found in the available literature. Ethyl methacrylate has,
however, been shown to cause teratogenic effects in rats.
Chronic occupational exposure to ethyl methacrylate has not been re-
ported in the available literature.
Data concerning the effects of ethyl methacrylate on aquatic organisms
were not found in the available literature.
-------
ETHYL METHACRVLATE
I. INTRODUCTION
Ethyl methacrylate (molecular weight 114.15) is the ethyl ester of
methacrylic 'acid. It is a crystalline solid that melts at less than 75°C,
has a boiling point of 117°C, a density of 0.9135, and an index of refrac-
tion of 1.4147. It is insoluble in water at 25°C and is infinitely solu-
ble in alcohol and ether (Weast, 1975). It possesses' a characteristic un-
pleasant odor (Austian, 1975).
•
Widely known as "Plexiglass" (in the polymer- form), ethyl methacrylate
is used to make polymers, which in turn are used for building, automotive,
aerospace, and furniture industries. It is also used by dentists as dental
plates, artificial teeth, and orthopedic cement (Austian, 1975).
II. EXPOSURE
Ethyl methacrylate is used in large quantities and therefore has poten-
tial for industrial release and environmental contamination. Ethyl methac-
rylate in the polymerized form is not toxic; however, chemicals used to pro-
duce ethyl methacrylate are extremely toxic. No monitoring data are avail-
able to indicate ambient air or water levels of the compound.
Human exposure to ethyl methacrylate from foods cannot be assessed due
to a lack of monitoring data.
Bioaccumulation data on ethyl methacrylate were not found in the avail-
able literature.
III. PHARMACOKINETICS
Specific information on the metabolism, distribution, absorption, or
elimination of ethyl methacrylate was not found in the available literature.
y
-------
No evidence has been found of the presence of ethyl methacrylate in the
human urine. Therefore, it is hypothesized that it is rapidly metabolized
and undergoes complete oxidation (Austian, 1975).
IV. EFFECTS
A. Carcinogenicity and Mutagenicity
Information on the carcinogenic and mutagenic effects of ethyl
methacrylate was not found in the available literature.
B. Teratogenicity
Ethyl methacrylate is teratogenic in rats. Female rats were given
intraperitoneal injections of 0.12 mg/kg, 0.24 mg/kg, and 0.41 mg/kg, on
days 5, 10, and 15 of gestation. These doses were 10, 20, and 33 percent,
respectively, of the acute intraperitoneal LD5g dose. Animals were sacri-
ficed one day before parturition (day 20).
Deleterious effects, were observed in the developing embryo and fetus.
Effects were compound and generally dose-related. A 0.1223 ml/kg injected
dose resulted in unspecified gross abnormalities and skeletal abnormalities
in 6.3 percent and 5.0 percent of the test animals, respectively, when com-
pared to the untreated controls. A dose of 0.476 ml/kg resulted in gross
abnormalities in 15.7 percent of the treated animals and skeletal abnor-
malities in 11.7 percent of the treated animals (Singh, et al. 1972).
C. Other Reproductive Effects and Chronic Toxicity
Information on other reproductive effects and chronic toxicity of
ethyl methacrylate was not found in the available -literature.
D. Acute Toxicity
Lower molecular weight acrylic monomers such as ethyl methacrylate
•
cause systemic toxic effects. Its administration results in an immediate
-------
increase in respiration rate, followed by a decrease after 15-40 minutes. A
prompt fall in blood pressure also occurs, followed by recovery in 4-5
minutes. As the animal approaches death, respiration becomes labored and
irregular, lacrimation may occur, defecation and urination increase, and
finally reflex activity ceases, and the animal lapses into a coma and dies
(Austian, 1975).
Acrylic monomers are irritants to the skin and mucous membranes.
When placed in the eyes of animals, they elicit a very severe response and,
if not washed out, can cause permanent damage (Austian, 1975).
As early as 1941, Qeichmann demonstrated that injection of 0.03
cc/kg body weight ethyl methacrylate caused a prompt and sudden fall in
blood pessure, while respiration was stimulated immediately and remained at
this level for 30 minutes. The final lethal dose (0.90-.12 cc/kg) brought
about respiratory failure, although the hearts of these animals were still
beating (Qeichmann, 1941).
Work by Mir, et al. (1974) demonstrated that respiratory system
effects alone may not kill the animal, .but that cardiac effects may also
contribute to the cause of death (Austian, 1975). Twelve methacrylate
esters and methacrylic acid were tested on isolated perfused rabbit heart.
Concentrations as low as 1 part in 100,000 (v/v) produced significant ef-
fects. The effects were divided into three groups according to the rever-
sibility of the heart response. Ethyl methacrylate was placed in "Group 1",
in which the heart response is irreversible at all concentrations
•* *'».
(1:100,000; 1:10,000; 1:1,000). Five percent (v/v) caused a 41.2 percent
decrease in the heart rate of isolated rabbit heart. The same concentration
•
reduced heart contraction by 64 percent and coronary flow by 61.5 percent
(Austian, 1975).
f
-V7 $$-.
ltt-6
-------
The findings of Deichmann (1941) that ethyl methacrylate affects
blood pressure and respiration is substantiated by studies of Austian
(1975). Response following administration of ethyl methacrylate was charac-
terized by a biphenic response, an abrupt fall in blood pressure followed by
a more sustained rise. Austian (1975) also found that the respiration rate
is increased, the duration of effect being approximately 20 minutes, after
which time the respiration rate returned to normal.
In the available literature LO^Q values were found for only rab-
bit and rat; these were established by Deichmanrr in 1941. The oral value
for the rat is 15,000 mg/kg, as opposed to 3,654-5,481 mg/kg for the rab-
bit. Inhalation values for the rat have been reported to be 3,300 ppm for 8
hours (Patty, 1962). Deichmann also established a skin toxicity LD5Q for
rabbit which was greater than 10 ml/kg. This was substantiated by another
test which showed that moderate skin irritation (in rabbits) does result
from ethyl methacrylate exposure (Patty, 1962).
VI. EXISTING GUIDELINES AND STANDARDS
Information on existing guidelines and standards was not found in the
available literature.
11 r>7-
* ff u i
-7
-------
ETHYL METHACRYLATE
References
Austian, J. 1975. Structure-toxicity relationships of acrylic monomers.
Environ. Health Perspect. 19: 141.
Oeichmann, w. 1941. Toxicity of methyl, ethyl, and n-outyl methacrylate.
Jour. Ind. Hyg. Toxicol. 23: 343.
Mir, G., et al. 1974. Journal of toxicological and pharmacological actions
of methacrylate monomers. III. Effects on respiratory and cardiovascular
functions of anesthetized dogs.-. Jour.-Pharm. Sci. 63: 376.
Patty, F.A. 1962. Industrial Hygiene and Toxicology, Vol. II. Inter-
science Publishers, New York. . ..
Singh, A.R., et al. -1972. Embryo-fetal toxicity and teratogenic effects of
a group of methacrylate esters in rats. Tox. Appl. Pharm. 22: 314.
Weast, R. C. 1975. Handbook of Chemistry and Physics. 56th ed. CRC
Press, Cleveland, Ohio.
-------
No. 102
Ferric Cyanide
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
FERRIC CYANIDE
I. INTRODUCTION
Ferric cyanide is a misnomer and is not listed as a specific compound
in the comprehensive compendia of inorganic compounds (Weast, 1978). There
are, however, a class of compounds known as "iron cyanide blues" consisting
of various salts where the anions are the ferricyanide, [FeCCN)^]3-, or
the ferrocyanide, [Fe(CN)6]4-, and the cations are either Fe(III) or
Fe(II) and sometimes mixtures of Fe(II) and potassium (Kirk and Othmer,
1967). The empirical formula of the misnamed ferric cyanide, Fe(CN),
corresponds actually to one of the ferricyanide compounds, the ferric ferri-
cyanide with the actual formula Fe[Fe(CN)6]} also known as Berlin green.
The acid from which these salts are derived is called ferricyanic acid,
H3[Fe(CN)g] (also known as hexacyanoferric acid), molecular weight
214.98, exists as green-blue deliquescent needles, decomposes upon heating,
and is soluble in water and alcohol. In this EPA/ECAO Hazard Profile only
ferric ferricyanide, Fe[Fe(CN)6]? and ferric ferrocyanide,
'^[^(CN)^]}, are considered; other ferrocyanide compounds are re-
ported in a separate EPA/ECAO Hazard Profile (U.S. EPA, 1980).
These compounds are colored pigments, insoluble in water or weak acids,
although they can form colloidal dispersions in aqueous media. These pig-
ments are generally used in paint, printing inks, carbon paper inks, cray-
ons, linoleum, paper pulp, writing inks and laundry blues. These compounds
are sensitive to alkaline decomposition (Kirk and Qthmer, 1967).
II. EXPOSURE
Exposure to these compounds may occur occupationally or through inges-
tion of processed food or contaminated water. However, the extent of Food
or water contamination from these compounds has not been described in the
-------
available literature. Prussian blue, potassium ferric hexacyanoferrata
(II), has been reported as an antidote against thallium toxicity. When
administered at a dose of 10 g twice daily by duodenal intubation, it pre-
vents the intestinal reabsorption of thallium (Dreisbach, 1977).
III. PHARMACOKINETICS
A. Absorption and Distribution
Pertinent data could not be located in the available literature.
B. Metabolism
There is no apparent metabolic alteration, of these compounds. As
for the other ferrocyanide and ferricyanide salts, these compounds are not
cyanogenic (Gosselin, et al. 1976).
C. Excretion
No information is available for ferric hexacyanoferrates (II) or
(III), but information is available for other related ferrocyanide and fer-
ricyanide salts (U.S. EPA, 1980; Gosselin, et al. 1976) which seems to be
' rapidly excreted in urine apparently without metabolic alteration.
IV. EFFECTS
A. Carcinogenicity, Mutagenicity, Teratogenicity, Chronic Toxicity,
and Other Reproductive Effects
Pertinent data could not be located in the available literature.
8. Acute Toxicity
No adequate toxicity data are available. All ferrocyanide and
ferricyanide salts are reported as possibly moderately toxic (from 0.5 to
5.0 mg/kg as a probable lethal dose in humans) (Gosselin, 'et al. 1976).
V. AQUATIC TOXICITY
Pertinent data could not be located in the available literature regard-
*
ing the aquatic toxicity of ferric cyanide.
-------
VI. EXISTING GUIDELINES AND STANDARDS
Pertinent data could not be located in the available literature.
i >n ~> -
"lit'-'
-------
REFERENCES
Oreisbach, R.H. 1977. Handbook of Poisoning, 9th edition. Lange Medical
Publications, Los Altos, CA.
Gosselin, R.E.:, et al. 1976. ,Clincial Toxicology of Commercial Products,
4th edition. Williams and Wilkins, Baltimore, Maryland.
Kirk,R.E. and O.F. Othmer. 1967. Kirk-Othmer Encyclopedia of Chemical
Technology, II edition, Vol. 12. Intersciencs Publishers, div. John Wiley
and Sons, Inc., New York.
U.S. EPA. 1980. Environmental Criteria and Assessment Office. Ferrocya-
nide: Hazard Profile. (Draft)
Weast, R.C. 1978. Handbook of Chemistry and Physics, 58th ed. The Chemi-
cal Rubber Company, Cleveland, Ohio.
,
/OSL.-6
-------
No. 103
Fluoranthene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
— ) / o s—
! I I *
-------
FLUORANTHENE
SUMMARY
No direct carcinogenic effects have been produced by
fluoranthene after administration to mice. The compound
has also failed to show activity as a tumor initiator or
promoter. However, it has shown cocarcinogenic effects
on the skin of mice when combined with benzo(a)pyrene, in-
•
creasing tumor incidence and decreasing tumor latency.
Fluoranthene has not shown mutagenicr teratogenic or ..
adverse reproductive effects.
Daphnia magna appears to have low sensitivity to fluoran—
thene with a reported 48-hour EC5Q of 325,000 ug/1. The '•
»
bluegill, however, is considerably more sensitive with an
observed 9-6-hour LC5Q value of 3,980. The 96-hour LC5Q
for mysid shrimp is 16 ug/1,. and a reported chronic value
is 16 ;ug/l. Observed 96-hour EC^Q values based on cell
numbers for fresh and saltwater algae are over 45,000 ug/1.
^^^^^_^^^^^^^^
-Hi) -
-------
FLDORANTHENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Fluoranthene (U.S. EPA, 1979).
Pluoranthene (1,2-benzacenapthene, M.W. 202) is a poly-
nuclear aromatic hydrocarbon of molecular formula C]_gH^Q.
Its physical properties include: melting point, 111°C; boil-
ing point, 375°C; water solubility, 265 pg/1 (U.S. EPA,
1978).
Fluoranthene is chemically stable, but may be removed
from water by biodegradation processes (U.S. EPA, 1979).
The compound is relatively insoluble in aqueous systems.
Fluoranthene may be adsorbed and concentrated on a variety
of particulate matter. Micelle formation through the action
of organic solvents or detergents may occur. (U.S. EPA,
1979). ,
Flouranthene is produced from the pyrolytic processing
of coal and petroleum and may result from natural biosyn-
thesis (U.S. EPA, 1979).
II. EXPOSURE
Fluoranthene is ubiquitous in the environment; it has
been monitored in food, water, air, and in cigarette smoke
(U.S. EPA, 1979). Sources of contamination include indus-
trial effluents and emissions, sewage, soil infiltration,
and road runoff (U.S. EPA, 1979). Monitoring of drinking
»
water has shown an average fluoranthene concentration of
27.5 ng/1 in positive samples (Basu, et al. 1978). Food
-------
levels of the compound are in the ppb range, and will in-
crease in smoked or cooked foods (pyrolysis of fats) (U.S.
EPA, 1979). Borneff (1977) has estimated that dietary in-
take of fluoranthene occurs mainly from fruits, vegetables,
and bread.
An estimated daily exposure to fluoranthene has been
prepared by EPA (1979):
•
Source Estimated Exposure
Water 0.017 ug/day
Food 1.6 - 16 ug/day
Air 0.040 - 0.080 ug/day
Based on the octanol/water partition coefficient, the
U.S. EPA (1979) has estimated weighted average bioconcen-
tration factor of 890 for fluoranthene for the edible por-
tion of fish and shellfish consumed by Americans.
III. PHARMACOKINETICS
A. Absorption
Based on animal toxici.ty data (Smythe, et al.
1962) , fluoranthene seems well absorbed following oral or
dermal administration. The related polynuclear aromatic
hydrocarbon (PAH), benzo(a)pyrene, is readily absorbed across
the lungs (Vainio, et al. 1976).
B. Distribution
Pertinent information could not be located in
»
the available literature. Experiments with benzo(a)pyrene
indicate localization in a wide variety of body tissues,
primarily in body fats (U.S. EPA, 1979).
-------
C. Metabolism
Pertinent information could not be located in
the available literature. 3y analogy with other PAH com-
pounds, fluoranthene may be expected to undergo metabolism
by the mixed function oxidase enzyme complex. Transforma-
tion products produced by this action include ring hydroxy-
lated products (following epoxide intermediate formation)
and conjugated forms of these hydroxylated products (U.S.
EPA, 1979).
D. Excretion
Pertinent information could not be located in
the available literature. Experiments with PAH compounds
indicate excretion through the hepatobiliary system and the -1
feces; urinary excretion varies with the degree of formation
of conjugated metabolites (U.S. EPA, 1979).
i
IV. EFFECTS
A. Carcinogenicity
Testing of fluoranthene in a marine carcinogenesis
bioassay failed to show tumor production following dermal
or subcutaneous administration of fluoranthene (Barry, et
al., 1935).
Skin testing of fluoranthene as a tumor promoter
or initiator in mice has also failed to show activity of
the compound (Hoffman, et al., 1972; Van Duuren and Gold-
schmidt, 1976).
Fluoranthene has been demonstrated to have car-
cinogenic activity (Hoffmann and Wynder, 1963; Van Duuran
-------
and Goldschmidt, 1976). The combination of fluoranthene
and benzo(a)pyrene produced an increased number of papil-
lomas and carcinomas, with shortened latency period (Van
Duuren and Goldschmidt, 1976).
B. Mutagenicity
Fluoranthene failed to show mutagenic activity
in the Ames Salmonella assay in the presence of enzyme activa-
tion mix (Tokiwa, et al. 1977; La Voie, et al. 1979).
C. Teratogenicity
Pertinent information could not be located in
the available literature. Certain PAH compounds (7,12-di-
methylbenz(a)anthracene and derivatives) have been shown
to produce teratogenic effects in the rat (Currie, et al.
1970; Bird, et al. 1970).
D. Other Reproductive Effects
Pertinent information could not be located in
the available literature.
E. Chronic Toxicity
Pertinent information could not be located in
the available literature.
V. AQUATIC TOXICITY
A. Acute Toxicity
The 96-hour LC5Q value for the. bluegill, Lepomis
macrochiruss is reported to be 3,980 ^ug/1 '(U.S. EPA, 1978).
The sheepshead minnow? Cyprinodon variegatus^ was exposed
•
to concentrations of fluoranthene as high as 560,000 ug/1
with no observed LC5Q value (U.S. EPA, 1978) . The fresh-
-------
water invertebrate Daphnia magna appears to have a low
sensitivity to fluoranthene with a reported 48-hour EC-g
value of 325,000 ug/1. The 96-hour LC5Q value for the salt-
water raysi'd shrimp, Mysidopsis bahia } is 16 ug/1.
B. Chronic. Toxicity
There are no chronic toxicity data presented on
exposure of fluoranthene to freshwater species. A chronic
value foe the mysid shrimp is 16 pg/L.
C. Plant Effects
The freshwater alga, Selenastrum capricornutum,
when exposed to fluoranthene resulted in a 96-hour ECeQ
value for cell number of 54,400 jag/1. On the same criterion,
the 96-hour ECSO value for the marine alga, Skeletonema
costatum, is 45,600 ug/1 (U.S. SPA, 1979).
D. Residues
»
No measured steady-state bioconcentration factor
(BCF) is available for fluoranthene. A 3CF of 3,100 can
be estimated using the octanol/water partition coefficient
of 79,000.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The World Health Organization (1970) has established
a recommended standard of 0.2 jug/1 for all--2AH compounds
in drinking water.
Based on the no-effect level determined in a single
»
animal study (Hoffman, et al. 1972), the U.S. EPA (1979)
has estimated a draft ambient water criterion of 200 ;ag/l
for fluoranthene. However, the lower level derived for
A
-------
total PAH compounds is expected to have precedence for fluor-
anthene.
B. Aquatic
'For fluoranthene, the draft criterion to protect
freshwater aquatic life is 250 pg/1 as a 24-hour average,
not to exceed 560 ug/1 at any time. For saltwater life,
the criterion is 0.30 ug/1 as a 24-hour average, not to
exceed 0.69 ug/1 at any time.
-------
FLUOROANTHENE
REFERENCES
Barry, G., et al. 1935. The production of cancer by pure
hydrocarbons-Part III. Proc. Royal Soc., London. 117: 318.
3asu, O.K., et al. 1978. Analysis of water samples for
polynuclear aromatic hydrocarbons. U.S. Environ. Prot.
Agency, P.O. Ca-8-2275B, Exposure Evaluation Branch, HERL,
Cincinnati, Ohio.
Bird, C.C., et al. 1970. Protection from the embryopathic
effects of 7-hydroxymethyl-12-methylbenz(a)anthracene by
2-methyl-I, 2-bis-{3 pyridyl)-l-propanone(metopirone ciba)
and£ -diethylaminoethyldiphenyl-n-propyl acetate (SKR 525-A).
Br. Jour. Cancer^ 24: 348.
Borneff, J. 1977. Fate of carcinogens in aquatic environ-
ment. Pre-publication copy received from author.
Currie, A.R., et al. 1970. Embryopathic effects of 7,12-
dimethylbenz(a)anthracene and its hydroxymethyl derivatives
in the Sprague-Dawley rat. Nature 226: 911.
Hoffmann, D., and E.L. Wynder. 1963. Studies on gasoline
engine exhaust. Jour. Air Pollut. Control Assoc. 13: 322.
Hoffmann, D., et al. 1972. Fluoranthenes: Quantitative de-
termination in cigarette smoke, formation by pyrolysis, and
tumor initiating activity. Jour. Natl. Cancer Inst. 49:
1165.
La Voie, E., et al. 1979. A comparison of the mutagenicity,
tumor initiating activity and complete carcinogenicity of
polynuclear aromatic hydrocarbons, ^n:Polynuclear Aromatic
Hydrocarbons. P.W. Jones and C. Leber (eds.). Ann Arbor
Science Publishers, Inc.
Smythe, H.F., et al. 1962. Range-finding toxicity data:
List VI. Am. Ind. Hyg. Assoc. Jour. 23: 95.
Tokiwa, H., et al. 1977. Detection of mutagenic activity in
particullate air pollutants.. Mutat. Res. 48: 237.
U.S. EPA. 1978. In-depth studies on health '&nd environmen-
tal impacts of selected water pollutants. -U.S. Environ.
Prot. Agency. Contract No. 68-01-4646.
U.S. EPA. 1979. Fluoranthene: Ambient Water Quality Cri7
teria. (Draft).
-------
Vainio, H., et al. 1976. The fate of intratracheally in-
stalled benzo(a)pyrene in the isolated perfused rat lung of
both control and 20-methylcholanthrene pretreated rats. Res,
Commun. Chem. Path. Pharmacol. 13: 259.
Van Duuren, B.L., and B.M. Goldschmidt. 1976. Cocarcino-
genic and tumor-promoting agents in tobacco carcinogenesis.
Jour. Natl. Cancer Inst. 51: 1237.
World Health Organization. 1970. European standards for
drinking water, 2nd ed., Revised^ Geneva.
-------
No. 104
Formaldehyde
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
soy-/
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
FORMALDEHYDE
SUMMARY
The ma.jor source of formaldehyde contamination in the envi-
ronment is combustion processes, especially automobile emissions.
Formaldehyde is a recognized component of photochemical smog. A
recent source of concern is the release of formaldehyde from
resins used in home construction and insulation.
Bioaccumulation of formaldehyde is considered unlikely due
to its high chemical reactivity. Formaldehyde rapidly degrades
in the atmosphere by photochemical processes? however, it can
also be formed by the photochemical oxidation of atmospheric
hydrocarbons.
Formaldehyde is rapidly absorbed via the lungs or gut? fol-
lowing- absorption into the blood, however, formaldehyde dis-
appears rapidly due to reactions with tissue components and
because of its metabolism.
The U.S. EPA1s Carcinogen Assessment Group recently con-
cluded that "there is substantial evidence that formaldehyde is
likely to be a human carcinogen." This finding was based on pre-
liminary results from a chronic inhalation study of formaldehyde
which reported carcinomas of the nasal cavity in 3 rats after 16
months of exposure. This type of tumor is extremely rare is
unexposed rats of the strain used in the study.
There is an extensive data base showing that formaldehyde is
rautagenic in microorganisms, plants, insects, cultured mammalian
cells, and mice. It was negative in a teratogenicity assay.
Formaldehyde is known to be a mucous membrane irritant in humans?
-' ^ * &
/ & * ^
-------
it is also known to be an allergen in sensitive individuals.
I. INTRODUCTION
This profile is based on a U.S. EPA report entitled "Inves-
tigation of Selected Potential Environmental Contaminants:
Formaldehyde" (1976) and other selected references.
Formaldehyde (HCHO; molecular weight 30.03) is a colorless
•
gas having a pungent odor and an irritating effect on mucous mem-
branes. It has the following physical/chemical properties (U.S.
EPA, 1976; Windholz, 1976):
Boiling Point: -19.2°C
Melting Point: -92°C
Density in Air: 1.067
Solubility: soluble in water and many
organic solvents.
A review of the production range (includes importation)
statistics for formaldehyde (CAS No. 50-00-0) which is listed in
the initial TSCA Inventory (1979a) has shown that between 2 bil-
lion and 7 billion pounds of this chemical were produced/imported
in 1977 JL/
Formaldehyde is usually sold as an aqueous solution contain-
ing 37% formaldehyde by weight; it is also available as a linear
—/ This production range information does not include any .
production/importation data claimed as confidential by the
person(s) reporting for the TSCA Inventory, nor does it
include any information which would compromise Confidential
Business Information. The data submitted for the TSCA
Inventory, including production range information, are subject
to the limitations contained in the Inventory Reporting
Regulations (40 CFR 710).
-------
polymer known as parafonnaldehyde and a cyclic trimer known as
trioxane. Formaldehyde is used in the production of urea-formal-
dehyde resins, phenol-formaldehyde resins, polyacetal resins,
various other resins, and as an intermediate in the production of
a variety of chemicals. Manufacture of resins consumes over 50%
of annual domestic formaldehyde production. Urea-formaldehyde
and phenol-formaldehyde resins are used as adhesives for particle
board and plywood, and in making foam insulation. Polyacetal
resins are used to mold a large variety of plastic parts for
automobiles, appliances, hardware, and so on (U.S. EPA, 1976).
II. EXPOSURE
HIOSH (1976) estimates that 1,750,000 workers are poten-
tially exposed to formaldehyde in the workplace.
A. Environmental Fate
Formaldehyde and nascent forms of formaldehyde can undergo
several types of reactions in the environment including depoly-
merization, oxidation-reduction, and reactions with other
atmospheric and aquatic pollutants. Formaldehyde can react
photochemically in the atmosphere to form H and HCO radicals;
once formed, these radicals can undergo a wide variety of
atmospheric reactions (U.S. EPA, 1976). Hyj3rogen peroxide can
also be formed during photodecomposition of formaldehyde (Purcell
and Cohen, 1967; Bufalini jt_ al., 1972). The atmospheric half-
»
life of formaldehyde is less than one hour in sunlight (Bufalini
et al., 1972).
-------
Even though formaldehyde is often used as a bacteriocide,
there are some microorganisms which can degrade the chemical
(U.S. EPA, 1976). Kamata (1966) studied biological degradation
of formaldehyde in lake water. Under aerobic conditions in the
laboratory, known quantities of formaldehyde were decomposed in
about 30 hours at 20"C; anaerobic decomposition took about 48
hours. No decomposition was noted in sterilized lake water.
Paraformaldehyde slowly hydrolyzes and depolymerizes as it
dissolves in water to yield aqueous formaldehyde. Trioxane has
more chemical and thermal stability? it is inert under aqueous
neutral or alkaline conditions. In dilute acid solutions, it
slowly depolymerizes (U.S. EPA, 1976).
B. Bioconcentration
Formaldehyde is a natural metabolic product and does not
bioconcentrate (U.S. EPA, 1976).
C. Environmental Occurrence
Environmental contamination from formaldehyde manufacture
and industrial use is small and localized compared with other
sources. Combustion and incineration processes comprise the
major sources of formaldehyde emissions. Stationary sources of
formaldehyde emissions include power plants, manufacturing facil-
ities, home consumption of fuels, incinerators, and petroleum
refineries. Mobile sources of formaldehyde emissions include
automobiles, diesels, and aircraft. The automobile, however,, is
the largest source of formaldehyde pollution. It is estimated
that over 800 million pounds of formaldehyde were released to the
air in the United States in 1975; of this amount, over 600
-ifTtf •—
I Wl
-------
million pounds are estimated to result from the use of automo-
biles. In addition to formaldehyde, automobile exhaust also
, .-•-*•
contains large quantities of hydrocarbons. Through photochemical
processes in the atmosphere, these hydrocarbons are oxidized to
formaldehyde, among other things, further adding to the environ-
mental load of formaldehyde (U.S. EPA, 1976).
Urea-formaldehyde foam insulation has been implicated as a
source of formaldehyde fumes in homes insulated with this
material. Wood laminates (plywood, chip board,' and particle
board) commonly used in the construction of mobile homes are also
known to release formaldehyde vapors into the home atmosphere
(U.S. EPA, 1979b).
III. PHARMACOKINETICS
A. Absorption
Under normal conditions formaldehyde can enter the "body
through dermal and occular contact, inhalation and ingestion. On
dermal contact, formaldehyde reacts with proteins of the skin
resulting in crosslinking and precipitation of the proteins.
Inhalation of formaldehyde vapors produces irritation and
inflammation of the bronchi and lungs; once in the lungs,
formaldehyde can be absorbed into the bloodi Ingestion of
formaldehyde is followed immediately by inflammation of the
mucosa of the mouth, throat, and gastrointestinal tract (U.S.
•
EPA, 1976). Absorption appears to occur in the intestines
(Malorny _et_ _al_., 1965).
-------
B. Distribution
Following absorption into the blood stream, formaldehyde
disappears rapidly due to condensation reactions with tissue
components and oxidation to formic acid (U.S. EPA, 1976).
C. Metabolism
The main metabolic pathway for formaldehyde appears to
involve initial oxidation to formic acid, followed by further
oxidation to CO2 and I^O. In rats fed radiolabeled formaldehyde,
40% of the radiolabel was recovered as respiratory COj (Buss et
al., 1964). Liver and red blood cells appear to be the major
sites for the oxidation of formaldehyde to formic acid (U.S. EPA,
1976; Malorny et_ _al_., 1965).
D. Excretion
Some of the formic acid metabolite is excreted in the urine
as the sodium salt; most, however, is oxidized to CO- and
eliminated via the lungs (U.S. EPA, 1976).
IV. HEALTH EFFECTS
A. Carcinogenicity
Watanabe et^ al. (1954) observed sarcomas at the site of
injection in 4 of 10 rats given weekly subcutaneous injections of
formaldehyde over 15 months (total dose 260 mg per rat). Tumors
of the liver and omentum were reported in two "'other rats. The
authors do not mention any controls.
»
Groups of mice were exposed to formaldehyde by inhalation at
41 ppm and 81 ppm for one hour a day thrice weekly for 35 weeks.
After the initial 35-week exposure to 41 ppm, the mice were
-------
exposed for an additional 29 weeks at 122 ppm. No tumors or
metaplasias, were found, although numerous changes were observed
in respiratory tissues (Horton et_ ^1^., 1963). The study is
considered flawed for several reasons: mice were not observed
for a lifetime; survival was poor; many tissues were not examined
histologically (U.S. EPA, 1976; U.S. EPA, 1979b).
In a lifetime inhalation study of the combination of hydro-
chloric acid (10.6 ppm) and formaldehyde (14.6 ppm) vapors in
rats, 25/100 animals developed squamous cell carcinomas of the
nasal cavity (Nelson, 1979). Nelson also reported that bis-
chloromethyl ether, a known carcinogen, was detected in the
exposure atmosphere; however, concentrations were not reported.
In a report of interim results (after 16 months of a 2-year
study) from a chronic inhalation study of formaldehyde in rats
and mice, the Chemical industry Institute of Toxicology (1979)
reported that squamous cell carcinomas of the nasal cavity were
observed in three male rats exposed to IS ppm of formaldehyde
(highest dose tested). This type of tumor is extremely rare in
unexposed rat of the strain used in this study.
Following receipt of the CUT (1979) study, the U.S. EPA's
Carcinogen Assessment Group (1979c) concluded that "there is
substantial evidence that formaldehyde is likely to be a human
carcinogen." The unit risk calculation (the lifetime cancer risk
associated with continuous exposure to 1 ug/m of formaldehyde)
based on the preliminary results from CUT is estimated to be 3.4
— 5
xJ-° . This estimate may change when the final results of "the
CUT study become available.
-------
B. Mutagenicity
There is an extensive data base showing that formaldehyde is
mutagenic in several species including mice, Drosophila, plants,
Saccharomyces cerevisiae, Neurospora Crassa, and several species
of bacteria. Formaldehyde also produced unscheduled DNA syn-
thesis in a human cell line. These and other early reports of
mutagenic activity have been reviewed by Auerbach et al. (1977)
and U.S. EPA (1976).
Reports in the recent literature have supported the finding
that formaldehyde is a mutagen: Magana-Schwencke £t_ ^1_. (1978)
in a study with S. cerevisiae; Wilkens and MacLeod (1976) in
E. coli; Martin ^t^ _al_. (1978) in an unscheduled DNA synthesis
test in human HeLa cells? Obe and Beek (1979) in sister chromatid
exchange assays in a Chinese hamster ovary (CHO) cell line and in
cultured human lymphocytes.
C. Teratogenicity
Formaldehyde has been found negative in teratogenicity
assays in beagle dogs (Hurni and Ohden, 1973) and rats (Gofmekler
and Bonashevskaya, 1969).
D. Other Reproductive Effects
No changes were observed in the testes of male rats exposed
to air concentrations of 1 mg/m of formaldehyde.for 10 days
(Gofmekler and Bonashevskaya, 1969).
E. Other Chronic Toxicity
•
Groups of rats, guinea pigs, rabbits, monkeys, and dogs were
continuously exposed to approximately 4.6 mg/m3 of formaldehyde
for 90 days. Hematologic values were normal, however, some
-------
interstitial inflammation occurred in the lungs of all species
(Coon _et_ ai^., 1970).
P. Other Relevant Information
Formaldehyde vapor is quite irritating and is a major cause
of the mucous membrane irritation experienced by people exposed
to smog. Dermatitis from exposure to formaldehyde is a common
problem in workers and consumers who contact the chemical
regularly. Formaldehyde is also known to be an .allergen in
sensitive individuals (U.S. EPA, 1976).
V. AQUATIC EFFECTS
The use of formalin (aqueous formaldehyde) as a chemothera-
peutant for control of fungus on fish eggs and ectoparasites on
fish is a widely accepted and successful technique. However,
unless certain criteria are met formalin may cause acute toxic
effects in fish (U.S. EPA, 1976). The acute toxicity of formalin
to fish has been reviewed by the U.S. Department of Interior
(1973). Analysis of toxicity levels indicates that a wide range
of tolerances exist for different species; striped bass appear to
be the most sensitive with an LCg0 of 15 to 35 ppm.
The LCjQ of formaldehyde for Daphnia magna is reported to
range between 100 to 1000 ppm (Dowden and Bennett, 1965). The
48-hour median threshold limit (TLm) for Daphnia"was about 2 ppm
(McKee and Wolf, 1971).
No effects were observed in crayfish (Procambarus blandingi)
exposed to 100 ul/1 of formalin (concentration unspecified) for
12 to 72 hours (Helm, 1964).
-------
VI. EXISTING GUIDELINES
The OSHA standard for formaldehyde in workplace air is a
time weighted average (TWA) of 3 ppm with a ceiling concentration
of 5 ppm (39 CFR 23540). The NIOSH recommended standard is a
ceiling concentration of 1.2 mg/m (about 0.8 ppm) (NIOSH, 1976).
The ACGIH (1977) recommends a ceiling value of 2 ppm (3 mg/m3).
-------
REFERENCES
American Conference of Governmental Industrial Hygenists (ACGIH).
1977. TLVs: Threshold limit values for chemical substances in
workroom air adopted. Cinninnati, Ohio.
Auerbach, C./ M. Moutschen-Dahen, and J. Moutschen. 1977.
Genetic and cytogenetical effects of formaldehyde and relative
compound. Mutat. Res. 39:317-361 (as cited in U.S. EPA, 1979c).
Bufalini, J.J., Gay, Jr., B.W. and Brubaker, K.L. 1972. Hydro-
gen Peroxide Formation from Formaldehyde Photoxidation and Its
Presence in Urban Atmospheres. Environ. Sci. Technol. ^(9), 816
(as cited in U-.S. EPA 1976).
Buss, J., Kuschinsky, K., Kewitz, H. and Koransky, W. 1964.
Enterale Resorption von Formaldehyde. Arch. Exp. Path. Pharmak.,
247, 380 (as cited in U.S. EPA, 1976).
Chemical Industry Institute of Toxicology. Statement Concerning
Research Findings, October, 1979.
Coon, R.S., Jones, R.A., Jenkins, L.J. and Siegel, J. 1970.
Animal Inhalation Studies on Ammonia, Ethylene Glycol, Formalde-
hyde, Dimethylamine, and Ethanol. Tox. Appl. Pharmacol, 16, 646
(as cited in U.S. EPA, 1976).
Dowden, B.F. and Bennett, H.J. 1965. Toxicity of Selected Chem-
icals to Certain Animals. J. Water Pollut. Cont. Fed., 37(9),
1308 (as cited in U.S. EPA, 1976).
Gofmekler, V.A. and Bonashevskaya, T.I. 1969. Experimental
Studies of Teratogenic Properties of Formaldehyde, Based on
Pathological Investigations. Gig. Sanit., _3_4J5), 266 (as cited
in U.S. EPA, 1976).
Helms, D.R. 1964. The Use of Formalin to Control Tadpoles in
Hatchery Ponds. M.S. Thesis, Southern Illinois University,
Carbondale, 111. (as cited in U.S. EPA, 1976).
Horton, A.W., Tye, R. and Stemmer, K.L. 1963. Experimental
Carcinogenesis of the Lung. Inhalation of'Gaseous Formaldehyde
on an Aerosol Tar by C3H Mice. J. Nat. Cancer Inst., .3_p_(l), 30
(as cited in U.S. EPA, 1976 and U.S. EPA, 1979c).
Hurni, H. and Ohder, H. 1973. Reproduction Study with
Formaldehyde and Hexamethylenetetramine in Beagle Dogs. Food
Cosmet. Toxicol., _11_(3), 459 (as cited in U.S. EPA, 1976).
Kamata, E. 1966. Aldehyde in Lake and Sea Water. Bull. Chem.
Soc. Japan, _3JL(6)' I227
-------
Induction of single strand breaks in DNA and their repair.
Mutat. Res. 50; 181-193 (as cited by U.S. EPA in 1979a).
Malorny, G./ Rietbrock, N. and Schneider, M. 1965. Die Oxyda-
tion des Forraaldeshyds zu Ameiscansaure im Blat. ein Beitrag Zum
Stoffwechsel des Formaldehyds. Arch. Exp. Path. Pharmak., 250>
419 (as cited in U.S. EPA, 1976).
Martin, C.N., A.C. McDermid, and R.A. Garner. 1978. Testing of
known carcinogens and non-carcinogens for their ability to induce
unscheduled DNA synthesis in HeLa cells. Cancer Res. 38; 2621-
2627 (as cited on U.S. EPA, 1979c).
McKee, J.E. and Wolfe, H.W. 1971. Water Quality Criteria, 2nd
Ed., California State Water Resources Control Board, Sacramento,
Publication 3-8 (as cited in U.S. EPA, 1976)
National Institute of Occupational Safety and Health (NIOSH).
1976. Criteria for a recommend standard. Occupational Exposure
to Formaldehyde. NIOSH Publication No. 77-126.
Nelson, N. (New York University) Oct. 19, 1979. Letter to
Federal Agencies. A status report on formaldehyde and HC1
inhalation study in rats.
Obe, G. and B. Seek. 1979. Mutagenic Activity of Aldehydes.
Drug Alcohol Depend., 4(1-2), 91-4 (abstract).
Purcell, T.C. and Cohen, I.R. 1967. Photooxidation of Formal-
dehyde at Low Partial Pressure of Aldehyde. Environ. Sci.
Technol., 1(10), 845 (as cited in U.S. EPA, 1976).
U.S. Department of the Interior. 1973. Formalin as a Thera-
peutant in Fish Culture, Bureau of Sport Fisheries and Wildlife,
PB-237 198 (as cited in U.S. EPA, 1976).
U.S. EPA. 1976. Investigation of selected potential environ-
mental contaminants: Formaldehyde. EPA-560/2-76-009.
U.S. EPA. 1979a. Toxic Substances Control Act Chemical Substance
Inventory, Production Statistics for Chemicals on the Non-Confi-
dential Initial TSCA Inventory.
U.S. EPA. 1979b. Chemical Hazard Information Profile on
Formaldehyde. Office of Pesticides and Toxics Substances.
U.S. EPA. 1979c. The Carcinogen Assessment Group's Preliminary
Risk Assessment on Formaldehyde. Type I - Air Programs. Office
of Research and Development.
Watanabe, F., Matsunaga, T., Soejima, T. and Iwata, Y. 1954.
Study on the carcinogenicity of aldehyde, 1st report. Experi-
mentally produced rat sarcomas by repeated injections of aqueous
solution of formaldehyde. Gann, 45, 451. (as cited in U.S. EPA,
1976 and U.S. EPA, 1979c)
-------
Wilkins, R.J., and H.D. MacLeod. 1976. Formaldehyde induced DNA
protein crosslinks in E. coli. Mutat. Res. 36:11-16.
Windholz, M,, ed. 1976. The Merck Index, 9th ed., Merck and
Company, Inc.
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No. 105
Formic Acid
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C. 20460
APRIL 30, 1980
/OS"/
-------
DISCLAIMER
This report represents a survey of the.potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
FORMIC ACID
Summary
There is no information available on the possible carcinogenic, muta-
genic, teratogenic, or adverse reproductive effects of formic acid.
Formic acid has been reported to produce albuminuria and hematuria in
humans following chronic exposure. Exposure to high levels of the compound
may produce circulatory collapse, renal failure, and secondary ischemic
lesions in the liver and heart.
Formic acid is toxic to freshwater organisms at concentrations ranging
from 120,000 to 2,500,000 ug/1. Daphnia magna was the most sensitive fresh-
water species tested. Marine crustaceans were adversely affected by expo-
sure to formic acid at concentrations from 80,000 to 90,000 ug/1.
/f
/of-3
-------
FORMIC ACID
I. INTRODUCTION
Formic acid (CAS registry number 64-18-6) is a colorless, clear, fuming
liquid with a pungent.odor (Hawley, 1571; Windholz, 1576; Walker, 1566). It
is a naturally formed product, produced by bees, wasps, and ants (Casarett
and Ooull, 1575). Formic acid has widespread occurrence in a large variety
of plants, including pine needles, stinging nettles, and foods (Furia and
Bellanca, 1971; Walker, 1966). Industrially, it is made by heating carbon
monoxide with sodium hydroxide under heat and pressure, or it may be formed
as a coproduct from butane oxidation (Walker, 1966). It has the following
physical and chemical constants (Windholz, 1976; Walker, 1966):
Property
Formula:
Molecular Weight:
Melting Point:
Boiling Point:
Density:
Vapor Pressure:
Solubility:
Demand (1979):
Pure
90%
8535
46.02
8.4°C
100. 5°C
1.220?°
4
-4°C
1.202^
-12°C
1.154;
25
'25
33.1 torr ® 20°C
Miscible in water, alcohol,
and ether; soluble in
acetone,benzene, and toluene
67.5 million lias. (CMR, 1579)
-------
Formic acid is marketed industrially in 85, 90, and 98 percent aqueous solu-
tions. It is also available at 99+ percent purity on a semicommercial
scale. Formic acid is used primarily as a volatile acidulating agent; in
textile dyeing' and finishing, including carpet printing; in chemical syn-
thesis and Pharmaceuticals; and in tanning and leather treatment (CMR, 1579;
Walker, 1966).
II. EXPOSURE
A. Water
Formic acid has been detected in xaw sewage, in effluents from
sewage treatment plants, and in river water (Mueller, et al. 1958). It has
also been identified in effluents from chemical plants and paper mills (U.S.
EPA, 1576).
B. Food
A large variety of plants contain free formic acid; it has been
detected in pine needles, stinging nettle, and fruits (Walker, 1966). It
has been identified in a number of essential oils, including petitgrain
lemon and bitter orange (Furia and Bellanca, 1571). Formic acid is also re-
ported to be a constitutent of strawberry aroma (Furia and Bellanca, 1971).
In the U.S. this chemical may be used as a food additive; allowable limits
in food range from 1 ppm in non-alcoholic beverages to 18 ppm in candy
(Furia and Bellanca, 1571). It may also occur in food as a result of migra-
tion from packaging materials (Sax, 1975).
C. Inhalation
Ambient air concentrations of formic acid range from 4 to 72 ppb
(Graedel, 1578). Emission sources include forest fires, plants, tobacco
smoke, lacquer manufacture, and combustion of plastics (Graedel, 1978). ' It
-------
has also been identified in the liquid condensate from the pyrolysis of
solid municipal waste (Orphey and Jerman, 1970).
0. Dermal
Pertinent data were not found in the available literature.
III. PHARMACOKINETICS
A. Absorption
Acute toxicity studies in animals and poisoning incidents in man
indicate that formic acid is absorbed from the respiratory tract and from
the gastrointestinal tract (Patty, 1563; NIQSH, 1977)'.
B. Distribution
Pertinent data were not found in the available literature.
C. Metabolism
Formate may be oxidized to produce carbon dioxide by the activity
of a catalase-peroxide complex, or it may enter the folate-dependent one
carbon pool following activation and proceed to carbon dioxide via these
reactions (Palese and Tephly, 1975). Species differences in the relative
balance of these two pathways for the metabolism of formate have been postu-
lated in order to explain the greater accumulation of formate in the blood
of monkeys administered methanol, compared to rats similarly treated (Palese
and Tephly, 1975).
D. Excretion
Following intraperitoneal administration of ^C formate to rats,
significant amounts of 14CCL were detected in these samples (Palese and
- * • •.
Tephly, J975).
IV. EFFECTS
A. Pertinent data could not be located in the available literature.'
-------
8. Chronic Toxicity
Chronic human exposure to formic acid has been reported to produce
albuminuria and hematuria (Windholz, 1976).
C. Other Pertinent Information
Formic acid is severely irritating to th skin, eyes, and respira-
tory tract (NIOSH, 1977). Gleason (1969) has indicated that exposure to
high levels of compound may produce circulatory collapse, renal failure, and
secondary ischemic lesions in the liver and heart.
V. AQUATIC TOXICITY
A. Acute Toxicity
Dowden and Bennett (1965) demonstrated a 24-hour LC_0 value of
175,000 ^ig/1 for bluegill sunfish (Lepomis macrochirus) exposed to formic
acid. Bringmann and Kuhn (1959) observed a 48-hour LC5Q vaiue of 120,000
/jg/1 for waterfleas (Daphnia maqna) exposed to formic acid.-
Verschueren (1979) reported that a formic acid concentration of
2,500,000 >jg/l was lethal to freshwater scuds (Gammarus pulex) and 1,000,000
jug/1 was a perturbation threshold value for the fish Trutta iridea.
Portmann and Wilson (1971) determined 48-hour LC5Q values rang-
ing from 80,000 to 90,000 xig/1 for the marine shore crab (Carcinus maenas)
exposed to formic acid in static renewal bioassays.
B. Chronic Toxicity
Pertinent data were not found in the available literature.
C. Plant Effects
McKee and Wolf (1963) reported that formic acid at a concentration
of 100,000xig/l was toxic to the freshwater algae, Scenedesmus sp.
0. Residue
Pertinent data were not found in the available literature.
- \S\ 1 "7^
*V oL*"^'
-------
VI. EXISTING GUIDELINES AND STANDARDS
A. Humsn
The eight-hour, TWA exposure limit for occupational exposure to
formic acid is 5 pprn (ACGIH, 1977).
B. Aquatic
Hahn and Jensen (1977) have suggested an aquatic toxicity rating
range of 100,000 to 1,000,000 /jg/1 based on 96-hour LC_Q values for aqua-
tic organisms exposed to formic acid.
-------
FORMIC ACID
References
American Conference of Government Industrial Hygienists. 1977. Threshold
limit 'values for chemical substances and physical agents in the workroom
environment with intended changes for 1977. American Conference of Govern-
mental Industrial Hygienists, Cincinnati, OH.
Bringmann, G. and R. Kuhn. 1959. The toxic effects of wastewater on aqua-
tic bacteria, algae and small crustaceans. Gesundheits-Ing 80: 115.
Casarett, L.J. and I. Doull. 1975. Toxicology: The Basic Science -of
Poisons. Macmillian Publishing Co., New York.
CMR. 1979. Chemical Profile. Formic acid. Chemical Marketing Reporter,
December 17, p. 9.
Dowden, B.F. and H.J. Bennett. 1965. Tgxicity of selected chemicals to
certain animals. Jour. Water Poll. Contr. Fed. 37: 1308.
Furia, T.E. and N. Bellanca (eds.) 1971. Fenaroli's Handbook of Flavor In-
gredients. The Chemical Rubber Company, Cleveland, 0.
Gleason, M. 1569. Clinical Toxicology of Commercial Products, 3rd ed.
Williams and Wilkins, Baltimore, MO.
Graedel, T.E. 1978. Chemical Compounds in the Atmopshere. Academic Press,
New York.
Hahn, R.W. and P.A. Jensen. 1977. Water Quality Characteristics of Hazard-
ous Materials. Texas A & M University. Prepared for National Oceanographic
and Atmospheric Administration Special Sea Grant Report. NTIS PB-285 946.
Hawley, G.G. (ed.) 1971. The Condensed Chemical Dictionary, 8th ed. Van
Nostrand Reinhold Co, New York.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria Resources Board,
California Water Quality Agency, Publication No. 3-A.
Mueller, H.F., et al. 1958. Chromatographic identification and determina-
tion of organic acids in water. Anal. Chem. 30: 41.
National Institute for Occupational Safety and Health. 1977. Occupational
Diseases: A Guide to Their Recognition. Washington", DC: U.S. DHEW, Publi-
cation No. 77-181.
Orphey, R.D. and R.I. Jerman. 1960. Gas chrpmatographic analysis of liquid
condensates from the pyrolysis of solid municipal waste. Jour. Chroma,to-
graphic Science. 8: 672.
Palese, M. and T. Tephly. 1975. Metabolism of formate in the rat. Jour.
Toxicol. Environ. Health. 1: 13.
- f
-------
Patty, F. 1563. Industrial Hygiene and Toxicology, Vol. II. 2nd ed.
Intersciencs, New York.
Portmsnn, J.E. and K.W. Wilson. 1971. The toxicity of 140 substances to
the brown shrimp arid other marine animals. Ministry of Agriculture, Fisher-
ies and Food, Fisheries Laboratory, Burnham-on-Crouch, Essex, Eng. Shellfish
Leaflet No. 22, AMIC-7701.
Sax, N.I. 1975. Dangerous Properties of Industrial Materials. 4th ed.
Van Nostrand Reinhold, Co, New York.
U.S. EPA. 1976. Frequency of organic compounds identified in water. U.S.
Environ. Prot. Agency, EPA-600/4-76-062.
Verschueren, K. 1979. Handbook of Environmental Data on Organic Chem-
icals. Van Nostrand Reinhold, Co, New York.
Walker, J.F. 1966. Formic acid and derivatives. In: Kirk-Othmer Encyclo-
pedia of Chemical Technologyt 2nd ed. A. Standen, (ed). John Wiley and
Sons, New York. Vol. 10, p. 99.
Windholz, M. (ed.) 1976. The Merck Index. 9th ed. Merck and Co., Rahway,
NJ.
IOS-16
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No. 106
Futnaronitrile
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect a-11 available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
FUMARONITRILE
Summary
Information on the carinogenic, mutagenic, or teratogenic effects of
fumaronitrile was not found in the available literature. LD5Q values for
injected mice and orally dosed rats were 38 and 50 mg/kg, respectively. Re-
ports of chronic toxicity studies were not found in the available literature.
-------
RJMARONITRILE
I. INTRODUCTION
This'profile is based upon relevant literature identified through
mechanized bibliographic searches such as TOXLINE, BIOSIS, Chemical
Abstracts, AGRICOLA and MEDLARS, as well as manual searches. Despite
approximately 70 citations for fumaronitrile, approximately 95 percent of
these concerned the chemistry of fumaronitrile or its reactions with other
chemicals. Apparently, the chief use of fumaronitrile is as a chemical in-
termediate in the manufacture of other chemicals, rather than end .uses as
fumaronitrile per se. Undoubtedly, this accounts for its low profile in the
toxicological literature.
Fumaronitrile or trans-l,2-dicyanoethylene (molecular weight
78.07) is a solid that melts at 96.8°c (Weast, 1975), has a boiling point
of 186°c, and a specific gravity of 0.9416 at 25°C. It is soluble in
water, alcohol, ether, acetone, chloroform, and benzene. Fumarcnitrile is
used as a bactericide (Law, 1968), and as an antiseptic for metal cutting
fluids (Wantanabe, et al., 1975). It is used to make polymers with styrene
numerous other compounds. This compound is easily isomerized to the cis-
form, maleonitrile, which is a bactericide and fungicide (Ono, 1979). It is
conveniently synthesized from primary amides under mild conditions (Cam-
pagna, et al., 1977).
II. EXPOSURE
Human exposure to fumaronitrile from foods cannot be assessed, due
to a lack of monitoring data.
3ioaccumulation data on fumaronitrile were not found in the avail-
able literature.
-------
III. PHARMACOKINETICS
Specific information on the metabolism, distribution, absorption,
or elimination of fumaronitrile was not found in the available literature.
IV. EFFECTS •
A. Carcinogenicity, Mutagenicity, Teratogenicity, Reproductive
Effects, and Chronic Toxicity
Pertinent data could not be located in the available literature.
8. Acute Toxicity
LD50 values for injected mice and orally dosed rats were 38 and
5Q mg/kg, respectively (Zeller, et al., 1969).
V. AQUATIC TOXICITY
Data concerning the effects of fumaronitrile to aquatic organisms
were not found in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
Data concerning existing guidelines and standards for fumaroni-
trile were not found in the available literature.
/0%'S
-------
REFERENCES
Campagna, F., et al. 1977. A convenient synthesis of nitriles from
primary amides under mild conditions. Tetrahendron Letters. 21: 1313.
Law, A. 1968. Fumaronitrile as a bactericide. Chen, Abst. 68: 1135.
Ono, T. 1979. Maleonitrile, a bactericide and fungicide. Chem. Abst.
32: 126.
Wantanabe, M., et al. 1975. Antiseptic for a metal cutting fluid. Chem.
Abst. .82: 208.
Weast, R. 1975. Handbook of Chemistry and Physics^ 56th ed. Chem. Rubber
Publ. Co. p. 2294.
•.
Zeller, H., et al 1969. Toxicity of nitriles: Results of animal
experiments and industrial experiences during 15 years. Chem. Abst.
71: 326.
0
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No. 107
Halomethanes
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
107-
-------
HALOMETHANES'
Summary
The halomethanes are a subcategory of halogenated hydrocarbons. There
is little known concerning the chronic toxicity of these compounds. Acute
toxicity results in central nervous system depression and liver damage. The
fluorohalomethanes are the least toxic. None of the halomethanes have been
demonstrated to be carcinogenic; however, chloro-, bromo-, dichloro-, bromo-
dichloro-, and tribromomethane have been shown to be mutagenic in the Ames
assay. There are no available data on the teratogenicity of the halo-
methanes, although both dichloromethane and bromodichloromethane have been
shown to affect the fetus.
Brominated methanes appear to be more toxic to aquatic life than chlor-
inated methanes. Acute toxicity data is rather limited in scope, but re-
veals toxic concentrations in the range of 11,000 to 550,000 jug/1.
-------
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Halomethanes (U.S. EPA, 1979).
The halomethanes are a sub-category of halogenated hydrocarbons. This
document summarizes the following halomethanes: chloromethane (methyl
chloride); bromomethane (methyl bromide, monobromomethane, embafume); di-
chloromethane (methylene chloride, methylene dichloride, methylene bichlor-
ide); tribromomethane (bromoform); trichlorofluoromethane (trichloromono-
fluoromethane, fluorotrichloromethane, Frigen 11, freon-11, Arcton 9); and
dichlbrodifluoromethane (difluorodichloromethane, Freon 12, Frigen 12, Arc-
ton 6, Genetron' 12, Halon, Isotron 2) and bromodichloromethane. These halo-
methanes are either colorless gases or liquids at environmental temperatures
and are soluble in water at concentrations from 13 x 10 to 2.5 x 10°
jug/1, except for tribromomethane which is only slightly soluble and bromodi-
chloromethane which is insoluble. Halomethanes are used as fumigants, sol-
vents, refrigerants, and in fire extinguishers. Additional information on
the physical/chemical properties of chloromethane, dichloromethane, bromo-
methane, and bromodichloromethane, can be found in the ECAO/EPA (Dec. 1979)
hazard profile on these chemicals.
II. EXPOSURE
A. water
The U.S. EPA (1975) has identified chloromethane, bromomethane, di-
chloromethane, tribromomethane, and bromodichloromethane -in finished drink-
ing waters in the United States. Halogenated hydrocarbons have been found
in finished waters at greater concentrations than in raw waters (Symons, et
»
al. 1975), with the concentrations related to the organic content of the raw •
water. The concentrations of halomethanes detected in one survey of U.S.
drinking waters are:
-------
Halomethanes in the U.S. EPA Region V
Organics Survey (83 Sites)
Compound
Bromodichloromethane
Tribromome thane
Oichloromethane
Percent of
Locations with
Positive Results
78
14
8
Concentrations (mq/1)
Median
0.006
0.001
0.001
Maximum
0.031
0.007
0.007
Source: U.S. EPA, 1975
Symons, et al. (1975) concluded that trihalomethanes resulting from chlori-
nation are widespread in chlorinated drinking waters. An unexplained in-
crease in the halomethane concentration of water samples occurred in the
distribution system water as compared to the treatment plant water.
B. Food
Bromomethane residues from fumigation decrease rapidly from both
atmospheric transfer and reaction with proteins to form inorganic bromide
residues. With proper aeration and product processing, most residual
bromomethane will disappear rapidly due to methylation reactions and
volatilization (Natl. Acad. Sci., 1978; Davis, et al. 1977). The U.S. EPA
(1979) has estimated the weighted average bioconcentration factors for
dichloromethane and tribromomethane to be 1.5 and 14, respectively, for the
edible portions of fish and shellfish consumed by Americans. This estimate
is based on the octanol/water partition coefficient of these two compounds.
Bioconcentration factors for the other halomethanes have not been determined.
C. Inhalation
Saltwater atmospheric background concentrations of chloromethane
and bromomethane, averaging about 0.0025 mg/m and 0.00036 mg/m respec-
tively, have been reported (Grimsrud and Rasmussen, 1975; Singh, et al.
1977). These values are higher than reported average continental background
-------
and urban levels suggesting that the oceans may be a major source of global
chloromethane and bromomethane. Outdoor bromomethane concentrations as high
as O.QOQ85 mg/m may occur near light traffic. This results from the com-
bustion of ethylene dibromide, a component of leaded gasoline (Natl. Acad.
Sci., 1978). Reported background concentrations of dichloromethane in both
continental and saltwater atmospheres are about 0.00012 mg/m , while urban
air concentrations ranged from less than 0.00007 to 0.0005 mg/m . Local
high indoor concentrations can be caused by the use of aerosol sprays or
solvents (Natl. Acad. Sci., 1978). Concentrations of dichlorodifluorometh-
ane and trichlorofluoromethane in the atmosphere over urban areas are sev-
eral times those over rural or oceanic areas. This probably indicates that
the primary modes of entry into the environment, i.e., use of refrigerants
and aerosols, are greater in industrialized and populated areas (Howard, et
al. 1974). Average concentrations of trichlorofluoromethane reported for
urban atmospheres have ranged from nil to 3 x IQ'^ mg/m5, and concen-
-3 2
trations for dichlorofluoromethane ranged from 3.5 x 10 to 2.9 x 10
mg/m .
III. PHARMACOKINETICS
A. Absorption
Absorption via inhalation is of primary importance and is fairly
efficient for the halomethanes. Absorption can also occur via the skin and
gastrointestinal tract, although this is generally more significant for the
nonfluorinated halomethanes than for the fluortJCarbons- (Natl. Acad. Sci.,
1978; Oavis, et al. 1977; U.S. EPA, 1976; Howard, et al. 1974).
107-6
-------
8. Distribution
Halomethanes are distributed rapidly to various tissues after ab-
sorption into the blood. Preferential distribution usually occurs to
tissues witlVhigh lipid content (U.S. EPA, 1979).
C. Metabolism
Chloromethane and bromomethane undergo reactions with sulfhydryl
groups in intracellular enzymes and proteins, while bromochloromethane in
the body is hydrolyzed in significant amounts to yield inorganic bromide.
Dichloromethane is metabolized to carbon monoxide which increases carboxy-
hemoglobin in the blood and interferes with oxygen transport (Natl. Acad.
Sci., 1978). Tribromomethane is apparently metabolized to carbon monoxide
by the cytochrome P-450-dependent mixed function oxidase system (Ahmed, et
al. 1977). The fluorinated halomethanes form metabolites which bind to cell
constituents, particularly when exposures are long-term (Blake and Mergner,
1974). Metabolic data for bromodichloromethane could not be located in the
available literature.
D. Excretion
Elimination of the halomethanes and their metabolites occurs mainly
through expired breath and urine (U.S. EPA, 1979).
IV. EFFECTS
A. Carcinogenicity
None of the halomethanes summarized in this document are considered
to be carcinogenic. Theiss and coworkers (1977). examined the tumorigenic
activity of tribromomethane, bromodichloromethane, --and dichloromethane in
strain A mice. Although increased tumor responses were noted with each, in
»
no case were all the requirements met for a positive carcinogenic response,
as defined by Shimkin and Stoner (1975). Several epidemiologic studies have
/07-7
-------
established an association between trihalomethane levels in municipal drink-
ing water supplies in the United States and certain cancer death rates (var-
ious sites) (Natl. Acad. Sci., 1978; Cantor and McCabe, 1977). Cantor, et
al. (1978) cautioned that these studies have not been controlled for all
confounding variables, and the limited monitoring data that were available
may not have been an accurate reflection of past exposures*
•B. Mutagenicity
Simmon, et al. (1977) reported that chloromethane, bromomethane,
_and dichloromethane were all mutagenic to Salmonella typhimurium strain
TA1QQ when assayed in a dessicator whose atmosphere contained the test com-
pound. Metabolic activation was not required. Only marginal positive re-
sults were obtained with bromoform and bromodichloromethane. Andrews, et
al. (1976) and Jongen, et al. (1978) have confirmed the- positive Ames re-
sults for chloromethane and dichloromethane, respectively. Oichloronethane
was negative in tnitotic recombination in S^ cerevisiae 03 (Simmon, et al.
1977) and in mutagenicity tests in Drosophila (~ilippova, et al. 1967K
Trichlorofluorcmethane and dichlorofluoromethane were negative in the Ames
assay (Uehleke, at al. 1977), and dichlorodifluoromethane in a rat feeding
study (Sherman, 1974) caused no increase in mutation rates over controls.
C. Teratogenicity
Pertinent information could not be located in the available litera-
ture.
0. Other'Reproductive Effects
Gynecologic problems have been reported in female workers exposed
to dichloromethane and gasoline vapors (Vozovaya, 1974). Evidence of fete-
»
embryotoxicity has been noted in rats and mice exposed to dichlorcmethane
(07-?
-------
vapor on gestation days 6 to 15 (Schwetz, et al. 1975). Some fetal anoma-
lies were reported in experiments in which mice were exposed to vapor of
bromodichloromethane at 8375 mg/m , 7 hours/day during gestation days 6 to
15 (Schwetz, et al. 1975).
E. Chronic Toxicity
Schuller, et al. (1978) have observed a. suppression of cellular and
humoral immune response indices in female ICR mice exposed by gavage for 90
days to bromodichloromethane at 125 mg/kg daily. Tribromomethane suppressed
reticuloendothelial system function (liver and spleen phagocytic uptake of
Listeria monocytoqenes) in mice exposed 90 days at daily doses of 125 mg/kg
or less (Munson, et al. 1977,1978). Information pertinent to the chronic
toxicity of the other halomethanes could not be located in the available
literature.
F. Other Relevant Information
In general, acute intoxication by halomethanes appears to involve
the central nervous system and liver function (U.S. EPA, 1979).
V. AQUATIC TOXICITY
A. Acute Toxicity
Acute toxicity studies for halomethanes have obtained acute LC5Q
values for the bluegill sunfish (Lepomis machrochirus) of 11,000 ug/1 for
methylbromide, 29,300 ug/1 for bromoform, 224,000 ug/1 for methylene chlor-
ide and 550,000 for methyl chloride. A static bioassay produced a 96-hour
LC5Q value of 310,000 ug/1 methylene chloride for. the fathead minnow
(Pimephales promelas) while a flow-through assay produced an LC5Q value of
193,000 /jg/1. In freshwater invertebrates two acute studies with Daphnia
/07-J
-------
maqna resulted in LC^ values of 46,500 .ug/1 for bromoform, and 224,000
pg/1 for methylene chloride. In marine fish, LC_Q values for the sheeps-
head minnow (Cyorinodon varieqatus) were 17,900 pg/1 for bromoform and
180,958 ug/1 for methylene chloride. For the tidewater silversides (Menidia
bervllina) LC5Q values of 12,000 pg/1 for methylbromide and 147,610 ug/1
for methylene chloride were obtained. Adjusted LC^ values for the marine
mysid shrimp (Mysidopsis bahia) were 24,400 ug/1 for bromoform and 256,000
pg/1 for methylene chloride (U.S. EPA, 1979).
8. Chronic Toxicity
The only chronic value for an aquatic species was 9,165 jug/1 for
the sheepshead minnow.
C. Plant Effects
Effective concentrations for chlorophyll a and cell numbers in
freshwater algae Selenastrum capricomutum ranged from 112,000 to 116,000
ug/1 for bromoform and 662,000 pg/1 for methylene chloride, while effective
concentrations for the marine algae (Sketonema costatum) were reported as
11,500 to 12,300 pg/1 for bromoform and 662,000 ug/1 for methylene chlor-
ide (U.S. EPA, 1979).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed.
A. Human
Positive associations between human cancer mortality rates and tri-
halomethanes (chloroform, bromodichloromethane, tribromomethane) in drinking
107-10
-------
water have been reported. There have also been positive results for tribro-
momethane using strain A/St. male mice in the pulmonary adenoma bioassay.
Bromomethane, chloromethane, dichloromethane, bromodichloromethane and tri-'
bromomethane have been reported as mutagenic in the Ames test without meta-
bolic activation. Dichlorodifluoromethane caused a significant increase in
mutant frequency in Neurospora crassa (mold), but was negative in the Ames
test. No data implicating trichlorofluoromethane as a possible carcinogen
have been published.
Because positive results for the mutagenic endpoint correlate with
positive results in in vivo bioassays for oncogenicity, mutagenicity data
for the halomethanes suggests that several of the compounds might also be
carcinogenic. Since carcinogenicity data currently available for the halo-
methanes were not adequate for the development of water quality criteria
levels, the draft criteria recommended for chloromethane, bromomethane, di-
chloromethane, tribromomethane and bromodichloromethane are the same as that
for chloroform, 2 /jg/1.
Chloromethane: OSHA (1976) has established the maximum acceptable
time-weighted average air concentration for daily 8-hour occupational expo-
sure at 219 mg/m .
Bromomethane: OSHA (1976) has a threshold limit value of 80
mg/m for bromomethane, and the American Conference of Governmental Indus-
trial Hygienists (ACGIH, 1971) has a threshold limit value of 78 mg/m3. .
Dichloromethane: OSHA (1976a,b) has established an 8-hour time-
weighted average for dichloromethane of 1,737 mg/m , however, NIOSH (1976)
has recommended a 10-hour time-weighted average exposure limit of 261
mg/m of dichloromethane in the presence of no more carbon monoxide than
9.9 mg/m3.
txrr
7-//
-------
Tribromomethane: QSHA (1976a,b) has established an 3-hour time-
weighted average for tribromomethane of 5 mg/m .
Bromodichloromethane: There is no currently established occupa-
tional exposure standard for bromodichloromethane.
Trichlorofluoromethane and dichlorodifluoromethane: The current
OSHA (1976) 8-hour time-weighted average occupational standards for tri-
chlorofluoromethane and dichlorodifluoromethane are 5,600 and 4,950 mg/m ,
respectively. The U.S. EPA (1979) draft'water quality criteria for tri-
chlorofluoromethane and dichlorodifluoromethane -are 32,000 and 3,000 /jg/1,
respectively.
8. Aquatic
Draft criteria for the protection of freshwater life have been
derived as 24-hour average concentrations for the following halomethanes:
methylbromide - 140 ug/1 not to exceed 320 ug/1; bromoform - 840 jjg/1 not to
exceed 1,900 ug/1; methylene chloride - 4,000 ug/1 not to exceed 9,000 ug/1;
and methyl chloride - 7,000 jug/1 not to exceed 16,000 ug/1.
Draft criteria for the protection of marine life have been derived
as 24- hour average concentrations for the following halomethanes: methyl-
bromide 170 ug/1 not to exceed 380 ug/1; bromoform - 180 pg/1 not to exceed
420 ug/1; methylene chloride - 1,900 jug/1 not to exceed 4,400 pg/1; and
methyl chloride - 3,700 ug/1 not to exceed 3,400 ug/1.
-------
HALOMETHANES
REFERENCES
Ahmed, A.E., et al. 1977. Metabolism of haloforms to carbon
monoxide, I. Ijn vitro studies. Drug. Metab. Dispos. 5: 198.
(Abstract).
American Conference of Governmental and Industrial Hygienists
1971. Documentation of the threshold limit value for sub-
stances in workroom air. Cincinnati, Ohio.
Andrews, A.W., et al. 1976. A comparison of the mutagenic
properties of vinyl chloride and methyl chloride. Mutat.
Res. 40: 273.
Blake, D.A., and G.W. Mergner. 1974. Inhalation studies on
the biotransf ormation and elimination of '(^C)-trichloro-
fluoromethane and (14C)-diphlorodifluoromethane in beagles.
Toxicol. Appl. Pharmacol. 30: 396.
Cantor, K.P., and L.J. McCabe. 1977. The epidemiologic
approach to the evaluation of organics in drinking water.
Proc. Conf. Water Chlorination: Environ. Impact and Health
Effects. Gatlinburg, Tenn. Oct. 31-Nov. 4.
Cantor, K.P. et al. 1978. Associations of halomethanes in
drinking water with cancer mortality. Jour. Natl. Cancer
Inst. (In press).
Davis, L.N., et al. 1977. Investigation of selected poten-
tial environmental contaminants: monohalomethanes. EPA 560/
2-77-007; TR 77-535. Final rep. June, 1977, on Contract No.
68-01-4315. Off. Toxic Subst. U.S.' Environ. Prot. Agency,
Washington, D.C.
Filippova, L.M., et al. 1967. Chemical mutagens. IV.
Mutagenic activity of geminal system. Genetika 8: 134.
Grimsrud, E.P., and R.A. Rasmussen. 1975. Survey and analy-
sis of halocarbons in the atmosphere by gas chromatography-
mass spectrometry. Atmos. Environ. 9: 1014.
Howard, P.H., et al. 1974. Environmental hazard assessment
of one and two carbon fluorocarbons. EPA 560/2-75-003. TR-
74-572-1. Off. Toxic Subst. U.S. Environ. Prot. Agency,
Washington, D.C.
Jongen, W.M.F., et al. 1978. Mutagenic effect of dichloro-
methane on Salmonella typhimurium. Mutat. Res. 56: 246.
-Tj? V—-
jf IA. I ^
-------
Munson, A.E.,.et al. 1977. Functional activity of the re-
ticuloendothelial system in mice exposed to haloalkanes for
ninety days. Abstract. 14th Natl. Reticuloendothelial Soc.
Meet. Tucson, Ariz. Dec. 6-9.
Munson, A.E., et al. 1978. Reticuloendothelial system func-
tion in mice exposed to four haloalkanes: Drinking water con-
taminants.- Submitted: Soc. Toxicol. (Abstract).
National Academy of Sciences. 1978. Nonfluorinated halo-
methanes in the environment. Washington, D.C.
National Institute for Occupational Safety and Health. 1976.
Criteria for a recommended standard: Occupational exposure to
methylene chloride. HEW Pub. No. 76-138. U.S. Dep. Health
Edu. Welfare, Cincinnati, Ohio.
Occupational Safety and Health Administration. 1976. Gener-
al industry standards. OSHA 2206, revised January, 1976.
U.S. Dept. Labor, Washington, D.C.
Schuller, G.B., et al. 1978. Effect of four haloalkanes on
humoral and cell mediated immunity in mice. Presented Soc.
Toxicol. Meet.
Schwetz, B.A., et al. 1975. The effect of maternally in-
haled trichloroethylene, perchloroethylene, methyl chloro-
form, and methylene chloride on embryonal and fetal develop-
ment in-mice and rats. Toxicol. Appl. Pharmacol. 32: 84.
Sherman, H. 1974. Long-term feeding studies in rats and
dogs with dichlorodifluoromethane (Freon 12 Food Freezant).
Unpubl. rep. Haskell Lab.
Shimkin, M.B., and G.D. Stoner. 1975. Lung tumors in mice:
application to carcinogenesis bioassay. Adv. Cancer Res.
21: 1.
Simmon, V.F., et al. 1977. Mutagenic activity of chemicals
identified in drinking water. S. Scott, et al., eds. In
Progress in genetic toxicology.
Singh, H.B., et al. 1977. Urban-non-urban relationships of
halocarbons, SFg, N20 and other atmospheric constituents.
Atmos. Environ. 11: 819.
Symons, J.M., et al. 1975. National organics "reconnaissance
survey for halogenated organics. Jour. Am.-• Water Works
Assoc. 67: 634.
Theiss, J.C., et al. 1977. Test for carcinogenicity of or,-
ganic contaminants of United States drinking waters by pul-
monarv tumor response in strain A mice. Cancer Res. 37:
2717."
-------
Uehleke, H., et al. 1977. Metabolic activation of haloal-
kanes and tests _in vitro for mutagenicity. Xenobiotica 7:
393.
U.S. EPA. 1975. Preliminary assessment of suspected carcin-
ogens in drinking water, and appendices. A report to Con-
gress, Washington, D.C.
U.S. EPA. 1976. Environmental hazard assessment report,
major one- and two- carbon saturated fluorocarbons, review of
data. EPA 560/8-76-003. Off. Toxic Subst. Washington,
D.C.
U.S. EPA. 1979a. Halomethanes: Ambient Water Quality Cri-
teria. (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment Of-
fice. Halomethanes: Hazard Profile (Draft).
Vozovaya, M.A. 1974. Gynecological illnesses in workers of
major industrial rubber products plants occupations. Gig.
Tr. Sostoyanie Spetsificheskikh Funkts. Rab. Neftekhim.
Khim. Prom-sti. (Russian) 56. (Abstract).
Wilkness, P.E., et al. 1975. Trichlorofluoromethane in the
troposphere, distribution and increase, 1971 to 1974.
Science 187: 832.
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No. 108
Heptachlor
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
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DISCLAIMER
This report represents a survey of the potential health*
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
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SPECIAL NOTATION
U.S; EPA1s Carcinogen Assessment Group (CAG) has evaluated
heptachlor and has found sufficient evidence to indicate
that this compound is carcinogenic.
-IAS*-
/Of" 3
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HEPTACHLOR
Summary
Heptachlor is an organochlorinated cyclodiene insecticide, and has been
used mostly in its technical, and hence, impure form, in most bioassays up
to the present. Nevertheless, it has been found that heptachlor and its
metabolite, heptachlor epoxide, induce liver cancer in mice and rats. Hep-
tachlor was mutagenic in two mammalian assays but not in the Ames test. In
long-term reproductive studies in rats, heptachlor caused reduction in lit-
ter size, decreased lifespan in suckling rats, and cataracts in both parents
and offspring. Little is known about other chronic effects of heptachlor
except that it induces alterations in glucose homeostasis. It causes con-
vulsions in humans. Heptachlor epoxid_e, its major metabolite, accumulates
in adipose tissue and is more acutely toxic than the parent compound. ,
Numerous studies indicate that heptachlor is highly toxic, both acutely
and chronically, to aquatic life. Ninety-six hour LC-Q values for fresh-
water fish range from 7.0 ug/1 to 320 pg/1 and 24 to 96-hour LC5Q values
for invertebrates from 0.9 ug/1 to 80 pg/1. The 96-hour values for salt-
water fish range from 0.8 to 194 ug/1. In a 40-week life cycle test with
fathead minnows, the determined no-adverse-effect concentration was 0.86
pg/1. All fish exposed at 1.84 ug/1 to heptachlor were dead after 60 days.
The fathead minnow bioconcentrated heptachlor and its biodegradation pro-
duct, heptachlor epoxide, 20,000-fold over ambient water concentrations
after 276 days exposure. The saltwater sheepshead minnow accumulated these
two compounds 37,000-fold after 126 days exposure." Heptachlor epoxide has
approximately the same toxicity values as heptachlor.
/6 8"',
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I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Heptachlor (U.S. EPA, 1979).
Heptachlor is a broad spectrum insecticide of the group of polycyclic
chlorinated hydrocarbons called cyclodiene insecticides. From 1971 to 1975
the most important use of heptachlor was to control agricultural soil in-
sects (U.S. EPA, 1979).
Pure, heptachlor (dnemical name l,4,5,6,7,8,8-heptachloro-3a,4,7,7a-
tetrahydro-4,7-fnethanoindene; C,J-lcCl7; molecular weight 373.35) is a
white crystalline solid with a camphor-like odor. It has a vapor pressure
of 3 x 10~4 mm Hg at 25°C, a solubility in water of 0.056 mg/1 at 25 to
29°C, and is readily soluble in relatively nonpolar solvents (U.S. EPA,
1979). i
Technical grade heptachlor (approximately 73 percent heptachlor; 21
percent trans chlordane, 5 percent heptachlor epoxide and 2 percent chlor-
dene isomers) is a tan, soft, waxy solid with a melting range of 46 to
74°C and a vapor pressure of 4 x 10"4 mm Hg at 25°C (U.S. EPA, 1979).
Since 1975, insecticidal uses and production volume have declined ex-
tensively because of the sole producer's voluntary restriction and the sub-
sequent issuance of a registration suspension notice by the U.S. EPA, August
2, 1976, for all food crop and home use of heptachlor. However, significant
commercial use of heptachlor for termite control and non-food crop pests
continues. - \-
Heptachlor persists for prolonged periods in the environment. It is
converted to the more toxic metabolite, heptachlor epoxide, in the soil
»
(Lichtenstein, 1960; Lichtenstein, et al. 1970, 1971; Nash and Harris,
1972), in plants (Gannon and Decker, 1958), and in mammals (Oavidow and
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Radomski, 1953a). Heptachlor, in solution or thin films, undergoes photode-
composition to photoheptachlor (Benson, et al. 1971) which is more toxic
than the parent compound to insects (Khan, et al. 1969), aquatic inverte-
brates (Georgacakis and Khan, 1971; Khan, et al. 1973) and rats, bluegill
(Lepomis machrochirus) and goldfish (Carassius auratus) (Podowski, et al.
1979). Photoheptachlor. epoxide is also formed in sunlight., and is more toxic
than the parent compound (Ivie, et al. 1972).
Heptachlor and its epoxide will bioconcentrate in numerous species and
will accumulate in the food chain (U.S. EPA, 1979).
II. EXPOSURE
A. Water
Various investigators have detected heptachlor and/or heptachlor
epoxide in the major river basins of the U.S. at a mean concentration for
both of 0.0063 pg/1 (U.S. EPA, 1976). Levels of heptachlor ranged from .001
jjg/1 to 0.035 ug/L and heptachlor/heptachlor apoxide were found in 25 per-
cent of all river samples (Breidenbach, et al. 1967). Average levels in
cotton sediments are around 0.8 ug/kg (U.S. EPA, 1979).
B. Food
In their market basket study (1974-1975) for 20 different cities,
the FDA showed that 3 of 12 food classes contained residues of heptachlor
epoxide ranging from 0.0006 to 0.003 ppm (Johnson and Manske, 1977). Hepta-
chlor epoxide residues greater than 0.03 mg/kg have been found in 14 to 19
percent of red meat, poultry, and dairy products "sampled from 1964-1974
(Nisbet, 1977). Heptachlor and/or heptachlor epoxide were found in 32 per-
cent of 590 fish samples obtained nationally, with whole fish residues from
»
0.01 to 8.33 mg/kg (Henderson, et al. 1969).
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The U.S. EPA (1979) has estimated the weighted average bioconcen-
tration factor for heptachlor in the edible portions of fish and shellfish
consumed by Americans to be 5,200. This estimate is based on measured
steady-state bioconcentration factors- for sheepshead minnows, fathead min-
nows, and spot (Leiostomus xanthuru).
Human milk can be contaminated with heptachlor epoxide. A nation-
wide survey indicated that 63.1 percent of 1,936 mothers' milk samples con-
tained heptachlor epoxide residues ranging from 1 to 2,050 ug/1 (fat adjust-
ed) (Savage, 1976). Levels of 5 ug/1 of the epoxide have been reported in
evaporated milk (Ritcey, et al. *1972).
C. Inhalation
Heptachlor volatilizes from treated surfaces, plants, and soil
(Nisbet, 1977). Heptachlor, and to a lesser extent heptachlor epoxide,. are
widespread in ambient air with typical mean concentratons of approximately
0.5 ng/m . On the basis of this data, typical human exposure was calcu-
lated to be 0.01 ug/person/day (Nisbet, 1977). Thus, it appears that inha-
lation is not a major route for human exposure to heptachlor. Air downward
from treated fields may contain concentrations as high as 600 ng/m . Even
after three weeks, the air from these fields may contain up to 15.4 ng/m3.
Thus, sprayers, farmers and nearby residents of sprayed fields may receive
significant exposures (Nisbet, 1977).
0. Dermal
Gaines (1960) found rat dermal LD^g "values • af 195 and 250 mg/kg
for males and females, respectively, compared with oral l-Dc0's of 100 and
162 mg/kg, respectively, for technical heptachlor. Thus, dermal exposures
»
roay be important in humans under the right exposure conditions.
(07-7
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III. PHARMACOKINETICS
A. Absorption
Heptachlor is readily absorbed from the gastrointestinal tract
(Radomski and Davidow, 1953; Mizyukova and Kurchatov, 1970; Matsumura and
Nelson, 1971). The degree- to which heptachlor is absorbed by inhalation has
not been reported (Nisbet, 1977). Percutaneous absorption is less efficient
than through the gastrointestinal tract, as indicated by comparison of the
acute toxicity resulting from dermal vs. oral exposures (Gaines, 1960).
8. Distribution and Metabolism
Heptachlor reaches all tissues of the rat within one hour of a sin-
gle oral dose and is metabolized to heptachlor epoxide. Heptachlor has been
found to bind to hepatic cytochrome P-450, an enzyme of the liver hydroxyla-
tion system (Donovan, et al. 1978). By the end of one month traces of heq-
tachlor epoxide were detectable only in fat and liver. Levels of the epox-
ide in fatty tissues stabilized 3 to 6 months after a single dose of hepta-
chlor (Mizyukova and Kurchatov, 1970). Human fat samples may also contain
nonachlor residues derived from technical heptachlor or chlordane exposure
(Sovocool and Lewis, 1975). When experimental animals were fed heptachlor
for two months, the highest levels of heptachlor epoxide were found in fat,
with lower levels in liver, kidney and muscle and none in brain (Radomski
and Davidow, 1953). There is evidence to show that the efficiency of con-
version to the epoxide in humans is less than in the rat (Tashiro and Matsu-
mura, 1978). Various researchers have found that heptachlor epoxide is more
toxic to mammals than the parent compound (U.S. EPA', 1979). There is an ap-
proximate ten to fifteen-fold increase in heptachlor residues found in body
fat, milk butterfat, and in the fat of poultry, eggs, and livestock as com-
pared to residue levels found in their normal food rations (U.S. EPA, 1976).
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Heptachlor and its epoxide pass readily through the placenta (U.S. EPA,
1979). The epoxide can be found in over 90 percent of the U.S. population
at approximate mean levels of 0.08 to 0.09 mg/kg (Kutz, at al. 1977).
C. Excretion
Elimination of non-stored heptachlor and its metabolites occurs
within the first five days, chiefly in the feces and to a lesser extent in
the urine (Mizyukova and Kurchatov, 1970). In addition, a primary route for
excretion in females is through lactation, mostly as the epoxide. Levels
can be as high as 2.05 mg/1 (Jonsson, et al. 1977).'
IV. EFFECTS
A. Carcinogenicity
The studies on rats have generated, much controversy, especially for
doses around 10 mg/kg/day. However, heptachlor and/or heptachlor epoxide (1
to 18 mg/kg/day of unspecified purities) have induced hepatocellular carci-
nomas in mice during three chronic feeding studies. Heptachlor epoxide
(also of unspecified purity) has produced the same response in rats in one
study (Epstein, 1976; U.S. EPA, 1977). Clearly, studies with chemicals of
specified purity still need to be performed to establish if contaminants or
species differences are responsible for the observed effects.
8. Mutagenicity
Heptachlor has been reported to be mutagenic in mammalian assays
but not in bacterial assays. Heptachlor (1 to 5 mg/kg) caused dominant
lethal changes in male rats as demonstrated by the number 'of resorbed fetus-
es in intact pregnant rats (Carey, et al. 1973). Bone marrow cells of the
treated animals showed increases in the incidence of abnormal mitoses, chro-
»
matid abnormalities, pulverization, and translocation. 9oth heptachlor and
heptachlor epoxide induced unscheduled DNA synthesis in SV-AO transformed
tlt^j /n -
* I ai V "
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human cells (VA-4) in culture with metabolic activation (Ahmed, et al.
1977). Neither heptachlor nor heptachlor epoxide was mutagenic for Salmo-
nella tvphimurium in the Ames test (Marshall, et al. 1976).
C. Teratogenicity
In long-term feeding studies with heptachlor, cataracts developed
in the parent rats and in the offspring shortly after their eyes opened
(Mestitzova, 1967).
D. Other Reproductive Effects
In long-term feeding studies in rats, heptachlor caused a marked
decrease in litter size and a decreased lifespan in suckling rats (Mestit-
zova, 1967). However, newborn rats were less susceptible to heptachlor than
adults (Harbison, 1975).
E. Chronic Toxicity
Little information on chronic effects is available. When admini-
stered to rats in small daily doses over a prolonged period of time, hepta-
chlor induced alterations in glucose homeostasis which were thought to be
related to an initial stimulation of the cyclic AMP-adenylate cyclase system
in liver and kidney cortex (Kacew and Singhal, 1973, 1974; Singhal and
Kacew, 1976).
F. Other Relevant Information
Heptachlor is a convulsant (St. Omer, 1971). Rats fed protein-de-
ficient diets are less susceptible to heptachlor and have lower heptachlor
epoxidase activities than pair-fed controls (Webb and Miranda, 1973; Miran-
da, et al. 1973; Miranda and Webb, 1974). Pnenobarbital potentiates the
toxicity of heptachlor in newborn rats (Harbison, 1975). Many liver and
brain enzymes are affected by heptachlor down to 2 mg/kg doses in pigs (U.S.
EPA, 1979).
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V. AQUATIC TOXICITY
A. Acute Toxicity
•Numerous studies on the acute toxicity of heptachlor to freshwater
fish and invertebrate species have been conducted. Many of these studies on
heptachlor have used technical grade material. Available data suggest that
toxicity of the technical material is attributable to the heptachlor and its
degradation product, heptachlor epoxide, and that toxicities of these com-
pounds are similar (Schimmel, at al. 1976). In addition, during toxicity
testing with heptachlor, there is apparently an appreciable loss of hepta-
chlor by volatilization due to aeration or mixing, leading to variability of
static and flow-through results (Schimmel, et al. 1976; Goodman, at al.
1978).
Fish are less sensitive to heptachlor than are invertebrate spe.-
cies. Ninety-six hour l_C50 values for fish range from 7.0 ug/1 for the
rainbow trout, Salmo qairdneri, (Macek, et al. 1969) to 320 ug/1 for the
.goldfish (Carassius auratus). Ten days after a dose of 0.863 ug/g C-
heptachlor to goldfish, 91.2 percent was unchanged, 5.4 percent was hepta-
chlor epoxide, 1 percent was hydroxychlordene, 1.1 percent was 1-hydroxy-
2,3-epoxychlordene and 1.2 percent was a conjugate (Feroz and Khan, 1979).
Reported values for invertebrate species range from 0.9 pg/1 for the stone-
fly, Pteronarcella badia, (Sanders and Cope, 1968) to 80 ug/1 for the clado-
ceran (Simoceohalus serrulatis). These data indicate that heptachlor is
generally highly toxic in acute exposures.
The relative toxicity of heptachlor to its' common degradation pro-
duct, heptachlor epoxide, is 52 ug/1 to 120 ug/1-as determined in a 26-hour
»
LCs Oaohnia maona bioassay (Frear and Soyd, 1967).
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Heptachlor has been shown to be acutely toxic to a number of salt-
water fish and invertebrate species. The 96-hour LC5Q values derived from
flow-through tests on four fish species range from 0.85 to 10.5 jjg/1 (Hansen
and Parrish, 1977; Korn and.Earnest, 1974; Schimmel, et al. 1976). Results
of static exposures of eight fish species are from 0.8 to 194 ug/1 (Eisler,
1970; Kutz, 1961). The commercially valuable pink shrimp (Penaeus duorarum)
is especially sensitive, with reported 96-hour values as low as 0.03 jjg/1
(Schimmel, et al. 1976). Other species such as the blue crab, Callinectes
sapidus, and American oyster, Crassostrea virginica, are 2,100 and 950 times
less sensitive, respectively, than the pink shrimp (Butler, 1963).
B. Chronic Toxicity
In a 40-week life cycle test with fathead minnows (Pimephales prom-
elas), the determined no-adverse-effect concentration was 0.86 jjg/1. All
•••IBM** ^
fish exposed to 1.84 ug/1 were dead after 60 days (Macek, et al. 1976).
Valid chronic test data are not available for any aquatic invertebrate spe-
cies.
In a 28-day exposure starting with sheepshead minnow embryo (Cypri-
nodon varieqatus) growth of fry was significantly reduced at 2.04 jug/l, the
safe dose being at 1.22 jug/1 (Goodman, et al. 1978). In an 18-week partial
life cycle exposure with this same species, egg production was significantly
decreased at 0.71 jug/1 (Hansen and Parrish, 1977).
C. Plant Effects
In the only study available, a concentration of 1,000 jug/1 caused a
94.4 percent decrease in productivity of a natural- saltwater phytoplankton
community after a 4-hour exposure to heptachlor (Butler, 1963).
0. Residues
The amount of total residues, heptachlor and heptachlor epoxide,
accumulated by fathead minnows after 276 days of exposure was found to be
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20,000 times the concentration in water (Macek, et al. 1976). Heptachlor
epoxide constituted 10-24 percent of the total residue. Adult sheepshead
minnows exposed to technical grade material for 126 days accumulated hepta-
chlor and heptachlor epoxide 37,000 times over the concentration of ambient
water (Hansen and Parrish, 1977). Juvenile sheepshead minnows exposed in
two separate experiments for 28 days bioconcentrated heptachlor 5,700 and
7,513 times the concentration in the water (Hansen and Parrish, 1977; Good-
man, et al. 1976).
VI. EXISTING GUIDELINES AND STANDARDS
The issue of the carcinogenicity of heptachlor in humans is being re-
viewed; thus, it is possible that the human health criterion will be changed.
A. Human
Based on the data for the carcinogenicity of heptachlor epoxide in
mice (Davis, 1965), and using the "one-hit" model, the U.S. EPA (1979) has
estimated levels of heptachlor/heptachlor epoxide in ambient water which
will result in risk levels of human cancer as specified in the table below. ,
Exposure Assumptions Risk Levels and Corresponding Draft Criteria
(per day)
0 10-7 10-6 iQ-5
2 liters of drinking water 0 0.0023 ng/1 0.023 ng/1 0.23 ng/1
and consumption of 13.7
grams fish and shellfish.
Consumption of fish and 0 0.0023 ng/1 0.023 ng/1 0.23 ng/1
shellfish only.
Existing Guidelines and Standard? ._
Agency Published Standard ' Reference
Occup. Safety 500 ug/m^* on skin from air Natl. Inst. Occyp.
Health Admin. Safety Health, 1977
Am. Conf. Gov. 500 ug/rn-^ inhaled Am. Conf. Gov. Ind.
Ind. Hyg. (TLV) Hyg., 1971
world Health Org. 0.5 ug/kg/day acceptable Natl. Acad. Sci., 1977
daily intake in diet
/ o r-LL
*T LA f I .
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U.S. Publ. Health Recommended drinking water Natl. Acad. Sci., 1977
Serv. Adv. Comm. standard (1968) 18 jjg/1 of
heptachlor and 18 )jg/l of
heptachlor epoxide
*Time-weighted average
B. Aquatic
For heptachlor the. draft criterion to protect freshwater aquatic
life is 0.0015 jjg/1 as a 24-hour average,- not to exceed 0.45 ug/1 at any
time. To protect saltwater aquatic life, the draft criterion is 0.0036 ug/1
as a 24-hour average, not to exceed 0.05 ug/1 at any time (U.S. EPA, 1979).
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HEPTACHLOR
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14
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I
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sions in the rat and cockerel. Jour. Neurochem. 18: 365.
Sanders, H.O., and O.B. Cope. 1968. The relative toxicities
of several pesticides to naiads of three species of stone-,
flies. Limnol. Oceanogr. 13: 112.
-------
Savage, E.P. 1976. National study to determine levels
of chlorinated hydrocarbon insecticides in human milk.
Unpubl. rep, submitted to U.S. Environ. Prot. Agency.
Schimmel, S.C., et al. 1976. Heptachlor: Toxicity to
and uptake by several estuarine organisms. Jour. Toxicol.
Environ. Health 1: 955.
Singhal, R.L., and S. Kacew. 1976. The role of cyclic
AMP in chlorinated hydrocarbon-induced toxicity. Federation
Proc. 35: 2618..
Sovocool, G.W., and R.G.. Lewis. 1975. The identification
of trace levels of organic pollutants in humans: compounds
related to chlordane heptachlor exposure. Trace Subst.
Environ. Health 9: 265.
Tashiro, S., and P. Matsumura. 1978. Metabolism of trans-
monachlor and related chlordane components in rats and man.
Arch. Environ. Contain. Toxicol. 7: 113.
U.S. EPA. 1976. Chlordane and heptachlor in relation to
man and the environment. EPA 540/476005.
U.S. EPA. 1977. Risk assessment of chlordane and hepta-
chlor. Carcinogen Assessment Group. U.S. Environ. Prot.
Agency, Washington, D.C. Unpubl. rep.
U.S. EPA. 1979. Heptachlor: Ambient Water Quality Cri-
teria (Draft).
Webb, R.E.., and C.L. Miranda. 1973. Effect of the quality
of dietary protein on heptachlor toxicity. Food Cosmet.
Toxicol. 11: 63.
i 1 >-*x
/ c* / (/ -
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No. 109
Heptachlor Epoxide
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
HEPTACHLOR EPOXIDE
SUMMARY
Heptachlor epoxide is the principal metabolite of hepta-
chlor in microorganisms, soil, plants, animals, and probably
man, and is more acutely toxic than the parent compound.
Its intrinsic effects are difficult to gauge since most
of the relevant data in the literature is a side product
of the effects of technical heptachlor. Heptachlor epoxide
(mostly of unspecified purity) has induced liver cancer
in mice and rats and was mutagenic in a mammalian assay
system, but. not in a bacterial system. Pertinent information
on teratogenicity and chronic toxicity could not be located
in the available literature. Heptachlor epoxide accumulates
in adipose tissue..
The chronic value for the compound derived from a 26-
hour exposure of Daphnia magna is reported to be 120 ug/1,
approximately the same value obtained for heptachlor.
Fathead minnows bioconcentrated heptachlor and its
biodegradation product, heptachlor expoxide, 20,000 times
after 276 days of exposure. Heptachlor epoxide constituted
between 10 and 24 percent of the total residue.
/09-J
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HEPTACHLOR EPOXIDE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Heptachlor (U.S. EPA, 1979a).
Heptachlor epoxide is the principal metabolite of hepta-
chlor in microorganisms, soil, plants, and mammals, although
the conversion in man may be less efficient (Tashiro and
Matsumura, 1978) . Since much of the data has been obtained
as a side-product of the effects of technical heptachlor
and the purity of the epoxide is often unspecified, there
is a paucity of reliable literature on its biological ef-
fects (U.S. EPA, 1979a).
Heptachlor epoxide is relatively persistent in the
environment but has been shown to undergo photodecomposi-
tion to photoheptachlor epoxide (Graham, et al. 1973).
Photoheptachlor epoxide has been reported to exhibit greater
toxicity than heptachlor epoxide (Ivie, et al. 1972). Hepta-
chlor epoxide will bioconcentrate in numerous species and
will accumulate in the food chain (U.S. EPA, 1979a).
II. EXPOSURE
A. Water
Heptachlor epoxide has been detected by various
investigators in the major river basins of the United States
(U.S. EPA, 1979a) at levels ranging from 0.001 to 0.020
ug/1 (Breidenbach, et al. 1967).
B. Food
The PDA showed in their market basket survey (1974-
1975) of 20 different cities that 3 of 12 food classes con-
-------
tained residues of heptachlor epoxide ranging from 0.0006
to 0.003 ppm (Johnson and Manske, 1977). Heptachlor epoxide
residues greater than 0.03 mg/kg were found in 14 to 19
percent of red meat, poultry, and dairy products during
the period 1964-1974. Average daily intake was estimated
to be between 0.3 to 3 ug from 1965 to 1974 (Nisbet, 1977).
Heptachlor and/or heptachlor epoxide were found in 32 per-
cent of 590 fish samples obtained nationally, with whole
fish residues containing 0.01 to 8.33 mg/kg (Henderson,
et al. 1969) . Human milk can be contaminated with hepta-
chlor epoxi.de; 63 percent of samples in 1975-1976 contained
1 to 2,050 ug/1 (fat adjusted) (Savage, 1976). Levels of
5 ng/1 have been reported in evaporated milk. Cooking did
not reduce the residue level in poultry meat by more than
one-half (Ritcey, et al. 1972).
The U.S. EPA (1979a) has estimated the weighted
average bioconcentration factor for heptachlor to be 5,200
for the edible portions of fish and shellfish consumed by
Americans.. This estimate is based on the measured steady-
state bioconcentration studies in three species of fish.
Since heptachlor epoxide is the primary metabolite of hepta-
chlor and shows greater persistence in body fat (U.S. EPA,
1976) , it may be assumed that heptachlor epoxide is bioconcen-
trated to at least the same extent as heptachlor.
C. Inhalation
Heptachlor epoxide is present in ambient air ,to
a lesser extent than heptachlor and is not thought to con-
-------
tribute substantially to human exposure except in areas
near sprayed fields, where concentrations of up to 9.3 pg/ra
may be encountered (Nisbet, 1977).
0. Dermal
Gaines (1960) found rat dermal LDen values of
195 and 200 mg/kg for males and females, respectively, com-
pared with oral LDcQ' s of 100 and 162 mg/kg, respectively,
for technical heptachlor. Thus, it is likely that dermal
exposure in humans can be important under certain conditions.
III. PHAEMACOKINETICS
A. Absorption
Heptachlor epoxide is readily absorbed from the
gastrointestinal tract (U.S. EPA, 1979a).
B. Distribution
Studies dealing directly with exposure to hepta-
chlor epoxide could not be located in the available litera-
ture. After oral administration of heptachlor to experi-
mental animals, high concentrations of heptachlor epoxide
have been found in fat, with much lower levels in liver,
kidney, and muscle, and none in brain (Radomski and Davidow,
1953). Another study (Mizyukova and Kurchatav, 1970) also
demonstrated the persistence of heptachlor epoxide in fat.
Levels in fatty tissues stabilize after three to six months
after a single dose. The U.S. EPA (1979a) states that
there is approximately 10- to 15-fold increase in heptachlor
»
residues found in body fat, milk butter fat, and in the fat
of poultry eggs and livestock as compared to residue levels
found in their normal food rations. "Heptachlor residues"
/of-/
-------
probably refers primarily to heptachlor epoxide. Heptachlor
epoxide passes readily through the placenta (U.S. EPA, 1979a)
and could be found in over 90 percent of the U.S. population
at average levels of around 90 ng/kg (Kutz, et al. 1977).
C. Metabolism and Elimination
Heptachlor epoxide accumulates in adipose tissue,
as discussed in the "Distribution" section. The primary
route for excretion is fecal (Mizyukova and Kurchatav, 1970).
When heptachlor epoxide was fed to rats over a period of
30 days, approximately 20 percent of the administered dose
(approximately 5 mg heptachlor epoxide/rat/30 day) was ex-
creted in the feces, primarily as 1-exo-hydroxyheptachlor
epoxide and 1,2-dihydroxydihydrochlordene (Matsumura and
Nelson, 1971; Tashiro and Matsuraura, 1978). In females,
a primary route for excretion is via lactation, usually
as the epoxide. Levels can be as high as 2.05 mg/1 (Jonas-
son, et al. 1977).
IV. EFFECTS
A. Carcinogenicity
Heptachlor epoxide of unspecified purity induced
hepatocellular carcinoma in a chronic feeding study with
mice and in one study with rats (Epstein, 1976; U.S. EPA,
1977) .
B. Mutagenicity
Heptachlor epoxide induced unscheduled DNA syn-
thesis in SV-40 transformed human cells (VA-4) in culture
when metabolically activated (Ahmed, et al. 1977), but was
-------
not mutagenic for Salmonella typhimurium in the Ames test
(Marshall, et al. 1976) .
C. Teratogenicity, Other Reproductive Effects and
Chronic Toxicity
Pertinent data could not be located in the avail-
able literature.
0. Other Relevant Information
Heptachlor epoxide is more acutely toxic than
heptachlor (U.S. EPA, 1979a) . It inhibits synaptic calcium
magnesium dependent ATPases in rats (Yamaguchi, et al. 1979).
V . AQUATIC TOXICITY
A. Acute Toxicity
Acute toxicity data could not be located in the
available literature relative to the effects of heptachlor
epoxide on fish or invertebrates.
3. Chronic Toxicity
In the only reported chronic study, the 26-hour
LCcn for • heptachlor epoxide in Daphnia magna was 120 ug/1
(Frear and Boyd, 1967) . In the same test, the corresponding
value for heptachlor was 52 ug/1.
C. Plant Effects
Data on the toxicity of heptachlor epoxide to
plants could not be located in the available literature.
D. Residues *
Macek, et al. (1976) determined 'the bioconcentra-
tion factor of 20,000 for heptachlor and heptachlor epoxide
»
in fathead minnows after 276 days' exposure. Heptachlor
epoxide residues were reported as constituting 10 to 24
percent of the total residue. The geometric mean bioconcen-
/or-3
-------
tration factor for heptachloc in all species of fish tested
is 11,400 (U.S. EPA, 1979a). As explained in the "Distri-
bution" section of this text, the bioconcentration factor
for heptachlor epoxide would be as least as great as that
for heptachlor.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The existing guidelines and standards for hepta-
chlor and heptachlor epoxide are:
AGENCY/ORG.
Occup. Safety
Health Admin.
Am. Conf. Gov.
Ind. Hyg. (TLV)
Fed. Republic
Germany
Soviet Union
World Health
Organ.**
U.S. Pub. Health
Serv. Adv. Comm.
STANDARD
500 ug/m * on skin from air
500 ug/m inhaled
500 ug/ra3 inhaled
10 ug/m ceiling value
inhaled
0.5 ug/kg/day acceptable
daily intake in diet
Recommended drinking water
standard (1968) 18 pg/1 of
heptachlor and 18 ug/1
heptachlor epoxide
REFERENCE
Natl. Inst. Occup.
Safety Health, 1977
Am. Conf. Gov. Ind.
Hyg., 1971
Winell, 1975
Winell, 1975
Natl. Acad. Sci.,
1977
Natl. Acad. Sci.,
1977
* Time weighted average
** Maximum residue limits in certain foods can be found in Food Agric,
Organ./World Health Organ. 1977, 1978
The U.S. EPA (1979a) is in the process of establish-
ing ambient water quality criteria for heptachlor and hepta-
chlor epoxide. Based on potential carcinogenicity of hepta-
chlor epoxide, the draft criterion is calculated on the esti-
-------
mate that 0.47 ng/raan/day would result in an increased addi-
tional lifetime cancer risk of no more than 1/100,000.
Based on this lifetime carcinogenicity study of heptachlor
epoxide at 10 ppm in the diet of C3Heb/Pe/J strain mice,
the recommended draft criterion is calculated to be 0.233
ng/1.
B. AQUATIC
No existing guidelines are available for hepta-
chlor epoxide. However, since heptachlor epoxide is a biode-
gradation product of heptachlor, the hazard profile on hepta-
chlor should be consulted *U.S. EPA, 1979b).
*
-------
HEPTACHLOR EPOXIDE
REFERENCES
Ahmed, F.E., et al. 1977. Pesticide-induced DNA damage and its repair in
cultured human cells. Mutat. Res. 42: 1612.
American Conference of Governmental Industrial Hygienists. 1971. Documen-
tation of the threshold limit values for substances in workroom air. 3rd.
«U
Breidenbach, A.W., et al. 1967. Chlorinated hydrocarbon pesticides in
major river basins, 1957-65. Pub. Health Rep. 82: 139.
Epstein, S.S. 1976. Carcinogenicity of heptachlor and chlordane. Sci.
Total Environ. 6: 103.
Frear, D.E.H. and J.E. Boyd. 1967. Use of Daphnia magna for the microbio-
assay and pesticides. I. Development of standardized techniques for rearing
Daohnia and preparation of dosage-mortality curves for pesticides. Jour.
Econ. Entomol. 60: 1228.
Gaines, T.B. 1960. The acute toxicity of pesticides to rats. Toxicol..
Appl. Pharmacol. 2:88. i
Graham, R.E., et al. 1973. Photochemical decomposition of heptachlor epox-
ide. Jour. Agric. Food Chem. 21: 284.
Henderson, C., et al. 1969. Organochlorine insecticide residues in fish
(National Pesticide Monitoring Program). Pestic. Monitor. Jour. 3: 145.
Ivie, G.W., et al. 1972. Novel photoproducts of heptachlor epoxide, trans-
chlordane, and trans-nonachlor. Bull. Environ. Contain. Toxicol. 7: 376.
Johnson, R.D. and D.D. Manske. 1977. Pesticide and other chemical residues
in total diet samples (XI). Pestic. Monitor. Jour. 11: 116.
Jonasson, V., et al. 1977. Chlorohydrocarbon pesticide residues in human
milk in greater St. Louis, Missouri, 1977. Am. Jour. Clin. Nutr. 30: 1106.
Kutz, F.w., et al. 1977. Survey of pesticide residues and their metabo-
lites in humans. In: Pesticide management and insecticide resistance.
Academic Press, New York.
Macek, K.J., et al. 1976. Toxicity of four pesticides to water fleas and
fathead minnows. U.S. Environ. Prot. Agency, EPA-600/3-76-099.
Marshall, T.C., et al. 1976. Screening of pesticides for mutagenic poten-
tial using Salmonella typhimurium mutants. Jour. Agric. Food Chem. 24: 560.
Matsumura, F. and J.O. Nelson. 1971. Identification of the major metabolic
product of heptachlor epoxide in rat feces. Bull. Environ. Contam. Toxicol.
5: 489.
/&?•//
-------
Mizyukova, I.G. and G.V. Kurchatav. 1970. Metabolism of heptachlor.
Russian Pharmacol. Toxicol. 33: 212.
National Academy of Sciences. 1977. Drinking water and health.
Washington, O.C.
National Institute for Occupational Safety and Health. 1977. Agricultural
chemicals and pesticides: a subfield of the registry of toxic effects of
chemical substances.
Nisbet, I.C.T. 1977. Human exposure to chlordane, heptachlor and their
metabolites. Unpubl. rev. prepared, for Cancer Assessment Group, U.S.
Environ. Prat. Agency, Washington, O.C.
Radmoski, J.L. and 8. Oavidow. 1953. The metabolite of heptachlor, its
estimation, storage, and toxicity. Jour. Phaimacol. Exp. Ther. 107: 266.
Ritcey, W.R., et al. 1972. Organochlorine insecticide residues in human
milk, evaporated milk and some milk substitutes in Canada. Can. Jour. Publ.
Health. 63: 125.
Savage, E.P. 1976. National study to determine levels of chlorinated
hydrocarbon insecticides in human milk. Unpubl. rep. submitted to U.S.
Environ. Prat. Agency.
4
Tashiro, S. and F. Matsumura. 1978. Metabolism of trans-nonachlor and re-
lated chlortane components in rat and man. Arch. Environ. Contain. Toxicol.
7: 113
U.S. EPA. 1977. Risk assessment of chlordane and heptachlor. Carcinogen
Assessment Group. U.S. Environ. Prat. Agency, Washington, O.C. Unpubl. rep.
"U.S. EPA. 1979a. Heptachlor: Ambient Water Quality Criteria (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Heptachlor
Epoxide: Hazard Profile. (Draft)
Winell, M.A. 1975. An international comparison of hygienic standards for
chemicals in the work environment. Ambio. 4: 34.
Yamaguchi, I., et al. 1979. Inhibition of synaptic atpases by heptachlor
epoxide in rat brain. Pest. Biochem. Physiol. 11: 285.
J
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No. HO
Hexachlorobenzene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20A60
APRIL 30, 1980
/to--/
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA13 Carcinogen Assessment Group (CAG) has evaluated
hexachlorobenzene and has found sufficient evidence to
indicate that this compound is carcinogenic.
//0-3
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HEXACHLOROBENZENE
Summary
Hexachlorobenzene is ubiquitous in the environment and has an extremely
slow rate of degradation. Ingested hexachlorobenzene is absorbed readily
when associated with lipid material and, once absorbed, is stored for long
periods of time in the body fat. Chronic exposures can cause liver and
spleen damage and can induce the hepatic microsomal mixed functional oxidase
enzyme. Hexachlorobenzene can pass the placenta! barrier and produce toxic
or lethal effects on the fetus. Hexachlorobenzene appears to be neither a
teratogen nor a mutagen; however, this compound has produced tumors in both
rats and mice.
In the only steady-state study with hexachlorobenzene, the pinfish,
Laqodon. rhoimboides, bioconcentrated this compound 23,000 times in 42 days
of exposure. The concentration of HC8 in muscle of pinfish was reduced only
16 percent after 28 days of depuration, a rate similar to that for DOT in
fish.
-------
HEXACHLOROBENZENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Chlorinated Benzenes (U.S. EPA, 1979).
Hexachlorobenzene (HCB; CgCl^; molecular weight 284.79) is a color-
less solid with a pleasant aroma. Hexachlorobenzene has a melting point of
230°C, a boiling point of 322°C, a density of 2.044- g/ml, and is vir-
tually insoluble in water. Hexachlorobenzene is used in the control of
fungal diseases in cereal seeds intended solely for planting, as a plasti-
cizer for polyvinyl chloride, and as a flame retardant (U.S. EPA, 1979).
Commercial production of hexachlorobenzene in the U.S. was discontinued
in 1976 (Chem. Econ. Hdbk., 1977). However, even prior to 1976, most, hexa-
chlorobenzene was produced as a waste by-product during the manufacture 4'of
perchloroethylene, carbon tetrachloride, trichloroethylene, and other chlor-
inated hydrocarbons. This is still the major source of hexachlorobenzene in
the U.S., with 2,200 kg being produced by these industries during 1972
(Mumma and Lawless, 1975).
II. EXPOSURE
A. Water
Very little is known regarding potential exposure to hexachloro-
benzene as a result of ingestion of contaminated water. Hexachlorobenzene
has been detected in specific bodies of water, particularly near points of
industrial discharge (U.S. EPA, 1979). Hexachlorobenzene has been detected
in the polluted waters of the Mississippi River (usually below 2 ng/kg) and
in the clean waters of Lake Superior (concentrations not quantitatively
measured). Hexachlorobenzene was detected in drinking water supdlies at
\io-s
-------
three locations, with concentrations ranging from 6 to 10 ng/kg, and in
finished drinking water at two locations, with concentrations ranging from 4
to 6 ng/kg (U.S. EPA, 1975).
B. Food
Ingestion of excessive amounts of hexachlorobenzene has been a con-
sequence of carelessness, usually from feeding seed grains to livestock.
Foods high in animal fat (e.g., meat, eggs, butter, and milk) have the high-
est concentrations of hexachlorobenzene. The daily intake of hexachloroben-
zene by infants from human breast milk in part of Australia was 39.5 jjg per
day per 4 kg baby. This exceeded the acceptable daily intake recommended by
the FAO/WHO of 2.4 jjg/kg/day (1974). The dietary intake by young adults (15
to 18-year old males.) was estimated to be 35 jug hexachlorobenzene per person
per day (Miller and Fox, 1973). The U.S. EPA (1979) has estimated the
weighted average bioconcentration factor for hexachlorobenzene to be 12,000
for the edible portions of fish and shellfish consumed by Americans. This
estimate is based on the octanol/water partition coefficient of hexachloro-
benzene.
C- Inhalation
Hexachlorobenzene enters the air by various mechanisms, such as
release from stacks and vents of industrial plants, volatilization from
waste dumps and impoundments, intentional spraying and dusting, and uninten-
tional dispersion of hexachlorobenzene-laden dust from manufacturing sites
(U.S. EPA 1979). No data is given on the concentrations of hexachloro-
benzene in ambient air. Significant occupational" exposure can occur par-
ticularly to pest control operators (Simpson and Chandar, 1972).
-------
0. Dermal
Hexachlorobenzene may enter the body by absorption through the skin
as a result of skin contamination (U.S. EPA, 1979).
III. PHARMACOKINETICS
A. Absorption
To date, only absorption of hexachlorobenzene from the gut has been
examined in detail. Hexachlorobenzene in aqueous suspensions is absorbed
poorly in the intestines of rats (Koss and Koransky, 1975); however, cotton
seed oil (Albro and Thomas, 1974) or olive oil (Koss and Koransky, 1975)
facilitated the absorption. Between 70 and 80 percent of doses of hexa-
chlorobenzene ranging from 12 mg/kg to 180 mg/kg were absorbed. Hexachloro-
benzene in food products will selectively partition into the lipid portion,
and hexachlorobenzene in lipids will be absorbed far better than that in an
aqueous milieu (U.S. EPA, 1979).
8. Distribution
The highest concentrations of hexachlorobenzene are found in fat
tissue (Lu and Metcalf, 1975). In rats receiving a single intraperitoneal
(i.p.) injection or oral dose of hexachlorobenzene in olive oil, adipose
tissue contained about 120-fold more hexachlorobenzene than muscle tissue;
liver, 4-fold; brain, 2.5-fold; and kidney, 1.5-fold (Koss and Koransky,
1975). Adipose tissue serves as a reservoir for hexachlorobenzene, and de-
pletion of fat deposits results in mobilization and redistribution of stored
hexachlorobenzene. However, excretion is not increased, and the total body
s
burden is not lowered (Villeneuve, 1975).
-------
C. Metabolism
Hexachlorobenzene is metabolized after i.p. administration in the
rat to pentachlorophenol, tetrachlorohydroquinone and pentachlorothicphenol
(Koss, et al. 1976). In another study using rats in which the metabolic
products were slightly different, only a small percentage of the metabolites
were present as glucuronide conjugates (Engst, et al. 1976). Hexachloroben-
zene appears to be an inducer of the hepatic microsomal enzyme system in
rats (Carlson, 1978). It has been proposed that both the phenobarbital type
and the 3-methylcholanthrene type microsomal enzymes are induced (Stonard,
1975; Stonard and Greig, 1976).
0. Excretion
Hexachlorobenzene is excreted' mainly in the feces and, to some ex-
tent, in the urine in the form of several metabolites which are more polar
than • the parent compound (U.S. EPA, 1979). In the rat, 34 percent of the
administered hexachlorobenzene was excreted in the feces, mostly as unalter-
ed hexachlorobenzene. Fecal excretion of unaltered hexachlorofaenzene is
presumed to be due to biliary secretion. Five percent, of the administered
HCB was excreted in the urine (Koss and Koransky, 1975).
IV. EFFECTS
A.. Carcinogenic!ty
Carcinogenic activity of hexachlorobenzene was assessed in hamsters
fed 4.3 or 16 mg/kg/day for life (Cabral, et al. 1977). Whereas 10 percent
of the unexposed hamsters developed tumors, 92 percent of the hamsters fed
16 mg/kg/day, 75 percent fed 8 mg/kg/day, and 56 percent fed 4 mg/kg/day
developed tumors. The tumors were hepatomas, haemangioendotheliomas and
thyroid adenomas. In a study on mice fed 6.5, 13 or 26 mg/kg/day for life,
£he only increase in tumors was in hepatomas (Cabral, et al. 1978). How-
-------
ever, the incidence of lung tumors in strain A mice treated three times a
week for a total of 24 injections of 40 mg/kg each was not significantly
greater than the incidence in control mice (Theiss, et al. 1977). Also, ICR
mice fed hexachlorobenzene at 1.5 or 7.0 mg/kg/day for 24 weeks showed no
induced hepatocellular carcinomas (Shirai, et al.. 1978).
B. Mutageriicity
Hexachlorobenzene was assayed for mutagenic activity in the domi-
nant lethal assay. Rats were administered 60 mg/kg/day hexachlorobenzene
orally for ten days; there was no significant difference in the incidence of
pregnancies (Khera, 1974).
C. Teratogenicity
Hexachlorobenzene does not appear to be teratogenic for the rat
(Khera, 1974). CO-1 mice receiving 100 mg/kg/day hexachlorobenzene oraily
on gestational days 7 to 11 showed a small increase in the incidence of ab-
normal fetuses per litter (Courtney, et al. 1976). However, the statistical
significance was not mentioned, and the abnormalities appeared in both the
exposed and unexposed groups.
D. Other Reproductive Effects
Hexachlorobenzene can pass through the placenta and cause fetal
toxicity in rats (Grant, et al. 1977). The distribution of hexachloro-
benzene in the fetus appears to be the same as in the adult, with the
highest concentration in fatty tissue.
E. Chronic Toxicity
In one long-term study where rats were given 50 mg/kg hexachloro-
benzene every other day for 53 weeks, an equilibrium between intake and
elimination was achieved after nine weeks. Changes in the histology of the
-------
liver and spleen were noted (Koss, et al. 1578). On human exposure for an
undefined time period, porphyrinuria has been shown to occur (Cam and
Nigogosyan, 1963).
F. Other Relevant Information
At doses far below those causing mortality, hexachlorobenzene en-
hances the capability of animals to metabolize foreign organic compounds.
This type of interaction may be of importance in determining the effects of
other concurrently encountered xenobiotics (U.S. EPA, 1979).
V. AQUATIC TOXICITY
A. NO pertinent information is available on acute and chronic toxicity
or plant effects.
B- Residues
Hexachlorobenzene (HCS) is bioconcentrated from water into tissues
of saltwater fish and invertebrates. Bioconcentration factors (BCF) in
short 96-hour exposures are as follow (Parrish, et al. 1974): grass shrimp,
Palaeomonetes puqio, - 4,116 jjg/1; pink shrimp, Penaeus duorarum, - 1,964
ug/1; sheepshead minnow, Cyprinodon variegatus, - 2,254 yg/1. In a 42-day
exposure, the pinfish, Lagodon rhomboides, BCF was 23,000. The concen-
tration of HCS in pinfish muscle was reduced only 16 percent after 28 days
of depuration; this slow rate is similar to that for DOT in fish.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived by U.S. EPA
(1979), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that 'these criteria will be
changed.
-------
A. Human
The value of 0.6 pg/kg/day hexachlorobenzene was suggested by
FAO/WHO as a reasonable upper limit for residues in food for human consump-
tion (FAO/WHO, 1974). The Louisiana State Department of Agriculture has set
the tolerated level of hexachlorobenzene in meat fat at 0.3 mg/kg (U.S. EPA,
1976). The FAO/WHO recommendations for residues in foodstuffs are 0.5 mg/kg
in fat for milk and eggs, and 1 mg/kg in fat for meat and poultry (FAO/WHO,
1974). Based on bioassay data, and using the "one-hit" model, the EPA
(1979) has estimated levels of hexachlorobenzene in ambient water which will
result in specified risk levels of human cancer:
Exposure Assumption Risk Levels and Corresponding Draft Criteria
(per day)
0 " . 10-7 10-6 io-5
2 liters of drinking water 0 0.0125 ng/1 0.125 ng/1 1.25 ng/1
and consumption of 18.7
grams fish and shellfish.
Consumption of fish and 0 0.0126 ng/1 0.126 ng/1 1.26 ng/1
shellfish only..
B. Aquatic
Pertinent information concerning aquatic criteria could not be
located in the available literature.
+f A r 3'
11*6-11
-------
HEXACHLOROBENZENE
REFERENCES
Albro, P.W., and R. Thomas. 1974. Intestinal absorption of
hexachlorobenzene and hexachlorocyclohexane isomers in rats.
Bull. Environ. Contam. Toxicol. 12: 289.
Cabral, J.R.P., et al. 1977. Carcinogenic activity of hexa-
chlorobenzene in hamsters. Nature (London). 269: 510.
Cabral, J.R.P., et al. 1978. Carcinogenesis study in mice
with hexachlorobenzene. Toxicol. Appl. Pharmacol. 45: 323.
Cam, C., and G. Nigogosyan. 1963. Acquired toxic porphyria
cutanea tarda due to hexachlorobenzene. Jour. Am. Med.
Assoc. 183; 88.
Carlson, G.-P. 1978. Induction of cytochrome P-450 by halo-
genated benzenes. Biochem. Pharmacol. 27: 361.
Chemical Economic Handbook. 1977. Chlorobenzenes-Salient
statistics. In: Chemical Economic Handbook, Stanford Res..
Inst. Int., Menlo Parkr Calif.. .
Courtney, K.D., et al. 1976. The effects of pentachloro-
nitrobenzene, hexachlorobenzene, and related compounds on
fetal development. Toxicol. Appl. Pharmacol. 35: 239.
Engst, R., et al. 1976. The metabolism of hexachlorobenzene
(HCB) in rats. Bull. Environ. Contam. Toxicol. 16: 248.
Pood and Agriculture Organization. 1974. 1973 evaluations
of some pesticide residues in food. FAO/AGP/1973/M/9/1; WHO
Pestle- Residue Ser. 3. World Health Org., Rome, Italy p.
291.
Grant, D.L., et al. 1977. Effect of hexachlorobenzene on
reproduction in the rat. Arch. Environ. Contam. Toxicol. 5:
207.
Khera, K.S. 1974. Teratogenicity and dominant lethal
studies on hexachlorobenzene in rats. Food Cosmet. Toxicol.
12: 471.
Koss, R., and W. Koransky. 1975. Studies on the toxicology
of hexachlorobenzene. I* Pharraacokinetics. Arch Toxicol.
34: 203.
Koss, G., et al. 1976. Studies on the toxicology of hexa-
chlorobenzene. II. Identification and determination of
metabolites. Arch. Toxicol. 35: 107.
-------
Koss, G., et al. 1978. Studies on the toxicology of hexa-
chlorobenzene. III. Observations in a long-term experiment.
Arch. Toxicol. 40: 285.
Lu, P.Y., and R.L. Metcalf. 1975. Environmental fate and
biodegradability of benzene derivatives as studied in a model
aquatic ecosystem. Environ. Health Perspect. 10: 269.
Miller, G.J., and J.A. Fox. 1973. Chlorinated hydrocarbon
pesticide residues in Queensland human milks. Med. Jour.
Australia 2: 261.
Mumma, C.E., and E.W. Lawless. 1975. "Task I - Hexachloro-
benzene and hexachlorobutadiene pollution from chlorocarbon
processes". EPA 530-3-75-003, U.S. Environ. Prot. Agency,
Washington, D.C.
Parrish, P.R., et al. 1974. Hexachlorobenzene: effects on
several estuarine animals. Pages 179-187 in Proc. 28th Annu.
Conf. S.E. Assoc. Game Fish Comm.
Shirai, T., et al. 1978. Hepatocarcinogenicity of poly-
chlorinated terphenyl (PCT) in ICR mice and its enhancement
by hexachlorobenzene (HCB). Cancer Lett. 4: 271.
Simpson, G.R., and A. Shandar. 1972. Exposure to chlori- .
nated hydrocarbon pesticides by pest control operators. Med..
Jour. Australia. 2: 1060.
Stonard, M.D. 1975. Mixed type hepatic microsomal enzyme
induction by hexachlorobenzene. Biochem. Pharmacol. 24:
1959.
Stonard, M.D., and J.B. Greig. 1976. Different patterns of
hepatic microsomal enzyme activity produced by administration
of pure hexachlorobiphenyl isomers and hexachlorobenzene.
Chem.-Biol. Interact. 15: 365.
Theiss, J.C., et al. 1977. Test for carcinogenicity of or-
ganic contaminants of United States drinking waters by pul-
monary tumor response in strain A mice. Cancer Res. 37:
2717.
U.S. EPA. 1975. Preliminary assessment of suspected carcin-
ogens in drinking water. Report to Congress. EPA 560/4-75-
003. Environ. Prot.. Agency, Washington, D.C.
U.S. EPA. 1976. Environmental contamination from hexachloro-
benzene. EPA 560/6-76-014. Off. Tox. Subst. 1-27.
U.S. EPA. 1979. Chlorinated Benzenes: Ambient Water Quality
Criteria. (Draft).
-------
villeneuve, D.C. 1975. The effect of food restriction on
the redistribution of hexachlorofaenzene in the rat. Toxicol.
Appl. Pharmacol. 31: 313.
-------
No. Ill
Hexachlorobutadiene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20A60
APRIL 30, 1980
- / "i n *»
/ <*. > >
111-1
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all. available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (GAG) has evaluated
hexachlorobutadiene and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
HEXACHLOROBUTADI EH E
SUMMARY
Hexachlorobutadiene (HCBD) is a significant by-product
of the manufacture of chlorinated hydrocarbons. HCBD has
been found to induce renal neoplasms in rats (Kociba, et al.,
1971). The mutagenicity of HCBD has not been proven conclu-
sively, but a bacterial assay by Taylor (1978) suggests a
positive result. Two studies on the possible teratogenic
effects of HCBD produced conflicting results.
Ninety-six hour LC50 values for the goldfish, snail,
and sowbug varied between 90 and 210 ug/1 in static renewal
tests. Measured bioconcentration factors after varying per-
iods of exposure are as follows: crayfish, 60; goldfish, 920-
2,300; Scuyemouth bass, 29; and an alga, 160.
///-y
-------
HEXACHLOROBUTADIEN E
I. INTRODUCTION
Hexachlorobutadiene (HCBD) is produced in the United
States as a significant by-product in the manufacture of
chlorinated hydrocarbons such as tetrachloroethylene, tri-
chloroethylene, and carbon tetrachloride.. This secondary
production in the U.S. ranges from 7.3 to 14.5 million pounds
per year, with an additional 0.5 million pounds being import-
ed (U.S. EPA, 1975).
HCBD is used as an organic solvent, the major domestic
users being- chlorine producers. Other applications include
its use as an intermediate in the production of rubber com-
pounds and lubricants. HCBD is a colorless liquid with a
faint turpentine-like odor. Its physical properties include:
boiling point, 210-220°C vapor pressure, 0.15 mm Hg; and
water solubility of .5 ug/1 at 20°C (U.S. EPA, 1979).
Environmental contamination by HCBD results primarily
during the disposal of wastes containing HCBD from chlori-
nated hydrocarbon industries (U.S. EPA, 1976). It has been
detected in a limited number of water samples. HBCD appears
to be rapidly adsorbed to soil and sediment from contaminated
water, and concentrates in sediment from water by a factor of
100 (Leeuwangh, et al., 1975).
II. EXPOSURE
v
A. Water
HCBD contamination of U.S. finished drinking water
supplies does not appear to be widespread. The problem is
localized in areas with raw water sources near industrial
111-5'
-------
plants discharging HBCD. From its physical and chemical pro-
perties, HBCD removal from water by adsorption into sediment
should be rapid (Laseter, et al., 1976). Effluents from
various industrial plants were found to contain HCBD levels
ranging from 0.04 to 240 ug/1 (Li, et al., 1976). An EPA
study of the drinking water supply of ten U.S. cities re-
vealed that HCBD was detected in one of the water supplies,
but the concentration was less than 0.01 ug/1 (U.S. EPA,
1975).
B. Food
Since the air, soil and water surrounding certain
chlorohydrocarbon plants have been shown to be contaminated
with HCBD (Li, et al., 1976), food produced in the vicinity
of these plants might contain residual levels of HCBD. A
survey of foodstuffs produced within 25 miles of tetrachloro-
ethylene and trichloroethylene plants did not detect measur-
able levels of HCBD. Freshwater fish caught in the lower
Mississippi contained HBCD residues in a range from 0.01 to
1.2 mgAg« Studies on HCBD contamination of food in several
European countries have measured levels as high as 42 ug/kg
in certain foodstuffs (Kotzias,'et al., 1975).
The U.S. EPA (1979) has estimated a HCBD bioconcen-
tration factor of 870 for the edible portions of fish and
shellfish consumed by Americans. This estimate is based on
measured steady-state bioconcentration studies in goldfish.
C. Inhalation
The levels of HCBD detected in the air surrounding
chlorohydrocarbon plants are generally less than 5 uc
-------
although values as high as 460 ug/ni have been measured
(Li, et al. 1976).
III. PHARMACOKINETICS
A. Absorption
Pertinent data were not found on the absorption of
HCBD in the available literature.
B. Distribution
HCBD did not have a strong tendency to accumulate
in fatty tissue when administered orally with other chlori-
nated hydrocarbons. Some of the chlorinated hydrocarbons
were aromatic compounds and accumulated significantly in fat
(Jacobs, et al. 1.974) .
C. Metabolism
Pertinent data were not found in the available
literature.
D. Excretion .-;
Pertinent data were not found in the available
literature.
IV. EFFECTS ON MAMMALS
A. Carcinogenicity
Kociba, et al. (1977) administered dietary levels
of HCBD ranging from 0.2 mg/kg/day to 20.0 mg/kg/day for two
years to rats. In males receiving 20 mg/kg/day, 18 percent
(7/39) had renal tubular neoplasms which were classified as
adenocarcinomas; 7.5 percent (3/40) of the females on the
»
high dose developed renal carcinomas. Metastasis to the lung
was observed in one case each for both male and female rats.
*
1/1-7
-------
No carcinomas were observed in controls, however, a nephro-
blastoma developed in one male and one female.
A significant increase in the frequency of lung
tumors was observed in mice receiving intraperitoneal injec-
tions of 4 mgAg or 8 mgAg of HCBD, three times per week un-
til totals of 52 mg and 96 mg, respectively, were admin-
istered (Theiss, et al... 1977).
B. Mutagenicity
Taylor (1978) tested the mutagehicity of HCBD on _S.
typhimurium TA100. A dose dependent increase in reversion
rate was noted, but the usual criterion for mutagenicity of
double the background rate was not reached.
C. Teratogenicity
Poteryaeva (1966) administered HCBD to nonpregnant
rats by a single subcutaneous injection of 20 mg/kg. After
mating, the pregnancy rate for the dosed rats was the same as
that of controls. The weights of the young rats from the
dosed mothers were markedly lower than the controls. Autop-
sies at 2-1/2 months revealed gross pathological changes in
internal organs including g-lomerulonephritis of the kidneys.
Degenerative changes were also observed in the red blood
cells.
D. Other Reproductive Effects
Schwetz, et al. (1977) studied the effects of di-
etary doses of HCBD on reproduction, in rats. Males and fe-
»
males were fed dose levels of 0.2 to 20 mg/kg/day HCBD start-
ing 90 days prior to mating and continuing through lactation.
At the two highest doses, adult rats suffered weight loss,
,
> *lAlS-
i J I "-
III-7
-------
decreased food consumption and alterations of the kidney cor-
tex, while the only effect on weanlings consisted of a slight
increase in body weight at 21 days of age at the 20 mg/kg
dose level. Effect on survival of the young was not effected.
E. Chronic Toxicity
The kidney appears to be the organ most sensitive
to HCBD. Possible chronic effects are observed at doses as
low as 2 to 3 mg/kg/day (Kociba, et al., 1971, 1977; Schwetz,
et al., 1977). Single oral doses as low as 8.4 mg/kg have
\
been observed to have deleterious effects on the kidney
(Schroit, et al. 1972). Neurotoxic effects in rats have been
reported at a dose of 7 mg/kg and effects may occur at even
lower dose levels (Poteryaeva, 1973? Murzakaev, 1967). HCBD
at 0.004 mg/kg gave no indication of neurotoxicity. Acute
HCBD intoxication affects acid-base equilibrium in blood and
urine (Popovich, 1975; Poteryaeva, 1971). Some investigators
report a cumulative effect for HCBD during chronic dosing by
dermal (Chernokan, 1970) or oral Poteryaeva, 1973) routes.
An increase in urinary coproporphyrin was observed in rats
receiving 2 mg/kg/day and 20 mk/kg/day HCBD for up to 24
months (Kociba, 1977).
F. Other Relevant Information
The possible antagonistic effect of compounds con-
taining mercapto (-SH) groups on HCBD have been suggested by
*•
two studies. Murzokaev (1967) demonstrated a reduction in
free -SH groups in cerebral cortex homogenate and blood serum
following HCBD injection in rats. Mizyukova, et al. (1973)
found thiols (-SH compounds) and amines to be effective anti-
-------
dotes against the toxic effects of HCBD when administered
prior to or after HCBD exposure.
V. AQUATIC TOXICITY
A. Acute Toxic ity
Goldfish, (Carassius auratus), had an observed 96-
hour LC50 of 90 ug/1 in a static renewal test (Leeuwangh, et
al. 1975). A snail, (Lymnaea stagnalis), and a sowbug,
(Asellus aquaicus), were both exposed for 96-hours to HCBD
resulting in EC5Q values of 210 and 130 v.g/1, respective-
ly (Leeuwangh, et al., 1975). No acute studies with marine
species have been conducted.
B. Chronic Toxic ity
Pertinent information was not found in the avail-
able literature.
C. Plant'Effects
Pertinent data was not found in the available
literature.
D. Residues
Measured bioconcentration factors are as follows:
crayfish, Procambaeus clarhi, 60 times after 10 days expo-
sure; goldfish, Caressius auretus, 920-2,300 times after 49
days exposure; large mouth bass, Microptorus salmoides, 29
times after 10 days exposure; and a freshwater alga, Oedogon-
ium cardiacum, .160 times after 7 days exposure (Laseter, et
al., 1976). Residue data on saltwater organisms are not
available.
-------
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived by
U.S. EPA (1979), which are summarized below, have gone
through the process of public review; therefore, there is a
possibility that these criteria may be changed.
A. Human
Standards or guidelines for exposure to HCBD are
not available.
The draft ambient water quality, criteria for HCBD
have been calculated to reduce the human carcinogenic risk
levels to ID"5, 10-6, and lO"7 (U.S. EPA, 1979).
The corresponding criteria are 0.77 ug/1, 0.077 ug/lf 0.0077
u.g/1, respectively.
B. Aquatic
Draft freshwater or saltwater criterion for hexa-
chlorobutadiene have not been developed because of insuffi-
cient data (U.S. EPA, 1979).
ll-Ht
-------
HEXACHLOROBUTAOIENE
REFERENCES
Chernokan, V.F. 1970. Some data of the toxicology of hexachlorobutadiene
when ingested into the organism through the skin. • Vop. Gig. Toksikol. Pes-
tits. Tr. Nauch. Tr. Sess. Akad. med. Nauk. SSSR. (no vol.): 169. CA:74:
97218r. (Translation)
Jacobs, A., et al. 1974. Accumulation of noxious chlorinated substances
from Rhine River water in the fatty tissue of rats. Vom. Wasser 43: 259.
Kociba, R.J., et al. 1971. Toxicologic study of female rats administered
hexachlorobutadiene or hexachlorobenzene for 30 days. Dow Chemical Co.,
Midland, Mich.
•.
Kociba, R.J., et al. 1977. Results of a two-year chronic toxicity study
with hexachlorobutadiene in rats. Am. Ind. Hyg. Assoc. 38: 589.
Kotzias, 0., et al. 1975. Ecological chemistry. CIV. Residue analysis of
hexachlorobutadiene in food and poultry feed. Chemosphere 4: 247.
Laseter, J.L., et al» 1976. An ecological study of hexachlorobutadiene
(HCSD). U.S. Environ. Prot. Agency, EPA-560/6-76-010.
Leeuwangh, P., et al. 1975. Toxicity of hexachlorobutadiene in aquatic or-
ganisms. In: Sublethal effects of toxic chemicals on aquatic animals.
Proc. Swedish-Netherlands Symp., Sept. 2-5. Elsevier Scientific Publ. Co.,
Inc., New York.
Li, R.T., et al. 1976. Sampling and analysis of selected toxic sub-
stances. Task IB - hexachlorobutadiene. EPA-560/6-76-015. U.S.. Environ.
Prot. Agency, Washington, O.C.
Mizyukova, I.G., et al. 1973. Relation between the structure and detoxify-
ing action of several thiols and amines during hexachlorobutadiene poison-
ing. Fiziol. Aktive. Veshchestva. 5: 22. CA:81:22018M. (Translation)
Murzakaev, F.G. 1967. Effect of small doses of hexachlorobutadiene on
activity of the central nervous system and morphological changes in the
organisms of animals intoxicated with it. Gig. Tr. Prog. Zabol. 11: 23.
CA:67:31040a. (Translation)
Popovich, M.I. 1975. Acid-base equilibrium and mineral metabolism follow-
ing acute hexachlorobutadiene poisoning. Issled. Abl. Farm. Khim. (no
vol.): 120. CA:86:26706K. (Translation)
••
Poteryaeva, G.E. 1966. Effect of hexachlorobutadiene on the offspring of
albino rats. Gig Sanit. 31: 33. ETIC:76:8965. (Translation)
»
Poteryaeva, G.E. 1971. Sanitary and toxicological characteristics of hexa-
chlorobutadiene. Vrach. Oelo. 4: 130. HAPAB:72:820. (Translation)
III'II
-------
Poteryaeva, G.E. 1973. Toxicity of hexachlorobutadiene during entry into
the organisms through the gastorintestinal tract. Gig. Tr. 9: 98. CA:85:
29271E. (Translation)
Schroit, I.G., et al. 1972. Kidney lesions under experimental hexachloro-
butadiene poisoning. Aktual. Vop. gig. Epidemiol. (no vol.): 73. CA:81:
73128E. (Translation)
Schwetz, 8.A., et al. 1977. Results of a reproduction study in rats fed
diets containing hexachlorobutadiene. Toxicol. Appl. Pharmacol. 42: 387.
Taylor, G. 1978. Personal communication. Natl. Inst. Occup. Safety Health.
Theiss, J.C., et. al. 1977. Test for carcinogenicity of organic contami-
nants of United States drinking waters by pulmonary tumor response in strain
A mice. Cancer Res. 37: 2717.
U.S. EPA. 1975. Preliminary assessment of suspected carcinogens in drink-
ing water. Rep. to Congress. U.S. Environ. Prot. Agency.
U.S. EPA. 1976. Sampling and analysis of selected toxic substances. Task
IB - Hexachlorobutadiene. EPA-560/6-76-015. Off. Tox. Subst. U.S. Envi-
ron. Prot. Agency, Washington, D.C.
U.S. EPA. 1978. Contract No. 6803-2624. U.S. Environ. Prot. Agency, Wash-
ington, D.C.
U.S. EPA. 1979. Hexachlorobutadiene: Ambient Water Quality Criteria
(Draft).
// /'-
-------
No. 112
ichlorocyclohexane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
//a-/
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
;//-*•
-------
SPECIAL NOTATION
U.S. EPA13 Carcinogen. Assessment Group (GAG) has evaluated
hexachlorocyclohexane and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
HEXACHLOROCYCLOHEXANE
Summary
Hexachlorocyclohexane (HCH), a broad spectrum insecticide, is a mixture
of five configurational isomers. HCH is no longer used in the United
States; however, its gamma-isomer, commonly known as lindane, continues to
have significant commercial use. Technical HCH, alpha-HCH, _beta-HCH, and
lindane (gamma-HCH) have all been shown to induce liver tumors in mice.
Most of the studies on hexachlorocyclohexanes deal only with lindane. Evi-
dence for mutagenicity of lindane is equivocal. Lindane was not teratogenic
for rats, although it reduced reproductive capacity in rats in a study of
four generations. Chronic exposure of animals to lindane caused liver en-
largement and, at higher doses, some liver damage and nephritic changes.
Humans chronically exposed to HCH suffered liver damage. Chronic exposure of
humans to lindane: produced irritation of the central nervous system. HCH
and lindane are convulsants. The U.S. EPA (1979) has estimated the ambient
water concentrations of hexachlorocyclohexanes corresponding to a lifetime
cancer risk for humans of 10 as follows: 21 ng/1 for technical HCH, 16
ng/1 for alpha-HCH, 28 ng/1 for beta-HCH, and 54 ng/1 for lindane (gammaHCH).
Lindane has been studied in a fairly extensive series of acute studies
for both freshwater and marine organisms. Acute toxic levels as low as 0.17
ng/1 have been reported for marine invertebrate species.
-------
HEXACHLOROCYCLOHEXANE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Hexachlorocyclohexane (U.S. EPA, 1979). 1,2,3,4,5,6-Hexachloro-
cyclohexane (CJ-LClj molecular weight 290.0) is a brownish-to-white
crystalline solid with a melting point of 65°C and a solubility in water
of 10 to 32 mg/1. It is a mixture of five configurational isomers and is
commonly referred to as BHC or benzene hexachloride. Lindane is the common
name for the gamma isomer of 1,2,3,4,5,6-hexachlorocyclohexane (U.S. EPA,
1979).
Technical • grade hexachlorobenzene (HCH) contains the hexachloro-
cyclohexane isomers in the following ranges: alpha-isomer, 55 to 70 per-
cent; beta-isomer, 6 to 8 percent; gamma-isomer , 10 to 18 percent; delta-
isomer, 3 to 4 percent; epsilon-isomer, trace amounts. Technical grade HCH
may also contain 3 to 5 percent of other chlorinated derivatives of cyclo-
hexane, primarily heptachlorocyclohexane and octachlorocyclohexane (U.S.
EPA, 1979).
Hexachlorocyclohexane (HCH) is a broad spectrum insecticide of the
group of cyclic chlorinated hydrocarbons called organochlorine insecticides.
Since the gamma-isomer (lindane) has been shown to be the insecticidally
active ingredient in technical grade HCH, technical grade HCH has had
limited commercial use except as the raw material for production of lin-
dane. Use of technical HCH has been banned in the U.S., but significant
commercial use of lindane continues. Lindane is used in a wide range of
applications including treatment of animals, buildings, man (for ectopara-
sites), clothes, water (for mosquitoes), plants, seeds, and soils (U.S. 'EPA,
1979).
-------
NO technical grade HCH or lindane is currently manufactured in the
U.S.; all lindane used in the U.S. is imported (U.S. EPA, 1979).
Lindane has a low residence time in the aquatic environment. It is
removed by sedimentation, metabolism, and volatilization. Lindane contri-
butes less to aquatic pollution than the other hexachlorocyclohexane isomers
(Henderson, et al. 1971).
Lindane is slowly degraded by soil microorganisms (Mathur and Saha,
1975; Tu, 1975, 1-976) and is reported to be isomerized to the alpha and/or
delta isomers in microorganisms and plants (U.S. EPA, 1979), though this is
controversial (Tu, 1975, 1976; Copeland and Chadwick, 1979; Engst, et al.
1977). It is-not isomerized in adipose tissues of rats, however (Copeland
and Chadwick, 1979).
II. EXPOSURE
A. Water
The contamination of water has occurred principally from direct
application of technical hexachlorocyclohexane (HCH) or lindane to water for
control of mosquitoes, from the use of HCH in agriculture and forestry, and,
to a lesser extent, from occasional contamination of wastewater from manu-
*
facturing plants (U.S. EPA, 1979).
In the finished- water of. Streator, Illinois, lindane has been de-
tected at a concentration of 4 pg/1 (U.S. EPA, 1975).
B. Food
The daily intake of lindane has been reported to be 1 to 5 ug/kg
body weight and the daily intake of all other HCH isoraers to be 1 to 3 ug/kg
body weight (Duggan and Ouggan, 1973). The chief sources of HCH residues in
the human diet are milk, eggs, and other dairy products (U.S. EPA, 1979),
and carrots and potatoes (Lichtenstein, 1959). Seafood is usually a minor
-------
source of HCH, probably because of the relatively high rate of dissipation
of HCH in the aquatic environment (U.S. EPA, 1979).
The U.S. EPA (1979) has estimated the weighted average biocon-
centration factor for lindane to be 780 for the edible portions of fish and
shellfish consumed by Americans. This estimate is based on measured steady-
state bioconcentration in bluegills.
C. Inhalation
Traces of HCH have been detected in the air of central and suburban
London (U.S. EPA, 1979). No further pertinent information could be found in
the available literature.
0. Dermal
Lindane has been used to eradicate human ectoparasites and few ad-
verse reactions have been reported (U.S. EPA, 1979).
III. PHARMACOKINETICS
A. Absorption
The rapidity of lindane absorption is enhanced by lipid mediated
carriers. Compared to other organochlorine insecticides, HCH and lindane
are unusually soluble in water, which contributes to rapid absorption and
excretion (Herbst and Bodenstein, 1972; U.S. EPA, 1979). Intraperitoneal
injection of lindane resulted in 35 percent absorption (Koransky, et al.
1963). Lindane is absorbed after oral.and dermal exposure (U.S. EPA, 1979).
8. Distribution
After administration to experimental animals, lindane was detected
in the brain at higher concentrations than in other organs (Laug, 1948;
^
Davidow and Frawley, 1951; Koransky, et al. 1963; Huntingdon Res. Center,
-------
1972). At least 75 percent of an intraperitonial dose of 14C-labeled lin-
dane was consistently found in the skin, muscle, and fatty tissue (Koransky,
et al. 1963). Lindane enters the human fetus through the placenta; higher
concentrations were found in the skin than in the brain and never exceeded
the corresponding values for adult organs (Poradovsky, et al. 1977;
Nishimura, et al. 1977).
C. Metabolism
Lindane is metabolized to gamma-3,4,5,6-tetrachlorocyclohexene in
rat adipose tissue, but is not isomerized (Copeiand and Chadwick, 1979);
other metabolites are 2,3,4,5,6-pentachloro-2-cyclohexene-l-ol, two tetra-
chlorophenols, and three trichlorophenols (Chadwick, et al. 1975; Engst, et
al. 1977). These are. commonly found in the urine as conjugates (Chadwick
and Freal, 1972). Lindane metabolic pathways are still matters of some con-
troversy (Engst, et al. 1977; Copeiand and Chadwick, 1979). Hexachloro-
cyclohexane isomers other than lindane are metabolized to trichlorophenols
and mercapturic acid conjugates (Kurihara, 1979). Both free and conjugated
chlorophenols are far less toxic than the parent compounds (Natl. Acad.
Sci., 1977). ;
D. Excretion
HCH and lindane appear to be eliminated primarily as conjugates in
the urine. Elimination of lindane appears to be rapid after administration
ceases. Elimination of beta-HCH is much slower (U.S. EPA, 1979). In fe-
males, HCH is excreted in the milk as well as in the urine. The beta-isomer
usually accounts for above 90 percent of the HCH -present in human milk
(Herbst and Bodenstein, 1972).
-------
IV. EFFECTS
A. Carcinogenicity
An increased incidence of liver tumors was reported in male and/or
female mice of various strains fed technical hexachlorocyclohexane (Goto, et
al. 1972; Hanada, et al. 1973; Nagasaki, et al. 1972), alpha-HCH (Goto, et
al. 1972; Hanada, et al. 1973; Ito, et al. 1973, 1975), beta-HCH (Goto, et
al. 1972; Thorpe and Walker, 1973) and lindane (gamma-HCH) (Goto, et al.
1972: Hanada, et al. 1973; Natl. Cancer Inst., 1977a; Thorpe and Walker,
1973). Male rats fed alpha-HCH also developed liver tumors (Ito, et al.
1975). A mixture containing 68.7 percent alpha-HCH, 6.5 percent beta-HCH
and 13.5 percent lindane in addition to other impurities (hepta- and octa-
chlorocyclohexanes), administered orally (100 ppm in the diet, or 10 mg/kg
body weight by intubation), caused tumors in liver and in lymph-reticular
tissues in male and female mice after 45 weeks. Application by skin paint-
ing had no effect (Kashyap, et al. 1979). A review by Reuber (1979)
suggests that lindane is carcinogenic on uncertain evidence.
B. Mutagenicity
Evidence for the mutagenicity of lindane is equivocal. Some alter-
ations in mitotic activity and the karyotype of human lymphocytes cultured
with lindane at 0.1 to 10 ug/ml have been reported (Tsoneva-Maneva, et al.
1971). Lindane was not mutagenic in a dominant-lethal assay (U.S. EPA,
1973) or a host-mediated assay (Buselmair, et al. 1973).
Gamma-HCH was found to be mutagenic in microbial assays using
Salmonella typhimurium with metabolic activation, the host-mediated assay,
and the dominant lethal test in rats. Other reports indicate that it does
not have significant mutagenic activity (U.S. EPA, 1979).
II-9
-------
C. Teratogenicity
Lindane given in the diet during pregnancy "at levels of 12 or 25
mg/kg body weight/day did not produce teratogenic effects in rats
(Mametkuliev, 1978; Khera, et al. 1979).
0. Other Reproductive Effects
Chronic lindane feeding in a study of four generations of rats in-
creased the average duration of pregnancy, decreased the number of births,
increased the proportion of stillbirths, and delayed sexual maturation in
F7 and F, females. In addition, some of the F. and F_ animals ex-
hibited spastic paraplegia (Petrescu, et al. 1974).
In rats and rabbits, lindane given in the diet during pregnancy in-
creased postimplanation death of embryos (Mametkuliev, 1978; Palmer, et al.
1978). Testicular atrophy has been observed for lindane in rats and mice
(National Cancer Institute, 1977b; Nigam, et al. 1979).
E. .Chronic Toxicity
Irritation of the central nervous system, with other toxic side ef-
fects (nausea, vomiting, spasms, weak respiration with cyanosis and blood
dyscrasia), was reported after prolonged or improper use of Hexicid (1 per-
cent lindane) for the treatment of scabies on humans (Lee, et al. 1976).
Production workers exposed to technical HCH exhibited symptoms including
headache, vertigo, irritation of the skin, eyes, and respiratory tract mu-
cosa. In some instances, there were apparent disturbances of carbohydrate
and lipid metabolism and dysfunction of the hypothalamo-pituitary-adrenal
system (Kazahevich, 1974; Besuglyi, et al. 1973). A' study of persons occu-
pationally exposed to HCH for 11 to 23 years revealed biochemical manifes-
»
tations of toxic hepatitis (Sasinovich, et al. 1974).
-------
In chronic studies with rats given lindane in oil, liver cell;
hypertrophy,(fat degeneration and necrosis) and nephritic changes were noted
at higher doses (Fitzhugh, et al. 1950; Lehman, 1952). Rats inhaling lin-
dane (0.78 mg/m-3) for seven hours, five days a week for 180 days showed
liver cell enlargement, but showed no toxic symptoms or other abnormalities
(Heyroth, 1952). The addition of 10 ppm lindane to the diet of rats for one
or two years decreased body weight after five months of treatment and
altered ascorbic acid levels in urine, blood, and tissues (Petrescu, et al.
1974). Dogs chronically exposed to lindane in the diet had slightly
enlarged livers (Rivett, et al. 1978).
F. Other-Relevant Information
Hexachlorocyclohexane is a convulsant.
Lindane is the most acutely toxic isomer of HCH. The toxic effects
of lindane are antagonized by pretreatment with phenobarbital (Litterst and
Miller, 1975) and by treatment with silymarin (Szpunar, et al. 1976) and
various tranquilizers (Ulmann, 1972).
V. AQUATIC TOXICITY
A. Acute Toxicity
Among 16 species of freshwater fish, LC_Q values from one flow-
through and 24 static bioassays for the gamma isomer of hexachloro-
cyclohexane ranged from 2 jug/1 for the- brown trout (Salmo trutta) (Macek and
McAllister, 1970) to 152 jjg/1 for the goldfish (Carassius auratus)
(Henderson, et al. 1959). In general,, the salmon tended to be more sensi-
tive to the action of lindane than did warm water species. Zebra fish
(Brachydanio rerio) showed a lindane LC5Q value of 120 ng/1, but rainbow
trout (Salmo qairdnerl) evidenced respiratory distress at 40 ng/1 (Slooff,
1979). Technical grade HCH was much less toxic than pure lindane; LC50
-------
values obtained for lindane in 96-hour studies of the freshwater goldfish
(Carassius auratus) ranged from 152 jjg/1 for 100 percent lindane to 8,200
jjg/1 for BCH (15.5 percent gamma isomer) (Henderson, et al. 1959). Static
tests on freshwater invertebrates revealed a range of LC5Q values of from
4.5 jug/1 (96-hour test) (Sanders and Cope, 1968) for the stonefly
(Pteronarcys californica) to • 880 jug/1 (48-hour test) (Sanders and Cope,
1968) for the clado- ceran (Simocephalus serralatus) for lindane. Canton
and Slooff (1977) re- ported an LC5(, value for the pond snail (Lymnaea
staqnalis) of l,200;jg/l for alpha-HCH in a 48-hour static test.
Among seven species of marine fish tested for the acute effects of
lindane, static test LC5Q values ranged from 9.0 ^g/1 for the Atlantic
silversides (Menidia menidia) to 66.0 ug/1 for the striped mullet (Mugil
cephalus) (Eisler, 1970). The results of six flow-through assays on five
species of marine fish produced LC5Q values from 7.3 jjg/l for the striped
bass (Morone saxatilis) (Korn and Earnest, 1974) to 240 jug/1 for the long .
nose killifish (Fundulus similis) (Butler, 1963). A single species, the
pinfish (Laqodon rhomboides), tested with technical grade hexachlorocyclo-
hexane, produced a 96-hour flow-through LC_Q value of 86.4 jjg/1 (Schimmel,
et al. 1977). Acute tests on marine invertebrates showed six species to be
quite sensitive to lindane, with LC5Q values from both static and flow-
through assays ranging from 0.17 jug/1-for the pink shrimp (Panaeus duorarum)
(Schimmel, et al. 1977) to 10.0 /jg/1 for the grass shrimp (Palaemonetas
vulqaris) (U.S. EPA, 1979). An LC5Q value of 0.34 jug/1 was obtained for
technical grade hexachlorocyclohexane for the pink shrimp (Schimmel, et al.
1977). The American oyster had an EC5Q of 450 jjg/1 based on shell 'decom-
position (Butler, 1963).
-------
8. Chronic
A chronic value of 14.6 jjg/1 for lindane was obtained in a life-
cycle assay of the freshwater fathead minnow (Pimephales promelas). For
three species of freshwater invertebrates tested with lindane, chronic
values of 3.3, 6.1, and 14.5 pg/l were obtained for Chironomus tentans,
Gammarus fasciatus, and Daphnia magna (Macek, et al. 1976).. No- chronic
marine data for any of the hexachlorobenzenes were available.
C. Plant Effects
Concentrations causing growth inhibition of the freshwater alga,
Scenedesmus acutus were reported to be 500, 1,000, 1,000, and 5,000 jug/1 for
alpha-HCH, technical grade HCH, lindane, and beta-HCH, respectively
(Krishnakumari, 1977). In marine phytoplankton communities, an effective
concentration value of 1,000 fig/1 (resulting in decreased productivity) was
reported for lindane; and for the alga, Acetabularia mediterranea an effec-
tive concentration of 10,000 jug/1 was obtained for lindane-induced growth
inhibition. No effect in 48 hours was observed for the algae Chlamydomonas
so. exposed to lindane at the maximum solubility limit. Irreparable damage
to Chlorella sp. occurred at lindane concentrations of more than 300 ;jg/l
(Hansen, 1979).
0. Residues
Bioconcentration factors for- lindane ranging from 35 to 938 were
reported for six species of freshwater organisms (U.S. EPA, 1979; Sugiura,
et al. 1979a). . In marine organisms, bioconcentration factors (after 28
days) for 39 percent lindane of 130, 218, and 617..were obtained for the
edible portion of the pinfish (Lagodon rhomboides), the American oyster
111-13
-------
(Crassostrea virqinica), and offal tissue of the pinfish (Schimmel, et al.
1977). Sugiura, et al. (1979a) found alpha-, beta-, and gamma-HCH had accu-
mulation factors of 1,216, 973 and 765 in golden orfe (Leuciscusidus
melanotus); 330, 273, and 281 in carp (Cyprinus carpio); 605, 658, and 442
in brown trout (Salmo trutta fario); and 588, 1,485, and 938 in guppy
(Poecila reticula), respectively. Further, these accumulation factors were
proportional to the lipid content of the fish. Accumulation occurred in the
adipose tissues and the gall bladder, with the alpha and beta-HCH being more
persistent (Sugiura, et al. 1979b).
Equilibrium accumulation factors of 429 to 602 were observed at
days 2 to 6 after exposure of Chlorella sp. to 10 to 400 ;jg/l of lindane in
aqueous solution (Hansen, 1979).
VI. EXISTING STANDARDS AND GUIDELINES
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979), which are summarized below, 'have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed.
A. Human
i
Based on the induction of liver tumors in male mice, and using the
"one-hit" model, the U.S. EPA (1979) has estimated the following levels of
technical hexachlorocyclohexane and its isomers in ambient water which will
result in specified risk levels of human cancer.
The water concentrations of technical HCH corresponding to a life-
icer risk for I"
Nagasaki, et al. (1972).
time cancer risk for humans of 10~ is 21 ng/1, "'based on the data of
^^^^.^u.
1 / JeL J
-------
The water concentrations of alpha-HCH corresponding to a lifetime
cancer risk for humans of 10 is 16 ng/1, based on the data of Ito, et
al. (1975).
The water concentrations of beta-HCH corresponding to a lifetime
cancer risk for humans of 10 is 28 ng/1, based on the data of Goto, et
al. (1972).
The water concentrations of lindane (gamma-HCH) corresponding to a
lifetime cancer risk for humans of 10 is 54 ng/1, based on the data of
Thorpe and Walker (1973).
Data for the delta and epsilon isomers are insufficient for the
estimation of cancer risk levels (U.S. EPA, 1979).
An ADI of 1 jjg/kg for HCH has been set by the Food and Agricultural
Organization and the World Health Organization (U.S. EPA, 1979).
Tolerance levels set by the EPA are as follows: 7 ppm for animal
fat, 0.3 ppm for milk, 1 ppm for most fruits and vegetables, 0.004 pm for
finished drinking water, and 0.5 ug/m3 (skin) for air (U.S. EPA, 1979).
8. Aquatic
For lindane, freshwater criteria have been drafted as 0.21 ug/1
with 24-hour average concentration not to exceed 2.9 ug/1. For marine or-
ganisms, criteria for lindane have not been drafted. No criteria for mix-
tures of isomers of hexachlorocyclohexane (benzene hexachloride) were draft-
ed for freshwater or marine organisms because of the lack of data.
-------
HEXACHLOROCYCLOHEXANE
REFERENCES
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having prolonged occupational contact with hexachlorocyclo-
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Buselmair, W., et al. 1973. Comparative investigation
on the mutagenicity of pesticides in mammalian test systems.
Mutat. Res. 21: 25.
Butler, P.A. 1963. Commercial fisheries investigations,
pesticide-wildlife studies, a review of fish and wildlife
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Fish Wildl. Circ. 167: 11.
».
Canton, J.H., and W. Sloof. 1977. The usefulness of Lymnaea
stagnalis L. as a biological indicator in toxicological
bioassays (model substance cA-HCH). Water Res. 11: 117.
Chadwick, R.W., and J.J. Freal. 1972. The identification
of five unreported lindane metabolites recovered from rat
urine. Bull. Environ. Contam. Toxicol. 7: 137.
Chadwick, R.W., et al. 1975. Dehydrogenation, a previously
unreported pathway of lindane metabolism in mammals. Pestic.
Biochem. Physiol. 6: 575.
Copeland, M.F., and R.W. Chadwick. 1979. Bioisomerization
of lindane in rats. Jour. Environ. Pathol. Toxicol. 2:
737.
Davidow, B. and J.P. Frawley. 1951. Tissue distribution
accumulation and elimination of the isomers of benzene hexa-
chloride (18631). Proc. Soc. Exp. Biol. Med. 76: 780.
Duggan, R.E., and M.B. Duggan. 1973. Residues of pesti-
cides in milk, meat 'and foods. Page 334 In: L.A. Edwards,
ed. Environ. Pollut. Pestic. London.
Eisler, R. 1970. Acute toxicities of organochlorine and
organophosphorus insecticides to estuarine fishes. Bur.
Sport Fish Wildl. Pap. No. 46.
Engst, R., et al. 1977. Recent state of lindane metabolism.
Residue Rev. 68: 59.
Fitzhugh, O.G., et al. 1950. Chronic toxicities of benzene
hexachloride, and its alpha, beta, and gamma isomers. Jour.
Pharmacol. Exp. Therap. 100: 59.
Goto, M., et al. 1972. Ecological chemistry. Toxizitat
von a-KCH in mausen. Chemosphere 1: 153.
-------
Hanada, M., et al. 1973. Induction of hepatoma in mice
by benzene hexachloride. Gann. 64: 511.
Hansen, P.D. 1979. Experiments on the accumulation of
lindane (gamma BHC) by the primary producers Chlorella spec.
and Chlorella pyrenoidosa. Arch. Environ. Contam. Toxicol.
8: 721.
Henderson, C., et al. 1959. Relative toxicity of ten chlori-
nated hydrocarbon- insecticides to four species of fish.
Trans. Am. Fish Soc. 88: 23.
Henderson, C., et al. 1971. Organochlorine pesticide resi-
dues in fish-fall 1969: Natl. Pestic. Monitor. Progr. Pestic.
Monitor. Jour. 5: A.
Herbst, M., and G. Bodenstein. 1972. tToxicology of lin-
dane. Page 23 In; E. Ulmann, (ed.) Lindane. Verlag K. Schil-
linger Publishers, Freiburg.
Heyroth, F.F. 1952. In; Leland, S.J., Chem. Spec. Manuf.
Ass. Proc. 6:110.
Huntingdon Research Center. 1972. In; Lindane: Monograph
of an insecticide E. Illmon (ed.). Lube Verlag K. Schil-
linger p. 97.
Itp, N., et al. 1973. Histologic' and ultrastructur.al stu-
dies on the hepatocarcinogenicity of benzene hexachloride
in mice. Jour. Natl. Cancer Inst. 51: 817.
Ito, N. , et al. 1975. Development of hepatocellular car-
cinomas in rats treated with benzene hexachloride. Jour.
Natl. Cancer Inst. 54: 801.
Kashyap, S.K., et al. 1979. Carcinogenicity of hexachloro-
cyclohexane (BHC) in pure inbred Swiss mice. Jour. Environ.
Sci. Health B14: 305.
Kazahevich, R.L. 1974. 'State of the nervous system in
persons with a prolonged professional contact with hexachlor-
ocyclohexane and products of its synthesis. Vrach. Delo.
2: 129.
Khera, K.S., et al. 1979. Teratogenicity studies on pesti-
cidal formulations of dimethoate, diuron and lindane in
rats. Bull. Environ. Contam. Toxicol. 22: 5.22.
Kocansky, w., et al. 1963. Absorption, distribution, and
elimination of alpha- and beta- benzene hexachloride. Arch.
Exp. Pathol. Pharmacol. 244: 564.
Korn, S., and R. Earnest. 1974. Acute toxicity of twenty
insecticides to striped bass, Marone saxatilis. Calif.
Fish Game 60: 128.
-/ ^ ~i /^
I ^) *.u
-------
Krishnakumari, M.K. 1977. Sensitivity of the alga Scene-
desmus acutus to some pesticides. Life Sci. 20: 1525.
Kurihara, H., et al. 1979. Mercapturic acid formation
from lindane in rats. Pest. Biochem. Physiol. 10: 137.
Laug, E.P. 1948. Tissue distribution of a toxicant follow-
ing oral ingestion of the gamma-isomer of benzene hexachlo-
ride by rats. Jour. Pharmacol. Exp. Therap. 93: 277.
Lee, B., et al. 1976. Suspected reactions to gamma benzene
hexachloride. Jour. Am. Med. Assoc. 236: 2846:
Lehman, A.J. 1952a. Chemicals in food: A report to the
Assoc. of Food and Drug officials. Assoc. Food and Drug
Off., U.S. Quart. Bull. 16: 85.
".
Lehman, A.J. 1952b. Chemicals in foods: A report to
the Association of Food and Drug officials on current develop-
ments. Part II. Pesticides Section V. Pathology. U.S.
Assoc. Food Drug Off., Quart. Bull. 16: 126.
Lichtenstein, E.P.. 1959. Absorption of some chlorinated
hydrocarbon insecticides from soils into various crops.
Jour. Agric. Food Chem. 7: 430.
Litterst, C.L., and E. Miller. 1975. Distribution of lin-
dane in brains of control and phenobarbital pretreated dogs
at the onset of lindane induced convulsions. Bull. Environ.
Contam. Toxicol. 13: 619.
Macek, K.J., and W.A. McAllister. 1970. Insecticide sus-
ceptibility of some common fish family representatives.
Trans. Am. Fish Soc. 99: 20.
Macek, K.J., et al. 1976. Chronic toxicity of lindane
to selected aquatic invertebrates and fishes. EPA-600/3-
76-046. U.S. Environ. Prot. Agency.
Mametkuliev, C.H. 1978. Study of embryotoxic and terato-
genic properties of the gamma isomer of HCH in experiments
with rats. Zdravookhr. Turkm. 20: 28.
Mathur, S.P., and J.G. Saha. 1975. Microbial degradation
of lindane-C-14 in a flooded sandy loam soil. Soil sci.
120: 301.
.-
Nagasaki, H. , et al. 1972. Carcinogenicity of benzene
hexachloride (BHC). Top. Chem. Carcinog., Proc. Int. Symp.,
2nd. 343.
National Academy of Sciences - National Research Council.
1977. Safe Drinking Water Committee. Drinking Water and
Health, p. 939.
-------
National Cancer Institute. 1977a. A bioassay for possible
carcinogenicity of lindane. Fed. Reg^ Vol. 42 No. 218.
National Cancer Institute. 1977b. Bioassay of lindane
for possible carcinogenicity. NCI Carcinogenesis Technical
Report, Series No. 14.
Nigam, S.K., et al. 1979. Effect of hexachlorocyclohexane
feeding on testicular tissue on pure inbred Swiss mice.
Bull. Environ. Contain. Toxicol. 23: 431.
Nishiraura, H., et al. 1977. Levels of polychlorinated
biphenyls and organochlorine insecticides in human embryos
and fetuses. Pediatrician 5: 45.
Palmer, A.K., et al. 1978. Effect of lindane on pregnancy
in the rabbit and rat. Toxicology 9: 239.
Petrescu, S., et al. 1974. Studies on the effects of long-
terra administration of chlorinated organic pesticides (lin-
dane, DDT) on laboratory white rats. Rev. Med. - Chir.
78: 831.
PoradovsJcy, R., et al. 1977. Transplacental permeation
of pesticides during normal pregnancy. Cesk Gynekol. 42:
405.
Reuber, M.D. 1979. Carcinogenicity of lindane. Environ.
Res. 19: 460.
Rivett, K.P., et al. 1978. Effects of feeding lindane
to dogs for periods of up to 2 years. Toxicology 9: 237.
Sanders, H.O., and O.B. Cope. 1963. The relative toxicities
of serveral pesticides to naiads of three species of stone-
.flies. Limnol. Oceanogr. 13: 112.
Sasinovich, L.M., et al. 1974. Toxic hepatitis due to
prolonged exposure to BHC. Vrach. Delo. 10: 133.
Schimmel, S.E., et al. 1977. Toxicity and bioconcentration
of BHC and lindane in selected estuarine animals. Arch.
Environ. Contain. Toxicol. 5: 355.
Sloof, W. 1979. Detection limits of a biological monitor-
ing system based on fish respiration. Bull. Environ. Contam.
Toxicol. 23: 517.
Sugiura, K., et al. 1979a. Accumulation of organochlorine
compounds in fishes. Difference of accumulation factors
of fishes. Chemosphere 5: 359,
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Sugiura, K., et al. 19795. Accumulation of organochlorine
compounds in fishes. Distribution of 2,4,5-T,
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No. 113
ganma-flexachlorocyclohexane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
1/3-1
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DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
7
-------
Disclaimer Notice
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.
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GAMMA-HEXACHLOROCYCLOHEXANE (Lindane)
Summary
Gamma-l,2,3,4,5,6-hexachlorocyclohexane, commonly known as lindane, can
induce liver tumors in mice. Evidence for mutagenicity of lindane is equi-
vocal. Lindane was not teratogenic for rats, although it reduced reproduc-
tive capacity over four generations. Chronic exposure of animals to lindane
caused liver enlargement and, at higher doses, some liver damage and nephri-
tic changes. Humans chronically exposed to HCH suffered liver damage.
Chronic exposure of humans to lindane produced irritation of the central
nervous system. Lindane is a convulsant.
Lindane has been extensively studied in a number of freshwater and
marine acute studies. Levels as low as 0.17 jjg/1 are toxic to marine inver-
tebrate species.
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GAMMA-HEXACHLOROCYCLOHEXANE (Lindane)
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Hexachlorocyclohexane (U.S. EPA, 1979).
Gamma-l,2,3,4,5,6-hexachlorocyclohexane or lindane (C^H^Cl^;
molecular weight 290.0) is a crystalline solid with a melting point of
112.8°C, a vapor pressure of 0.003 mm Hg at 20°C (U.S. EPA, 1979), a
solubility in water at 25°C of 7.8 rag/1 (Hansen, 1979), and a solubility
in ether of 20.8 g/100 g at 20°C (U.S. EPA, 1979). Other trade names in-
clude Jacutin, Lindfor 90, Lindamul 20, Nexit-Staub, Prodactin, gamma-HCH,
gamma-SHC, and purified BHC (U.S. EPA, 1979). Technical grade hexachlorocy-
clohexane contains 10 to 18 percent lindane.
Lindane is a broad spectrum insecticide, and is a member of the cyclic
*
organo-chlorinated hydrocarbons. It is used in a wide range of applications
including treatment of animals, buildings, man (for ectoparasites), cloth-
ing, water (for mosquitoes), plants, seeds, and soil. Lindane is not cur-
rently manufactured in the U.S.; all lindane used in the U.S. is imported
(U.S. EPA, 1979).
Lindane has a low residence time in the aquatic environment. It is re-
moved by sedimentation, metabolism, and volatilization. Lindane contributes
less to aquatic pollution than the other hexachlorocyclohexane isomers (Hen-
derson, et al. 1971).
Lindane is slowly degraded by soil microorganisms (Mathur and Saha,
1975; Tu, 1975, 1976) and is reported to be isomerized to the alpha- and/or
delta- isomers in microorganisms and plants (U.S. EPA, 1979), but not in
rats (Copeland and Chadwick, 1979). The metabolic pathway in microorganisms '
is still controversial (Tu, 1975, 1976; Copeland and Chadwick, 1979).
-------
II. EXPOSURE
A. Water
The contamination of water has occurred principally from direct
application of technical hexachlorocyclohexane (HCH) or lindane to water for
control of mosquitoes or from the use of HCH in agriculture and forestry;
and to a lesser extent from occasional contamination of wastewater from
manufacturing plants (U.S. EPA, 1979).
Lindane has been detected in the finished water of Streator, Illi-
nois, at a concentration of 4 ug/1 (U.S. EPA, 1975).
B. Food
The daily intake of lindane has been reported at 1 to 5 ug/kg body
weight and the daily intake of all other HCH isomers at 1 to 3 ug/kg body
weight (Duggan and Duggan, 1973). The chief sources of HCH residues in the
human diet are milk, eggs, and other dairy products (U.S. EPA, 1979) and
carrots and potatoes (Lichtenstein, 1959). Seafood is usually a minor
source of HCH, probably because of the relatively high rate of dissipation
of HCH in the aquatic environment (U.S. EPA, 1979).
The U.S. EPA (1979) has estimated the weighted average bioconcen-
tration factor for lindane to be 780 for the edible portions of fish and
shellfish consumed by Americans. This estimate is based on measured steady-
state bioconcentration studies in bluegills.
C. Inhalation
Traces of HCH have been detected in the air of central and suburban
London (Abbott, et al. 1966). Uptake of lindane by , inhalation is estimated
at 0.002 jug/kg/day (Barney, 1969).
0. Dermal '
Lindane has been used to eradicate human ectoparasites, -a few ad-
verse reactions have been reported (U.S. EPA, 1979).
113-6
-------
III. PHARMACOKINETICS
A. Absorption
The rapidity of lindane absorption is enhanced by lipid-mediated
carriers. Compared to other organochlorine insecticides, lindane is unusu-
ally soluble in water which contributes to its rapid absorption and excre-
tion (Herbst and Bodenstein, 1972; U.S. EPA, 1979). Intraperitoneal injec-
tions of lindane resulted in 35 percent absorption (Koransky, et al. 1963).
Lindane is also absorbed after oral and dermal exposure (U.S. EPA, 1979).
B. Distribution
After administration to experimental animals, lindane was detected
in the brain at higher concentrations than in other organs (Laug, 1948;
Davidow and Frawley, 1951; Koransky,_ et al. 1963; Huntingdon Research Cen-
ter, 1971). At least 75 percent of an intraperitoneal dose of C-labeJ,ed
lindane was consistently found in the skin, muscle, and fatty tissue (Koran-
sky, et al. 1963). Lindane enters the human fetus through the placenta;
higher concentrations were found in the skin than in the brain, but never
exceeded the corresponding values for adult organs (Poradovsky, et al. 1977;
Nishimura, et al. 1977).
C. Metabolism
Copeland and Chadwick (1979) found that lindane did not isomerize
in adipose tissues in rats, but noted dechlorination to T*-3,4,5,6-tetra-
chlorocyclohexene. Some other metabolites reported have been 2,3,4,5,6-pen-
tachloro-2-cyclohexene-l-ol, pentachlorophenol, tetrachlorophenols, and
three trichlorophenols (Chadwick, et al. 1975; Engst, et al. 1977), all of
which were found in the urine as conjugates (Chadwick and Freal, 1972).
»
Lindane metabolic pathways are still matters of some controversy (Engst, et
. isii / -
' I JJU
1/3-7
-------
al. 1977; Copeland and Chadwick, 1979). Both free and conjugated chlorophe-
nols with the possible exception' of pentachlorophenol (Engst, et al. 1977)
are far less toxic than lindane (Natl. Acad. Sci., 1977).
0. Excretion
Metabolites of lindane appear to be eliminated primarily as conju-
gates in the urine. Very little unaltered lindane is excreted (Laug, 1948).
Elimination of lindane appears to be rapid after administration ceases (U.S.
EPA, 1979).
IV. EFFECTS
A. Carcinogenicity
Nagasaki, et al. (1972b) fed *{,/&, T~, and 0 isomers separately
in the diet to mice at levels of 100, 250, and 500 ppm. At termination of
the experiment after 24 weeks, multiple liver tumors, some as large as 2.0
centimeters in diameter were observed in all animals given ^-HCH at the 500
ppm level. The 250 ppmV -HCH level resulted in smaller nodules, while no
lesions were found at levels of 100 ppm. The various dosages did not pro-
duce any tumors with respect to the other isomers. Pathomorphological in-
vestigations by Didenko, et al. (1973) established that the IT isomer did
not induce tumors in mice given intragastric administration at doses of 25
mg/kg twice a week for five weeks.
Hanada, et al. (1973) fed six-week-old mice a basal diet of 100,
300, and 600 ppm t-HCH and the^(, $,• IT isomers for a period of 32 weeks.
After 38 weeks, liver tumors were found in 76.5 percent of the males and
43.5 percent of the females fed t-HCH, indicating males were more highly
susceptible to HCH-induced tumors than females. Multiple nodules were found
in the liver, although no peritoneal invasion or distinct metastasis was
found. Thep -isomer-treated animals had no tumors.
-------
Goto, et al. (1972) essentially confirmed the findings of the above
study using diets containing 600 ppm levels over a 26 week period. The com-
bination of/?-, T-, or 0 -HCH with the highly carcinogenic action of °(-
HCH revealed no synergistic or antagonistic effect on the production of
tumors by °( -HCH for dd strains of mice (Ito, et al. 1973). Kashyap, et al.
(1979) found that 2T-HCH (14 percent lindane) at 100 ppm levels in the diet
or at 10 mg/kg/day caused liver and lymphoreticular tissue tumors in both
male and female mice after 45 weeks. Application by skin painting had no
effect.
The National Cancer Institute conducted a bioassay for the possible
carcinogencity of 0 -HCH to Osbome-Mendel rats and 86C3F1 mice. Adminis-
tration continued for 80 weeks at two dose levels: time-weighted average
dose for male rats was 236 and 472 ppm; for female rats, 135 and 275 ppm;
and for all mice, 80 and 160 ppm. NO statistically significant incidence of
tumor occurrence was noted in any of the experimental rats as compared to
the controls. At the lower dose concentration in male mice, the incidence
•' of hepatocellular carcinoma was significant when compared to the controls,
but not significant in the higher dose males. "Thus, the incidence of hepa-
tocellular carcinoma in male mice cannot clearly be related to treatment."
The incidence of hepatocellular carcinoma among female mice was not signifi-
cant. Consequently, the carcinogenic activity of T'-HCH in mice is ques-
tionable (Natl. Cancer Inst., 1977).
B. Mutagenicity
Some alterations in mitqtic activity and the karyotype of human ly-
phocytes cultured with lindane at 0.1 to 10 mg/ml have been reported (Tsone-
va-Maneva, et al. 1971). %" -HCH was mutagenic in assays using Salmonella
typhimurium with metabolic activation, the host-mediated assay, and the
-------
dominant lethal assay in rats. Other reports indicate that it does not have
significant mutagenic activity (U.S. EPA, 1979; Buselmair, et al. 1973).
C. Teratogenicity
Lindane given in the diet during pregnancy at levels of 12 or 25
mg/kg body weight/day did not produce teratogenic effects in rats (Mametku-
liev, 1978; Khera, 1979).
0. Other Reproductive Effects
Chronic lindane feeding in a study of four generations of rats in-
creased the average duration of pregnancy, decreased the number of births,
increased the proportion of stillbirths, and delayed sexual maturation in F2
and F3 females. In addition, some of the Fl and F2 animals exhibited spas-
tic paraplegia (Petrescu, et al. 1974 )_.
In rats and rabbits, lindane given in the diet during pregnancy in-
creased postimplantatlon death of embryos (Mametkuliev, 1978; Palmer, et al.
1978). Testicular atrophy has been observed in rats and mice (National Can-
cer Institute, 1977; Nigam, et al. 1979).
E. Chronic Toxicity
Irritation of the central nervous system with other toxic side ef-
fects (nausea, vomiting, spasms, weak respiration with .cyanosis and blood
dyscrasia) have been reported after prolonged or improper use of Hexicid (1
percent lindane) for the treatment of scabies on humans (Lee, et al. 1976).
In chronic studies with rats given lindane in oil, liver cell hy-
pertrophy (fat degeneration and necrosis) and nephritic changes were noted
at higher doses (Fitzhugh, et al. 1950; Lehman," 1952a,b). Rats inhaling
lindane (0.78 mg/m ) for 7 hours, 5 days a week for 180 days showed liver
»
cell enlargement but showed no clinical symptoms or other abnormalities
(Heyroth, 1952). The addition of 10 ppm lindane to the diet of rats for one
in-/*
-------
or two years decreased body weight after five months of treatment and al-
tered ascorbic acid levels in urine, blood, and tissues (Petrescu, et al.
1974). Dogs chronically exposed to lindane in the diet had friable and
slightly enlarged livers (Rivett, et al. 1978).
F. Other Relevant Information
Lindane is a convulsant and is the most acutely toxic isomer of
hexachlorocyclohexane. The toxic effects of lindane are antagonized by pre->.
treatment with phenobarbitol (LLtterst and Miller, 1975) and by treatment
with silymarin (Szpunar, et al. 1976), and various tranouilizers (Ulmann,
1972).
V. AQUATIC TOXICITY
A. Acute Toxicity
The range of adjusted LC5Q values for one flow-through and'24
static bioassays for lindane in freshwater fish ranged from 1 pg/l for the
brown trout Salmo trutta (Macek,- et al. 1970) to 83 jug/1 for the goldfish
(Carassius auratus), and represents the results of tests on 16 freshwater
fish species (U.S. EPA, 1979). Zebrafish (Brachydanio rerio) showed an
LC5Q value of 120 ;jg/l but rainbow trout (Salmo qairdneri) exhibited re-
spiratory distress at 40 jug/1 (Slooff, 1979). Among eight species of fresh-
water invertebrates studied with lindane, stone flies (Pteronarcys califomi-
ca) and three species of crustaceans: scuds (Gammarus lacustris and G^ faci-
atus) and sowbugs (Ascellus brevicaudus) were most sensitive, with adjusted
LC5Q values ranging from 4 to 41 jug/1. Three species of cladocerans
(Daohnia pulex, D^ maqna and Simocephalus serralatus) were most resistant
with LC5Q values of 390 to 745 jjg/1. The midge (Chironomus tentans) was
intermediate in sensitivity with LC5Q values of 175 pg/1 (U.S. EPA, 1979).
-------
Among eight species of marine fish tested in static bioassays with
lindane, the Atlantic silversides (Menidia menidia) was most sensitive, with
an acute LC5Q of 9 jjg/1 (Eisler, 1970), while the striped mullet (Muqil
cephalus) was reported as having an acute static LC5Q of 66.0 ug/1 (U.S.
EPA, 1979). The results of six flow-through assays on five species of
marine fish revealed that the striped bass (Morone saxatilis) was most sen-
sitive with an acute LC_0 of 7.3 jug/1 (Korn and Earnest, 1974); and the
longnose killifish (Fundulus similis) was most resistant with a reported
LC-., of 240 jjg/1. Acute studies with six species of marine invertebrates
showed these organisms to be extremely sensitive to lindane, with LC5Q
values ranging from 0.17 jjg/1 for the pink shrimp, Panaeus duorarum (Schim-
mel, et al. 1977), to 8.5 ug/1 for the grass shrimp (Palaemonetes vulqaris).
B. Chronic
A chronic value of 14.6 ug/1 was obtained for lindane in a life-
cycle assay of the freshwater fathead minnow (Pimephales promelas). Chronic
values of 3.3, 6.1, and 14.5 ug/1 were obtained for three freshwater inver-
tebrates, Chironomus tentans, Gammarus fasciatus, and Daphnia maqna (Macek,
et al. 1976). No marine chronic studies were available.
C. Plant Effects
For freshwater algae, Scenedesmus acutus, the effective concentra-
tion for growth inhibition was 1,000 ug/1. Effective concentrations for
marine phytoplankton communities and the algae, Acetabularia mediterranea,
were 1,000 and 10,000 pg/1, respectively. Irreparable damage to Chlorella
spec, occurred at concentrations greater than 300 ug/1 (Hansen, 1979).
0. Residues
»
Bioconcentration factors for lindane ranging from 35 to 938 have
been obtained for six species of freshwater fish and invertebrates. No bio-
concentration factors for lindane have been determined for marine organisms
/ -7 {('
X /' ->' >" '^
-------
(U.S. EPA, 1979; Sugiura, et al. 1979). Equilibrium accumulation factors of
429 to 602 were observed at days 2 to 6 after exposure of Chlorella spec, to
10 to 400 ug/1 -of lindane in aqueous solution (Hansen, 1979).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed.
A. Human
Using the "one-hit" model, the U.S. EPA (1979) has estimated that
the water concentration of lindane (gamma-HCH) corresponding to a lifetime
cancer risk for humans of 10 is 54 ng/1, based on the data of Thorpe and
Walker (1973) for the induction of liver tumors in male mice.
Tolerance levels set by the U.S. EPA are as follows: 7 ppm for
animal fat; 0.3 ppm for milk; 1 ppm for most fruits and vegetables; 0.004
ppm for finished drinking water; and 0.5 mg/m (skin) for air (U.S. EPA,
1979). It is not clear whether these levels are for hexachlorocyclohexane
or for lindane.
3, Aquatic
The criterion has been drafted to protect freshwater organisms as a
0.21 ug/1 24-hour average concentration not to exceed 2.9 ug/1. Data are
insufficient to draft criterion for the protection of marine life from gam-
ma-hexachlorocyclohexane (lindane).
I > 3
-------
. GAMMA-HEXACHLOROCYCLOHEXANE(LINDANE)
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-------
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»
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-------
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»
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-------
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IIZ-I7
-------
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No. 114
Hexachlorocyclopentadiene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
/ '^^ f I
111-I
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DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
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HEXACHLOROCYCLOPENTADIENE
Summary
Hexachlorocyclopentadiene (HEX) is used as a chemical intermediate in
the manufacture of chlorinated pesticides. Evidence is not sufficient to
categorize this compound as a carcinogen or non-carcinogen; HEX was not
mutagenic in either short-term in vitro assays or a mouse dominant lethal
study. Teratogenic effects were not observed in rats receiving oral doses
of HEX during gestation.
The reported 96-hour LC5Q value for the fathead minnow under static
and flow-through conditions using larval and adult fish ranges from 7.0 pg/1
to 104 jug/1. The chronic value for fish in an embryo-larval test is 2.6
pg/1.
-------
HEXACHLOROCYCLOPENTADIENE
I. INTRODUCTION
Hexachlorocyclopentadiene (HEX; C5Clg) is a pale to greenish-yellow
liquid. Other physical properties include: molecular weight, 272.77; solu-
bility in water, 0.805 mg/1; and vapor pressure, 1 mm Hg at 78-79°C. HEX
is a highly reactive compound and is used as a chemical intermediate in the
manufacture of chlorinated pesticides (Kirk-Othmer, 1964). Recent govern-
ment bans on the use of chlorinated pesticides have restricted the use of
HEX as an intermediate to the endosulfan and decachlorobi-2,4-cyclo-
pentadiene-1-yl industries. Currently, the major use of HEX is as an inter-
mediate in the synthesis of flame retardants (Sanders, 1978; Kirk-Othmer,
1964). Production levels of HEX approximate 50 million, pounds per year
(Bell, et al. 1978).
. Environmental monitoring data for HEX are lacking, except for levels
measured in the vicinity of industrial sites. The most likely route of
entry of HEX into the environment arises from its manufacture or the manu-
facture of HEX-containing products. Small amounts of HEX are present as
impurities in pesticides made from it; some HEX has undoubtedly entered the
environment via this route.
HEX appears to be strongly adsorbed to soil or soil components, al-
though others have reported its volatilization from soil (Rieck, 1977a,
1977b). HEX degrades rapidly by photolysis, giving water-soluble
degradation products (Natl. Cancer Inst., 1977). Tests on its stability
towards hydrolysis at ambient temperature indicated ''a half-life of about 11
days at pH3-6, which was reduced to 6 days at pH 9.
lit-
-------
II. EXPOSURE
A. Water
HEX has been detected in water near points of industrial discharge
at levels ranging from 0.156 to 18 mg/1 (U.S. EPA, 1979). Other than this,
there is little information concerning HEX concentrations in surface or
drinking waters. Due to its low solubility, photolability, and tendency to
volatize, one would not expect HEX to remain in flowing water.
8. Food
HEX has been identified in a few samples-- of fish taken from waters
near the Hooker Chemical Plant in Michigan . (Spehar, et al. 1977). No
reports concerning HEX contamination of other foods could be located.
The U.S. EPA. (1979) has estimated the weighted average bioconcen-
tration factor of HEX for the edible portions of fish and shellfish consumed
by Americans to be 3.2. This estimate is based on measured steady-state
bioconcentration studies in fathead minnows.
C. Inhalation
The most significant chronic exposure to HEX occurs among persons
engaged directly in its manufacture and among production workers fabricating
HEX-containing products. Inhalation is the primary mode of exposure to HEX
in the event of accidental spills, illegal discharges, or occupational situ-
ations.
III. PHARMACOKINETICS
A. Absorption
Kommineni (1978) found in rats that HEX is absorbed through the
squamous epithelium of the nonglandular part of the stomach, causing
»
necrotic changes, and that the major route of elimination of HEX is through
the lungs. This information is based on morphological changes in rats
-------
administered HEX by gayage. Further study-with guinea pigs showed that HEX
was absorbed through the skin; but, unlike the rat stomach, the squamous
epithelium of these animals did not undergo necrotic changes.
B. Distribution
The tissues of four rats administered single oral doses of HEX re-
tained only trace amounts of the compound after 7 days (Mehendale, 1977).
For example, approximately 0.5 percent of the total dose was retained in the
kidney and less than 0.5 percent in the liver. Other organs and tissues -
fat, lung, muscle, blood, etc. - contained even less HEX. Tissue homoge-
nates from rats receiving injections of C-HEX showed that 93 percent of
the radioactivity in the kidney and 68 percent in the liver were associated
with the cytosol fraction (Mehendale, 1977).
C. Metabolism
At least four metabolites were present in the urine of rats admini-
stered HEX (Mehendale, 1977). Approximately 70 percent of the metabolites
were extractable using a hexane:isopropanol mixture.
0. Excretion
Mehendale (1977) found that approximately 33 percent of the total
dose of HEX administered to rats via oral intubation was excreted in the
urine after 7 days. About 87 percent of that (28.7 percent of the total
dose) was eliminated during the first 24 hours. Fecal excretion accounted
for 10 percent of the total dose; nearly 60 percent of the 7 day fecal
excretion occurred during the first day. These findings suggest that elim-
ination of HEX may occur by routes other than urine and feces, and it has
been postulated that a major route of excretion may be the respiratory.tract.
-------
Whitacre (1978) did not agree with-the study by Mehendale (1977).
This recent study of HEX excretion from mice and rats showed that excretion
was mainly by the fecal route with no more than 15 percent in the urine.
Approximately nine percent of an injected dose of HEX was excreted
in the bile in one hour (Mehendale, 1977). Because this quantity is equi-
valent to that excreted in the feces over seven days, enterohepatic circu-
lation of this compound is probable.
IV. EFFECTS
A. Carcinogenicity
Only .one in vitro test of HEX for carcinogenic activity could be
located. Litton Bionetics (1977) reported the results of a test to deter-
mine whether HEX could induce malignant transformation in BALB/3T3 cells.
HEX was found to be relatively toxic to cells, but no significant carcino-
genic activity was reported with this assay.
The National Cancer Institute (1977) concluded that toxicological
studies conducted thus far have not been adequate for evaluation of the car-
cinogenicity of HEX. Because of this paucity of information and HEX's high
potential for exposure, HEX has been selected for the NCI's carcinogenesis
testing program.
B. Mutagenicity
HEX has been reported to be non-mutagenic in short-term in vitro
mutagenic assays (Natl. Cancer Inst., 1977; Industrial Bio-Test Labora-
tories, 1977; Litton Bionetics, 1978a) and in a mouse dominant lethal assay
.-
(Litton Bionetics, 1978b).
-------
C. Teratogenicity
International Research and Development Corporation (1978) studied
the effect of oral doses of up to 300 mg/kg/day of HEX administered to rats
on days 6 through 15 of gestation. Teratogenic effects were not reported at
doses up to 100 mg/kg/day; the highest dosage (300 mgAg/day) resulted in
the death of all rats by day ten of'gestation. In this study, elimination
via the respiratory tract did not appear to be significant.
0. Other Reproductive Effects
Pertinent information could not be located in the available liter-
ature.
E. Chronic Toxicity
There are very few studies concerning the chronic toxicity of HEX
in laboratory animals. Naishstein and Lisovskaya (1965) found that daily
administration of 1/30 the median lethal dose (20 mg/kg) for 6 months res-
ulted in the death of two of ten animals. The investigators judged the cum-
ulative effects of HEX to be weak; no neoplasms or ether abnormalities were
reported. Naishstein and Lisovskaya (1965) applied 0.5 to 0.6 ml of a solu-
tion of 20 pom HEX daily to the skin of rabbits for 10 days and found no
significant adverse effects from exposure. Treon, et al. (1955) applied
430-6130 mg/kg HEX to the skin of rabbits. Degenerative changes of the
brain, liver, kidneys, and adrenal glands of these animals were noted, in
addition to chronic skin inflammation, acanthosis, hyperkeratosis, and epil-
ation. Further study by Treon, et al. (1955) revealed slight degenerative
changes in the liver and kidney of guinea pigs, rabbits, and rats exposed to
0.15 ppm HEX for daily seven-hour periods over approximately seven months.
Four of five mice receiving the same dosage died within this period.
-------
There is virtually no information, regarding the human health ef-
fects of chronic exposure to HEX. According to Hooker's material safety
data sheet for HEX, (1972) acute exposure to the compound results in irrita-
tion of the eyes and mucous membranes, causing lacrimation, sneezing, and
salivation. Repeated contact with the skin can cause blistering and burns,
and inhalation can cause pulmonary edema. Ingestion can cause nausea, vom-
iting, diarrhea, lethargy, and retarded respiration.
V. AQUATIC TOXICITY
A. Acute Toxicity
The . reported 96-hour LC5Q values for the fathead minnow
(Pimephales promelas) under static and flow-through conditions with larval
and adult fish range from 7.0 fjg/1 to 104 jjg/1. The effect of water hard-
ness is minimal (Henderson 1956; U.S. EPA, 1978). There are no reports of
studies of the acute toxicity of HEX on saltwater organisms.
B. Chronic Toxicity
In the only chronic study reported, the lowest chronic value for
the fat- head minnow (embryo-larval) is 2.6 jjg/1 (U.S. EPA, 1978).
C. Plant Effects
Pertinent information could not be located in the available liter-
ature.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979a), which are summarized below, have gone through the process of public
.•
review; therefore, there is a possibility that these criteria will be
changed. »
-------
A. Human
The Occupational Safety and Health Administration has not set a
standard for occupational exposure to HEX. The American Conference of
Governmental Industrial Hygienists has adopted a threshold limit value (TLV)
of 0.01 ppm (0.11 mg/m ) and a short term exposure limit of 0.03 ppm (0.33
mg/m3) (ACGIH, 1977).
The draft ambient water quality criterion for HEX is 1.0 ug/1 (U.S.
EPA, 1979).
8. Aquatic
For HEX, the draft criterion to protect freshwater aquatic life is
0.39 ;jg/l as a 24-hour average, not to exceed 7.0 jug/1 at any time (U.S.
EPA, 1979). Criteria., have not been proposed for saltwater species because
of insufficient data.
\ I if-in
-------
HEXACHLOROCYCLOPENTADIENE
REFERENCES
American Conference of Governmental Industrial Hygienists. 1977, TLV's:
threshold limit values for chemical substances and physical agents in the
workroom environment with intended changes for 1977. Cincinnati, Ohio.
Bell, M.A., et al. 1978. Review of the environmental effects of pollutants
XI. Hexachlorocyclopentadiene. Report by Battelle Columbus Lab. for U.S.
EPA Health Res. Lab., Cincinnati, Ohio.
Henderson, D. 1956. Bioassay investigations for International Joint Com-
mission. Hooker Electrochemical Co., Niagara Falls, N.Y. U.S. Dep. of
Health Educ. Welfare, Robert A. Taft Sanitary Eng. Center, Cincinnati,
Ohio. 12 p.
Hooker Industrial Chemicals Division. 1972. Material safety data sheet:
Hexachlorocyclopentadiene.- Unpublished internal memo dated April, 1972.
Industrial Bio-Test Laboratories, Inc. 1977. Mutagenicity of PCL-HEX
incorporated in the test medium tested against five strains of Salmonella
typhimurium and as a volatilate against tester strain TA-100. Unpublished
report submitted to Velsicol Chemical Corp.
International Research and Development Corp. 1978. Pilot teratology study
in rats. Unpublished report submitted to Velsicol Chemical Corp.
Kirk-Othmer Encyclopedia of chemical technology. 2nd ed. 1964. Intersci-
ence Publishers, New York.
Kommineni, C. 1978. Internal memo dated February 14, 1978, entitled:
Pathology report on rats exposed to hexachlorocyclopentadiene. U.S. Dep. of
Health Ed. Welfare, Pub. Health Serv. Center for Dis. Control, Natl. Inst.
for Occup. Safety and Health.-
Litton Bionetics, Inc. 1977. Evaluation of hexachlorocyclopentadiene in
vitro malignant transformation in BALB/3T3 cells: Final rep. Unpublished
report submitted to Velsicol Chemical Corp.
Litton Bionetics, Inc. 1978a. Mutagenicity evaluation of hexachlorocyclo-
pentadiene in the mouse lymphoma forward mutation assay. Unpublished rep.
submitted to Velsicol Chemical Corp.
Litton Bionetics, Inc. 1978b. Mutagenicity evaluation of hexachloropenta-
diene in the mouse dominant lethal assay: Final report. Unpublished rep.
submitted to Velsicol Chemical Corp.
Mehendale, H.M. 1977. The chemical reactivity - absorption, retention,
metabolism, and elimination of hexachlorocyclopentadiene. Environ. Health,
Perspect. 21: 275.
11
-------
Naishstein, S.Y., and E.V. Lisovskaya. 1965. Maximum permissible concen-
tration of hexachlorocyclopentadiene in water bodies. Gigiena i Sanitariya
(Translation) Hyg. Sanit. 30: 177.
National Cancer Institute. 1977. Summary of data for chemical selection.
Unpublished internal working paper, Chemical Selection Working Group, U.S.
Dep. of Health Edu. Welfare, Pub. Health Serv., Washington, O.C.
Rieck, C.E. 1977a. Effect of hexachlorocyclopentadiene on soil microbe
populations. Unpublished report submitted to Velsicol Chemical Corp.,
Chicago, 111.
Rieck, C.E. 1977b. Soil metabolism of 14C-hexachlorocyclopentadiene.
Unpublished report submitted to Velsicol Chemical Corp., Chicago, 111.
Sanders, H.J. 1978. Flame retardants. Chem. Eng. News: April 24,
1978: 22.
Spehar, R.L., et al. 1977. A rapid assessment of the toxicity of three
chlorinated cyclodiene insecticide intermediates to fathead minnows. Off.
Res. Oev. Environ. Res. Lab., Ouluth, Minn. U.S. Environ. Prot. Agency.
Treon, J.F., et al. '1955. The toxicity of hexachlorocyclopentadiene.
Arch. Ind. Health. 11: 459.
Whitacre, O.M. 1978. Letter to R. A. Ewing, Battelle Columbus Labora-
tories, dated August 9, 1978. Comments on documpnt entitled: Review of
Environmental Effects of Pollutants XI. Hexachlorocyclopentadiene.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646. U.S. Environ. Prot.
Agency,.Washington, 0.C.
U.S. EPA. 1979. Hexachlorocyclopentadiene: Ambient Water Quality Criteria
(Draft).
-------
No. 115
Hexachloroethane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
HEXACHLOROETHANE
SUMMARY
Results of a National Cancer Institute (NCI) carcinogenesis bioassay
showed that hexachloroethane produced an increase in hepatocellular car-
cinoma incidence in mice.
Testing of hexachloroethane in the Ames Salmonella assay showed no
mutagenic effects. No teratogenic effects were observed following oral or
inhalation exposure of rats to hexachloroethane, but some toxic effects on
fetal development were observed.
Toxic symptoms produced in humans following hexachloroethane exposure
include central nervous system depression and liver, kidney, and heart
degeneration.
Hexachloroethane is one of the more toxic of the chlorinated ethanes
reviewed for aquatic organisms with marine invertebrates appearing to be the
most sensitive organisms studied. This chlorinated ethane also had the
greatest bioconcentration factor, 139 for bluegill sunfish, observed in this
class of compounds.
//S--3
-------
HEXACHLOROETHANE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Chlorinated Ethanes (U.S. EPA, 1979a).
The chloroethanes are hydrocarbons in which one or more of the hydrogen
atoms are replaced by chlorine atoms. Water solubility and vapor pressure
decrease with increasing chlorination, while density and melting point in-
crease. Hexachloroethane (Perchloroethane; M.w. 236.7) is a solid at room
temperature with a boiling point of 186°C, specific gravity of 2.091; and
is insoluble in water (U.S. EPA, 1979a).
The chloroethanes are used as solvents, cleaning and degreasing agents,
and in the chemical synthesis of a number of compounds. Hexachloroethane
does not appear to be commercially produced in the U.S., but 730,000 kg were
imported in 1976. (U.S. EPA, 1979a).
The chlorinated ethanes form azeotropes with water (Kirk and Othmer,
1963). All are very soluble in organic solvents (Lange, 1956). Microbial
degradation of the chlorinated -ethanes has not been, demonstrated (U.S. EPA,
1979a).
The reader is referred to the Chlorinated Ethanes Hazard Profile for a
more general discussion of chlorinated ethanes (U.S. EPA, 1979b).
II. EXPOSURE
The chloroethanes are present in raw and finished waters due primarily
to industrial discharges. Small amounts of the chloroethanes may be formed
by chlorination of drinking water or treatment of sewage. Air levels are
produced by evaporation of volatile chloroethanes.
»
Sources of human exposure to chloroethanes include water, air, contam-
inated foods and fish, and dermal absorption. Fish and shellfish have shown
-------
levels of chloroethanes in the nanogram range (Dickson and Riley, 1976).
Information on the levels of hexachloroethane in foods is not available.
U.S. EPA (1979a) has estimated the weighted average bioconcentration
factor for hexachloroethane to be 320 for the edible portion of fish and
shellfish consumed by Americans. This estimate is based on the octanol/
water partition coefficient.
III. PHARMOKINETICS
Pertinent data could not be located in the available literature on
hexachloroethane for absorption, distribution, metabolism, and excretion.
However, the reader is referred to a more general treatment of chloroethanes
(U.S. EPA, 1979b) which indicates rapid absorption of chloroethanes follow-
ing oral or inhalation exposure; widespread distribution of the chloro-
ethanes through the body; enzymatic dechlorination and oxidation to the
alcohol and ester forms; and excretion of the chloroethanes primarily in the
urine and in expired air.
IV. EFFECTS
A. Carcinogencitiy
Results of an NCI carcinogenensis bioassay for hexachloroethane
showed that oral administration of the compound produced an increase in the
incidence of hepatocellular carcinoma in mice. No statistically significant
tumor increase was seen in rats.
8. Mutagenicity
The testing of hexachloroethane in the Ames Salmonella assay or in
a yeast mutagenesis system failed to show any mutagenic activity (Weeks, et
al. 1979).
-------
C. Teratogenicity
Teratogenic effects were not observed in pregnant rats exposed to
hexachloroethane by inhalation or intubation (Weeks, et al. 1979).
0. Other Reproductive Effects
Hexachloroethane administered orally to pregnant rats decreased the
number of live fetuses per litter and increased the fetal resorption rate
(Weeks, et al. 1979).
E. Chronic Toxicity
Toxic symptoms produced in humans following hexachloroethane expo-
sure include liver, kidney, and heart degeneration, and central nervous
system depression (U.S. EPA, 1979a).
Animal studies have shown that chronic exposure to hexachloroethane
produces both hepatotoxicity and nephrotoxicity (U.S. EPA, 1979a).
V. AQUATIC TOXICITY
A. Acute Toxicity
Among freshwater organisms, the bluegill sunfish (Lepomis
macrochirus) was reported to have the lowest sensitivity to hexachloro-
ethane, with a 96-hour static LC5Q value of 980 pg/1. The 48-hour static
LC5Q value of the freshwater Cladoceran (Daphnia maqna) was reported as
8,070 ug/1 (U.S. EPA, 1978). For the marine fish, the sheepshead minnow
(Cyprinodon varieqatus). a 96-hour LC-0 value of 2,400 /jg/1 was reported
from a static assay. The marine mysid shrimp (Mysidopsis bahia) was the
most sensitive aquatic organism tested, with a 96-hour static LC5Q value
of 940pg/l (U.S. EPA, 1978).
B. Chronic Toxicity
»
Pertinent data could not be located in the available literature.
//«
-------
C. Plant Effects
For the freshwater algae, Selenastrum capricornutum, the 96-hour
ECcn effective concentrations based on chlorophyll and cell number were
j\j
87,000 and 93,200 ug/1 for chlorophyll a production and cell growth,
respectively. The marine algae, Skeletonema costatum, was much more
sensitive, with effective concentrations from 7,750 to 8,570 ug/1 being
reported.
0. Residues
A bioconcentration factor of 139 was dbtained for the freshwater
bluegill sunfish (U.S. EPA, 1979a).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979a), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed.
A. Human
By applying a linear, non-threshold model to the data from the NCI
bioassay for carcinogenesis, the U.S. EPA (1979a) has estimated the level of
hexachloroethane in ambient water that will result in an additional risk of
10"5 to be 5.9 ug/1.
The eight-hour TWA exposure standard established by OSHA for hexa-
chloroethane is 1 ppm.
8. Aquatic Toxicity
»•
The proposed criterion to protect freshwater aquatic life is 62
ug/1 as a 24-hour average and should not exceed 140 /jg/1 at any time. The
drafted criterion for saltwater aquatic life is a 24-hour average concen-
tration of 7 ug/1 not to exceed 16 pg/1 at any time.
-------
HEXACHLOROETHANE
REFERENCES
Dickson, A.G., and J.P. Riley. 1976. The distribution
of short-chain halogenated aliphatic hydrocarbons in some
marine organisms. Mar. Follut. Bull. 79: 167.
Kirk, R., and D. Othxner. 1963. Encyclopedia of Chemical
Technology. 2nd ed. John Wiley and Sons, Inc. New York.
Lange, N. (ed.) 1956. Handbook of Chemistry. 9th ed.
Handbook Publishers, Inc. Sandusky, Ohio.
National Cancer Institute. 1978. Bioassay of hexachloro-
ethane for possible carcinogenicity. Natl. Inst. Health,
Natl. Cancer Inst. DHEW Publ. No. (NIH) 78-1318. Pub.
Health Serv. U.S. Oept. Health Edu. Welfare.
U.S. EPA. 1978. In-depth studies on health and environ-
mental impacts of selected water pollutants. U.S. Environ.
Prot. Agency. Contract No. 68-01-4646.
a.S. EPA. 1979a. Chlorinated Ethanes: Ambient Water Qual-
ity Criteria (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment
Office. Chlorinated Ethanes: Hazard Profile (Draft).
Van Dyke, R.A., and C.G. Wineman. 1971. Enzymatic dechlori-
nation: Dechlorination of chloroethane and propanes in-
vitro. Biochem. Pharmacol. 20: 463.
Weeks, M.H.,•et al. 1979. The toxicity of hexachloroethane
in laboratory animals. Am. Ind. Hyg. Assoc. Jour. 40: 137.
//r-r
-------
No. 116
Hexachlorophene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
HEXACHLOROPHENE
Summary
Oral, dermal, and subcutaneous administration of hexachlorophene in
animal studies has failed to show significant carcinogenic effects.
Mutagenic effects of hexachlorophene exposure have been reported in one
study which indicated increased chromosome aberrations in rats. Testing of
hexachlorophene in the host mediated assay or the dominant lethal assay did
not produce positive effects.
Several reports have indicated that hexachlorophene may produce some
teratogenic and embryotoxic effects. A three generation feeding study in
rats failed to show any teratogenic activity. Hexachlorophene has shown
some adverse effects on male reproductive performance.
Chronic administration of hexachlorophene has produced central nervous
system effects and muscular paralysis.
-------
I. INTRODUCTION
Hexachlorophene (C13H6a2CL6, molecular weight 406.9) is a white
powder which melts between 166°c and 167°C. The compound is practically
insoluble in water but is soluble in ethanol, ether, and other organic sol-
vents. Under alkaline conditions, hexachlorophene forms water-soluble salts
(IARC,- 1979).
The principle uses of hexachlorophene have been for the manufacture of
germicidal soaps, as a topical anti-infective agent for humans, as a vet-
erinary anti-helminthic, for disinfection of hospital equipment, and as a
broad-spectrum soil fungicide (IARC, 1979). Limitation of drugs and cos-
metics containing hexachlorophene was instituted by the FDA in 1972.
Commercial hexachlorophene produced from 2,4,5-trichlorophenol contains
less than 15 ug/kg of 2,3,7,8-tetrachlorodibenzo-para-dioxin (IARC, 1979).
II. EXPOSURE
There are no available estimates on daily exposure levels of humans to
hexachlorophene from air, water, or food. .
Water monitoring studies have detected hexachlorophene in two finished
drinking water samples (Shackelford and Keith, 1976) and in effluents of
sewage treatment plants at levels of 3.2 to 44.3 ug/1 (Sims.and Pfaender,
1975), as well as in creek sediments (9.3 to 377 jjg/kg).
Data on hexachlorophene levels in aquatic organisms indicate that the
compound is bioaccumulated (Sims and Pfaender, 1975).
Hexachlorophene has been detected in human milk at levels up to 9 ;jg/l
(West, et al. 1975). Blood levels of the compound in users of soap con-
»
taining hexachlorophene have been reported (0.02 to 0.14 mg/1 blood)
(Butcher, et al. 1973); blood levels fall after use is discontinued.
A 1974 survey by NIOSH indicated that exposure to hexachlorophene was
primarily in hospitals, sanitariums, and convalescent homes (IARC, 1979).
-------
III. PHARMACOKINETICS
A. Absorption
Systemic toxicity following dermal application or ingestion of
hexachlorophene indicates that the compound is absorbed through the skin and
the gastrointestinal tract (AMA Drug Evaluations, 1977).
B. Distribution
Whole-body autoradioigraphs of the murine fetus during late ges-
tation following administration of labelled hexachlorophene indicate an even
distribution pattern of the compound . The compound crosses the placenta;
fetal retention increases during the course of pregnancy (Brandt, et al.
\
1979). Hexachlorophene has been detected in human adipose samples at levels
of 0.80 jug/kg (Shafik, 1973).
C. Metabolism
Hexachlorophene is metabolized by the liver, producing a glucu-
ronide conjugate. The clearance of blood hexachlorophene is dependent on
this hepatic activity (Klaassen, 1979).
0. Excretion
Within three hours of hexachlorophene administration to rats, 50
percent of the initial dose was excreted in the bile (Klaassen, 1979). Oral
administration of the compound to a cow resulted in excretion of 63.8 per-
cent of the initial dose in the feces and 0.24 percent in the urine (St.
John and Lisk, 1972).
IV. EFFECTS
A. Carcinogenicity
The lifetime dermal application of 25-percept and 50-percent so-
lutions of hexachlorophene to mice failed to produce significant car-
cinogenic effects (Stenback, 1975); the levels of compound used caused nigh
toxicity. Rudali and Assa (1978) were unable to produce carcinogenic
effects in mice by lifetime feeding or subcutaneous injection at birth of
hexachlorophene. Oral lifetime feeding of hexachlorophene to rats (17 to
150 ppm) also failed to show carcinogenic effects (NCI, 1978).
-------
B. Mutagenicity
Single intraperitoneal injections of 2.5 or 5.0 mg/kg
hexachlorophene failed to induce dominant lethal mutations in mice (Arnold,
et al. 1975).
Desi, et al. (1975) have reported that hexachlorophene admin-
istered to rats produced chromosome aberrations (dose and route not
specified).
C. Teratogenicity
Kennedy, et al. (1975a) reported that the fetuses of pregnant rats
«.
exposed to hexachlorophene at 30 mg/kg on days 6 to 15 of gestation show a
low frequency of eye defects and skeletal abnormalities (angulated ribs).
Fetuses of rabbits exposed to this compound at 6 mg/kg on days 6 to 18 of
gestation showed a low incidence of skeletal irregularities, but no soft
tissue anomalies (Kennedy, et al. 1975a). A three-generation feeding study
of hexachlorophene to rats at levels of 12.5 to 50 ppm did not show tera-
togenic effects (Kennedy, et al. 1975b).
A single retrospective Swedish study on infants born to nurses
regularly exposed to antiseptic soaps containing hexachlorophene has sug-
gested that the incidence of malformations in this infant population is in-
creased (Hailing, 1979).
D. Other Reporductive Effects
Gellert, et al. (1978) have reported that male neonatal rats
washed for eight days with three percent hexachlorophene solutions showed as
adults a decreased fertility due to inhibited reflex ejaculation.
Oral administration of hexachlorophene to rats has been reported
to.produce degeneration of spermatogenic cells (Casaret and Doull, 1975).
Subcutaneous injection of hexachlorophene to mice at various periods of ges-
tation produced increased fetal resorptions (Majundar, et al. 1975).
-------
E. Chronic Toxicity
Administration of hexachlorophene by" gavage (40 mg/kg) produced
hind leg paralysis and growth impairment after two to three weeks (Kennedy
and Gordon, 1976). Histological examination showed generalized edema or
status spongiosus of the white matter of the entire central nervous system.
These gross effects and histopathological lesions have been reported to be
reversible (Kennedy, et al. 1976).
Central nervous system effects in humans following chronic ex-
posure to hexachlorophene include diplopia, irritability, weakness of lower
extremities, and convulsions (Sax, 1975).
V. AQUATIC TOXICITY
A. Acute and Chronic Toxicity and Plant Effects
Pertinent data were not found in the available literature.
8. Residues
Sims and Pfaender (1975) found levels of hexachlorophenol in
aquatic organisms ranging from 335 ppb in sludge worms to 27,800 ppb in
water boatman (Sigara spp.).
VI. EXISTING GUIDELINES
A. Human
Hexachlorophene is permitted as a preservative in drug and cos-
metic products at levels up to 0.1 percent (USFDA, 1972).
B. Aquatic
Pertinent data were not found in the available literature.
-------
American Medical Association. 1977. AMA Council on Drugs, Chicago.
Arnold, 0., et al. 1975. Mutagenic evaluation of hexachlorophene.
Toxicol. Appl. Phaimacol. 33: 185.
Brandt, I., et al. 1979. Transplacental passage and embryonic-fetal
accumulation of hexachlorophene in mice. Toxicol. Appl. Pharmacol. 49: 393.
Butcher, H./ et al. 1973. Hexachlorophene concentrations in blood of
operating room personnel. Arch. Surg. 107: 70.
Casaret, L. and J. Doull. 1975. Toxicology: The Basic Science of
Poisons. MacMillan, New York.
\
Oesi, I., et al. 1975. Animal experiments on the toxicity of
hexachlorophene. Egeszsegtudomany 19: 340.
Gellert, R.J., et al. 1978. Topical exposure of neonates to
hexachlorophene: Long-standing effects on mating behavior and prostatic
development in rats. Toxicol. Appl. Pharmacol. 43: 339.
Hailing, H. 1979. Suspected link between exposure to hexachlorophene and
malformed infants. Ann. NY. Acad. Sci. 320: 426.
International Agency for Research on Cancer. 1979. IARC monographs on the
evaluation of the carcinogenic risk of chemicals to humans. Vol. 20, Some
Halogenated Hydrocarbons, p. 241. IARC, Lyon.
Kennedy, G.L., Jr. and D.E. Gordon. 1976. Histopathologic changes produced
by hexachlorophene in the rat as a function of both magnitude and number of
doses. Bull. Environ. Contain. Toxicol. 16: 464.
Kennedy, G.L., Jr., et al. 1975a. Evaluation of the teratological
potential of hexachlorophene in rabbits and rats. Teratology. 12: 83.
Kennedy, G.L. Jr., et al. 1975b. Effect of hexachlorophene on reproduction
in rats. J. Agric. Food Chem. 23: 866.
Kennedy, G.L. Jr., et al. 1976. Effects of hexachlorophene in the rat and
their reversibility. Toxicol. Appl. Pharmacol. 35: 137.
Klaassen, C.D. 1979. Importance of hepatic function on the plasma
disappearance and biliary excretion of hexachloroghene. Toxicol. Appl.
Pharmacol. 49: 113.
It 6'
-------
Majundar, S., et al. 1975. Teratologic evaluation of hexachlorophene in
mice. Proc. Pennsylvania Acad. Sci. 49: 110.
National Cancer Institute. 1978. Bioassay of Hexachlorophene for Possible
Carcinogenicity (Tech. Rep. Ser. #40). DHEW, Publication No. 78-840,
Washington.
Rudali, G. and R. Assa. 1978. Lifespan carcinogenicity studies with
hexachlorophene in mice and rats. Cancer Lett. 5: 325.
Sax, N. 1975. Dangerous Properties of Industrial Materials.. 4th ed. Van
Nostrand Reinhold, New York.
Shafik, T. 1973. The determination of pentachlorophenol and
hexachlorophene in human adipose tissue. Bull. Environ. Contamin. Toxicol.
10: 57.
v
Shackelford, W. and L. Keith. 1976. Frequency of organic compounds
identified in water. U.S. EPA, 600/4-76-062, p. 142.
Sims, J. and F. Pfaender. 1975. Distribution and biomagnification of
hexachlorophene in urban drainage areas. Bull. Environ. Contamin. Toxicol.
14: 214.
St. John, L. and 0. Lisk. 1972. The excretion of hexachlorophene in the
dairy cow. J. Agr. Food Chem. 20: 389.
Stenback, F. 1975. Hexachlorophene. in mice. Effects after long-term
percutaneous applications. Arch. Environ. Health, 30: 32.
West, R., et al. 1975. Hexachlorophene concentrations in human milk.
Bull. Environ. Contamin. Toxicol. 13: 167.
±4 *7 7
) J r }
\\t~1
-------
No. 117
Hydrofluoric Acid
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
, HYDROFLUORIC ACID
Summary
Hydrofluoric acid (HF) has produced mutagenic effects in plants and
Drosophila, and lymphocyte chromosome aberrations in rats. _Chromosome ef-
fects were not observed in mice following sub-chronic inhalation exposure to
the compound.
No data are avilable on the possible carcinogenic or teratogenic ef-
fects of HF.
Chronic exposure to the compound has produced skeletal, fluorosis, den-
tal mottling and pulmonary function impairment.
One short-term bioassay test demonstrated that a concentration of
50,000 ug/1 HF was lethal to bluegill sunfish in one hour.
It 7-J
-------
• HYDROFLUORIC ACID
I. INTRODUCTION
Hydrofluoric acid (CAS registry number 7664-39-3) (HF) is a colorless,
clear, fuming corrosive liquid made by treating fluorspar fGaF-x)-Kith sul-
furic acid. An unusual property of HF is that it will dissolve glass or any
other silica-containing material. It has the following physical and chem-
ical properties (Windholz, 1976; Hawley, 1971; Weast, 1972):
Pure Constant Boiling
Formula: HF HF/H^
Molecular Weight: 20.01 —
Melting Point: -83.55QC —
Boiling Point: 19.51QC —
Density: 0.987 1.15 - 1.18
Vapor Pressure: 1 atm i 19.5loc
Solubility: Very soluble in water;
soluble in many organic
solvents, e.g., benzene,
toluene, xylene, etc.
HF is used in the aluminum industry, for the production of fluoro-
carbons, for uranium processing, for petroleum alkylation, for the produc-
tion of fluoride salts, and as a pickling agent for stainless steel. It has
many other minor uses (CMR, 1978).
II. EXPOSURE
A. Water
Other than occasional leaks and spills, very small amounts of HF
are released into water from manufacturing and production facilities (Union
Carbide, 1977; U.S. EPA, 1977a). HF is released into the air from coal
-------
fires (U.S. EPA, 1977b) and from manufacturing and production facilities
(Union Carbide, 1977). HF released into the air has a high affinity for
water, and it is expected that it will rain out (Fisher, 1976). The amounts
of HF in water and the extent of its presence could not be determined from
the available literature. Under alkaline conditions, HF will form aqueous
salts.
8. Food •
Pertinent data were not found in the available literature.
C. Inhalation
HF occurs in the atmosphere from coal fires and from manufacturing
and production facilities (see above), as well as from the photochemical re-
action of &Lf2 with NO and humid air (Saburo, et al. (1977). It is
present in the stratosphere (Zander, et al. 1977; Orayson, et al. 1977;
Farmer and Paper, 1977). The extent and amounts of HF in the atmosphere
could not be determined from the available literature.
D. Dermal
Pertinent data were not found in the available literature.
III. PHARMACOKINETICS
A. Absorption
The major route of HF absorption is by the respiratory system;
penetration of liquefied anhydrous HF through the skin has been reported
(Burke, et al. 1973). Fatal inhalation of HF fumes resulted in a blood
fluoride level of 0.4 mg/100 ml (Greendyke and Hodge, 1964),. while skin
penetration of anhydrous HF produced a maximum blood fluoride concentration
of 0.3 mg/100 ml (Burke, et al. 1973). These levels are 100-fold higher
-------
than normal serum fluoride levels (Hall et al. 1972). Forty-five percent of
fluoride present in the air in gaseous or particulate form is absorbed on
inhalation (Dinman, et al. 1976).
B. Distribution
Absorbed fluoride is deposited mainly in the skeleton and teeth;
it is also found in soft tissues and body fluids (NAS, 1971; NIOSH, 1975;
NIOSH, 1976)> Fluoride reaches fetal circulation via the placenta and is
deposited in the fetal skeleton (NAS, 1971).
Fluoride deposition in bone is not irreversible (NAS, 1971). How-
ever, laboratory animals chronically exposed to HF gas retained abnormally
high levels of fluoride in the skeleton for up to 14 months after exposure
(Machle and Scott, 1935).
C. Metabolism
The physiological or biochemical basis of fluoride toxicity has
not been established, although it appears that enzymes involved in vital
functions are inhibited by fluoride (NAS, 1971). Examination of the data of
Collins, et al. (1951) indicates that metabolism of absorbed fluoride is the
same whether it is inhaled as a particulate inorganic or gas (as HF) (NIOSH,
1976).
0. Excretion
Fluoride is excreted in the urine, feces and sweat, and in trace
amounts in milk, saliva, hair and probably tears. Data are lacking regard-
ing loss of fluoride by expired breath (NAS, 1971).
*•
The primary route of fluoride elimination is through the urine.
The urinary fluroide concentration is influenced by factors such as total
absorption, the form of fluoride absorbed, frequency of exposure and general
-------
health (MAS, 1971). It is recognized that urinary fluoride levels are di-
rectly related to the concetration of absorbed fluoride (NAS, 1571).
In a relatively unexposed person, about one-half of an acute dose
of fluoride is excreted within 24 hours in the urine, and about one-half is
deposited in the skeleton (NAS, 1571).
IV. EFFECTS
A. Carcinogenic!ty
Pertinent data were not found in the available literature.
B. Mutagenicity
Mohamed (1563) has reported various aberrations in second genera-
tion tomato plants following parenteral treatment with HF at 3 ^g/m^.
These results could not be duplicated by Temple and Weinstein (1576).
Rats inhaling 0.1 mg HF/m5 chronically for two months were re-
ported to develop lymphocyte chromosomal aberrations; aberrations could not
be.detected in sperm cells of mice administered the same levels of HF-
(Voroshilin, et al. 1573).
Weak mutagenic effects in the offspring of Drosophila exposed to
air bubbled through 2.5 percent HF have been reported (Mohamed, 1571).
C. Teratogenicity
Pertinent data were not found in the available literature.
0. Other Reproductive Effects
Reduced fertility in Drosophila and decreased egg hatch have been
reported following exposure to 2.5 ppm HF (Gerdes, et al. 1571).
E. Chronic Toxicity
Among the adverse physiologic effects of long-term exposure to HF
are skeletal fluorosis, dental mottling and pulmonary impairment (NAS, 1571;
NIOSH, 1575; NIOSH, 1576). Skeletal fluorosis is characterized by increased
-------
bone density, especially in the pelvis and spinal column, restricted spinal
motion, and ossification of ligaments. Nasal irritation, asthma or short-
ness of breath, and in some cases pulmonary fibrosis are associated with
HF-induced pulmonary distress (NIOSH, 1976). Digestive disturbances have
also been noted (NIOSH, 1976}. Fluoride-induced renal pathology has not
been firmly established in man (Adler, et al. 1970). Causal relationships
in industrial exposures are difficult to determine because exposure often
involves other compounds in addition to fluorides (NIOSH, 1976).
Laboratory animals chronically exposed to 15.2 mg HF/m3 devel-
oped pulmonaryr kidney and hepatic pathology (Machle and Kitzmiller, 1935;
Machle, et al. 1934), while animals exposed to 24.5 mg HF/m3 developed
lung edema (Stokinger, 1949). Testicular pathology was also observed in
dogs at 24.5 mg HF/m3 (Stokinger, 1949). Several animal studies have
demonstrated that inhalation of HF increased fluoride deposition in the
bones (NIOSH,. 1976).
F. Other Relevant Information
Fluoride has anticholinesterase character which, in conjunction
with the reduction in plasma calcium observed in fluoride intoxication, may
be responsible for acute nervous system effects (NAS, 1971). The severe
pain accompanying skin injury from contact with 10 percent HF has been at-
tributed to immobilization of calcium, resulting in potassium nerve stimula-
tion (Klauder, et al 1955).
Inhibition of enolase, oxygen uptake, and tetrazolium reductase
.•
activity has been demonstrated in vitro from application of HF to excised
guinea pig ear skin (Carney, et al. 1974).
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
McKee and Wolf (1963) reported that HF was toxic to. fish
(unspecified at concentrations ranging from 40,000 to 60,000 ;jg/l. Bonner
and Morgan (1576) observed that 50,000 ^ig/1 HF was lethal to bluegill sun-
fish (Lepomis macrochirus) in one hour.
B. Chronic Toxicity, Plant Effects, and Residue
Pertinent data were not found in the available literature.
C. Other Relevant Information
Bonner and Morgan (1976) observed a marked increase in the oper-
cular "breathing" rate of bluegill sunfish exposed to a concentration of
25,000 ug/1 for four hours. The fish recovered within three days.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
In 1976, NIOSH proposed a workplace environmental limit for HF of
2.5 mg/nh5 (3 pom) as a time-weighted average to provide protection from
the effects of HF over a working lifetime (NIOSH, 1976). A ceiling limit of
5 mg HF/nv5 based on 15-minute exposures was also recommended to prevent
acute irritation from HS (NIOSH, 1976).
B. Aquatic
Pertinent data were not found in the available literature.
. ^JS^
•*; j J u
117-f
-------
HYDROFLUORIC ACID
References
Adler, P., et al. 1970. Fluorides and Human Health. World Health Organi-
zation, Monograph 59, Geneva.
Sonner, W.P. and E.L. Morgan. 1976. On-line surveillance of industrial ef-
fluents employing chemical-physical methods of fish as sensorsa. Dept. of
Civil Engineering, Tennessee Technological University, Cookeviller-
Tennessee. Prepared for the Offica of Water Research and Technology.
Available from NTIS: PB261-253.
Burke, W.J., et al. 1973. Systemic fluoride poisoning resulting from a
fluoride skin burn. Jour. Occup. Med. 15: 39.
Carney, S.A., et al. 1974. Rationale of the treatment of hydrofluoric acid
burns. Br. Jour. Ind. Med. 31: 317.
Chemical Marketing Reporter. 1978. Chemical Profile - Hydrofluoric acid.
Chem. Market. Rep. August 21.
Collins, G.H., Jr.., et al. 1951. Absorption and excretion of inhaled
fluorides. Arch. Ind. Hyg. Occup. Med. 4: 585.
Dinman, D.B., et al. 1976. Absorption and excretion of fluoride immedi-
ately after exposure. Pt. 1. Jour. Occup. Med. 18: 7.
Drayson, S.R., et al. 1977. Satellite sensing of stratospheric halogen
compounds by solar occulation. Part 1. Low resolution spectroscopy.
Radiat. Atmos. Pap. Int. Symp. p. 248.
Farmer, C.B. and O.F. Raper. 1977. The hydrofluoric acid: Hydrochloric
acid ratio in the 14-38 km region of the stratosphere. Geophys. Res. Lett.
4: 527.
Fisher, R.W. 1976. An air pollution assessment of hydrogen fluoride. U.S.
NTIS. AD Rep. AS-AS027458, 37 pp.
Gerdes, R., et al. 1971. The effects of atmospheric hydrogen fluoride upon
Drosophila melanogaster. I. Differential genotypic response. Atmos.
Environ. 5: 113.
Greendyke, R.M. and H.C. Hodge. 1964. Accidental death due to hydrofluoric
acid. Jour. Forensic Sci. 9: 383.
Hall, L.L., et al. 1972. Direct potentiometric deterination of total ionic
fluoride in biological fluids. Clin. Chem. 18: 1455.
»
Hawley, G.G. 1971. The Condensed Chemical Dictionary. 8th ed. Van
Nostrand Reinhold Co., New York.
/ / /-/O
-------
Klauder, J.V., et al. 1955. Industrial uses of compounds of fluorine and
oxalic acid. Arch. Ind. Health. 12: 412 •
Machle, W. and K. Kitzmiller. 1935. The effects of the inhalation of hy-
drogen fluoride — II. The response following exposure to low concentra-
tion. Jour. Ind. Hyg. Toxicol. 17: 223.
Machle, W. and E.W. Scott. 1935. The effects of inhalation of hydrogen
fluoride — III. Fluorine storage following exposure to sub-lethal concen-
trations. Jour. Ind. Hyg. Toxicol. 17: 230.
Machle, W., et al. 1934. The effects of the inhalation of hydrogen fluor-
ide — I. The response following exposure to high concentrations. Jour.
Ind. Hyg. 16: 129.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria. California State
Water Quality Control Board Resources Agency Publication No. 3-A.
Mohamed, A. 1968. Cytogenetic effects of hydrogen fluoride treatment in
tomato plants. Jour. Air Pollut. Cant. Assoc. 18: 395.
Mohamed, A. 1971. Induced recessive lethals in second chromosomes of
Drosoghila melanogaster. by hydrogen fluoride. In: Englung, H., Berry, W.,
eos. Proc. 2nd internet. Clean Air Cong.- New YorT<: Academic Press.
National Academy of Sciences. 1971. Fluorides. U.S. National Academy of
Sciences, Washington, DC.
National Institute for Occupational Safety and Health. 1975. Criteria for
a recommended standard - occupational exposure to inorganic fluorides. U.S.
OHEW, National Institute for Occupational Safety and Health.
National Institute for Occupational Safety and Health. 1976. Criteria for
a recommended standard - occupational exposure to hydrogen fluoride, U.S.
OHEW National Institute for Occupational Safety and Health, March 1976.
Pub. No. 76-43.
Saburo, K., et al. 1977. Studies on the photochemistry of aliphatic halo-
genated hydrocarbons. I. Formation of hydrogen fluoride and hydrogen
chloride by the photochemical reaction of dichlorodifluoromethane with ni-
trogen oxides in air. Chemosphere p. 503.
Stokinger, H.E. 1949. Toxicity following inhalation of fluorine and hydro-
gen fluoride. In: Voegtlin, Hodge, H.C., eds. Pharmacology and Toxicology
of Uranium Compounds. McGraw-Hill Book Co., Inc., New York. p. 1021.
Temple, P. and L. Weinstein. 1976. Personal communication. Cited in:
Drinking Water and Health. Washington, DC: National Research Council, p.
486.
»
Union Carbide. 1977. Environmental monitoring report, United States Energy
Research and Development Administration, Paducah gaseous diffusion plant.
NTIS Y/UB-7.
-------
U.S. EPA. 1977a. Industrial process profiles for environmental use:
chapter 16. The fluorocarbon-hydrogen fluoride industry. U.S. Environ.
Prot. Agency. U.S. DHEW PB281-483.
U.S. EPA. 1977b. A survey of sulfate, nitrate and acid aerosol emissions
and their control. U.S. Environ. Prot. Agency. U.S. DHEW PB276-558.
Voroshilin, S.I., et al. 1973. Cytological effect of inorganic compounds
of fluorine on human and animal cells in vivo and in vitro. Genetika 9: 115.
Weast, R.C.. 1972. Handbook of Chemistry and Physics. 53rd ed. Cleveland,
OH: Chemical Rubber Co.
Windholz, M. 1976. The Merck Index. 9th ed. Merck and Co., Inc., Rahway-,
N.J.
Zander, R., et al. 1977. Confirming the presence of hydrofluoric acid in
the upper stratosphere. Geophys. Res. Lett. 4: 117.
-------
No. 118
Hydrogen Sulfide
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
11 *-3L
-------
Hydrogen Sulfide
Summary
Pertinent information could not be located on the
carcinogenicity, mutagenicity, or teratogenicity of H£S.
Hydrogen, sulfide is very toxic to humans via inhalation
and has been reported to cause death at concentrations of
800 to 1000 ppm.
Hydrogen sulfide is reported to be very toxic to fish
with toxic effects resulting from 1 to 100 ppm.
-------
I. INTRODUCTION
Hydrogen sulfide (^S; CAS No. 7783064) is a colorless
flammable gas with a rotten egg odor. It has the following
physical properties:
Formula t^S
Molecular Weight 34.08
Melting Point -85.5°C
Boiling Point -60.4°C
Density 1.539 gram per liter at 0°C
Vapor Pressure 20 atm. at 25.5°C
Hydrogen sulfide is soluble in water, alcohol, and
glycerol (ITII, 1976). Hydrogen sulfide is a flammable gas
and the vapor may travel considerable distance to a source of
ignition and flash back.
Hydrogen sulfide and other sulfur compounds occur to some
extent in most petroleum and natural-gas deposits. Very
substantial quantities of this gas are liberated in coking
operations or in the production of manufactured gases from
coal (Standen, 1969). Hydrogen sulfide is used to produce
substantial tonnages of elemental sulfur, sulfuric acid, and
a variety of other chemicals. Completely dry hydrogen sulfide,
whether gaseous or liquid, has no acidic properties. Aqueous
solutions, however, are weakly acidic (Standen, 1969). In
1965, some 5.2 million metric tons of H2S was recovered from
»
fossil fuels (Standen, 1969).
-------
II. EXPOSURE
A. Water
Bacterial reduction of sulfates accounts for the
occurrence of I^S in numerous bodies of water, such as the
lakes near El Agheila, Libya. Hydrogen sulfide is familiarly
formed as a bacterial decomposition product of protein
matter, particularly of animal origin (Standen, 1969) and this
gas can be found in most sewage treatment plant and their
piping systems.
B. Food
H2S may be formed within the gastrointestinal tract
after the ingestlon of inorganic sulfide salts or elemental
sulfur due to the actions of gastric acid and of colonic
bacteria. (Division of Industrial Hygiene, 1941).
C. Inhalation
Wherever sulfur is deposited, pockets of hydrogen
sulfide may be encountered, thus it is found at coal, lead,
gypsum, and sulfur mines. Crude oil from Texas and Mexico
contain toxic quantities of H2S (Yont and Fowler, 1926). The
decay of organic matter gives rise to the production of I^S
in sewers and waste from industrial plants where animals
products are handled. Thus, there has been accidental poisoning
from H2§ in tanneries, glue factories, fur-dressing and
felt-making plants, abattoirs, and beet-sugar factories; for
example, in Lowell, Massachusetts five men were poisoned
»
(three died) when sent to repair a street sewer which drained
waste from a tannery (Hamilton and Hardy, 1974).
-------
Hydrogen sulfide is formed in certain industrial processes
such as the production of sulfur dyes, the heating of rubber
containing sulfur compounds, the making of artificial silk or
rayon by viscose process (Hamilton and Hardy, 1974).
D. Dermal
Pertinent information could not be found in the
available literature.
III. PHARMACOKINENTICS
A. Absorption
By far the greatest danger presented by hydrogen
sulfide is through inhalation, although absorption through
Ithe skin has been reported (Patty, 1967).
B. Distribution
Pertinent information could not be. found in the
available literature.
C. Metabolism and Excretion
Evidence has been obtained for the presence of a
sulfide oxidase in mammalian liver (Baxter and Van Reen,
1958; Sorbo, 1960), but important nonenxymatic mechanisms for
sulfide detoxication are also recognized. Sulfide tends to
undergo spontaneous oxidation to non-toxic products such as
polysulfides, thiosulfates or sulfates (Gosselin, 1976).
When free sulfide exists in the circulating blood a
certain amount of hydrogen sulfide is excreted in the exhaled
breath, this is sufficient to be detected by odor, but the
greater portion, however, is excreted in the urine, chiefly as
sulfate, but some as sulfide (Patty, 1967).
11 -
-------
IV. EFFECTS
A.. Carcinogenic! ty
Pertinent information could noc be found in the
available literature.
B. Mutagenicity
Pertinent information could not be found in the
available literature.
C. Teratogenicity
Pertinent information could not be found in the
available literature.
D. Other Reproductive Efforts
Pertinent information could not be found in the
available literature.
E. Chronic Toxicity
At low concentrations of hydrogen sulfide (e.g., 50
to 200 ppm) the toxic symptoms are due to local tissue
irritation rather than to systemic actions. The most
characteristic effect is on the eye, where superficial injury
to the conjunctiva and cornea is known to workers in tunnels,
caissons, and sewers as "gas eye" (Grant, 1972). More
prolonged or intensive exposures may lead to involvement of
the respiratory tract with cough, dyspnea and perhaps pulmonary
edema. Evidence of severe pulmonary edema has been found at
autopsy and in survivors of massive respiratory exposures
»
(Gosselin, 1976). The irritating action has been explained
on the basis that I^S combines with alkali present in moist
tissues to form sodium sulfide, a caustic (Sax, 1979). Chronic
-------
poisoning results in headache, inflammation of the conjunctivas
and eyelids, digestive disturbances, loss of weight, and
general debility (Sax, 1979).
F. Other Relevant Information
Hydrogen sulfide is reported with a maximum safe
concentration of 13 ppm (Standen, 1969), although at first
this concentration can be readily recognized by its odor, H2S
may partially paralyze the olfactory nerve to the point at
which the presence of the gas is no longer sensed. Hamilton
and Hardy (1974) report that at a concentration of 150 ppm,
the olfactory nerve is paralyzed.
Exposures of 800-1000 ppm may be fatal in 30 minutes,
and high concentrations are instantly fatal (Sax, 1979).
There are reports of exceptional cases of lasting injury,
after recovery from acute poisoning, which point to an
irreversible damage to certain cells of the body resulting
from prolonged oxygen starvation (Hamilton and Hardy, 1974).
Hydrogen sulfide has killed at concentrations as low as
800 ppm (Verschueren, 1974).
V. AQUATIC TOXICITY
A. Acute Toxicity
Verschueren (1974) has reviewed the effects of H2S
on several aquatic organisms. Goldfish have been reported to
die at a concentration of 1 ppm after long time exposure in
»
hard water. Verschueren (1974) reports a 96-hour LC50 value of
10 ppm for goldfish. Verschueren also reports on a large number
of fresh water fish with toxic effects resulting from exposure
-------
Co H2§ at concentrations ranging from 1 to 100 ppm.
Verschueren (1974) reports median threshold limit values
for Arthropoda: Asellus, 96-hour at 0.111 mg/1; Crangonyx,
96 hour at 1.07 mg/1; and Gammarus, 96-hour at 0.84 mg/1.
B. Chronic Toxicity, Plant Effects and Residues
Pertinent information could not be located in the
available literature.
C. Other Relevant Information
Verschueren (1974) reports that sludge digestion is
inhibited at 70-200 mg/1 of ^S in wastewater treatment plants
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The 8-hour, time-weighted average occupational
exposure limit for H£S has been set in a number of countries
and are tabled below (Verschueren, 1974):
T.L.V.: Russia 7 ppm
U.S.A. 20 ppm "peak"
Federal German 10 ppm
Republic
#2$ is a Department of Transportation flammable and
poisonous gas and must be labelled prior to shipment.
B. Aquatic
Maximum allowable concentration of .0.1 mg/1 for
Class I and Class II waters has been established in Romania
and Bulgaria for I^S (Verschueren, 1974).
11 Co
) -J/ U
-------
References
Baxter, C. F. and R. Van Reen. 19S8a. Some Aspects of
Sulfide Oxidation by Rat Liver Preparations. Biochem.
Biophys. Acta 28: 567-572. The Oxidation of Sulfide
to Thiosulfate by Metalloprotein Complexes and by
Ferritin. Loc. cit. 573-578. 1958b.
Division of Industrial Hygiene. 1941. Hydrogen Sulfide,
its Toxicity and Potential Dangers. National Institute
of Health, U.S. Public Health Service. Public Health
Rep. (U.S.) 56: 684-692.
Gosselin, R. £., et al. 1976. Clinical Toxicology of
Commercial Products. The Williams and Wilkins Company,
Baltimore.
Grant, W. M. 1972. Toxiciology of the Eye. 2nd ed.
Charles C. Thomas, Springfield, Illinois.
Hamilton, A. and Harriet Hardy. 1974. Industrial
Toxicology. Third edition. Publishing Science Group, Inc.
ITII. 1976. Toxic and Hazardous Industrial Chemicals
Safety Manual for Handling and Disposal with Toxicity
and Hazard Data. The International Technical Information
Institute. Toranomon-Tachikawa Building, 6-5, 1 Chome,
Nishi-Shimbashi, Minato-ku, Tokyo, Japan.
Patty, F. 1967. Industrial Hygiene and Toxicology.
Interscience Publishers. New York.
Sax, N. Irving. 1979. Dangerous Properties of Industrial
Materials. Van Nostrand Reinhold Company, New York.
Sorbo, B. On the Mechanism of Sulfide Oxidation in Bio-
logical Systems. Biochem. Biophys. Acta 38: 349-351.
Standen, A. et. al. (editors). 1969. Kirk-Othmer
Encyclopedia of Chemical Technology. Interscience
Publishers. New York.
Verschueren, K. 1977. Handbook of Environmental Data
on Organic Chemicals. Van Nostrand Reinhold Company, New
York.
Yant, W. P. and H. C. Fowler. 1926. Hydrogen Sulfide
Poisoning in the Texas Panhandle. Rep. Invest. U.S. Bureau
of Mines. Number 2776.
-------
No. 119
Indeno (1,2,3-aOpyTene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
n j-l
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA1s Carcinogen Assessment Group (CAG) has evaluated
indeno(l,2,3-c,d)pyrene and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
INDENO[1,2,3-cd]PYRENE
Summary
IndenoC1,2,3-cd]pyrene (IP) is a member of the polycyclic aromatic
hydrocarbon (PAH) class. Several compounds in the PAH class are well
known to be potent animal carcinogens. However, IP is generally regarded
as only a weak carcinogen to animals or man. There are no reports
available concerning the chronic toxicity of IP. Exposure to IP in the
environment occurs in conjunction with exposure to other PAH; it is not
known how these compounds may interact in human systems.
There are no reports available concerning standard acute or chronic
toxicity tests of this chemical in aquatic organisms..
-------
I. INTRODUCTION
This profile is based primarily on the Ambient Water Quality Criteria
Document for Polynuclear Aromatic Hydrocarbons (U.S. EPA, 1979a) and the
Multimedia Health Assessment Document for Polycyclic Organic Matter (U.S.
EPA, 1979b).
IndenoCl,2,3-cd]pyrene (IP; 022^12) is one of fcne family of polycyclic
aromatic hydrocarbons (PAH) formed as a result of incomplete combustion
of organic material. Its physical and chemical properties have not been
well-characterized.
PAH, including IP, are ubiquitous in the environment. They have
been identified in ambient air, food, water, soils, and sediments (U.S.
EPA, 1979b). The PAH class contains several potent carcinogens (e.g.,
benzCblfluoranthene), weak carcinogens (benzCa]anthracene), and cocarcinogens
(e.g., fluoranthene), as well as numerous non-carcinogens (U.S. EPA,
1979b).
PAH which contain more than three rings (such as IP) are relatively
stable in the environment, and may be transported in air and water by
adsorption to particulate matter. However, biodegradation and chemical
treatment are effective in eliminating most PAH in the environment. The
reader is referred to the PAH Hazard Profile for a more general discussion
of PAH (U.S. EPA, 1979o).
II. EXPOSURE
A. Water
Basu and Saxena (1977, 1978) have conducted monitoring surveys
of U.S. drinking water for the presence of six representative PAH, including
»
IP. They found the average total level of the six PAH (fluoranthene,
benzolk]fluoranthene, benzoCjlfluoranthene, benzoCajpyrene, benzoCg,h,i]-
perylene, and indenoC1,2,3-cd]pyrene) to be 13.5 ng/1.
-------
B. Food
Levels of IP are not routinely monitored in food, but it has
been detected in foods such as butter and smoked fish (U.S. EPA, 1979a).
However, the total intake of all types of PAH through the diet has been
estimated at 1.6 to 16 ug/day (U.S. EPA, 1979b). The U.S. EPA (1979a)
has estimated the bioconcentration factor of IP to be 15,000 for the
edible portion of fish and shellfish consumed by Americans. This estimate
is based upon the octanol/water partition coefficient for IP.
C. Inhalation
There are several studies in which IP has been detected in
ambient air (U.S. EPA, 1979a). Measured concentrations ranged from 0.03
to L.34 ng/m^ (Gordon, 1976; Gordon and Bryan, 1973). Thus, the human
daily intake of IP by inhalation of ambient air may be in the range of
0.57 to 25.5 ng, assuming that a human breathes 19 m3 of air per day.
III. PHARMACOKINETICS
There are no data available concerning the pharmacokinetics of IP,
or other PAH, in humans. Nevertheless, some experimental animal results
were published on several other PAH, particularly benzo[a]pyrene.
A. Absorption
The absorption rate of IP in humans or other animals has not
been studied. However, it is known (U.S. EPA, 1979a) that, as a class,
PAH are well-absorbed across the respiratory and gastrointestinal epithelia
membranes. The high lipid solubility of compounds in the PAH class supports
this observation.
-------
B. Distribution
Based on an extensive literature review, data on the distribution
of IP in mammals were not found. However, it is known (U.S. EPA, 1979a)
that other PAH are widely distributed throughout the body following their-
absorption in experimental rodents. Relative to other tissues, PAH tend
to localize in body fat and fatty tissues (e.g., breast).
C. Metabolism
The metabolism of IP in animals or man has not been directly
studied. However, IP, like other PAH, is most likely metabolized by the
microsomal mixed-function oxidase enzyme system in mammals (U.S. EPA,
1979b). Metabolic attack on one or more of the aromatic rings leads to
the formation of phenols and isomeric dihydrodiols by the intermediate
formation of reactive epoxides. Dihydrodiols are further metabolized by
microsomal mixed-function oxidases to yield diol epoxides, compounds
which are known to be biologically reactive intermediates for certain
PAH. Removal of activated intermediates by conjugation with glutathione
or glucuronic acid, or by further metabolism to tetrahydrotetrols, is a
key step in protecting the organism from toxic interaction with cell
macromolecules.
D. Excretion
The excretion of IP by mammals has not been studied. However,
the excretion of closely related PAH is rapid, and occurs mainly via the
feces (U.S. EPA, 1979a). Elimination in the bile may account for a
significant percentage of administered PAH. It is unlikely that PAH will
accumulate in the body as a result of chronic low-level exposures.
119-7
-------
IV. EFFECTS
A. Carcinogenicity
IP is regarded as only a weak carcinogen (U.S. EPA, 1979b). LaVoie
and coworkers (1979) reported that IP had slight activity as a tumor initiator
and no activity as a complete carcinogen on the skin of mice which is known
to be highly sensitive to the effects of carcinogenic PAH.
B. Mutagenicity
LaVoie and coworkers (1979) reported that IP gave positive results
in the Ames Salmonella assay.
C. Teratogenicity and Other Reproductive Effects
There are no data available concerning the possible teratogenicity
or other reproductive effects as a result of exposure to IP. Other related
PAH are apparently not significantly teratogenic in mammals (U.S. EPA, l979aX.
V. AQUATIC TOXICITY
Pertinent information could not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived by U.S. EPA (1979a),
which are summarized below, have not gone through the process of public
review; therefore, there is a possibility that these criteria may be changed.
A. Human
There are no established exposure criteria for IP. However, PAH,
as a class, are regulated by several authorities. The World Health Organization
(1970) has recommended that the concentration of PAH in drinking
water (measured as the total of fluoranthene, benz[g,h,i]perylene, benzCb]-
fluoranthene, benz[h]fluoranthene, indeno[1,2,3-cd]pyrene, and benz[a]p,yrene)
not exceed 0.2 ug/1. Occupational exposure criteria have been established
X
-------
for coke oven emissions, coal tar products, and coal tar pitch volatiles,
all of which contain large amounts of PAH, including IP (U.S. EPA, 1979a).
The U.S. EPA O979a) draft recommended criteria for PAH in water are
based upon the extrapolation of animal carcinogenicity data for benzCa]-
pyrene and dibenz[a,h]anthracene.
B.. Aquatic
There are no standards or guidelines concerning allowable concen-
trations of IP in aquatic environments.
//
-------
INDENO[1,2,3-cd]PYRENE
REFERENCES
Basu, O.K., and J. Saxena. 1977. Analysis of raw and drinking water
samples for polynuclear aromatic hydrocarbons. EPA P.O. No. CA-7-2999-A,
and CA-8-2275-B. Exposure Evaluation Branch, HERL, Cincinnati, Ohio.
Basu, O.K. and J. Saxena. 1978. Polynuclear aromatic hydrocarbons in
selected U.S. drinking waters and their raw water sources. Environ. Sci.
Technol., 12: 795.
LaVoie, et al. 1979. A comparison of the mutagenicity, tumor initiating
activity, and complete carcinogenicity of polynuclear aromatic hydrocarbons
In: "Polynuclear Aromatic Hydrocarbons". P.W. Jones and P. Leber (eds.).
Ann Arbor Science Publishers, Inc.
Gordon, R.J. 1976. Distribution of airborne polycyclic aromatic hydro-
carbons throughout Los Angeles, Environ. Sci. Technol. 10: 370.
Gordon, R.J. and R.J. Bryan. 1973. Patterns of airborne polynuclear
hydrocarbon concentrations at four Los Angeles sites. Environ. Sci. 7:
T050.
U.S. EPA. 1979a. Polynuclear aromatic hydrocarbons. Ambient water
quality criteria. (Draft).
.U.S. EPA. 1979. Multimedia health assessment document for polycylic
organic matter. Prepared under contract by J. Santodonato, et al., Syracuse
Research Corp.
U.S. EPA. 1979. Environmental Criteria and Assessment Office. Poly-
chlorinated Aromatic Hydrocarbon: Hazard Profile. (Draft).
World Health Organization. 1970. European standards for drinking water,
Ind ed. Revised, Geneva.
-------
No. 120
Isobutyl Alcohol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-777V
-------
If 7
Isobutyl Alcohol
I. Introduction
Isobutyl alcohol (2-methyl-l-propanol, C,ILQ0; molecular weight
74.12) is a flaaanabla, colorless, refractive liquid with an odor like of
amyl alcohol,, but weaker. Isobutyl alcohol is used in Che manufacture of
esters for fruit flavoring essences, and as a solvent in paint and varnish
removers. This compound is soluble in approximately 20 parts water, and is
miscible with alcohol and ether.
II. Exposure-
No data were readily available.
III. Pharmacokinetics
A. Absorption
Isobutyl alcohol is absorbed through che intestinal cract and
the lungs.
B. Distribution
No data were readily available.
C. Metabolism
Isobutyl alcohol is oxidized Co isobutyraldehyde and isofaucyric
acid in che rabbit, with further metabolism proceeding Co acetone and carbon
dioxide. Some conjugation with glucuronic acid occurs in che rabbic and dog.
D. E
Approximately 141 of isobutyl alcohol is excreted as urinary
conjugates in che rabbic.
IV. Effects
A. Carcinogenic!£7
Rats receiving isobutyl alcohol, either orally or subcucaneously,
one co cvo times a week for 495 co 643 days showed liver carcinomas and
' // "->
/ /'-c.
/ifl- ?
-------
sarcomas, spleen sarcomas and myeloid leukemia (Gibel, £C_ al_., Z. Exp.
Chir. Chir. Forsch. 7: 235 (1974).
B. Teratogenicity
No data were readily available.
C. Other Reproductive Effects
No data were readily available.
D. Chronic Toxicity
Ingestion of one molar solution of isobutyl alcohol in water by
rats for 4 months did not produce any inflammatory reaction of the liver.
On ingestion of two molar solution for two months rats developed Mallory's
alcoholic hyaline bodies in the liver, and were observed to have decreases
in fat, glycogen, and RNA in the liver.
E. Other Relevent Information
Acute exposure to isobutyl alcohol causes narcotic effects, and
irritation to the eyes and throat in humans exposed to 100 ppm for repeated
8 hour periods. Formation of facuoles in the superficial layers of the
cornea, and loss of appetite and weight were reported among workers subjected,
to an. undetermined, but apparently high concentration of isobutyl alcohol and
butyl acetate. The oral LD_Q of isofautyl alcohol for rates if 2.46 g/kg
(Smith et. al., Arch.. Ind. Hyg. Occup. Med. 10_: 61, 1954).
V. Aquatic Toxicity
A. Acute Toxicity
The LC_- of isobutyl alcohol for 24-hour-old Daphnia magna is
between 10-1000 mg/1.
VI. Existing Guidelines and Standards
OSHA - 100 ppm
NIOSH - None
ACGIH - 50 ppm
-------
711. Information Sources
1. NQi Toxicology Data Bank.
2. March. Index, 9th ad.
3. NIOSH Registry of Toxic Effects of Chemical Substances, 1978.
4. NCM Toxline.
3. Sax, I. "Dangerous Properties of Industrial Materials."
6. Proctor, N. and Hughes, J. " Chemical Hazards of ehe Workplace"
Lippincott Co., 1978.
7. Occupational Diseases. A Guide to Their Recognition, NIOSH
publication Ho. 77-181, 1977.
3. Hunter, D. "The Diseases of Occupations" 5th ad., Hodder and
Stoughton, 1975.
,- >'((('
'' i r '/**
-------
No. 121
Lead
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D,C. 20460
APRIL 30, 1980
,
JU-I
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources/ this short profile
may not reflect all - available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
LEAD
SUiMMARY
The hazards of human exposure to lead have been well-
recognized for centuries. The hematopoietic system is the
most sensitive target organ for lead in humans, although
subtle neurobehavioral effects are suspected in children
at similar levels of exposure. The more serious health
effects of chronic lead exposure, however,, involve neuro-
logical damage, irreversible renal damage, and adverse repro-
ductive effects observed only at higher levels of lead expo-
sures. Although certain inorganic lead compounds are car-
cinogenic to some species of experimental animals, a clear
association between lead exposure and cancer development
has not been shown in human populations.
The effects of lead on aquatic organisms have been
extensively studied, particularly in freshwater species.
As with other heavy metals, the toxicity is strongly depen-
dent on the water hardness. Unadjusted 96-hour LC^Q values
with the common fathead minnow, Pimephales promelas, ranged
from 2,400-7,480 pg/l in. soft water to 487,000 pg/1 in hard
water. Toxicity is also dependent on the life stage of
the organism being tested. Chronic values ranged from 32
jug/1 to 87 /jg/1 for six species of freshwater fish. Lead
at 500 jug/1 can reduce the rate of photosynthesis by 50
percent in freshwater algae. Lead is bioconcentrated by •
all species tested - both marine and freshwater - including
-------
fish, invertebrates, and algae. The mussel, Mytilus edulis,
concentrated lead 2,568 times that found in ambient water.
Two species of algae concentrated lead 900-1000-fold.
-------
LEAD
I. INTRODUCTION
This hazard profile is based primarily upon the Ambient
Water Quality Criteria Document for Lead (U.S. EPA, 1979).
A number of excellent comprehensive reviews on the health
hazards of lead have also been recently published. These
include the U.S. EPA Ambient Air Quality Criteria Document
for Lead and the lead criteria document of the National
Institute for Occupational Safety and Hearth (1978).
Lead (Pb, At. No. 82) is a soft gray acid-soluble metal
used in electroplating, metallurgy, and the manufacture
of construction materials, radiation protection devices,
plastics, electronics equipment, storage batteries, gasoline
antiknock additives, and pigments (NIOSH, 1978). The solu-
bility of lead compounds in water depends heavily on pH
and ranges from about 10 pg/1 at pH 5.5 to 1 /ag/1 at pH
9.0 (U.S. EPA, 1979). Inorganic lead compounds are most
stable in the +2 valence state, while organolead compounds
are more stable in the -t-4 valence state (Standen, 1967) .
Lead consumption in the United States has been fairly
stable from year to year at about 1.3 x 10 metric tons
annually. Consumption of lead as an antiknock additive
to gasoline (20 percent annual production) is expected to
decrease steadily. Since lead is an element, it will remain
indefinitely once released to the environment (U.S. EPA,
1979).
-------
II. EXPOSURE
A. Water
Lead is ubiquitous in nature, being a natural
constituent of the earth's crust. Most natural groundwaters
have concentrations ranging from 1 to 10 ug/1.
Lead does not move readily through stream beds
because it easily forms insoluble lead sulfate and carbonate.
Moreover, it binds tightly to organic ligands of the dead
and living flora and fauna of stream beds.-- However, lead
has been found at high concentrations in drinking water
(i.e., as high as 1000 ug/1), due primarily to conditions
of water softness, storage, and transport (Beattie, et al.
1972).
The magnitude of"the problem of excessive lead
in drinking water is not adequately known. In one recent
survey of 969 water systems, 1.4 percent of all tap water
samples exceeded the 50 pg/1 standard (McCabe, 1970). The
U.S. EPA (1979) has not estimated a bioconcentration factor
for lead in aquatic organisms.
B. Food
It is generally believed that food constitutes
the major source of lead absorption in humans. The daily
dietary intake of lead has been estimated by numerous investi-
gators, and the results are generally consistent with one
another. This dietary intake is approximately 241 jig/day
for adults (Nordman, 1975; Kehoe, 1961). For children (ages'
3 months to 3.5 years) the dietary intake is 40 to 210 ug
of lead per day (Alexander, et al. 1973).
-------
C. Inhalation
A great deal of controversy has been generated
regarding the contribution of air to total daily lead absorp-
tion. Unlike the situation with food and water, ambient
air lead concentrations vary greatly. In metropolitan areas,
average air lead concentrations of 2 jjg/m , with excursions
of 10 ug/m in areas of heavy traffic or industrial point
sources, are not uncommon (U.S. EPA, 1979). In non-urban
areas average air lead concentrations are ..usually on the
order of 0.1 pg/m2 (U.S. EPA, 1979).
III. PHARMACOKINETICS.
A. Absorption
The classic studies of Kehoe (1961) on lead metabo-
lism in man indicate that on the average and with consider-
able day-to-day excursions, approximately eight percent
of the normal dietary lead (including beverages) is absorbed.
More recent studies have confirmed this conclusion (Rabino-
witz, et al. 1974). The gastrointestinal absorption of
lead is considerably greater in children than in adults
(Alexander, et al. 1973; Ziegler, et al. 1978).
It has not been possible to accurately estimate
the extent of absorption of inhaled lead aerosols. To vary-
ing degrees,, depending on their solubility and particle
size, lead aerosols will be absorbed across the respiratory
epithelium or cleared from the lung by mucociliary action
and subsequently swallowed.
Very few studies concerning dermal absorption
of lead in man or experimental animals are available. A
I ! ! ""I j —
<* '/ V1 BL I
-------
recent study by Rastogi and Clausen (1976) indicates that
lead is absorbed through intact skin when applied at high
concentrations in the form of lead acetate or naphthenate.
B. Distribution
The general features of lead distribution in the
body are well known/ both from animal studies and from human
autopsy data. Under circumstances of long-term exposure,
approximately 95 percent of the total amount of lead in
the body (body burden) is localized in the skeleton after
attainment of maturity (U.S. EPA, 1979). By contrast, in
children only 72 percent is in bone (Barry, 1975). The
amount in bone increases with age but the amount in soft
tissues, including blood, attains a steady state early in
adulthood (Barry, 1975; Horiuchi and Takada, 1954).
The distribution of lead at the organ and cellular
level has been studied extensively. In blood, lead is pri-
marily localized in the erythrocytes (U.S. EPA, 1979).
The ratio of the concentration of lead in the cell to lead
in the plasma is approximately 16:1. Lead crosses the pla-
centa readily, and its concentration in the blood of the
newborn is quite similar to maternal blood concentration.
C. Excretion
There are wide interspecies differences concerning
routes of excretion for lead. In most speci.es biliary ex-
cretion predominates in comparison to urinary excretion,
except in the baboon (Eisenbud and Wrenn, 1970). It also
appears that urinary excretion predominates in man (Rabino-
x
- j ,Y i o ^
^^^F^^^C^
-------
witz, et al. 1973). This conclusion, however, is based
on very limited data.
IV. EFFECTS
A. Carcinogenicity
At least three studies have been published which
report dose-response data for lead-induced malignancies
in experimental animals (Roe, et al. 1965; Van Esch, et
al. 1962; Zollinger, 1953; Azar, et al. 1973). These studies
established that lead caused renal tumors in rats.
Several epidemiologic studies have been conducted
on persons occupationally exposed to leaa (Dingwall-Fordyce
and Lane, 1963; Nelson, et al. 1973; Cooper and Gaffey,
1975; Cooper, 1978). These reports do not provide a con-
sistent relationship between lead exposure and cancer develop-
ment.
B. Mutagenicity
Pertinent information could not be located in
the available literature concerning mutagenicity of lead.
However, there have been conflicting reports concerning
the occurrence of chromosomal aberrations in lymphocytes
of lead-exposed workers (O'Rioraan and Evans, ly74; Forni,
et al. 1976).
C. Teratogenicity
In human populations exposed to high concentra-
tions of lead, there is evidence of embryotoxic effects
»
although no reports of teratogenesis have oeen published
(U.S. £PA, 197y). In experimental animals, on the other
hana, leaa has repeatedly produced teratogenic effects (Cat-
-------
zione ana Gray, 1941; Karnofsky ana Ridgway, 195
-------
(Kline, 1960), electrocardiographic abnormalities (Kosmider
and Pentelenz, 1962), impaired liver function (Dodic, et
al. 1971), impaired thyroid function (Sandstead, et al.
1969) , and intestinal colic (Beritic, 1971).
V. AQUATIC TOXICITY
A. Acute Toxicity
The available data base on the toxic effects of
lead to freshwater organisms is quite large and clearly
demonstrates the relative sensitivity of freshwater orga-
nisms to lead. The data base shows that the different lead
salts have similar LC^Q values, and that LCcQ values for
lead are greatly different in hard and soft water. Between
soft and hard water; the LC values varied by a factor
of 433 times for rainbow trout, 64 times for fathead min-
nows, and 19 times for bluegills (Davies, et al. 1976; Picker-
ing and Henderson, 1966).
Some 96-hour LC^Q values for freshwater fish are
2,400 to 7,480 pg/1 for fathead minnows in soft water (Tarz-
well and Henderson, 1960; Pickering and Henderson, 1966),
482,000 for fathead minnows in hard water (Pickering and
Henderson, 1966), 23,800 ug/1 for bluegills in soft water
(Pickering and Henderson, 1966), and 442,000 ug/1 for blue-
gills in hard water (Pickering and Henderson, 1966).
For invertebrate species, Whitely (1968) reported
24-hour LC5Q values of 49,000 and 27,500 ug/1 for sludge
worms (Tubifex sp.) obtained from tests conducted at pH
/r
hi* «£-
*•/ 7 9-J
-------
levels of 6.5 and 8.5, respectively. The effects of water
hardness on toxicity of lead to invertebrates could not
be located in the available literature.
The acute toxicity data base for saltwater orga-
nisms is limited to static tests with invertebrate species.
The LC5Q values ranged from 2,200 to 3,600 ug/1 for oyster
larvae in a 48-hour test (Calabrese, et al. 1973) to 27,000
ug/1 for adult soft shell clams (Eisler, 1977) in a 96-hour
test.
B. Chronic Toxicity
Chronic tests in soft water have been conducted
with lead on six species of fish. The chronic values ranged
from 32 ug/1 for la'ke trout (Sauter, et al. 1976) to 87
ug/1 for the white sucker (Sauter, et al. 1976), both being
embryo-larval tests.
Only one invertebrate chronic test result was
found in the literature. This test was with Daphnia magna
in soft water, and the resulting chronic value was 55 jug/1,
about one-eighth the acute value of 450 ug/1 (Biesinger
and Christensen, 1972).
Life cycle or embryo-larval tests conducted with
lead on saltwater organisms could not be located in the
available literature.
C. Plant Effects
Fifteen tests on eight different species of aqua-
tic algae are found in the literature. Most studies mea-
14
sured the lead concentration which reduced CO- fixation
by 50 percent. These values range from 500 ug/1 for Chlorella
-------
sp. (Monahan, 1976) to 28,000 for a diatom, Navicula (Malan-
chuk and Gruendling, 1973).
Pertinent data could not be located in the avail-
able literature on the effects of lead on marine algae.
D. Residue
The mayfly (Ephemerella grandis) and the stonefly.
(Pteronarcys californica) have been studied for their ability
to bioconcentrate lead (Nehring, 1976). The bioconcentra-
tion factor for lead in the mayfly is 2,366 and in the stone-
fly 86, both after 14 days of exposure.
Schulz-Baldes (1972) reported that mussels (Mytilus
edulis) could bioconcentrate lead 2,568-fold. Two species
of algae bioconcentrate lead 933 and 1,050-fold (Schulz-
Baldes, 1976).
VI EXISTING GUIDELINES AND STANDARDS
A. Human
As of February 1979, the U.S. Occupational Safety
and Health Administration has set the permissible occupa-
tional exposure limit for lead and inorganic lead compounds
at 0.05 mg/m of air as an 8-hour time-weighted average.
The U.S. EPA (1979) has also established an ambient airborne
lead standard of 1.5 pg/m .
The U.S. EPA (1979) has derived a draft criterion
for lead of 50 jug/1 for ambient water. This draft criterion
is based on empirical observation of blood lead in human
population groups consuming their normal amount of food ,
and water daily.
A
-------
B. Aquatic
For lead, the draft criterion to protect fresh-
water aquatic life is:
e(1.51 In (hardness) - 3.37
as a 24-hour average, where e is the natural logarithm;
the concentration should not exceed:
e(1.51 In (hardness) - 1.39)
at any time (U.S. EPA, 1979).
For saltwater aquatic life, no draft criterion
for lead was derived.
-------
LEAD
REFERENCES
Alexander, F.W., et al. 1973. The uptake and excretion
by children of lead and other contaminants. Page 319 in
Proc. Int. Symp. Environ. Health. Aspects of Lead. ATnster-
dam, 2-6 Oct., 1972. Comm. Eur. Commun. Luxembourg.
Azar, A., et al. 1973. Review of lead studies in animals
carried out at Haskell Laboratory - two-year feeding study
and response to hemorrhage study. Page 199 iji Proc. int.
Symp. Environ. Health, Aspects of Lead. Amsterdam, 2-6
Oct., 1972. Comm. Eur. Commun. Luxembourg.
Barry, P.S.I. 1975. A comparison of concentrations of lead
in human tissues. Br. Jour. Ind. Med. 32: 119.
Beattie, A.D., et al. 1972. Environmental lead pollution
in an urban soft-water area. Br. Med. Jour. 2: 4901.
Beritic, T. 1971. Lead concentration found in human blood
in association with lead colic. Arch. Environ. Health. 23:
289.
Biesinger, K.E., and G.M. Christensen. 1972. Effect of
various metals on survival, growth, reproduction and metabo-
lism of Daphnia magna. Jour. Fish. Res. Board Can. 29:
1691.
Calabrese, A., et. al. 1973. The toxicity of heavy metals
to embryos of the American oyster Crassostrea virginica.
Mar. Biol. 18: 162.
Carpenter, S.J., and V.H.. Ferm. 1977. Embryopathic effects
of lead in the hamster. Lab. Invest. 37: 369.
Catzione, 0., and P. Gray..1941. Experiments on chemical
interference with the early morphogenesis of the chick.
II. The effects of lead on the central nervous system. Jour.
Exp. Zool. 87: 71.
Chisolm, J.J. 1968. The use of chelating agents in the
treatment of acute and chronic lead, intoxication in child-
hood. Jour. Pediatr. 73: 1.
Chisolm, J.J., et. al. 1975. Dose-effect and dose-response
relationships for lead in children. Jour. Pediatr. 87:
1152.
»
Clarkson, T.W., and J.E. Kench. 1956. Urinary excretion
of amino acids by men absorbing heavy metals. Biochem. Jour.
62: 361.
-------
Cooper, W.C. 1978. Mortality in workers in lead production
facilities and lead battery plants during the period 1971-
1975. A report to International Lead Zinc Research Organiza-
tion, Inc.
Cooper, W.C., and W.R. Gaffey. 1975. Mortality of lead
workers. Jour. Occup. Med. 17: 100.
Cramer, K., et al. 1974. Renal ujtrastructure renal func-
tion and parameters of lead toxicity in workers with dif-
ferent periods of lead exposure. Br. Jour. Ind. Med 31:.
113.
Davies, P.H., et al. 1976. Acute and chronic toxicity
of lead to rainbow trout (Salmo gairdneri) in hard and soft
water. Water Res. 10: 199.
Dingwall-Fordyce, J., and R.E. Lane. 1963. A follow-up
study of lead workers. Br. Jour. Ind. Mech. 30: 313.
Dodic, S., et al. 1971. Stanjc jetre w pojedinih profesion-
alnih intosksikaiija In: III Jugoslavanski Kongres Medicine
Dela, Ljubljana, 1971.
Eisenbud, M., and M.E. Wrenn. 1970. Radioactivity studies.
Annual Rep. NYO-30896-10. Natl. Tech. Inf. Serv. 1: 235.
Springfield, Va.
Eisler, R. 1977. Acute toxicities of selected heavy metals
to the softshell clam, Mya arenaria. Bull. Environ. Contain.
Toxicol. 17: 137.
Forni, A., et al. 1976. Initial occupational exposure
to lead. Arch. Environ. Health 31: 73.
Horiuchi, K., and I. Takada. 1954. Studies on the indus-
trial lead poisoning. I. Absorption, transportation, deposi-
tion and excretion of lead. 1. Normal limits of lead in
the blood, urine and feces among healthy Japanese urban
inhabitants. Osaka City Med. Jour. 1: 117.
Jacquet, P., et al. 1975. Progress report on studies into
the toxic action of lead in biochemistry of the developing
brain and on cytogenetics of post-meiotic germ cells. Eco-
nomic Community of Europe, Contract No. 080-74-7, Brussels,
Belgium.
Jacquet, P., et al. 1977. Cytogenetic investigations on
mice treated with lead. Jour. Toxicol. Environ. Health
2: 619.
Karnofsky, D.A., and L.P. Ridgway. 1952. Production of
injury to the central nervous system of the chick embryo
by lead salts. Jour. Pharmacol. Exp. Therap. 104: 176.
-------
Kehoe, R.A. 1961. The metabolism of lead in man in health
and disease. The Harben Lectures, 1960. Jour. R. Inst.
Publ. Health Hyg. 34: 1.
. Kimmel, C.A., et al. 1976. Chronic lead exposure: Assess-
ment of developmental toxicity. Teratology 13: 27 A (ab-
stract) .
Kline, T.S. 1960. Myocardial changes in lead poisoning.
AMA Jour. Dis. Child. 99: 48.
Kosmider, S., and T. Pentelenz. 1962. Zmiany elektro kardio-
• grayficzne u. starszychosol, 2. prezwleklym zauo-dowym zatru-
ciem olowiem. Pol. Arch. Med. Wein 32: 437.
• Lancranjan, I., et al. 1975. Reproductive ability of work-
men occupationally exposed to lead. Arc'h. Environ. Health
30: 396.
• Lane, R.E. 1949. The care of the lead worker. Br. Jour.
Ind. Med. 6: 1243.
Malanchuk, J.L., and G.K. Gruendling. 1973. Toxicity of
lead nitrate to algae. Water Air and Soil. Pollut. 2: 181.
. McCabe, L.J. 1970. Metal levels found in distribution sam-
ples. AWWA Seminar on Corrosion by Soft Water. Washing-
ton, D.C.
McClain, R.M., and B.A. Becker. 1975. Teratogenicity,
fetal toxicity and placental transfer of lead nitrate in
rats. Toxicol. Appl. Pharmacol. 31: 72.
• Monahan, T.J. 1976. Lead inhibition of chlorophycean micro-
algae. Jour. Psycol. 12: 358.
Morgan, B.B., and J.D. Repko- 1974. In C. Xintaras, et
al. eds. Behavioral toxicology. Early detection of occu-
pational hazards. U.S.Dep- Health Edu. Welfare. Washington,
D.C.
Nehring, R.B. 1976. Aquatic insects as biological monitors
of heavy metal pollution. Bull. Environ. Contain. Toxicol.
15: 147.
Nelson, W.C. , et al. 1973.. Mortality among orchard workers
exposed to lead arsenate spray: a cohort study. Jour.
Chron. Dis. 26: 105.
NIOSH. 1978. Criteria for a recommended standard. Occupa-
tional exposure to inorganic lead. Revised criteria 1978.
National Institute for Occupational Safety and Health.
DHEW (NIOSH) Publication No. 78-158.
-------
Nogaki, K. 1958. On action of lead on body of lead refinery
workers: Particularly conception, pregnancy and parturition
in case of females and their newborn. Excerp. Med. XVII.
4: 2176.
Nordman, C.N. 1975. Environment lead exposure in Finland.
A study on selected population groups. Ph.D. thesis. Univer-
sity of Helsinki.
O'Riordan, M.L., and H.J. Evans. 1974. Absence of signifi-
cant chromosome damage in males occupationally exposed to-
lead. Nature (Lond.) 247: 50.
Pickering, Q.H., and C. Henderson. 1966. The acute toxicity
of some heavy metals to different species of freshwater
fishes. Air. Water Pollut. Int. Jour. 10: 453.
>.
Rabinowitz, M.B., et al. 1974. Studies of human lead metabo-
lism by use of stable isotope tracers. Environ. Health
Perspect. Exp. Issue 7: 145.
Rastogi, S.C., and J. Clausen. 1976. Absorption of lead
through the skin.- Toxicol. 6: 371.
Roe, F.J.C., et al. 1965. Failure of testosterone or xanthop-
terin to influence the induction of renal neoplasms by lead
in rats. Br. Jour. Cancer 19: 860.
Sandstead, H.H., et al. 1969. Lead intoxication and the
thyroid. Arch. Int. Med. 123: 632.
Sauter, S., et al. 1976. Effects of exposure to heavy
metals on selected freshwater fish. Ecol. Res. Ser. EPA
600/3-76-105.
Schulz-Baldes, M. 1972. Toxizitat und anreicherung von
Blei bei der Miesmuschel Mytilis edulis im Laborexperiment.
Mar. Biol. 16: 266.
Schulz-Baldes, M. 1976. Lead uptake in two marine phyto-
plankton organisms. Biol. Bull. 150: 118.
Standen, A., ed. 1967. Kirk-Othmer encyclopedia of chemi-
cal technology. Interscience Publishers, New York.
Stowe, H.D., and R.A. Goyer. 1971. The reproductive ability
and progeny of F, lead-toxic rats. Fertil. Steril. 22:
755. i
Tarzwell, C.M., and C. Henderson. 1960. Toxicity of less
common metals to fishes. Ind. Wastes 5: 12.
\n^ o _
) i J<^-
-------
U.S. EPA. 1979. Lead: Ambient Water Quality Criteria.
U.S. Environ. Prot. Agency, Washington, D.C.
Van Esch, G.J., et al. 1962. The induction of renal tumors
by feeding basic lead acetate to rats. Br. Jour. Cancer
16: 289.
Wedeen, R.P., et al. 1975. Occupational lead nephropathy,
Am. Jour. Hed. 59: 630.
Whitley, L.S. 1968. The resistance of tubificid worms
to three common pollutants. Hydrobiologia 32: 193.
Ziegler, E.E., et al. 1978. Absorption and retension of
lead by infants. Pediatr. Res. 12: 29.
Zollinger, H.U. 1953. Durch Chronische Bleivergiftung Er-
zeugte Nierenadenome und Carcinoma bei Ratten und Ihre Bezie-
hungen zu Den Entsprechenden Neubildung des Menschen. (Kid-
ney adenomas and carcinomas in rats caused by chronic lead
poisoning and their relationship to corresponding human
neoplasma). Virchow Arch. Pathol. Anat. 323: 694.
-IT
-------
No. 122
Maleic Anhydride
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical.. This document has undergone scrutiny to
ensure its technical accuracy..
)/li£-
<^ I } JJ
-------
151
MALEIC ANHYDRIDE
SUMMARY
Maleic anhydride is readily soluble in water where it
hydrolyzes to form maleic acid. It is readily biodegraded by
microorganisms and is not expected to bioconcentrate.
Maleic anhydride induced local tumors in rats following
repeated subcutaneous injections. Maleic anhydride is an acute
irritant and can be an allergen in sensitive individuals.
I. INTRODUCTION
A. Chemical Characteristics
Maleic anhydride (C4H203; 2,5-furandione; CAS No. 108-31-6)
is a white, crystalline solid with an acrid odor. The chemical
has the following physical/chemical properties (Windholz, 1976):
Molecular Weight: 98.06
Boiling Point: 202. O'C
Melting Point: 52. 80°C
Solubility: Soluble in water and many
organic solvents
A review of the production range (includes importation)
statistics for maleic anhydride (CAS No. 108-31-6) which is
listed in the initial TSCA Inventory (1979a) has shown thai
VJUJt-3
-------
between 200 million and 300 million pounds of this chemical were
produced/imported in 1977. _V
Maleic anhydride is used as a chemical intermediate in the
production of unsaturated polyester resins, fumaric acid,
pesticides, and alkyd resins (Hawley, 1977).
II. EXPOSURE
A. Environmental Fate
Maleic anhydride is readily soluble in water where it
hydrolyzes to form maleic acid (Hawley, 1977; Windholz, 1976).
Matsui e t_ al. (1975) reported that maleic anhydride in wastewater
is easily biodegraded by activated sludge.
B. Bioconcentration
Maleic anhydride is not expected to bioaccumulate (U.S. EPA,
1979b).
C. Environmental Occurrence
The major source of maleic anhydride emissions is associated
with release of the chemical as a byproduct of phthalic anhydride
manufacture. Emissions can also occur during the production and
handling of maleic anhydride and its derivatives (U.S. EPA,
1976).
*/This production range information does not include any
production/importation data claimed as confidential by the
person(s) reporting for the TSCA Inventory, nor does it include
any information which would compromise Confidential Business
Information. The data submitted for the TSCA Inventory,
including production range information, are subject to the
limitations contained in the Inventory Reporting Regulations (40
CFR 710).
-------
III. PHABMACOKINETICS
No data were found. Nonetheless, it is expected that any
maleic anhydride that is absorbed would be hydrolyzed to maleic
acid and then neutralized to a maleate salt. Maleate should be
readily metabolized to COj and HjO.
IV. HEALTH EFFECTS
A. Carcinogenicity
Dickens (1963) reported that local fibrosarcomas developed
in rats after repeated subcutaneous injections of maleic
anhydride suspended in arachis oil. Multiple injections of
arachis oil alone or a hydrolysis product derived from maleic
anhydride (sodium maleate) did not produce any tumors at the
injection site.
A long term dietary study of maleic anhydride in rats for
possible carcinogenicity is now in progress. Terminal necropsies
are schedules for January, 1980 (CUT, 1979).
B. Other Toxicity
Maleic anhydride vapors and dusts are acute irritants of the
eyes, skin, and upper respiratory tract (ACGIH, 1971). Repeated
exposures to maleic anhydride concentrations above 1.25 ppm in
air have caused asthmatic responses in workers. Allergies have
developed in which workers have become sensitive to even lower
concentrations of the compound. An increased incidence of bron-
chitis and dermatitis has also been noted among workers with*
long-term exposure to maleic anhydride. One case of pulmonary
edema in a worker has been reported (U.S. EPA, 1976).
-------
V. AQUATIC EFFECTS
The 24 to 96-hr median threshold limit (TLm) for maleic
anhydride in mosquito fish is 230-240 mg/1. The 24-hr TLm for
bluegill sunfish is 150 mg/1 (Verschueren, 1977).
VI. EXISTING GUIDELINES
The existing OSHA standard for maleic anydride is an 8-hour
time weighted average (TWA) of 0.25 ppm in air (39CFR23540).
-------
REFERENCES
American Conference of Governmental Industrial Hygienist (1971).
Documentation of Threshold Limit Values for Substances in Work-
room Air, 3rd ed. , 263.
Chemical Industry Institute of Toxicology (1979). Research
Triangle Park, N. C. , Monthly Activities Report (Nov-Dec 1979).
Dickens, F. (1963). Further Studies on the Carcinogenic and
Growth-Inhibiting Activity of Lactones and Related Substances.
3r. J. Cancer. 17(1);100.
Hawley, G. G. (1977). Condensed Chemical Dictionary, 9th ed. Van
Nostrand Reinhold Co.
Matsui, S. _et_ _al_. (1975). Activated sludge degradability of
organic substances in the waste water of the Kashima petroleum
and petro chemical industrial complex in Japan. Prog. Water
Technol. 2:645-659
U.S. EPA (1976). Assessment of Maleic Anhydride as a Potential
Air Pollution Problem Vol. XI. PB 258 363.
U.S. EPA (1979a). Toxic Substances Control Act Chemical Sub-
stances Inventory, Production Statistics for Chemicals Listed on
the Non-Confidential Initial TSCA Inventory.
U.S. EPA (1979b). Oil and Hazardous Materials. Technical
•Assistance Data System (OHMTADS DATA BASE).
Verschueren, K (1978). Handbook of Environmental Data on Organic
Chemicals. Van Nostrand Reinhold Co.
Windholz, M. (1976). The Merck Index, 9th Edition. Merck and
Company, Inc.
-------
No. 123
Malononitrlle
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
DISCLAIMER
This report represents a brief assessment of the potential health and
environmental hazards from exposure to the subject chemical. The informa-
tion contained in the report is drawn chiefly from secondary sources and
available reference documents. Because of the limitations of such sources,
this short profile may not reflect all available information on the subject
chemical. This document has undergone scrutiny to ensure its technical ac-
curacy .
-------
MALONONITRILE
Summary
Nitriles, as a group, are sources of the cyanide ion, which interferes
with basic cellular oxidative mechanisms. Malononitrile has effects on the
cardiovascular, renal, hepatic and central nervous systems. This compound
can take effect after inhalation, dermal contact or ingestion. No carcino-
genic, mutagenic or teratogenic effects have been reported.
Malononitrile has been used in the treatment of various forms of mental
illness. A thorough documentation of the side effects of this compound
exists. The only human toxicity data on malononitrile found in the avail-
able literature are those reported during clinical psychiatric use.
-------
MALONONITRILE
I. INTRODUCTION
Malononitrile (NCCH2CH), CAS registry number 109-77-3, is an odor-
less, yellow crystalline chemical with a molecular weight of 66.06 and a
specific gravity of 1.049. Its melting point, is between 30°c and 31°C.
Malononitrile is soluble in water, acetone, alcohol and ether, but is insol-
uble in ethanol (Weast, 1974). When heated to decomposition, nitriles emit
toxic fumes containing cyanides (Sax, 1968).
Malononitrile is used in the following applications: as a lubricating
oil additive, for thiamine synthesis, for pteridine-type anti-cancer agent
synthesis, and in the synthesis of photosensitizers, acrylic fibres, and
dyestuffs (Eur. Chem. News, 1975; Lonza Inc., 1978).
Imports of malononitrile, which currently is not manufactured in the
United States, were 60,000 pounds for 1976 (NIOSH, 1978).
.II. EXPOSURE
A. Water and Food
Pertinent data were not found in the available literature.
8. Inhalation
Research by Panov (1969) indicates that malononitrile was readily
absorbed by the lungs of animals. As test chamber temperatures increased,
the mortality rate also increased, presumably due to higher absorption.
The major occupational exposure to nitriles occurs principally by
inhalation of vapor or aerosols and by skin absorption. The likelihood of
such exposure increases during the handling, transferring and quality con-
»
trol sampling of these compounds.
IJL3-5
-------
C. Dermal
Panov (1969) reported that malononitrile was readily absorbed
through the eyes of rabbits. He also reported that mice and rabbits absorb
the compound through the skin. Extreme irritation resulted from both modes
of application.
III. PHARMACOKINEJICS
A. Absorption
Animal studies indicated that malononitrile is absorbed through
the lungs and by the skin (Panov, 1969).
8. Distribution
Hicks (1950) determined that, to some extent, malononitrile exerts
tissue specificity (brain, liver, kidney, lung and thyroid) in its action.
The formation of thiocyanate in vitro from malononitrile and thio-
sulfate was .highest in the presence of liver tissue, lowest with brain, and
intermediate with kidney (Stem et al., 1952).
C- Metabolism
The dinitrile compounds (such as malononitrile) presumably can ex-
ert a greater toxic effect than the mononitriles due to the more rapid re-
lease of cyanide from the parent compound. Malononitrile released cyanide
j£ vivo and was ultimately excreted as thiocyanate after oxidation
(Ghiringhelli, 1955).
The CSN group may be converted to a carboxylic acid derivative and
ammonia, or may be incorporated into cyanocobalamine. Ionic cyanide also
reacts with carboxyl groups and with disulfides (McKee et al., 1962).
Jt
< n,ii
I ) > 9*
-------
Stern et al. (1952) found that in vitro respiration of brain, kid-
ney, and liver slices was inhibited by 0.01 M malononitrile. The same in-
vestigators also demonstrated the formation of thiocyanate from malononi-
trile and thiosulfate in liver and kidney tissues in vitro. The release of
cyanide from dinitriles suggests that their mechanism of acute toxicity may
be similar to that of the mononitriles.
The enzyme rhodanase,. which catalyzed the formation of thiocyanate
from cyanide and thiosulfate, was ineffective in the catalysis of thiocya-
nate from malononitrile. In vivo thiocyanate formation apparently came from
an intermediate metabolite and not the malononitrile molecule.
D. Excretion
After absorption, malononitrile may be metaboilized to an organic
cyanide, which is oxidized to thiocyanate and excreted in the urine (McKee
et al, 1962). No evidence of respiratory excretion was found in the avail-
able literature.
IV. EFFECTS
A. Carcinogenic!ty, Mutagenicity, Teratogenicity and Reproductive
Effects
Pertinent data were not found in the available literature.
B. Chronic Toxicity
The only available human toxicity data on malononitrile are those
reported during the clinical use of the compound in the treatment of mental
illness.
Hyden and Hartelius (1948) reported on the clinical use of malo-
nonitrile during psychiatric treatment. Its intended purpose was to stimu-
late the production of proteins and nucleic acids in the pyramidal cells, of
the frontal cortices of psychiatric patients, particularly those who were
depressed or schizophrenic. All patients experienced tachycardia 10 to 20
-------
minutes after the infusion of malononitrile (1-6 mg/kg). Facial redness,
headache, nausea, vomiting, shivering, cold hands and feet, muscle spasms
and numbness were also reported with varying frequency. Similar results
were also submitted by MacKinnon et al. (1949), Hartelius (1950), and Meyers
et al. (1950) in the treatment of mental patients.
Hicks (1950) reported that malononitrile poisoning induced brain
lesions in rats. The compound produced demyelinating lesions of the optic
tract and nerve, the cerebral cortex, the olfactory bulb and the substantia
nigra.
Panov (1969) found the repeated exposure to malononitrile (36
mg/m5 for 2 hours per day for 35 days) was slightly toxic to rats- The
exposure caused slight anaplasia of bone.marrow, i.e. a lower hemoglobin
level and elevated reticulocyte count.
F. Acute Toxicity
Panov (1969) subjected mice to a single, 2-hour inhalation expo-
sure to malononitrile. The mice showed signs of restlessness and increased
respiration rate in the early post-treatment period followed by Lassitude,
decreased respiration rate, cyanosis, noncoordination of movement, tremb-
ling, convulsions and eventual death of some animals. The exposure concen-
tration was not noted.
Panov (1969) reported that liquified malononitrile applied to the
eyes of rabbits caused tearing, blepharospasm. hyperemia of the conjunctiva,
and swelling of the eyelids. Panov also applied malononitrile solution
(concentration not stated) to the tails of mice. The -animals showed signs
of restlessness, rapid respiration and slight cyanosis of the extremities
»
and the mucosa of the lips. He also observed trembling and skin irritation
following dermal application of malononitrile to a rabbit.
-------
Nuclear changes in neurons and satellite spiral ganglia were seen
in rats administered single doses (6-8 mg/kg) of malononitrile (Van Breeman
and Hiraoka, 1961).
V. AQUATIC TOXICITY
Pertinent data were not found in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
Because malononitrile is about three times as toxic as isobutyro-
nitrile, NIOSH recommends that employee exposure to malononitrile not exceed
3 ppm (8 mg/nv5) as a TWA limit for up to 10-hour workshift in a 40-hour
work week (NIOSH, 1978).
B, Aquatic
Pertinent data were not found in the available literature.
-------
MALONONITRILE
References
Eur. Chem. News. 1975. Lonza develops malononitrile process for wide ap-
plication. March 15, 1975.
Ghiringhelli, L. 1955. Toxicity of adipic nitrile—Clinical picture and
mechanism of poisoning. Med. Lav. 46: 221.
Hartelius, H. 1950. Further experiences in the use of malononitrile in the
treatment of mental illnesses. Am. Jour. Psychiatry. 107: 95.
Hicks, S.P. 1950. Brain metabolism in vivo—II. The distribution of le-
sions caused by azide malononitrile, plasmocid and dinitrophenol poisoning
in rats. Arch. Pathol. 50: 545.
Hyden, H., and H. Hartelius. 1948. Stimulation of the nucleo-
protein-production in the nerve cells by malononitrile and its effect on
psychic functions in mental disorders. Acta. Psychiatr. Neurol. Suppl.
48: 1-
Lanza, Inc. 1978. Malononitrile—Production Information. Fairlawn, NJ.
MacKinnon, I.H., et al_ 1949. The use of malononitrile in the treatment of
mental illness. Am. Jour. Psychiatry. 105: 686.
McKee, H.C., et al. 1962. Acetonitrile in body fluids related to smoking.
Public Health Rep. 77: 553.
Meyers, 0., et al. 1950. Effect of malononitrile on physical and mental
status of schizophrenic patients. Arch. Neurol. Psychiatry. 63: 586.
National Institute for Occupational Safety and Health. 1978. Criteria for
a recommended standard...occupational exposure to nitriles. U.S. DHEW
(NIOSH) Report No. 78-212.
Panov, I.K. 1969. Study of acute dicyanomethane toxicity in animals.
Jour. Eur. Toxicol. 2: 292.
Sax, N.I. 1968. Dangerous Properties of Industrial Materials, 3rd ed. Van
Nostrand Reinhold Co., New York.
Stem, J., et al. 1952. The effects and the fate of malononitrile and re-
lated compounds in animal tissues. Biochem. Jour. 52: 114.
Van Breeman, V.L. and J. Hiraoka. 1961(abst.) Ultra structure of nerve and
satellite cells in spinal ganglia of rats treated with malononitrile. Am.
Zool. 1: 473.
Weast, R.C. (ed.) 1974. CRC Handbook of Chemistry and Physics — A Ready
Reference Book of Chemical and Physical Data, 54th ed.
-I H
-------
No. 124
Mercury
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy. .
-------
MERCURY
SUMMARY
Short chain alkyl mercurials represent a toxic species
that distributes widely and accumulates in the liver, kidneys
and other organs. These compounds are eliminated from the body
at a slow rate. In humans, mercurials have been associated with
neurological disorders, sensory impairment and tremors. Prenatal
exposure has produced psychomotor disorders.v Brain development
is impaired by accumulation of mercurials, and lesions in the
cerebral and cerebellar areas have been observed.
Methylmercury crosses the placental barrier and is secreted
in milk. Methylmercury and mercuric chloride have been shown
to produce teratogenic effects in animals. Reproductive effects
in animals of alkyl mercury compounds involve reversible inhibi-
tion of spermatogonia and damage to unfertilized gametes. A
high infant mortality rate has been reported in a study of mothers
exposed to high levels of mercurials.
Mercurials have induced chromosome breakage in plant cells
and point mutations in Drosophila. Mercurials have not been
shown to produce carcinogenic effects other than non-specific
injection site sarcomas. The U.S. EPA (1979) has calculated
an Acceptable Daily Intake (ADI) for mercury of 200 pg/day.
Mercury can be bioconcentrated many-fold in fish and other
aquatic organisms because of rapid uptake and the excretion of
-------
mercury from their tissues. In general, the methylmercury com-
pounds are more toxic than the inorganic forms of mercury. Toxi-
city varies widely among species. Concentrations as low as 0.1
ug/1 have been shown to be toxic to freshwater crayfish.
-------
MERCURY
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Mercury (U.S. EPA, 1979).
Mercury (Hg; atomic weight 200.59) is a silver-white metal,
which is a liquid at room temperature. It has the following
physical properties: melting point, -38.87°C; boiling point, •
356-358°C; specific gravity, 13.546; and vapor pressure at 20°C,
0.0012 mm Hg (Stecher, 1968).
Mercury exists in three oxidation states: elemental (0),
mercurous (+1) , and mercuric (+2). The solubilities of some
common mercuric salts are as follows: HgCl2 (1 g/13.5 ml water),
Hg(N03)2 (soluble in a "small amount" of water), Hg(CH3COO)2
(1 g/2.5 ml water) (Stecher, 1968). Mercurous salts are much
less soluble in water; Hg2Cl2 is practically insoluble in water
(Stecher, 1968).
Major usage of mercury include the following: as a cathode
in the electrolytic preparation of chlorine and caustic soda,
in electrical apparatus, in industrial and control instruments,
in general laboratory applications, in dental amalgams, in anti-
fouling and mildew-proofing paints, and as a fungicide in treat-
ing seeds, bulbs, and plants. However, mercury is no longer
registered by the U.S.. EPA for this last application.
Elemental mercury can be oxidized to the mercuric form
in water in the presence of oxygen (Stock and Cucuel, 1934);
this transformation in water is facilitated by the presence of
organic substances (Jensen and Jernelov, 1972). The mercuric
-------
ion is a substrate for biomethylation reactions; both dimethyl
and monomethyl mercury may be formed by bacteria present in sedi-
ments (Wood, 1976 and Cotton and Wilkinson, 1966). Considerable
bacterial demethylation of methylmercury occurs in the environ-
ment, limiting the buildup of methylmercury (Tonomura and Konzaki,
1969). The degree of oxygenation, pH, and the presence of inor-
ganic and organic ligands are determining factors regulating
which state of mercury is present in water. On thermodynamic
grounds, one would expect inorganic mercury to be present mainly
as mercuric compounds in well-oxygenated water and, in an increas-
ing fraction of total mercury, as the elemental form or the sul-
fide form under reducing conditions (NAS, 1978).
II. EXPOSURE
Mercury undergoes a global cycle of emission and deposi-
tion. Total entry of mercury into the atmosphere is approximately
40,000 to 50,000 metric tons per year, mainly from natural sources
(NAS, 1978 and Korringa and Hagel, 1974). Deposition from the
atmosphere into the ocean is estimated at about 11,000 tons per
year (NAS, 1978). These waters represent a relatively large
mercury pool that maintains a stable concentration (U.S. EPA,
1979).
Industrial release of mercury involves both organic and
inorganic forms. These emissions are from the burning of fossil
fuels, discharges of waste from the chloralkali industries, dis-
charges of methylmercury from chemical manufacturers, and runoff
from the use of ethyl and methylmercury fungicides (U.S. EPA, •
1979) .
-------
Based on available monitoring data, the U.S. EPA (1979)
has estimated the uptake of mercury by adult humans from air,
water, and food:
Adult - ug/day
Source
Air
Water
Food
Minimum
0.3
0.1
3.0
Maximum
0.8
0.4
5.0
Predominant form
elemental
mercuric
methylmercury
Total
3.4
6.2
Fish and shellfish represent a source of high methylmercury
intake. The U.S. EPA (1979) has estimated average bioconcen-
tration factors of 1,700 for mercuric chloride and 6,200 for
methylmercury in the edible portions of fish and shellfish con-
sumed by Americans. This estimate is based on bioconcentration
studies in several species, and on other factors.
III. PHARMACOKINETICS
A. Absorption
Inorganic mercury salts are absorbed poorly by the
human gastrointestinal tract; less than 15 percent absorption
was reported (Rahola, et al., 1971). Inhalation of mercuric
oxide has been shown to produce pulmonary deposition and absorp-
tion of the compound, with 45 percent of the administered dose
cleared within 24 hours (Morrow, et al., 1964). Dermal absorp-
tion of mercuric chloride has been reported in studies with guinea
pigs (Friberg, et al., 1961; Skog and Vahlberg", 1964).
Metallic mercury is not absorbed significantly from
the gastrointestinal tract. Friberg and Nordberg (1973) calculate
that less than 0.01 percent of an orally administered- dose is
absorbed. Studies with human subjects reveal approximately 80
X
-------
percent of inhaled mercury vapor is retained (Hursh, et al.,
1976}, with alveolar regions indicated as the probable site of
absorption into the bloodstream (Berlin, et al., 1969). Animal
studies indicate dermal absorption of metallic mercury can occur
(Juliusberg, 1901; Schamberg, et al., 1918).
Methylraercury shows virtually complete absorption
from the gastrointestinal tract (Aberg, et al., 1969; Miet-
tinen, 1973). Inhalation of alkyl mercurials leads to high
retention, perhaps as high as 80 percent (Task Group on
Metal Accumulation, 1973). Severe poisoning of humans follow-
ing topical methylmercury applications indicates some dermal
absorption of the compound (U.S. EPA, 1979).
B. Distribution
Methylmercury, after absorption from the gastrointes-
tinal tract, distributes readily to all tissues in the body (WHO
Expert Committee, 1976), with the highest concentrations being
found in the kidney cortex and red blood cells. Approximately
five percent of an ingested dose is found in the blood compart-
ment following tissue distribution. Human studies with a radio-
actively labeled compound have indicated that approximately ten
percent of the body burden may be transferred to the head region
following complete tissue distribution (Aberg, et al., 1969).
The ratio of methylmercury in the brain to levels in the blood
may be as high as 10:1 (U.S. EPA, 1979). In muscle tissue, an-
alysis of the mercury present indicates that it is almost entirely
methylmercury, while liver and kidney contain a substantial amount
of demethylated, inorganic forms (Magos, et al., 1976).
-------
Determination of methylmercury in cord blood and fetal
red cells indicates that the compound is transported across pla-
cental membranes (Tejing, 1970; Suzuki, et al., 1971). Methyl-
mercury is secreted in mother's milk and may average as much
as five percent of the maternal blood level (Bakir, et al., 1973).
Mercury in the mercuric form concentrates in the kid-
neys following inhalation of mercury vapor. Animal studies show
that up to 90 percent of an administered dose may localize at
this site (Rothstein and Hayes, 1964). Experiments using radio-
labeled mercury in human volunteers have shown approximately
seven percent accumulation of the inhaled compound in the head
region (Hursch, et al., 1976). Oxidation of absorbed elemental
mercury to the mercuric form takes place _iri vivo, probably largely
through the enzymatic activities of red blood cells (Clarkson,
et al., 1978).
Mer.cury has been shown to be transferred into the
fetus after maternal exposure. The rate of transfer of elemental
mercury appears to be greater than ionic forms of mercury (Clark-
son, et al., 1972).
Animal studies with inorganic mercury salts indicate
the distribution pattern is similar to the pattern observed after
exposure to mercury vapors (Friberg and Vostal, 1972); however,
the ratio of mercuric ion in red cells to plasma levels is lower
(Rahola, et al., 1971).. The major site of mercuric ion accumula-
tion is the kidney (U.S. EPA, 1979).
C. Metabolism
»
Methylmercury undergoes cleavage of the carbon mercury
bond, resulting in the production of inorganic mercury in vivo.
-------
Plasma, liver, and kidney all contain substantial amounts of
inorganic mercury following administration of the organic form
of the compound (Bakir, et al., 1973). Norseth and Clarkson
(1971) have suggested that gut microflora may aid in this bio-
transformation. Bakir, et al. (1973) have determined a mean
half-life value of 65 days for 16 hospital cases. However, a
wide range of blood half-lives have been determined in human
studies (U.S. EPA, 1979). Whole body half-life values for methyl-
mercury appear to be in the same range (-<-52^93 days) as blood
clearance half-lives (Miettinen, 1973).
Elemental mercury can undergo oxidation in the body
to the mercuric form, which is then capable of interacting with
many tissue ligands CClarkson, et al., 1978). Limited experi-
ments with subjects exposed to mercury vapor indicate a two com-
ponent loss of mercury from the bloodstream. Clarkson (1978)
has estimated half-lives of 2.4 days for the fast component and
14.9 days for the slow component following a brief exposure to
mercury vapor. Hursh, et al. (1976) have estimated that the
whole body half-life of elemental mercury is comparable with
that of methyl mercury.
D. Excretion
The excretion of methylmercury occurs predominantly
by the fecal route in humans. Less than ten percent of excretion
occurs in the urine (U.S. EPA, 1979). Norseth and Clarkson (1971)
have determined significant biliary secretion of methylmercury
in animals, raising the possibility that biotransforraation to»
the inorganic form might be affected by microflora in the gut.
-------
Elemental mercury exposure has been shown to lead
to mercury excretion predominantly through the feces and urine
(Lovejoy, et al., 1974). As kidney levels of mercury increase,
a greater urinary excretion of the compound occurs (Rothstein
and Hayes, 1964). Urinary excretion values from 13 percent to
58 percent have been determined. Elimination of inhaled mercury
has been observed in expired air (7 percent) (Cherian, et al.,
1978) and in sweat (Lovejoy, et al., 1974).
Human studies with small ingested*, doses of mercuric
salts have indicated that following excretion of the unabsorbed
compound, urinary and fecal excretion of inorganic mercury were
approximately equal (Rahola, et al., 1971).
IV. EFFECTS
A.. Carcinogenicity
Intraperitoneal injection of metallic mercury into
rats produced injection site sarcomas (Druckrey, et al., 1957).
Pertinent data could not be located in the available
literature indicating that mercury is carcinogenic.
B. Mutagenicity
Methylmercury has been shown to block mitosis in plant
cells and in human leukocytes treated in vivo, and human cells
in vitro, as well as to induce chromosome breakage in plant cells
and point mutations in Drosophila (Swedish Expert Group, 1971;
Ramel, 1972).
No evidence for the mutagenic effects of elemental
or inorganic mercury could be located in the available literature.
-------
C. Teratogenicity
Oharazawa (1968) reported increased frequency of cleft
palate in mice treated with an alkyl mercury compound. Embryo-
toxic effects without gross teratological effects were reported
by Fujita (1969) in mice. Prenatal exposure to methylmercury
has produced histological evidence of brain damage in several
species (Matsumoto, et al., 1967; Nonaka, 1969; Morikawa, 1961).
Spyker and Smithburg (1972) and Olson and Massaro (1977) have
also reported anatomical malformations in animals exposed pre-
natally to methylmercury.
Teratological effects of mercuric chloride have been
reported in animals (Gale and Perm, 1971). However, data are
not available on the teratogenicity of inorganic mercury in human
populations.
• Exposure of rats prenatally to mercury vapor produced
fetal toxicity without evidence of teratological effects (Baranski
and Szymczyk, 1973).
D. Other Reproductive Effects
A high mortality rate in infants born to women suffer-
ing mercury poisoning has been reported (Baranski and Szymczyk,
1973) .
Methylmercury has been reported to interfere with
reproductive capability in adult animals treated with this com-
pound (Ramel, 1972; Suter, 1975). Khera (1973) has observed
that administration of alkyl mercury compounds to rats may damage
gametes prior to fertilization. Reversible inhibition of spesma-
togonial cells in mice treated with mercuric chloride has been
reported (Lee and Dixon, 1975).
-------
E. Chronic Toxicity
Chronic exposure to methylmercury has produced several
outbreaks of poisoning, characterized by neurological symptoms
following central nervous system damage (Nordberg, 1976; NAS,
1978). Adult exposure to methylmercury has produced symptoms
of paresthesia of the extremities, impaired peripheral vision,
slurred speech, and unsteadiness of gait and of limbs (U.S. EPA,
1979). Neuropathological investigation showed cerebellar atrophy
and focal atrophy of the calcarine cortex (Hunter and Russell,
1954) .
Prenatal exposure to methylmercury produced psycho-
motor brain abnormalities (Engleson and Herner, 1952; Harada,
1968) . Brain development was shown to be disturbed, and both
cerebral and cerebellar lesions were observed (U.S. EPA, 1979).
An epidemiological study on school children in the Minamata Bay
area has reported a higher incidence of neurological deficits,
learning difficulties, neurological symptoms, and poor performance
on intelligence tests for these residents of a high methylmercury
exposure region (Med. Tribune, 1978).
An ethylmercury poisoning outbreak indicated renal
and cardiac damage following this exposure (Jalili and Abbasi,
1961).
Mercury vapor poisoning may produce signs of mental .
disturbances, tremors, and gingivitis (U.S. EPA, 1979). Exposure
to extremely high concentrations can damage lung tissue causing
acute mercurial pneumonitis. Kidney dysfunction (proteinuria)
»
in workers exposed to mercury vapor has also been reported (Kazantzis,
et al., 1962; Joselow and Goldwater, 1967).
^ . >i / 4 -
**) } v -> *
/a/-/3
-------
V.. AQUATIC TOXICITY
A. Acute Toxicity
Observed LC^Q values for three flow-through and two
static-renewal assays for mercuric chloride with the rainbow
trout as the test species ranged from 155 to 903 ug/1. The re-
sults of two flow-through and three static-renewal assays on
rainbow and brook trout provide an LC50 range for methylmercuric
compounds from 24 to 84 ug/1, with the rainbow trout being from
three to five times as sensitive as the brook trout. For five
other mercury compounds, LC5Q values ranged from 5.1 for phenyl-
mercuric acetate to 39,910 ug/1 for merthiolate. Ethyl- and
phenylmercury compounds generally were more toxic while merthio-
late and pyridylmercuric acetate were less toxic. A total of
14 freshwater invertebrate species have been tested in static
and static-renewal bioassays for acute toxicity to mercuric chloride
and mercuric nitrate. LCCQ values ranged from 0.02 to 2,100
ug/1 (U.S. EPA, 1979). Heit and Pingerman (1977) and Beisinger
and Christensen (1972) reported the more sensitive species to
be the crayfish Faxonella clypeata and the daphnid, Daphnia magna,
respectively. Warnick and Bell (1969) reported that the mayfly
(Ephemerella subvaria), the stonefly (Acroneuria lycorius), and
the caddisfly (Hydropsyche betteni) were among the most resistant
freshwater invertebrates to mercuric chloride. Two static tests
have produced 96-hour LC5Q values of 800 and 2,000 ug/1 for mer-
curic chloride to the marine fish, the mummichog (Fundulus heter-
clitus). Among marine invertebrates exposed to mercuric chloride,
LCgg values ranged from 3.6 to 32,000 pg/1 for 21 species. Embryo
itf
-------
stages of the oyster (Crassostrea virginica), the hard-shell
clam (Mercenaria mercenaria), and the mysid shrimp (Mysidopsis
bahia), the latter in the only acute flow-through test reported,
were the more sensitive species reported. Lockwood and Inman
(1975) provide the only acute study for methylmercuric chloride
with a adjusted 96-hour LC5Q value of 150 ug/1.
B. Chronic Toxicity
McKim, et al. (1976) offered the single source reported
for chronic effects to freshwater fish. Examining the long-term
effects of methylmercury chloride on three generations of the
brook trout (Salvelinus fontinalis), adverse effects were reported
at 0.93 ug/1,.but not at 0.29 pg/1. Brook trout were from three
to four times more resistant than rainbow trout (Salmo gairderi).
Sosnowski, et al. (1979) have examined the effects of mercuric
chloride by a flow-through, life-cycle bioassay on the mysid
shrimp, Mysidppsis bahia. The highest concentration producing
no-observed-effect was 0.82 ug/1.
C. Plant Effects
A number of different parameters have been used to
determine the toxic effects of mercury compounds on freshwater
plants. Effective concentrations .of mercuric chloride ranged
from 60 to 2,590 pg/1. Blinn, et al. (1977) demonstrated altered
photosynthetic activity in a summer assemblage of algal species
at 60 pg/1. Two of these studies on the effects of methylmercury
chloride to freshwater algae revealed enzyme inhibition at 1,598
pg/1 in Anklstrodesmus braunii' and 50 percent growth inhibition
to Coelastrum microporum at concentrations of 2.4 to 4.8 pg/1.
For other organomercury compounds, effective concentrations ranged
if
^tii tS-
^^^^^^^^^
/ay-AT
-------
from less than 0.6 to 200.6 ug/1. Using 18 marine species, Ber-
land, et al. (1976) measured growth inhibition at mercuric chloride
concentrations from 5 to 15 pg/1 and lethalities from 10 to 50
ug/1. Effective concentrations for the alga Isochrysis galbana
ranged up to 2,000,000 jig/1, at which no growth was observed
(Davies, 1976). For other organomercury compounds, effective
concentrations ranged from 0.1 to less than 2,000 ug/1. Harriss,
et al. (1970) reported reduced photosynthetic activity to methyl-
mercury hexachlorophthalimine in the diatom,. Nitzchia delictissima,
. , *
at the level of 0.1 ug/1. Methylmercury chloride was reported
by Overnell (1975) to reduce photosynthetic activity at concen-
trations of less than 2,000 ug/1.
D. Residues
Bioconcentratlon data for freshwater species for various
mercury compounds can be summarized by the following.bioconcen-
tration factors': 33,800 for the algae Synedra ulna (Fujita and
Hashizuma, 1972) exposed to mercuric chloride; 4,532 to 8,049
for juvenile rainbow trout exposed to methylmercury chloride
(Reinert, et al., 1974); 12,000 to 20,000 for brook trout exposed
to methylmercury chloride (McKin, et al., 1976); and 62,898 for
the fathead minnow exposed to methylmercury chloride (Olson,
et al., 1975). It should be noted that for the high bioconcen-
tration value for the fathead minnow, the fish were allowed to .
forage on aquatic organisms growing within the mercury enriched
exposure chambers; therefore, this measurement may more closely
reflect actual field data. The trout were fed a pelleted diet.
A variety of marine organisms have been used to demonstrate the
'rapid accumulation of inorganic and organic mercury compounds.
-------
Bioconcentration values for marine algae ranged from 853 to 7,400,
with exposure periods of two to eight days for mercuric chloride.
A 30-day bioconcentration factor of 129 for the lobster, Homarus
americanus, has been reported by Thurberg, et al. (1977), and
a range of 2,800 to 10,000 reported for adult oysters, Crassostrea
virginica, (both species for mercuric chloride). Kopfler (1974)
reports a biomagnification value of 40,000 for the oyster C.
virginica to methylmercury and phenyl-mercury chloride. The
biological half-lives of rapidly accumulated., mercuric compounds
indicate that clearance is not rapid even after several months.
VI. EXISTING GUIDELINES
A. Human
The U.S. EPA has recommended a drinking water standard
of 2 ug Hg/1 to protect human health (U.S. EPA, 1973).
Calculation of an acceptable daily intake (ADI) of
mercury by the U.S. EPA (1979) has produced a tentative criterion
of 0.2 pg/1 (with an uncertainty factor applied) for ambient
water.
B. Aquatic
The criteria for mercury are divided into tentative
recommendations for inorganic and organic mercury. Freshwater
criteria have been drafted as follows: for inorganic mercury,
the draft criterion is 0.064 pg/1 for a 24-hour average exposure,
not to exceed 3.2 pg/1 at any time. For methylmercury, the draft
criterion is 0.016 pg/1 for a 24-hour average, not to exceed
•
8.8 pg/1 at any time. To protect marine life from inorganic
mercury, the draft criterion is 0.19 pg/1 for a 24-hour average,
not to exceed 1.0 pg/1 at any time. For methylmercury, the tenta-
-------
tive criterion is 0.025 ug/1 as a 24-hour average not to exceed
2.6 pg/1 at any time (U.S. EPA, 1979).
The above criteria have not yet gone through the pro-
cess of public review; therefore, there is a possibility that '
the criteria may be changed.
-------
MERCURY
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16
-------
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- i(Ml -
I } /I1'1*
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Nonaka, I. 1969. An electron microscopic study of the experi-
mental congenital Minamata Disease in rat. Kumamoto Med.
Jour. 22: 27.
Nordberg, G.F., ed. 1976. Effects and dose-response of
toxic metals. Elsevier-Amsterdam.
Norseth, T. and T.W. Clarkson. 1971. Intestinal transport
of Hg-labelled methyl mercury chloride; role of biotrans-
formation in rats. Arch. Environ. Health 22: 258.
Oharazawa. 1968. Chromosomal abnormalities and teratogenesis
induced by ethyl mercuric phosphate in pregnant mice. Nippon
Sanka-Fujinka Gakka: Zasshi 20: 1479.
Olson, F.C., and E.J. Massaro. 1977. Pharmacodynamics
of methyl mercury in the marine maternal/embryo fetal unit.
Toxicol. Appl. Pharmacol. 39: 263.
Olson, G.F., et al. 1975. Mercury residue's in fathead
minnows, Pimephales promelas Rafinesque, chronically exposed
to merthyimercury in water. Bull. Environ. Contain. Toxicol.
14: 129.
•
Overnell, J. 1975. The effect of heavy metals on photo-
synthesis and loss of cell potassium in two species of marine
algae, Dunaliella tertiolecta and Phaeodactvlum tricornutum.
Mar . BToTT"29 : 957
-------
Rahola, T., et-al- 1971. The biological half-time of inorgan-
ic mercury (Hg ) in man. Scand. Jour. Clin. Invest. Abst.
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trout (Salmo gairdneri). Jour. 'Fish. Res. Board Can. 31:
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cury in rats exposed repeatedly to inhalation of vapor.
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cury exposure on the mysid shrimp. Mysidopsis bahia Abst.
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-------
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No. 125
Me thorny 1
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical, accuracy.
i If "T Ctr
•* /"J1 ) O
-------
Disclaimer Notice
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.
-------
METHOMYL
Summary
Methomyl is a toxic carbamate insecticide used on field crops and
fruit. It is readily absorbed through inhalation or dermal exposure ana is
almost completely eliminated from the body within 24 hours. Chronic tox-
icity studies in rats and dogs show that no effects occur below 100 ppm.
The threshold limit value for methomyl in air is 2.5 fig/m^. Methomyl in-
hibits the activity of cholinesterase in the boay. Studies have shown that
methomyl is not carcinogenic in rats and dogs or mutagenic in the Ames oio-
assay. However, a different type of bioassay showed mutagenic activity at a
methomyl concentration of 50 ppm. A potential product of the reaction of
methomyl with certain nitrogen compounds in the environment or in mammalian
systems is nitrosomethomyl, which is a potent mutagen, carcinogen, ana tera-
togen.
Methomyl is toxic to many aquatic organisms with 96-hour LC5Q levels
ranging from 0.1 to 3.4 ppm.
-------
METHOMYL
I. INTRODUCTION
Methomyl is a broad-spectrum insecticide used on many vegetables, field
crops, certain fruit crops, and ornamentals (3erg, et al. 1977). Introduced
by DuPont in 1966 as an experimental insecticide-nematacide (Martin and
Worthing 1974), methomyl -is now manufactured by DuPont and Shell (Stanford
Research Institute 197A) and used commercially as a foliar treatment to con-
trol aphids, army worms, cabbage looper, tobacco_budworm, tomato fruitworm,
cotton leaf perforator, and ballworm (Martin and Worthing 1974). About
three million pounds (1360 "tonnes) of methomyl were produced" in'the united
States in 1974 under the trade name Lannate® (Pest Control, 1975). Wastes
*
associated with methomyl production may contain methylene chloride. Metho-
myl formulations may contain pyridine as a contaminant (Sittig, 1977).
Methomyl is highly soluble in water. Its bioconcentration factor is 1.0;
octanol/water coefficient, 2.0 (see Table 1).
II. EXPOSURE
A. Water
Methomyl is considered stable in ground water ana decomposes at a
rate of less than 10 percent in 5 days in a river environment. In a lake
environment, methomyl decomposes at a rate of less than 85 percent per year
(U.S. EPA 1980).
B. Food
After the application of methomyl from 0.25 to 0.50 kilograms per
hectare (kg/ha) on tomatoes, plant residues were below 0.2 ppm.. Application
of 1 kg/ha left residues of 0.3, 0.13, and 0.06 ppm at 1, 2, and 3 days, re-
spectively, after spraying (Love and Steven, 1974). Methomyl applied at a
rate of 3 oz/acre (0.2 kg/ha) left a 17 ppm residue on rape plants immediate-
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TABLE 1. PHYSICAL AND CHEMICAL PROPERTIES OF METHOMYL
Synonyms: S-methyl N-(methylcarbamoyl)oxy)thioac3tamidate;
l-(methylthio)ethylideneamino methylcarbamate;
l-(methylthio)acetaldehyde 0-methylcarbamoyloxime;
methyl N-(((methylamino)carbonyl)oxy)ethanimidothioate;
CAS Registry No. (16752-77-5); OuPont 1179; Lannate;
Mesomile; Nudrin
Chemical Formula: (CH3S)(CH3)C=N-0(C=0)NHCH3
Molecular Weight: 162.2
Description: White crystal solid
Slight sulfurous odor
Soluble in organic solvents
24
Specific Gravity and/or DensityJ d = 1.2946
Melting and/or Boiling Points: nip 78 to 79QC -
Stability: Stable in aqueous solution .
Subject to decomposition in moist soil
Overall degradation rate constant (0.01/day)
Half-life approximately 50 days
Solubility (water): 5.3 g/ioo'ml at 25Qc
sediment . .5
H20 ' 1
Vapor Pressure: 5 x 10-5 mm Hg at 25°C
Bioconcentration Factor (BCF) and/or
Octanol/water partition coefficient (Kow): KQW =2.0
BCF = 1.0
Source: Martin and worthing, 1974; Fairchild, 1977;
Windholz, 1976, U.S. EPA, 1980.
X
- >U.^^
S*) I u u
-------
ly after application. This concentration declined rapidly to 1.5, 1.0, 0.4,
and 0.2 ppm, 1, 2, 5, and 9 days later, respectively. Methomyl resioues
were not detected (less than 0.02 ppm) in seed harvested 22 days after
application. Rape plant leaves collected after the application of methomyl
at 3 to 4 oz/acre (0.2-0.3 kg/ha) had 2.5 to 16 ppm residues (Lee, et al.
1972).
Methomyl has a half-life in plants of 3 to 7 days. Harvey (1975)
detected methomyl residue, its oxime, and small polar fractions one month
after application. Methomyl residue standards for crops are noted in the
Existing Guidelines and Standards Section of this report.
C. Inhalation and Dermal
Data are not available indicating the number of people exposed to
methomyl by inhalation or dermal contact. Most human exposure would appear
to occur during production and application. The U.S. EPA (1976) listed the
frequency of illness among occupational groups exposed to pesticides. In
1157 reported cases, most illnesses occurred among ground applicators (229)
and mixer/ loaders (142). The lack of or refusal to use safety equipment
was a major factor of this contamination, other groups affected were gar-
deners (101), field workers exposed to pesticide residues (117), nursery and
greenhouse workers (75), soil fumigators in agriculture (29), equipment
cleaners and mechanics (28), tractor drivers and irrigators (23), workers
exposed to pesticide drift (22), pilots (crop dusters) (17), and flaggers
for aerial application (6). Most illnesses resulted from carelessness, lack
of knowledge of the hazards, and/or lack of safety equipment. Under dry,
hot conditions workers tended not to wear protective clothing. Such condi-
tions also tended generally to increase pesticide levels and dust on the
»
workers.
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III. PHARMACOKINETICS
A. Absorption and Distribution
Methomyl is a highly water-soluble carbamate insecticide which can
be absorbed readily by moist mucous membranes or through the skin (Guerzoni,
et al. 1976). Methomyl applied to the skin is less toxic than methomyl ao-
ministered orally (Kaplan" and Sherman, 1977). Kaplan and Sherman (1977)
noted that there was no buildup of methomyl in fish after a 30-day feeding
study, indicating that methomyl was not distributed or retained in any one
specific organ of the body. In another study, there was ho cumulative oral
toxicity in rats (Harvey, et al. 1975). The investigators measured a total
clearance rate of less than 24 hours after oral administration of methomyl
%
to rats.
B. Metabolism
Harvey, et al. (1973) administered l4C-labeled methomyl to
rats. The radioactive methomyl was eliminated in the form of carbon ai-?
oxide, acetonitrile, and urinary metabolites. They noted the absence of
methomyl, S-methyl N-hydroxythioacetimioate, methyl S,S-aioxide,. and conju-
gates of the former two compounds. Radiolabeled methomyl administereo in
the rat by Huhtanen and Oorough (1976) also was metabolized to carbon dioxide
and acetonitrile. Carbon dioxide was also found in soils treated with
methomyl (Heywood 1975), without the presence of sulfoxide or sulfone (Baron
1978).
Han (1975) investigated the formation of nitrosomechomyl from
cured meats containing methomyl and residual sodium nitrite. The samples
were incubated under simulated stomach conditions (pH^) for 1 and 3
hours. Nitrosomethyl was not founo in the test material; the detection
limit was less than 1 ppb.
-------
C. Excretion
Methomyl is eliminated primarily through the urinary system
(Harvey, et al. 1975).
IV. EFFECTS
A. Carcinogenicity
No evidence of methomyl carcinogenicity was observed in tests with
rats and dogs (Kaplan and Sherman, 1977). LLjinsky and Schmaehl (1978) con-
cluded that if nitrosomethyl carbamates (nitrosomethomyl) were formed by the
reaction of the parent insecticide (methomyl) with nitrite in the environ-
ment or in the stomach, the carcinogenic risk of the parent compound could
increase.
In pesticide workers, two cases of embryonal cell carcinoma have
been associated with exposure, to methomyl and- three other pesticides
(carbaryl, paration, and dimethoate). One of the pesticide workers under-
went surgery for a testicular mass; the second worker died of metastatic em-
bryonal cell carcinoma. These cases led the authors to suggest that testi-
cular cancer may be related to agricultural chemical exposure (Prabhakar and
Fraumeni, 1978).
B. Mutagenicity
Blevins, et al. (1977) screened methomyl and its nitroso deriva-
tive for mutagenic activity. Using histidine auxotrophs of S^_ typhimurium
derived by Ames, they noted that methomyl, unlike its nitroso derivative,
did not cause a significant increase in the number of revertant colonies in
any of the strains used. Thus, while nitrosomethomyl appeared to oe a po-
tent mutagen, they considered methomyl to be non-mutagenic.
Guerzoni, et al. (1976) tested methomyl for mutagenic activity on
Saccharomyces cerevisiae. Methomyl was considered mutagenic at 50 ppm. The
-------
authors noted, however, that the mutagenic effect depended on the S^
cerevisiae strain.
C. Teratogenicity and Other Reproductive Effects
Methomyl was fed to pregnant New Zealand White raobits on days 3
to 16 of gestation. Teratogenic effects were not found at any of three die-
tary levels, 0, 50, and 100 ppm (Kaplan and Sherman, 1977). The same
authors also reported on a 3-generation, 6-litter reproduction study with
rats with the same dietary levels. Methomyl did not have adverse effects on
reproduction and lactation performance; in addition, pathological changes
were not observed in the third-generation weanling pups, using a model eco-
system, Howe (1978) did not see effects on quail egg production or egg fer-
tility from a diet of 10, 40, and 30 ppm methomyl.
Blevins, et al. (1977) treated normal human skin cells with six
insecticidal esters of N-
-------
0. Chronic Toxicity
Rats of both sexes were fed nutritionally complete diets con-
taining 0, 10,-50, 125, and 250 ppm of methomyl in a 90-day feeding study
and 0, 50, 100, 200., and 400 ppm of methomyl in a 22-month feeding study.
The weight gain for the high-dose males was significantly lower than that of
controls. No clinical, hematological, biochemical, urinary, or pathologic
evidence of toxicity was observed at 90 days. However, in the 22-month
study, decreased Hb values were noted in the two higher-dose female test
groups. A higher testis/body weight ratio was observed in the high-dose
males. Histopathologic alterations were observed in kidneys of male and
female rats receiving 400 ppm and in spleens of the female rats receiving
200 and 400 ppm of methomyl. Beagles of both sexes fed nutritionally com- •
plete diets containing 0, 50, 100, and 400 ppm of methomyi in 90-day and
2-year feeding studies showed no nutritional, clinical, urinary, or bio-
chemical evidence of toxicity. In the 2-year study, an additional dietary
level of 1000 ppm caused some clinical signs of toxicity and mortality.
Similar to findings in the 22-month feeding study in rats, histopathologic
changes were observed after 2 years in the kidney, spleen, and liver at the
two higher feeding levels. Dogs receiving the high-level diet showed a com-
pound-related anemia. Results of the long-term studies indicated that the
no-effect level for rats and dogs was 100 ppm (Kaplan and Sherman, 1977).
E. Other Relevant Information
Several incidents of acute occupational exposure have been re-
ported in the literature. In the first incident, four crews of fiela
workers harvesting vegetables and fruits treated with pesticides including
methomyl were studied. One crew had depressed blood cholinesterase activity
-------
after harvesting corn treated with methomyl. Forty-eight percent of another
crew had significant cholinesterase depression after harvesting treated
citrus, tomatoes, and gladiolas (Owens, et al. 1978).
A second incident involved 120 grape pickers where IQb displayed
symptoms suggesting pesticide poisoning. Methomyl and other cnolin-
esterase-inhibiting pesticides, such as dimethorate and torak, were named in
a legal complaint against the grower. The major symptoms claimed by the ex-
posed workers were headache, dermatitis, vomiting, nausea, fatigue, and eye
' pain (McClure, 1976).
Kumagaya, et al. (1978) reported on two cases of poisoning from
swallowing methomyl. The general symptoms were loss of consciousness, re-
spiratory failure, miosis, myofibrillary twitching, increase in airway se-
cretions, and reduced serum cholinesterase activity. Complications of pul-
monary edema, hepatitis, and polyneuritis were also observed.
The oral LD^ values for rats, mice, ducks, and wild biros have
been reported as 17, 10, 15, and 10 mg methomyl per kilogram body weight
(mg/kg), respectively. The oral LD5Q values for dogs, monkeys, guinea
pigs, and chickens are reportedly 30, 40, 15, and 15 mg/kg, respectively.
Inhalation i_C5Q values for rats, quails, and ducks are 77, 3680, and Ib90
ppm, respectively. The dermal LD5Q for rabbits is 5000 mg/kg. NO adverse
effects were noted when bootail quail and aloino rabbits were sprayed six
times (at 5-day intervals) with 1.1 kg/ha of a 90 percent formulation of
methomyl. Methomyl is relatively non-toxic to bees, once the spray has dried
(Fairchild, 1977; Martin and worthing, 1974).
Carbamate pesticides, such as methomyl, have cholinergic proper-
ties similar to those of the organic phosphates, out of shorter duration.
Methomyl inhibits both RBC and plasma cnolinesterase activity. The period
-------
of inhibition of the cholinesterases is approximately 1-2 hours, and re-
covery usually occurs between 24 and 48 hours after contact. Atropine ad-
ministration is the treatment of choice (Simpson and Bermingham, 1977).
V. AQUATIC TOXICITY
A. Acute and Chronic Toxicity
Methomyl 24-hour TLm (median toxic limit) values for carp
(Cyprinus carpio) and tilapia fish range from 1.054 to 3.16 mg/1 (El-Refai,
et al. 1976). The LC5Q (96-hour exposure) for rainbow trout (Salmo
gainneri) was 3.4 ppm; for bluegill (Lepomis macrochirus), 0.87 ppm; and for
goldfish (Carrasius auratus), greater than 0.1 ppm (Martin and Worthing,
1974). Following exposure (4-48 hours) of marine or estuarine fishes to
carbamate pesticide, the acetylcholinesterase activity in the brain was in-
hibited by 77 to 89 percent (Coppage, 1977).
B. Plant Effects and Residues
Pertinent data could not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The threshold limit value for air is established at 2.5 mg/m-3
(Fairchild, 1977). The Office of Water and Waste Management is in the pro-
cess of conducting preregulatory assessment of methomyl under the Safe
Drinking Water Act. The Office of Toxic Substances has promulgated regula-
tions for methomyl under Section 3 of the Federal Insecticide, Fungicide and
Rodenticide Act.
Methomyl residue concentrations in crops are regulated as
follows: 0.1 ppm for lentils and pecans; 1 ppm for forage, hay, barley
»
(grain), and oats (grain); 2 ppm for strawberries and avocados; 5 ppm for
Chinese cabbage; 6 ppm for blueberries, beets, collard, danoelions, kale,
-------
mustard greens, parsley, swiss chard, turnip greens, and watercress; 10 ppm
for wheat, rye, barley, and oats used as hay, straw, or forage; and 40 ppm
for bermuda grass hay (Federal. Register [43(98): 21700, 1978; 43 and (112):
25120, 1978; 44(63): 18972; 44(83): 24846; 44(129): 38844; 44(160): 47934,
and 44(227): 67117, 1979]);
B. Aquatic -
Guidelines or standards to protect aquatic life coulo not be lo-
cated in the available literature.
-------
REFERENCES
Baron, R.L. 1978. Terminal residues of carbamate insecticides. Pure Appl.
Chem. 50: 503.
Berg, Gil., et al., (ed) 1977. Farm Chemicals Handbook Meister Publishing
Company, Willoughby, Ohio.
Blevins, R.O., et al. 1977. Mutagenicity screening of five methyl car-
bamate insecticides and. their nitroso derivatives using mutants of
Salmonella typhimurium LT2. Mutat. Res. 56: 1.
Coppage, O.L. 1977. - Anticholinesterase action of pesticide carbamates in
the central nervous system of poisoned fishes. Physiological Response Mar.
Biota. Pollut. Proc. Symp. pg. 93.
El-Refai, A., et al. 1976. Toxicity of three insecticides to two species
of fish. Int.-Pest Control, 18: 4.
Fairchild, E.J. (ed.) 1977. Agricultural Chemicals and Pesticides: A sub-
file of the NIOSH Registry of toxic effects of chemical substances, U.S.
Dept. of HEW, July.
Guerzoni, M.E., et al. 1976. Mutagenic activity-of pesticides. Riv. Sci.
Tecnol. Alimenti. Nutr. Urn., 6: 161.
Han, J. C-Y, 1975. Absence of nitroso formation from (14-C) methomyl and
sodium nitrite under simulated stomach conditions. Jour. Agric. Food Chem.
23: 892.
Harvey, J.J., et al. 1973. Metabolism of methomyl in the rat. Jour. Agr.
Food Chem., 21: 769.
Harvey, J.J. 1975. Metabolism of aldicarb and methomyl. Environmental
Quality Saf., Suppl. Vol. 3, ISS Pesticides, 389.
Heywood, O.L. 1975. Degradation of carbamate insecticides in soil.
Environ. Qual. Saf., 4: 128.
Howe, G.J. 1978. The effects of various insecticides applied to a terres-
trial model ecosystem or fed in the diet on the serum cholinesterase level
and reproductive potential of coturnix quail. Oiss. Abstr. Int. 3.
38: 4785.
Huhtanen, K. and H.W. Dorough 1976. Isomerization.ana Beckman rearrange-
ment reactions in the metabolism of methomyl in.rats. Pest. Biochem.
Ftiysiol. 6: 571.
Kaplan, A.M. and H. Sherman 1977. Toxicity studies with methyl
N-(((methylamino)carbonyl)oxy)ethanimidothioate. Toxicol. Appl. Pharmacol.
40: 1.
XL
-------
Kumagaya, S., et al. 1978. Pesticide Intoxication. Yamaguchi Igaku
27: 211.
Lee, Y.M., et al. 1972. Residues of methomyl in rape plant ana seed
following its application for the control of bertha army worm, Mamestra
configurata Lepidoptera Noctuidae.
Lijinsky, w. and 0. Schmaehl 1978. Carcinogenicity of N-nitroso deriva-
tives of N-methylcarbamate insecticides in rats. Ecotoxicol. Environ. Saf.,
2: 413.
Love, J.L. and 0. Steven 1974. Methomyl residues on tomatoes. N ana J.
Exp. Agric., 2: 201. ••••-•
Martin and worthing (ed.), 1974. Pesticide Manual, 4th edition.
McClure, C.O. 1976. Public health concerns in the exposure of grape
pickers to high pesticide residues in Madera County, Calif. Public Health
Report-.93: 421, September.
Owens, C.O., et al. 1978. The extent of exposure of migrant workers to
pesticide and pesticide residues. Int. Jour. Chronobiol. 5: 428.
Pest Control 1975. pg. 314.
Prabhakar, J.M. and J.F. Fraumeni 1978. Possible relationship of insecti-
cide exposure to embryonal cell carcinoma. Jour. Am. Med. Assoc. 240: 288.
Simpson, G.R. and S. Birmingham 1977. Poisoning by carbamate pesticides. .
Med. Jour. Aust. 2: 148.
Sittig, M. 1977. Pesticides Process Encyclopedia, Chemical Technology
Review no. 81. Noyes Data Corporation, Park Ridge, N.J.
Stanford Research Institute. 1977. Directory of Chemical Producers. Menio
Park, California.
U.S. Environmental Protection Agency. 1976. Organophosphate Exposure from
Agricultural Usage, EPA 600/1-76-025.
U.S. Environmental Protection Agency. 1980. Aquatic Fate and Transport
Estimates for Hazardous Chemical Exposure Assessments. Environmental
Research Laboratory,. Athens, Georgia.
windholz, M. 1976. The Merck Index, Ninth Edition, Merck and Co., Inc.,
Rahvvay, N.J., USA.
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No. 126
Methyl Alcohol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in tha report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental inpacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
BIOLOGIC EFFECTS OF EXPOSURE
Extent of Exposure
Methyl alcohol, CH30H, also called methanol, is the first member of a
homologous series of monohydric aliphatic alcohols. At room temperature,
-' .
methyl alcohol is a colorless, neutral liquid possessing a mild distinctive
odor. [1] Additional chemical and physical properties of methyl alcohol
are presented in Table XIII-1. [2,3,4]
The greater part of methyl alcohol manufactured in the US is produced
synthetically. [5] One widely used synthetic process is the "medium
pressure process" which involves the reduction of carbon monoxide
(containing small amounts of carbon dioxide) with hydrogen. The reduction
step is carried out at 250-400 C and at 100-600 atmospheres pressure using
a catalyst. [1]
; " During the years 1968-»73, synthetic methyl alcohol production in the
US increased at an average annual rate of over 13.2%. In 1973, the
production of synthetic methyl alcohol amounted to slightly over seven
billion pounds, around one billion gallons. In addition, an estimated 10
million pounds (1.5 million gallons) of "natural" (eg, from wood
distillation) methyl alcohol were produced. [5]
Methyl alcohol is used in a variety of industrial processes. The
major use is in 'the production of formaldehyde which amounted to 39% of the
• r • '
methyl 'alcohol consumed in the US in 1973.. [5] "Other commercial uses of
methyl alcohol are in the production of chemical derivatives, such as
dimethyl terephthalate, methyl halides, methyl methacrylate, acetic a'cid,
and methylamines, and because of its solvent properties, methyl alcohol is
-------
also used in paints, varnishes, cements, and other formulations such as
inks and dyes. [1,5] Table XIII-2 lists the consumption of methyl alcohol
by product and quantity produced in the US for the year 1973. [5]
A. number of occupations with potential exposure to methyl alcohol are
listed in Table SLII-3. [6]
NIOSE estimates, .that approximately 175,000 workers in the US.,ara
ipotentially exposed to methyl alcohol:
EFFECTS ON HUMANS
Burk [26] attributed the toxic effects of methyl alcohol to
formaldehyde and formic acid, indicating that both compounds were oxidation
products of methyl alcohol. The author stated that the diagnosis of methyl
alcohol poisoning is sometimes very difficult, and would be more easily
verified by quantitative determinations of formic acid in the urine of
persons suspected of being poisoned with methyl alcohol.
^rcutaneous absorption of methyl alcohol can lead
to serious consequences, including death.. In 1968, Gimenez et al [27]
reported an analysis of 19 cases of children, ranging in age from 1.5
months to 4 years, who were poisoned as a result of having cloths soaked in
methyl alcohol applied to their, abdomens to relieve gastrointestinal
troubles or other unspecified complaints. There were 2 additional cases
reviewed in which both methyl and ethyl alcohols had been employed in this
way, making a total of 21 cases. Although absorption of methyl alcohol via
the resoiratory tract was possible in these cases, the fact that the cloths
were held in place by rubber baby pants would favor percutaneous absorption
of the alcohol as the significant route of exposure. The length of time
between application and onset of symptoms of intoxication was 1-13 hours
(7 1/4 hours average) . The aarly signs of intoxication were described* 'oy
the authors as central nervous system depression with 13 children having
-------
exhibited severe respiratory depression and U. of these having convulsions.
Slood pH in the 21 patients ranged from 6.4 to 7.38 (normal: 7.36-7.41
[23])> indicating acidosis in most cases. Twelve of the 21 children died
of cardiac or respiratory arrest 2-10 days after hospital admission. The
survivors recovered without apparent permanent damage. Papilledema and
. > .
ocular fundus bleeding were observed in 2 of the infants who subsequently
died. Abdominal skin lesions were present in 5 patients, 3 of the
erythematous type and '2 of the scaling type.^ The authors [27] commented
that while there was no relationship between methyl alcohol blood levels as
tested in 11 children (57-1,130 mg%) and prognosis, there was a
relationship between the initial blood pH and the subsequent course of the
illness. In general, treatment consisted of administering sodium
bicarbonate, glucose, ethyl alcohol, fluids, and electrolytes. Other forms
of treatment included peritoneal dialysis, exchange transfusion, mechanical
raspiration,. and the administration of anticonvulsant drugs. It must be
pointed out that the absorptive properties of the skin of infants are
probably different from those of adults and consequently infant
susceptibility to, and manifestations of, methyl alcohol intoxication may
not parallel those seen, in adults. :
In 1952, Leaf and Zatman [30] reported on experiments in which 5 male
voluntaers ingested 2.5-7.0 ml of methyl alcohol diluted to 100 ml with
water. These amounts of methyl alcohol corresponded to doses of 29-84
ing/kg. Two blood samples were taken from 3 subjects, 2-5 hours after the
ingestion. Urine was collected frequently for 11-16 hours following methyl
alcohol administration. Both the blood and urine samples were analyzed for
methyl alcohol by a colorimetric method based on the oxidation of methyl
alcohol to formaldehyde and formation of a colored complex with a modified
»
Schiff's reagent. The results of this experiment indicated that under
these conditions methyl alcohol was rapidly absorbed from the
gastrointestinal tract. The maximum methyl alcohol concentration in the
urine was achieved approximately one hour after ingestion and then
decreased exponentially. .. The ratio of blood to urine methyl alcohol
-------
concentrations remained almost constant for the 3 subjects in which it was
determined, and the authors [20] concluded that che change in the
concentration of methyl alcohol in the urine was an accurate .indicator of
the change in aethyl alcohol concentration in the body. At the levels used
in this experiment, the concentration of methyl alcohol in the urine
declined to control values within 13-16 hours after ingestion. Leaf and
Zatmaa [30] also stated'that only 0.4-1.2Z of the ingested methyl alcohol
I > •
was eliminated unchanged in the urine.
In another experiment in the same study, [30] 2 male volunteers
ingested 15 ml of ethyl alcohol and 4 ml of methyl alcohol simultaneously.
They then ingested 10 ml of ethyl alcohol every hour for the next 7 hours.
j .
The same individuals served as their own controls in a previous experiment
in which they ingested only 4 ml of methyl alcohol. Urine was collected
hourly and analyzed for methyl alcohol. The maximum urinary methyl alcohol
concentrations for those individuals who ingested both methyl alcohol and
ethyl alcohol were 8.82 and 9.20 mg/100 ml, compared to values of 6.05 and
5.50 mg/100 ml when methyl alcohol alone was ingested. Moreover, the total
amount of methyl alcohol excreted unchanged in the urine in the first 7
hours after ingestion was 107.1 tag and 125.5 mg (3.7 and 3.96% of the
administered dose respectively) when both methyl alcohol and ethyl alcohol
were ingested, whereas only from 18.2 to 30.8 mg (0.57-0.97% of the
administered dose) was excreted unchanged in a similar time period after
ingestion of 4 ml methyl alcohol alone. The authors [30] concluded that in
humans ethyl alcohol interfered, with the normal oxidation of methyl
alcohol, causing more of it to be excreted 'unchanged in the urine.
Moreover, according to the authors' conclusion, higher concentrations of
methyl alcohol in the blood are maintained in the presence of ethyl alcohol
at any given time after absorption, as compared to concentrations achieved
In che absence of ethvl alcohol.
-------
Ethyl alcohol may inhibit the oxidation of
methyl alcohol in vivo by competing (competitive inhibition) for the
alcohol dehydrogenase system. It is conceivable, therefore, that chronic
alcoholics might exhibit measurable concentrations of methyl alcohol in the
blood or urine even though they have not been exposed to methyl alcohol. L.3?J
In summary, an integration of in vitro [33-35] and in vivo studies
[29-31,37]- indicates that in humans methyl alcohol is oxidized primarily
by alcohol dehydrogenase. The results discussed in the section on Animal
Toxicity, however, suggest that in nonprimates methyl alcohol is oxidized
primarily by the catalase-peroxidase system.
. ANIMAL TOXICITY
Gilger and Potts [42] concluded from their studies that the results.
of oral administration of methyl alcohol to* rats, rabbits, and dogs
differed from those reported on humans in 4 important areas, namely, lethal
dose, time course of development and signs of intoxication, eye effects,
and acidosis. The authors also concluded that, following intoxication with
methyl alcohol, the responses of primates more closely approximated human
responses than, did those of nonprimates. An extensive review of the
literature dealing with the oral toxicity of methyl alcohol in humans and
nonprimates was supportive of their conclusion. The authors concluded that
the approximate lethal oral dose of methyl alcohol in humans (0.85-1.4
g/kg) was 1/3 the equivalent dose in monkeys and 1/9 the equivalent dose in
rats. Moreover, nonprimates exhibited severe early intoxication with
narcosis lasting until death whereas primates showed much less early
intoxication followed by a symptomless latent period, then by sickness and
death. The only eye changes observed with certainty in nonprimatea were
early pupillary changes and corneal opacities following exposure keratitis.
Some monkeys, however, and many humans developed partial or complete
i >'n->
.-• ) i > 7 "
-------
blindness accompanied by eyeground changes such as hyperemia of the optic
discs and venous engorgement. Finally, humans and monkeys often developed
severe acidosis (COZ-combining capacity less than 20 volumes 7,} after
methyl alcohol ingestion; this condition was rare in nonprimates and
occurred only at near lethal or lethal doses.
Correlation of Exposure and Effect
Well-documented studies that correlate environmental, levels of methyl
alcohol with observed toxic effects have not been found in the literature,
nor have any long-term epidemiologic studies of chronic low-level
occupational exposure been found.
Effects seen from either of the 2 most common routes of occupational
exposure (inhalation and percutaneous absorption) include: headache
[14,16,17,39]; dizziness [13,19]; nausea [16,17,26]; vomiting [17];
weakness (unspecified) [16]; vertigo [17,26]; chills [13]; shooting pains
in the lower extremities [13]; unsteady gait [17]; dermatitis [U];
multiple neuritis characterized by paresthesia, numbness, prickling, and
shooting pain in the back of the hands and forearms, as well as edema of
the arms [15]; nervousness [19]; gastric pain [19]; insomnia [19]; acidosis
[19]; and formic acid in the urine. [26] Eye effects,'such as blurred
vision, [16,17] constricted visual fields, [17,19,25] blindness, [13,25]
changes in color perception, [17] double vision, [19] and general visual
-------
disturbances [17] have been reported. Eye examinations have shown sluggish
pupils, [13,17] pallid optic discs, [13] retinal edema, [17] papilledema,
[26] ' hyperemia of the optic discs with blurred edges and dilated veins.
[17]
The study by Bennett et al [40] showed similar symptoms resulting
> •
from ingestion. These are acidosis, headache, visual disturbances,
dizziness, nausea and vomiting, severe upper abdominal pain, dilated and
nonreactive pupils. Eyeground examinations showed hyperemia of the optic
discs and retinal edema. The eyeground changes were almost always found in
acidotic patients. This finding is suggestive of a correlation between
acidosis and visual disturbances. However, a number of patients, with and
without acidosis, complained of visual disturbances. Additionally, blood
tests showed elevated serum amylase levels in 14 of 21 patients. This
finding in conjunction with complaints of upper abdominal pain and
pancreatic necrosis seen at autopsy led the authors [40] to conclude that
hemorrhagic pancreatitis resulted from acute methyl alcohol intoxication.
However, reports of acute hemorrhagic pancreatitis by parenteral routes
have-not been found.
Direct skin contact with methyl alcohol has been said to cause
dermatitis, [14] erythema, and scaling. [27] The reported variability in
susceptibility [14] is probably largely becaus.e of variations in tine of
contact with methyl alcohol; it is evident that sufficient -dermal contact
.,with any lip id solvent such as methyl alcohol has the potential for causing
skin irritation.
Basis for the Recommended Environmental Standard
Epidemiologic studies incorporating comprehensive environmental
surveys, well-planned surveillance, a sufficient study population, and
statistical analysis have not been found in the literature. It is
therefore difficult to recommend an environmental limit based upon
unequivocal scientific data... .
r '/rffl—
**?)//
-------
TABLES AND FIGURE
TABLE XIII-1
PHYSICAL AND CHEMICAL PROPERTIES OF METHYL ALCOHOL
Molecular formula
j
Formula weight
Apparent specific gravity at 20 C
Boiling point at 760 mmHg
Vapor pressure at 20 C
Melting point
Solubility in water
Solubility in alcohols, ketones, esters,
and halogenated hydrocarbons
Flash point, Tag open cup
Flash point, Tag closed cup
Flammable limits
(% in air)
Vaoor density
CH30H
32.04
0.7910
64.5 C
96 nmHg
-97.6 C
Miscible
Miscible
16 C
12 C
6.72-36.50
1.11
(air-1)
Corrosivity
Conversion factors
(760 tnmHg and 25 C)
Noncorrosive at
normal atmospheric
temperatures.
Exceptions: lead and
aluminum
1 ppm-"l.310 mg/cu m
1 mg/cu o».763 ppm
Adapted from ANSI 237 [2], Che Manufacturing Chemists Association [3],
and the Handbook of Chemistry and Physics [4]
ISL
-------
f
i."
I
*
TABLE XIII-2
US METHYL ALCOHOL CONSUMPTION, 1973
-
Formaldehyde
Dimethyl terephthalate
Solvent usage
Methyl halides
Methylamines
Methyl methacrylate
Inhibitor for formaldehyde
Exports
Glycol methyl ethers
Acetic acid
Miscellaneous
Total
Million Pounds
2,778
435
565
435
232
265
66
824
81
240
1,207
7,128
Million Gallons
420
66
85
66
35
40
10
124
12
36
181
1,075
From Blackford [5]
I-It
-------
TABLE XIXI-3
POTENTIAL OCCUPATIONAL EXPOSURES TO METHYL ALCOHOL
Acetic acid makers
Adhesive workers
Alcohol distillery workers
Alcohol lamp users
Aldehyde pumpmen
Antifreeze workers
Art glass workers
Automobile painters
Aviation fuel handlers
Bookbinders
Bronzers
Brushmakers
Denatured alcohol workers
Dimethyl sulfate makers
Drug makers
Drycleaners
Dye makers
Dyers
Ester makers
Explosives workers
Feather workers
Felt-hat makers
Flower makers, artificial
Formaldehyde makers
Foundry workers
Furniture polishers
Gilders
Glassmakers, safety
Hectograph operators
Incandescent lamp makers
Inkmakers
Japan makers
Japanners
Jet fuel workers
Lacquerers
Lacquer makers
Lasters
Leather workers
Linoleum makers
Lithographers
Metal polishers
Methyl acrylate makers
Methyl alcohol workers
Methyl amine makers
Methylation workers
Methyl bromide makers
Methyl chloride makers
Methyl methacrylate makers
Millinery workers
Motor fuel blenders
Organic chemical synthesizers
Painters
Paintmakers
Paint remover workers
Patent leather makers
Perfume makers
Photoengravers
Photographic film makers
Polish makers
Printers
Rayon makers
Resin makers
Rocket fuel handlers
Rocket fuel makers
Rubber shoe cementers
Rubber workers
Shellackers
Shellac makers
Shea factory workers
Shoe finishers
Shoe heel coverers, wood
Shoe stitchers
Soapmakers
Straw-hat makers
Sugar refiners
Textile printers
Type cleaners
Vacuum tube makers
Varnish workers
Vulcanizers
Wood alcohol distillers
Wood stainers
Wood stain makers
From Gafafer [6]
-------
TABLE XIII-4
ANIMAL EXPERIMENTATION RESULTS
OF METHYL ALCOHOL EXPOSURE
Species
Route of
Exposure
Dose
Effect
Ref-. .
erence
Monkeys
Inhalation
5,000 ppm
duration
unknown
The monkey survived for
an unstated period of time.
47
1,000 ppm
duration
unknown
The monkey died promptly 47
upon exposure at this level.
Dogs
450-500 ppm
8 hr/day
7 days/week
for 379 days
Blood levels of methyl
alcohol were found to range
from 10 to 15 mg/100 ml
of blood and on occassion
went as high as 52 rag/100 ml.
No abnormal eye findings
were reported.
41
Oral
2.5 to 9.0 Of the 9 treated dogs, 2
g/kg died at doses of 4 and
body weight 9 g/kg. C02 combining
capacities dropped below
normal in 2 dogs, and no
ophthalmoscopic changes
were noted.
42
-------
TABLE XIII-4 (CONTINUED)
ANIMAL EXPERIMENTATION RESULTS
OF METHH. ALCOHOL EXPOSURE
Species
Route of
Exposure
Dose
Effect
Ref-
erence
Monkeys
Oral
1.0 to 3.0 Acidosis developed in
g/kg monkeys receiving doses
ranging from 3.0 to 6.0
g/kg. The animal receiving
1.0 g/kg did not develop
acidosis. Definite eye-
ground change occurred to
2 of the acidotic monkeys.
42
Rats
4.75 g/kg 70% mortality 42
4.5 g/kg None of the 9 tested rats 42
developed acidosis.
Rabbits
3.5 g/kg One animal receiving this
dose died in less than 24
hours. No eye fundus
changes were reported.
42
Rabbits
2.1 g/kg Of the 3 animals tested at 42
this dose, all died between
24 hours, and 3 days after
dosing.
Intra- 10 ing and At 10 nig, there was no skin 49
cutaneous 35 mg reaction, .whereas at 35
mg, a 9-sq mm skin reaction
occurred.
-------
TABLE XIII-4 (CONTINUED)
ANIMAL EXPERIMENTATION RESULTS
OF METHYL ALCOHOL EXPOSURE
Species
Route of
Exposure
Dose
Effect
Ref-
erence
Monkeys
i.p. inj
0.5 g/kg of
14 C-methyl
alcohol with
an equimolar
amount of
ethyl al-
cohol
The ethyl alcohol reduced
the oxidation of methyl
alcohol 90%.
52
1.0 g/kg The methyl alcohol was
14 C-methyl oxidized at a rate of
alcohol and 37 mg/kg/hour between the
6.0 g/kg first and fourth hour. The
14C-raethyl C02 formation was linear at
alcohol the high dose; the oxidation
rate was 47 mg/kg/hour which
is a significant difference.
52
Rats
1.0/kg 14C- The oxidation rate of the 51
methyl methyl alcohol was 24 mg/kg/hr
alcohol for the first 28 hours. At
the end of 36 hours 77% of
the methyl alcohol had been
oxidized to 14C-labled C02
and 24% was excreted unchanged
in approximately equal amounts
by the pulmonary' and combined
urinary and fecal routes.
-------
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Recommended Practice, ed 13. Lansing, Michigan, ACGIH, 1974
78. American National Standards Institute: Fundamentals Governing the
Design and Operation of Local Exhaust Systems, Z9.2-1971. Mew York,
American National Standards Institute Inc, 1971
79. Bowditch M, Drinker CK, Drinker P, Haggard HH, Hamilton A: Code for
safe concentrations of certain common toxic substances used in
industry. J Ind Hyg Toxicol 22:251, 1940
80. Cook WA: Maximum allowable concentrations of industrial atmospheric
contaminants. Ind Med 14:936-46, 1945
81. Methyl alcohol (methanol), AIHA Hygienic Guide Series. Southfield,
Michigan, American Industrial Hygiene Association, 1964
82. American Conference of Governmental Industrial Hygienists, Committee
on Threshold Limit Values: Documentation of Threshold Limit Values
for Substances in Workroom Air, ed 3. Cincinnati, ACGIH, 1971, pp
155-56
83. American Conference of Governmental Industrial Hygienists: .TLVs—
J Ji Threshold Limit Values for Chemical Substances and Physical Agents in
the Workroom Environment with Intended Changes for 1974. Cincinnati,
ACGIH, 1974
84. Winell MA: An international comparison of hygienic standards for
chemicals in the work environment. Ambio 4:34-36, 1975, p 2J
/3.6-3-f
-------
85. Smelyanskiy ZB, Ulanova IP: [New standards for peraissible levels of
coxic gases, fumes, dust in che air of work areas.] Gig Tru Prof
Zabol 5:7-15, 1959 (Rus)
86. Czechoslovakia Committee of HAG (J Teisinger, chmn): Documentation
of MAC in Czechoslovakia. Prague, June 1969, pp 114-15
87. Elkins, HB, in Patty FA (ed): Industrial Hygiene and Toxicology, rev
ed 2; Toxicology (Fassett DW, Irish DD, eds). New York, Interscience
Publishers, 1963, vol 2, pp 1409-22,
88. Methyl alcohol (methanol), AIHA Hygienic Guide Series. Southfield,
Michigan, American Industrial Hygiene Association, 1964
•
89. Methanol—Storage and Handling. Wilmington, Delaware, du Pont de
Nemours Ca, W74, 10 pp
90. National Electric Code 1975, NFPA No. 70-1975. Boston,
Massachusetts, National Fire Protection Association, 1975
91. American National Standards—Occupational and Educational Eye and
Face Protection, Z87.1. New York, American National Standards
Institute Inc, 1968
' ~s ' ^
*•"'/_!) /<*.
-------
No. 127
S,S'-Methylene - 0,0,0',o'-Tetraethyl Phosphorodithioate
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracv.
i i~
*«*Tj / /'
-------
PHOSPHORODITHOIC ACID,
S,S'-METHYLENE,0,0,0',0'-TETRAETHYL ESTER (ETHIQN)
Summary
The S,S'-methylene,0,0,0',0'-tetraethyl ester of phosphorodithoic acid,
ethion, has not shown mutagenic effects in mice or teratogenic effects in
fowl. Subcutaneous injection of the compound into atropinized chickens pro-
duced neurotoxic effects. There is no available information on the possible
carcinogenic effects of ethion.
Ethion has shown acute toxicity in stonefly naiads at a 96-hour LC5Q
range from 1.8 to 4.2 jjg/1.
J3.7-J
-------
I. INTROOUCTON
0,0,0',0'-Tetraethyl-S,S'-methylene bisphosphorodithioate (CAS registry
number 563-12-2), also called ethion, is an insecticide and miticide made
from phosphorus pentasulfide (SRI, 1976). Ethion has the following physical
and chemical properties -(Windholz, 1576; FAQ, 1569):
Formula: C9H22°4P2S4
Molecular Weight: 384.48
Melting Point: -12°C to -13°C
Density:. 1.22020
Vapor Pressure: Practically non-volatile at
ordinary temperatures
Solubility: Insoluble in water, soluble in
organic solvents
Consumption: 0.7 million Ibs/year (SRI, 1576)
Ethion is a pre-harvest topical insecticide used primarily on citrus
fruits, deciduous fruits, nuts and cotton (SRI, 1976). It is also used as a
cattle dip for ticks and 'as a back-line treatment for buffalo flies (FAO,
1969):
'll. EXPOSURE
A. Water
Pertinent data could not be located in the available literature.
Water contamination from ethion manufacturing may be minimal due to the com-
mon use of industrial wastewater treatment plants (U.S. EPA, 1977).
3. Food
Residues on a variety of foods have been reported (FAO, 1969). A
sampling shows the residues on fruits and vegetables .range from 10.4 ppm for
raisins to less than 0.1 ppm for almonds. The majority are less than 1 ppm.
Treated cotton showed no residue in the seed. Tea at harvest showed 'resi-
dues of up to 7 ppm; since tea is blended prior to sale, residues are lower
-------
when consumed. Lactating cows fed up to 20 ppm radioactive ethion showed no
residues in their milk. In meat, the highest radioactivity was in the
liver; however, chemical analysis showed these residues were not ethion but
metabolites. , When animals were dipped, residues from' skin absorption of
ethion were found in the body fat.
C. Inhalation and Dermal
Pertinent data could not be located in the available literature.
III. PHARMACOKINETICS
A. Absorption
Results of acute toxicity studies in animals indicate that ethion
is absorbed following oral and dermal exposure (Gaines, 1969).
3. Distribution
Following feeding of dairy cattle with ethion, small amounts of
the unchanged compound were found in milk and fatty tissues (Vettorazzi,
1976) . '
C. Metabolism
Rao and McKinley (1969) have reported that _in_ vitro metabolism of
ethion occurs through oxidative desulfuration of the compound by chicken
liver homogenates.
D. Excretion
Pertinent data could not be located in the available literature.
Based on studies of other organophosphorous insecticides, it may be antici-
pated that ethion metabolites would be eliminated primarily in the urine
(Matsumura, 1975).
IV . EFFECTS
A. Carcinogenicity
Pertinent data could not be located in the available literature.
-------
8. Mutagenicity
Vettorazzi (1976) has cited an unpublished study which found no
dominant lethal effects in mice administered ethion.
C. Teratogenicity
Oral administration of ethion (100 ppm) to chickens, chukars, and
quail failed to produce teratogenic or adverse reproductive effects (Abbott
and Walker, 1972).
0. Other Reproductive Effects
Oral feeding of ethion to chickens, chukar, and quail failed to
affect egg hatch (Abbott and Walker, 1972).
E. Chronic Toxicity
Subcutaneous injection of atropinized chickens with 400 mg/kg eth-
ion produced neurotoxic effects '(flaccid paralysis) (Gaines, 1969). Ethion
will produce anti-cholinesterase effects in mammals (Vettorazzi, 1976),
V. AQUATIC TOXICITY
A. Acute Toxicity
Sanders and Cope (1968) observed 96-hour LCCQ values ranging
from 1.3 to 4.2 ug/1 for stonefly naiads (Pteronarcys califomica) exposed
to ethion.
3. Chronic Toxicity, Plant Effects and Residues
Pertinent data could not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The World Health Organization (FAO, 1969) 'has established an ADI
level of 0.005 mg/kg for ethion based on cholinesterase inhibition studies.
' 9. Aquatic
Pertinent data could not be located in the available literature.
/ S\a
/ _> I Q *
7
I2.T-B
-------
REFERENCES
Abbott, U. and N. Walker. 1972. Effects of pesticides and related com-
pounds on several avian species, chemistry and toxicology of agricultural
chemicals. Summary Report 1971. Food Protection and Toxicology Center.,..
University of California at Davis, p. 9.
Food and Agriculture Organization/World Health Organization. 1969. Evalua-
tions of some pesticide residues in food. The monographs FAO/WHO/Pl:1968/-
M/9/1.
Gaines, T. 1969. Acute toxicity of pesticides. Toxicol. Appl. Pharmacol.
14: 515.
Matsumura, F. 1975. Toxicology of Insecticides. Plenum Press, New York.
p. 223.
Rao, S. and w. McKinley. 1969. Metabolism of organophosphorus insecticides
by liver homogenates from different species. Can. Jour. Biochem. 47: 1155.
Sanders, H.O. and 0.8. Cope. 1968. The relative toxicities of several pes-
ticides to naiads of three species of stoneflies. Limnol. Oceanogr.
13: 112.
Stanford Research Institute. 1976. Chemical Economics Handbook, Insecti-
cides..
U.S. EPA. 1977. Industrial process profile for environmental use: chapter
8, pesticides industry. U.S. Environ. Prot. Agency, U.S. NTIS PB 266 225.
Vettorazzi, G. 1976. State of the art of the toxicological evaluation car-
ried out by the joint FAO/WHO meeting on pesticides residues. II. Carbamate<
and organophosphorus pesticides used in agriculture and public health.'
Residue Reviews. 63: 1.
Windholz, M. (ed.) 1976. The Merck Index, 9th ed. Merck and Co., Inc.,
Rahway, New Jersey.
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No. 128
Methyl Ethyl Ketone
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-J *s* A -
J y ^^
/a ?-
-------
. DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
> r*>'i.it--
y j ^i
-------
SJ-27-10
Methyl Ethyl Ketone
I. INTRODUCTION
Methyl 'ethyl ketone or (MEK) as it is commonly referred
to i3 a clear, colorless, volatile liquid (VP of 100 mm at 25°C)
with a molecular weight of 72.12. It has a melting point of
-86.35°C and a boiling point of 76.6°C. It is very soluble
in water (25.5 g/loo at 2 percent) and soluble in all
proportions in alcohol, ether, acetone and benzene.2 it is
also highly flammable (22"? - open cup).3
MEK is produced and used as a solvent in nitrocellulose
coatings and vinyl films; in the synthesis of colorless
resins; in the manufacture of smokeless powder; in paint
removers, cements, adhesives, and cleaning fluids; in printing
industry; as a catalyst carrier; in lube oil dewaxing and in
acrylic coatings.^
II. ROUTES OP EXPOSURE
MEK is rapidly absorbed through Che skin by inhalation.
III. PHA&MACOKINETICS
MEK occurs in trace amounts in normal human urine and
may have a dietary origin.^ Most probable precursor is
- methylacetoacetic acid.^-
Urine of rabbits exposed to MEK reported to contain
glucuronide of 2-butanol.3-
IV . EFFECTS ON MAMMALS
The chief effect of MEK is narcosis but is also a strong*
irritant of the mucous membranes of the eyes and nose. The
oral LD50 for rats is 3.3 g/kg and the inhalation LC50 is
/2.S--.3
-------
around 700 ppm.l
Repeated exposure of guinea pigs for 12 weeks to 235 ppm
caused no symptoms.^
Lethal doses in animals caused marked congestion of
internal organs and slight congestion of brain. Lungs showed
emphysema (see Table 1) .
Slight throat irritation in humans occured at 100 ppm
and in eyes at 200 ppm.
Dermatoses among workers having direct contact and
exposed to vapors are not uncommon. Some workers complained
of numbness of fingers and arms.-'-
-------
Table 1
Effects of Methyl Ethyl Ketone on Animals
Concentration/
Duration
Animal
Methyl
Ethyl
Ketone
33,000-100,000 ppm/200 tain. Guinea Pigs
3,300 ppm/810 min.
1,125 ppm/24 hr/3,55d
1,126 or 2,618 ppm/7 hr/d
on d 6-15 of gestation
Guinea Pigs
Rats
Pregnant
Rats
Effects
Gasping, death,
emphysema, slight
congestion of the
brain, marked
congestion of the
systemic organs
especially the
lungs and corneal
opacities
No abnormal signs
No evidence of
peripheral neuro-
pathy
Embryo toxicicy,
facotoxicity and
possible terato-
genicity
-------
References
1. Toxicity and Metabolism of Industrial Solvents.
2. Ketonic Solvents, Open File Report, Working Draft prepared
by Clement Associates, Inc., September 19, 1978.
3. Sax, N. Irving, Dangerous Properties of Industrial Materials,
Fourth Edition, '1975, Van Nostrand Reinhold, New York,
New York 10001
4. Patty, F. A., Schrenk, H. H., Yant W. P.: Acute Respone of
guinea Pigs to Vapors of Some New Commercial Organic
Compounds—VIII. Butanone. U.S. Public Health Pep 50:
1217-28, 1935.
5. Spencer, P. S., Schaumburg, H. H. : Feline Nervous System
Response to Chronic Intoxication With Commercial Grades
of Methyl n-Butyl Ketone, Methyl Isobutyl Ketone, and
Methyl Ethyl Ketone. Toxicol. Appl. Pharmacol. 37:301-11,
1976.
6. Griggs, J. H. , Waller, E. M. , Palmisano, P. A., Niedermeier,
W.: The Effect of Noxious Vapors on Embryonic Chick Develop-
ment, Ala. J Med. Sci. 8:342-45, 1971.
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No. 130
Methyl Methacrylate
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
METHYL METHACRYLATE
Summary
Oral or skin painting studies in rats have failed to show carcinogenic
effects of administration of methyl methacrylate. Implantation of the com-
pound in mice also failed to produce tumors.
Exposure of rats to a mixture of chloroprene and methyl methacrylate
produced an increase in lymphocyte chromosome aberrations. Increased chrom-
atid breaks and chromosome breaks have been reported in workers exposed to
this same chemical mixture.
Teratogenic effects (hemangiomas) have been reported following intra-
peritoneal administration of methyl methacrylate to pregnant rats. Inhala-
tion exposure of pregnant rats to an acrylic cement containing methyl metha-
crylate failed to produce significant teratogenic effects.
Ninety-six hour LC5Q values for four species of fish range from 159
to 368 ppm. Inhibition of cell multiplication of an alga begins at 120 ppm.
s
730-3
-------
I. INTRODUCTION
Methyl methacrylate, CAS registry number 80-62-6, is a colorless,
clear, volatile liquid. It is made from acetone cyanohydrin which is hydro-
lyzed in sulfuric acid to yield methacrylamide sulfate, which is then treat-
ed with methanol to yield methyl methacrylate. It has the following physi-
cal and chemical properties (Windholz, 1976; Hawley, 1971; Weast, 1972;
Verschueren, 1977):
Formula: C5H802
Molecular Weight: 100.12
Melting Point:. -48.2°C
Boiling Point: 101°c
Density: 0.944020
Vapor Pressure: 28 torr 1 20°C
Solubilityr Sparingly soluble in water, miscible
in alcohol, benzene, ether, etc.
Production: 706 million Ibs (1973) (Gruber, 1975)
virtually all the methyl methacrylate produced in this country is used
for polymers, e.g., surface coating resins and plastics (plexiglass, lu-
cite), ion exchange resins, dentures, etc.
II. EXPOSURE
A. Water
According to Gruber (1975), about 1.8 g of methyl methacrylate per
kilogram final product (methyl methacrylate) is present in wastewater. The
amount of methyl methacrylate entering domestic, water supplies is probably
small.
B. Food
Polymethyl methacrylate is used for food storage. A very .small
amount of residual monomer may migrate into food from the polymer.
If
-------
C. Inhalation
Fugitive emissions from production, storage, and transportation
probably constitute the only major sources of methyl methacrylate in the
air. The concentration would most likely be highest in production facili-
ties. Production was estimated to be 7.9 million pounds in 1974 (U.S. EPA,
1976). A 550-million pound-per-year production facility with 0.5 percent
loss emits 39.6 grams of methyl methacrylate per second. If this is consi-
dered to be a virtual point source, the downwind concentration 500 meters
avray would be 1.5 ppm one-hour average (U.S. EPA, 1976).
0. Dermal
Pertinent data could not be located in the available literature.
III. PHARMACQKINETICS
A. Absorption and Distribution
Pertinent data could not be located in the available literature.
3. Metabolism
Bratt and Hathway (1977) found that up to 88 percent of a single
methyl(^C) methacrylate dose of 5.7 mg/kg body weight was expired as C07
within 10 days. Neither- the route of administration nor the specific label-
ling of the propylene residue changed this value. Small amounts of several
metabolites were excreted in the urine, including i4C-methylmalonate,
^•4C-succinate, 2-formylpropionate, and possibly ^C-/-hydroxybutyrate.
Corkill, et al. (1976) found that the disappearance of methyl
methacrylate in human blood _!£ vitro showed a first order dependence on
methyl methacrylate concentration. The calculated half-life was 20 to 40
minutes, irrespective of the sex or age of the blood donor. More than 40
percent of the initial dose of methyl methacrylate was converted to metha-
crylic acid within 90 minutes.
no-s
-------
C. Excretion
Pertinent data could not be located in the available literature.
IV. EFFECTS
A. Carcinogenicity
The International Agency for Research on Cancer (IARC, 1979) has
evaluated the available data and concluded that there is not enough informa-
tion to determine the potential carcinogenicity of methyl methacrylate to
humans. Borzelleca, et al. (1964) observed no treatment-related tumors in
male and female Wistar rats administered 6, 60, or 2,000 mg/1 methyl metha-
crylate in their drinking water for two years. Oppenheimer, et al.. (1955)
found no local tumors in ten Wistar rats painted with methyl methacrylate
three times per week for four months and"observed for their entire life span.
Another study, by Spealman, et al. (1945), in which male and
female mice received implants consisting of 0.075 gm of methyl methacrylate
in a gelatin capsule also yielded negative results.
8. Mutagenicity '
The only data available on the mutagenic effects of methyl metha-
crylate are two studies involving exposure to a mixture of chloroprene and
methyl methacrylate (Bagramjan, et al. 1976; Bagramjan and Babajan, 1974).
In both studies, an increased frequency of chromosomal aberrations were
found in rats exposed to the mixture. Bagramjan, et al. (1976) also mea-
sured a significant increase in chromatid breaks and chromosome breaks in
the lymphocytes of workers exposed to a mixture of chloroprene and methyl
methacrylate.
C. Teratogenicity
Singh, et al. (1972a,b) and Autian (1975) injected intraperito-
neally three groups of pregnant Sprague-Oawley rats with methyl methacrylate
at doses of 0.1, 0.2, or 0.4 g/kg body weight on days 5, 10, and 15 of ges-
-------
cation. In animals administered the two higher doses, a significantly
greater number of hemangiomas were seen at various sites. All three groups
exhibited reduced fetal, weights, but no significant increase in skeletal
defects was observed in any group.
McLaughlin, et'al. (1978) exposed pregnant mice to a vapor concen-
tration of 1,330 ppm methyl methacrylate (as acrylic cement, Simplex p) for
two hours two times per day for days 6 through 15 of gestation. No feto-
toxic'or teratogenic effects were noted other than a slight decrease in the
average fetal weight.
0. Other Reproductive Effects
Pertinent data could not be located in the available literature. .
E. Chronic Toxicity
Spealman, et al. (1945) conducted a series of sub-chronic
inhalation ex- periments involving guinea pigs, and dogs. Guinea pigs
exposed to 39.0 mg/1 methyl methacrylate for two hours per day for three
days exhibited significant liver degeneration, while dogs exposed to 46.3
mg/1 methyl methacrylate for two hours per day for 8 to 15 days exhibited
liver degeneration and tubular degeneration of the kidneys.
Sorzelleca, et al. (1964) administered 6, 60, and 2,000 ppm of
methyl methacrylate in drinking water to male and female rats for a period
of two years. Weight gain was decreased for the first few weeks in animals
given the highest dose. No changes in hematological values or urine concen-
trations of protein and reducing agents were noted.. Females receiving the
highest dose level exhibited an increase in kidney to 'body weight ratios.
Blagodatin, et al. (1970) reported symptoms of headache, pain in
the- extremities, fatigue, sleep disturbance, loss of memory, and irritabi-
lity in 152 workers exposed to concentrations of 0.5 to 50 ppm methyl metha-
crylate. Most of the workers had been employee for longer than 10 years.
]^^£r
"f J J U "'
S30-7
-------
F. Acute Toxicity
No detectable acute effects were noted in workers employed in
manufacturing polymethyl methacrylate sheets (Cromer and Kronoveter, 1976).
The airborne concentrations of methyl methacrylate varied from 4 to 49 ppm.
V. AQUATIC TOXICITY .
A. Acute Toxicity
Pickering and Henderson (1966) observed the fallowing 96-hour
^50 va^ues f°r fish exposed to methyl methacrylate: fathead minnow
(Pimephales. promelas) - 159 ppm in soft water (20 mg/1); fathead minnow -
311 ppm in hard water (360 mg/1); bluegill (Lepomis macrochirus) - 357 ppm
in soft water (20 mg/1); goldfish (Carassius auratus) - 277 ppm in soft
water (20 mg/1); guppies (Lebistes retieulatus) - 368 ppm in soft water (20
mg/1).
B. Chronic Toxicity
Pertinent data could not be located in the available literature.
C. Plant Effects
Inhibition of cell multiplication of the alga, Microcystis aerugi-
nosa, by methyl methacrylate begins at 120 ppm (Bringmann and Kuhn 1976).
D. Residues
Pertinent data could not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
Guidelines have been established for exposure to methyl methacry-
late by the American Conference of Governmental Industrial Hygienists and
QSHA. Both the TLV and the federal standard have been set at 100 ppm (or
410 mg/rn3) (ACGIH, 1977; 29 CFR 1910).
-------
B. Aquatic
No guidelines have been established for the protection of aquatic
organisms from acute or chronic methyl methacrylate toxicity because of the
lack of pertinent data.
-------
REFERENCES
American Conference of Governmental Industrial Hygienists. 1977. Threshold
limit values for chemical substances and physical agents in the workroom
environment. Cincinnati, Ohio.
Autian, J.' 1975. Structure-toxicity relationships of acrylic monomers.
Environ. Health Perspect. 11: 141.
Bagramjan, S.B.. and E'.A. Babajan. 1974. Cytogenetic study of the mutagenic
activity of chemical substances isolated from Nairit latexes MKH and LNT-1.
(Russ.) Biol. Zh. Arm. 17: 102.
"Bagramjan, S.B., et al. 1976. Mutagenic effect of small concentrations'of
volatile substances emitted from polychloroprene latexes LNT-1 and MKH, dur-
ing their combined uptake by the animal. (Russ.) Biol. Zh. Arm. 19: 98.
Blagodatin, V.M., et al. 1970. Issues of industrial hygiene and occupa-
tional pathology in the manufacture of organic glass. (Russ.) Gig. Tr.
Prof. Zabol. 14: 11.
Borzelleca, J.F., et al. 1964. Studies on the chronic oral toxicity of
monomeric ethyl aerylate and methyl methacrylate. Toxicol. Appl. Pharmacol.
6: 29.
Bratt, H. and O.E. Hathway. 1977. Fate of methyl methacrylate in rats.
Br. Jour. Cancer. 36: 114.
Bringmann, G. and R. Kuhn. 1976. Vergleichende Befunde der Schadwirkung
wassergefahrdender Stoffe genen Bakterien (Speudomonas putida) und Blaualgen
(Microcystis aeruginosa). Nwf-Wasser/Abwasser, (117) H.9.
Corkill, J.A., et al. 1976. Toxicology of methyl methacrylate: The rate of
disappearance of methyl methacrylate in human blood i.n vitro. Clinica Chim-
ica Acta. 68: 141.
Cromer, J. and K. Kronoveter. 1976, A study of methyl methacrylate expo-
sures and employee health. National Institute for Occupational Safety and
Health, Cincinnati, Ohio. DHEW 77-119.
Gruber, G.I. 1975. Assessment of industrial hazardous waste practices,
organic chemicals, pesticides, and explosive industries. TRW Systems Group,
NTIS PB-251 307.
Hawley, G.G. (ed.) 1971. The Condensed Chemical Dictionary. 8th ed., Van
Nostrand Reinhold Co., New York.
International Agency for Research on Cancer. 1979. IARC monographs on the
evaluation of the carcinogenic risk of chemicals to humans. Vol. 19,.Methyl
methacrylate: 187.
McLaughlin, R.E., et al. 1978. Methyl methacrylate: a study of teratogeni-
city and fetal toxicity of the vapor in the mouse. Jour. Bone Jt. Surgery
Am. Vol. 60A: 355.
-------
Oppenheimer, 3.S., at al. 1955. Further studies of polymers as carcino-
genic agents in animals. Cancer Res. 15: 333.
Pickering, Q.H. and C. Henderson. 1966. Acute toxicity of some important
petrochemicals to fish. Jour. Water Poll. Con. Fed. 38: 1419.
Singh, A.R.', et al. 1972a. Embryonic-fetal toxicity and teratogenic ef-
fects of a group of methacrylate esters in rats. Jour. Dent. Res. 51: 1532.
Singh, A.R., et al. 1972b. Embryo-fetal toxicity and teratogenic effects
of a group of methacrylate esters in rats (Abstract No. 106). Toxicol.
Appl. Pharmacol. 22: 314. .
Spealman, C.R., et al. 1945. Monomeric methyl methacrylate: Studies • on
toxicity. Ind. Med. 14: 292.
U.S. EPA. 1976. Assessment of methyl methacrylate as a potential air pol-
lution problem. U.S. Environ. Prat. Agency, NTIS P8-258 361.
verschueren, K. 1977. Handbook of Environmenal Data, on Organic Chemicals.
Van Nostrand Reinhold Co., New York.
Weast, R.C. 1972. Handbook of Chemistry and Physics. 53rd ed., Chemical
Rubber Company, Cleveland, Ohio.
Windholz, M. (ed.) 1976. Merck Index. 9th ed., Merck and Co., Inc., Rah-
way, New Jersey.
I 3 o-lt
-------
No. 131
Naphthalene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
NAPHTHALENE
Summary
Naphthalene is present in ambient water as well as drinking water.
Naphthalene can be absorbed by any route, although the efficiency of
absorption has not been determined. The toxicological properties are due
to the formation of highly reactive metabolites. Chronic exposure produces
cataracts, hemolytic anemia, and kidney disease. Naphthalene can cross
the placenta and produce these effects on newborns. Naphthalene has been
found to be nonmutagenic in several microsomal/bacterial assay systems.
Chronic toxicity studies of naphthalene have shown it to be noncarcinogenic.
Naphthalene has been shown to be acutely toxic in freshwater fish
*
with LC5Q values of 150,000 ug/1 being reported in one static bioassay.
Freshwater invertebrates were more sensitive with LC5Q values of 8,570
jig/1, as were marine fish with LC5Q values ranging from 2,350 to 2,600 .
-------
INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Naphthalene (U.S. EPA, 1979).
Maphthalene (CigHs; molecular weight 128.16) is a bicyclic, aromatic
hydrocarbon which in a pure grade, forms a white crystalline solid at
room temperature (Windholz, 1976). Pure naphthalene has a melting point
of 80.2°C, a boiling point of 217.96°C (Manufacturing Chemists Assoc.,
1956) and a vapor pressure of 0.0492 mm Hg at 19.8°C (Gil'denblat, et
al. 1960). Naphthalene is water soluble, with solubility ranging from
30,000 ug/1 (Mitchell, 1926) to 40,000 ug/1 (Josephy and Radt, 1948).
Naphthalene vapor and dust can form explosive mixtures with air (Windholz,
1976). Naphthalene is used as an intermediary in the production of dye
compounds, in the formulation of solvents, lubricants and motor fuels,
and as a feedstock in the synthesis of phthalic anhydride. Naphthalene
is also used directly as a moth repellant, insecticide, antihelminthic ,
vermicide, and an intestinal antiseptic (U.S. SPA, 1979). In. 1974,
production of naphthalene was approximately 2.9 x 10^ metric tons (U.S.
SPA, 1976).
II. EXPOSURE
A. Water
The two major sources of naphthalene in the aquatic environment
are from industrial effluents and from oil spills. The final effluents
of sewage treatment plants receiving discharges from these industrial
facilities have been noted to have up to 22 ug/1 naphthalene, while. natural
waters have up to 2.0 ug/1, and drinking water supplies have up to 1.4
naphthalene (U.S. EFA, Region IV, unpublished data).
131-1
-------
B. Food
The U.S. EPA (1979) has estimated the weighted average bio-
concentration factor for naphthalene to be 60 for the edible portions of
fish and shellfish consumed by Americans. This estimate was based on
octanol/water partition coefficients.
C. Inhalation
In the ambient air, inhalation of naphthalene is negligible
with vapor concentrations ranging from 0.00005 to 0.0001 ug/m3 and
particulate concentrations ranging from 0.000003 to 0.00025 ug/m^
(Krstulovic, et al. 1977). Industrial exposure can range from 0.72 yig/m^
to 1.1 x 10^ ug/m3 in the vapor phase (Bjrseth, et al., 1978b; Robbins,
1951) and from 0.09 ug/m3 to 4.40 pg/m^ in particulates (Bjrseth, 1978a,
1978b). Naphthalene has also been found in cigarette smoke condensate
(Akin, et al. 1976).
III. PHARMACOKINETICS
A. Absorption
Little detailed information is available on the absorption of
naphthalene in man or animals. Adequate amounts of naphthalene can be
absorbed when ingested as a solid, or by inhalation, to cause significant
toxicity (U.S. EPA, 1979). Absorption seems to be facilitated if naphthalene
is dissolved in oil (Solomon, 1957), and hindered if naphthalene, is bound
to protein (Sanborn and Malins, 1977).
B. Distribution
Naphthalene distributes widely after absorption. In mallards,
the relative distribution of naphthalene was as follows: greatest* in
skin, followed by liver, brain, blood, muscle, and heart (Lawler, et al.
1978).
-------
C. Metabolism
Naphthalene is first metabolised by hepatic mixed-function
oxidases to an epoxide, which is an obligatory step in the metabolism of
naphthalene. Further metabolism can occur leading to the formation of a
variety of compounds. Most of these compounds are enzymatically conjugated
with glucuronic acid or sulfate. During metabolism a number of highly
reactive compounds are formed such as 1,2-dihydroxynaphthalene and 1,2-
naphthoquinone (U.S. EPA, 1979).
Naphthalene metabolites undergo further conversions in the eye.
This multi-step pathway can lead to the formation of 1,2-naphthaquinone
which can irreversibly bind to lens protein and amino acids (Van Heyningen
and Pirie, 1966).
D. Excretion
Naphthalene has not been identified in urine after absorption. •
With sufficient absorption of naphthalene to result in toxicity to an 18
month old infant, Mackell, et al. (1951) noted metabolites of naphthalene
in the urine that were still identifiable two weeks after exposure but
which had disappeared 18 days after exposure.
1-Napthol is the predominant spontaneous decomposition product of
the epoxide of napohthalene. 1-Napthol is excreted unchanged as well as
congugated with glucuronic acid or sulfate prior to excretion. The finding
of 1,4-nathoquinone in the urine of a child poisoned with naphthalene
(Mackell, at al. 1951) suggests that 1-napthol can also be further oxidized
in mammals (Cerniglia and Gibson, 1977).
IV. EFFECTS
A. Carcinogenicity
In attempts to demonstrate its carcinogenicity, naphthalene has
Seen given orally, subcutaneously, implanted in the bladder, and painted
-------
on the backs of a number of animal species (U.S. EPA, 1979). In these
experiments naphthalene caused no increase in tumor formation. Two
experiments have produced increases in lymphosarcoma and lymphatic
leukemia after treatment with coal tar derived naphthalene. The first of
these studies (Knake, 1956) was complicated by the presence of 10 percent
impurities in the naphthalene and the painting of the injection site with
carbolfuchsin, a known experimental carcinogen, prior to injection. In
the second study (Knake, 1956) where excess leukemia was noted, naphthalene
was dissolved ,in benzene, a known human leukemogenic agent, and painted on
the backs of mice. Benzene treatment resulted in no leukemia. Skin
papillomas have been produced on mice following painting with 1,4— naththa-
quinone, a metabolite of naphthalene (Takizawa, 19^0). Also, Pirie (1968)
noted abnormal mitotic figures in metaphase and cell overgrowth in the
*
epithelial cells of the lens of rabbits given 1 g/kg/day of naphthalene
by gavage.
8. Mutagenicity
Naphthalene has been found to be nonmutagenic in several microsomal/
bacterial assay systems (McCann, et al. 1975; Kraemer, et al. 1974).
C. Teratogenicity
Pertinent data could not be located in the available literature.
D. Other Reproductive Effects
Naphthalene or its metabolites can cross the placenta in sufficient
amounts to cause fetal toxicity (Zinkham and Childs, 1958; Anziulewicz,
et al. 1959)- When a metabolite of naphthalene," 2-naphthol, was admin-
istered to pregnant rabbits, their offspring were born with cataracts and
evidence of retinal damage (Van der Hoeve, 1913).
-------
E. Toxicity
Oral administration of two percent naphthalene or 2-napthol to
rats for at Least 60 days resulted in the development of cataracts
(Fitzhugh adn Busckke, 19^9). Van Heyningen and Pirie (1976) dosed rabbits
daily by gavage with 1000 mg/lcg of naphthalene for a maximum of 28 days.
Lens changes developed after the first dose, and retinal changes developed
after the second dose. Rabbits fed 1000 mg/kg/day developed cataracts
between day 3 and 46. Topical application of a 10 percent solution in oil
to the eyes of rabbits did not produce cataracts after a period of 50 days.
Intraperitoneal injection of 500 mg/kg of naphthalene in an oily solution
produced weight loss over a period of 50 days (Ghetti and Mariani, 1956).
Hemolytic anemia- with associated jaundice and occasionally renal disease
from precipitated hemoglobin has been described in newborn infants, 4
children and adults after exposure to naphthalene by ingestion, inhalation,
or possibly by skin contact (U.S. EPA, 1979). The extent or duration of
exposure was not given. Mahvi, et al. (1977) noted a dose related damage
to bronchiolar epithelial cells in mice given intraperintoneal injections
of naphthalene in corn oil. Bronchiolar epithelial changes were not
noted in two control groups. The authors noted minor bronchiolar epithelial
changes in the treated group receiving 67.4. mg/kg of naphthalene.
Those mice receiving higher doses (128 and 256 mg/kg of naphthalene)
developed reversible necrosis of bronchiolar cells.
F. Other Relevent Information
Alexandrov and Frayssinet (1973) demonstrated that naphthalene
administered intraperitoneally to rats could inhibit the mixed-function
»
tnicrosomal oxidase enzyme system, and could also inhibit the induction of
these enzymes by 3-
-------
V. AQUATIC TOXICITY
A. Acute
For the freshwater mosquitofish (Gambusia affinis) a 96-hour
ststic bioas'say provided an LCcg value of 150,000 ug/1 (Wallen, et al.
1957), while the freshwater cladoceran (Daphnia magna) was shown to have
an US-hour LC5Q value of 8,570 ug/1 (U.S. EPA, 1978). Marine organisms
tended, to be somewhat more sensitive to naphthalene with an 24-hour static
^050 value of 2,400 ug/1 for the sheepshead minnow (Cyprinodon variegatus).
Two 24-hour static LC5Q values of 2,500,' 2,600 were obtained for two
species of marine shrimp, (Penaeus aztecus) and (Palaemonetes pugio),
respectively (Anderson, et al. 1974). A 96-hour LC5Q value of 2,350 ug/1
was obtained for grass shrimp (Palaemonetes pugio) (Tatem, 1976).
B. Chronic Toxicity
A single embryo-larval test on the fathead minnow (Piaephales
promelas) stated that no effects were observed at concentrations as high
as 440 ug/1 (U.S. EPA, 1978).
Data pertaining to the chronic toxicity of naphthalene for any
marine species could not be located in the available literature.
C. Plant Effects
A 48-hour EC5Q value of 33,000 ug/1 for reduced cell numbers
has been reported for the freshwater algae (Chlorella vulgaris) exposed
to naphthalene. Data pertaining to the effects of naphthalene to marine
plants could not be located in the available literature.
D. Residues
Using the octanol/water partition coefficient of 2,300 for
naphthalene, a bioconcentration factor for aquatic organisms with an 8
percent lipid content has been estimated as 210. Bioconcentration
-------
factors determined for niarine invertebrates ranged from 50 to 60 in the
marine copepod Calanus helgolandicus after one day (Harris, et al. I977a,
I977b) .to 5,000 in the copepod Eurytemcra affinis, after nine days,
(Harris, et al. I977b) indicating that equilibrium may not occur rapidly.
Bioconcentration factors of 32 to 77 after 1 to 24 hours were reported
for these 3 species of marine fish and one species of mussel (Lee, at al.
1972a; 1972b).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived by U.S.
SPA (1979'), which are summarized below, have gone through the process of
public review; therefore, there is a possibiliity that these criteria
will be changed.
A. Human
The Occupational Safety and Health Administration standard for
exposure to vapor for a time-weighted industrial exposure is 50 tng/m3.
The American Conference of Governmental Industrial Hygienists (ACGIH,
1971) threshold limit value is 75 tng/m3, while at present the ACGIH also
suggests a maximum 15 minute exposure value of 75 mg/m3 (ACGIH, 1978).
The acceptable daily intake for naphthalene is 448 ^ug/day for a 70 kg
person. The U.S. EPA (1979) draft ambient water criterion for
naphthalene is 143 ug/1.
B. Aquatic
Criterion can not be derived for naphthalene for either fresh-
water or marine organisms, because of the lack of sufficient toxicological
data.
l-3/r/O
-------
NAPHTHALENE
REFERENCES
Akin, F.J., at al. 1976. Identification of polynuclear aromatic hydro-
carbons in- cigarrette smoke and their importance as tumorigens. Jour. Natl.
Cancer Inst. 57: 191.
Alexandrov, K. and- C. Frayssinet. 1973. In vitro effect of some
naphthalene-related compounds on aryl hyrocarbcn (benzo(a)pyrene) hydroxy-
lase. Jour. Natl. Cancer Inst. 51: 1067.
American Conference of Governmental Industrial -Hygienists. 1971. Docu-
mentation of the threshold limit values for substances in workroom air. 3rd
ed. Cincinnati, Ohio.
American Conference of Governmental Industrial Hygienists. 1978. Threshold
limit values for chemical substances and physical agents in the workroom
environment with intended changes for 1978. Cincinnati, Ohio.
Anderson, J.w. et al. 1974. The effects of oil on estuarine animals:
Toxicity uptake and depuration, respiration. In; pollution and physiology
of marine orgasnisms. Adademic Press.' New York
•<«
Anziulewicz, J.A., et al. 1959. Transplacental naphthalene poisoning. Am.
Jour. Obstet. Gynecol. 78: 519.
Bjorseth, A. et al. 1978a. Polycyclic aromatic hydrocarbons in the work
atmosphere. II. Determination in a coke plant. Scand. Jour. Work. Environ.
Health. 4: 212.
Bjorseth, A. et al. 1978b. Polycyclic aromatic hydrocarbons in the work
atmosphere. I. Determination in an aluminum reduction plant. Scand. Jour.
Work Environ. Health. 4: 212.
Cerniglia, C.E. and D.T. Gibson. 1977. Metabolism of napthalene by
Cunninqhamella eleoans. Appl. Environ. Microbiol. 34: 363.
Fitzhugh, O.G. and W.H. Buschke. 1949. Production of cataract in rats by
beta-tetralol and other derivatives of naphthalene. Arch. Ophthal. 41: 572.
Ghetti, G. and L. Mariani. 1956. Eye changes due to naphthalene. Med.
Lavoro. 47: 524.
Gil'denblat, I.A., et al. 1960. Vapor pressure over crystalline naphtha-
lene. Jour. Appl. Chem. USSR. 33: 245.
Harris, R.P. et al. 1977a. Factors affecting the retention of a petroleum
hydrocarbon by marine planktonic copepods. In: Fate and Effetts of
petroleum hydrocarbons in marine ecosystems and organisms. Proc. Symp. 286.
Harris, R.P. et al. 1977b. Accumulation of carbon-14-l-napthalene by an
oceanic and an estuarine copepod during long-term exposure to low-level con-
centrations. Mar. Biol. 42: 187.
/3/-V
-------
Josephy, E. and F. Radt, (eds.) 1948. Encyclopedia of organic chemistry:
Series III. Elsevier Publishing Co., Inc., New York.
Xnake, E. 1956. Uber schwache geschwulsterzengende Wirkung von Naphthalin
und Benzol. Virchows Archiv. Pathol. Anat. Physiol. 329: 141.
Kraemer, M.,' et al. 1974. S^ typhimurium and §_._ coli to detect chemical
mutagens. Arch. Pnarmacol. 284: B46.
Xrstulovic, A.M., et al. 1977. Distribution of some atmospheric poly-
nuclear aromatic hydrocarbons. Am. Lab. 9(7): 11.
Lawier, G.C., et al. 1978. Accumulation of aromatic hydrocarbons in
tissues of petroleum-exposed mallard ducks (Anas olatyrhynchos). Environ.
Sci. Technol. 12: 51.
Lee,. R.F.. et al. 1972a. Uptake, metabolism and discharge of polycyclic aro-
matic hydrocarbons by marine fish. Mar. Biol. 17: 201.
Lee, R.F. et al. 1972b. Petroleum hydrocarbons: uptake and discharge by
the marine mussel Mytilus edulis. Science. 177: 344.
Mackell, J.V., et al. 1951. Acute hemolytic anemia due to ingestion of
napthalene moth balls. Pediatrics. 7: 722.
A
Mahvi, D., et al. 1977. Morphology of a naphthalene-induced bronchiolar
lesion. Am. Jour. Pathol. 86: 559.
•.
Manufacturing Chemists Assoc. 1956. Chemical safety data sheets SD-58:
Napthalene. Washington, O.C.
McCann, J., et al. 1975. Detection of carcinogens as mutagen in the
Salmonella/microsome test. Assay of 300 chemicals. Proc. Natl. Acad. Sci.
72: 5135.
Mitchell, S. 1926. A method for determining the solubility of sparingly
soluble substances. Jour. Chem. Soc. 129: 1333.
Pirie, A. 1968. Pathology in the eye of the naphthalene-fed rabbit. Exp.
Eye Tes. 7: 354.
Robbins, M.C. 1951. Determination of Napthalene in air. Arch. Ind. Hyg.
Occuo. Med. 4: 85.
Sanborn, H.R. and D.C. Malins. 1977. Toxicity and metaoolism of naphtha-
lene: a study with marine larval invertebrates. Proc- Soc. Exp. 3iol. Med.
154: 151.
Solomon, T. 1957. A manual of pharmacology and its applications to th^ra-
peutics and toxicology. 3th ed. W.3. Saunders Co., Philadelphia.
Takizawa, N. 1940. Carcinogenic action of certain quinones. Proc. Imp.
Acad. (Tokyo) 16: 309.
13 l-
-------
Tatem, H.E. 1976. Toxicity and physiological affects of oil and petroleum
hydrocarbons on astuarine grass shrimp, Palaeminetes pugio. Holthuis Ph.D.
dissertation. Texas A and M University. 133 pp.
U.S. EPA.. 1971-1977. Unpublished data from Region IV, Atlanta, Ga.
U.S. EPA. 1976. Organic chemical producer's data base program. Chemical
No. 2701. Radian Corporation.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract NO. 68-01-4646, U.S. Environ. Prot.
Agency.
U.S. EPA. 1979. Naphthalene: Ambient Water Quality Criteria. (Draft)
Van Heyningen, R. and A. Pirie. 1966. Naphthalene cataract. In: M.U.S.
Dardenne, ed. Symposium on the biochemistry of the eye. Karger, Asel,
Switzerland.
Van Heyningen, R. and A. Pirie. 1976. Naphthalene cataract in pigmented
and albino rabbits. Exp. Eye Res. 22: 393.
Van der Hoeve, J. 1913. Wirkung von napbthol auf die augen von menschen,
tieren, und auf fatale augen. Graele Arch. Ophthal. 85: 305.
Wallen, I.E., et al. 1957. Toxicity of Gambusia affinis of certain pure
chemicals in turbid waters. Sewage Ind. Wastes. 29: 695.
Windholz, M., ed. 1976. The Muck Index, 9th ed. Muck and Co. Rahway, N.J.
Zinkham, W.J. and 8. Childs. 1958. A defect of glutathione metabolism in
erythrocytes from patients with a naphthalene-induced hemolytic anemia".
Pediatrics 22: 461.
I 3 H3
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No. 132
1,4-Naphthoquinone
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENC7
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may'not- reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
itA
I 1,4-NAPHTHOQUTNONE '
| SUMMARY.
1,4-Naphthoquinone is used as a polymerization regulator and an
intermediate. Some data are available which indicate that 1,4-naphtho-
quinona is biodegradable.
The most consistent findings reported in the literature for health
effects of 1,4-naphthoquinone involve hematological changes, irritant and
allergenic activity, and inhibition of biochemical oxidation processes.
One study found 1,4-naphthoquinone to be oncogenic. Some evidence of
inhibition of in vitro endocrine function and of nerve activity was re-
ported.
I. INTRODUCTION.
1,4-Naphthoquinone (1,4-aaphthalenedione; CiQH,0 • molecular weight 158.15)
is a solid at room temperature. It occurs as a greenish yellow powder or
as yellow triclinlc needles. It has a melting point of 123-126 C and begins
to sublime at 100 C; its density is 1.422. 1,4-Naphthoquinone is only
slightly soluble in water; it is soluble in a variety of organic solvents
(Windholz 1976; Hawley 1971).
Current production (including importation) statistics for 1,4-naphtho-
quinone (CAS Mo. 130-15-4) listed in the initial TSCA Inventory (U.S. EPA 1979)
show that between 1,000,000 and 9,000,000 pounds of this chemical were
*
produced/imported in 1977.
1,4-Naphthoquinone is used as a polymerization regulator for rubber
and polyester resins, in the synthesis o'f dyes and Pharmaceuticals, and as
a fungicide and algicide (Hawley 1971).
II. EXPOSURE
A. Environmental Fate
No specific information on the biological, chemical or photochemical
transformation of 1,4-aaphthoquinone under environmental conditions was
identified in the literature. Napthoquinones undergo few substitution
* This production range information does not include any production/importation
1 data claimed as confidential by the person(s) reporting for the TSCA Inventory,
nor does it include any information which would compromise Confidential
Business Information. The data submitted for the TSCA Inventory, including
production range information, are subject to the limitations contained in
the Inventory Reporting Regulations (40 CFR 710).
-------
reactions (Thirtle 1965). Like other quinones, 1,4-naphthoquinone can
interconvert with its corresponding hydroquinone iny an oxidation-reduction
X-
system.
Talakin (1964) reported that 1,4-naphthoquinone in river water apparently
undergoes slow biochemical oxidation, based on an observed increase in
BOD. Verschueren (1977) reports that the BOD- is 0.81, using the standard
dilution technique with normal sewage as seed material,'and that the theoretical
oxidation demand is 2.1. .'..
B. Bioconcentration
No information was found on the bioconcentration potential of 1,4-naph-
thoquinone. Based on its low water solubility and its solubility in organic
solvents, 1,4-naphthoquinone could be expected to bioconcentrate to some
extent.
C. Environmental Occurrence
No information was found on the presence of 1,4-naphthoquinone in
environmental media.
In addition to its potential entry into the environment from its
manufacture, processing and uses, 1,4-naphthoquinone may also enter the.
environment as a degradation product of certain naphthalene derivatives.
For example, the U.S. EPA (1975) reported studies showing that the pesticide
carbaryl (1-naphthyl-n-methyl-carbamate) undergoes hydrolysis to 1-naphthol,
which is then converted by bacteria to 1,4-naphthoquinone and other products.
III. PHAKMACOKINETICS
No information was obtained.
IV. HEALTH EFFECTS
A. Carcinogenicity
1,4-Naphthoquinone was found to induce neoplasm when applied dermally
to mice for 28 weeks. The total dose applied was 2000 mg/kg. (Proceedings
of the Imperial Academy of Tokyo 16:309, 1940, as cited in NIOSH 1975).
-------
3. Reproductive Effects
I,4-Naphthoquinone completely inhibited the gametokinetic effect
of human chorionic gonadotropin in toads (Pakrashi 1963) .
C. Other Toxicity
The oral LD5Q for rats was reported as 190 mg/kg (NIOSH, 1975) . The
LD.QQ of 1,4-naphthoquinone in rats was 0.5 g/kg, 0.25 g/kg, and 0.5 g/kg
for intraventricular, subcutaneous, and intraperitoneal' administrations,
respectively. The LC.nn in air was 0.45 mg/L for a one-hour exposure.
Acute (0.5 g/kg) and subchronic (0.3 g/kg for 4 days) exposure of rats re-
sulted in the formation of 39 and 13% methemoglobin, respectively, followed
by the appearance of Heinz bodies and development of hemolytic anemia.
A decrease in total respiration and hypothermia due to disturbances in
oxidation-reduction processes was also observed. According to the authors,
"threshold concentrations of 1,4-oaphthoquinone detected for rats and rabbits
in single-exposure and chronic experiments were 0.0004 and 0.0007 mg/L with
respect to their irritant and toxic, effects" (Slyusar et al. 1964). !
D. Other Relevant Information
1,4-Naphthoquinone exerted an allergenic effect in guinea pigs
(Kryzhanovskaya et al. 1966). A possible role for 1,4-naphthaquinone
in drug-induced thrombocytopenia was suggested by Niewig et al. (1973)
as 1,4-naphthoquinone was found to be involved in the destruction of normal
blood platelets by serum antibodies in vitro. 1,4-Naphthoquinone blocks
the biosynthesis of adrenal steroids by bovine adrenal cortex in vitro
(Kahnt and Neher 1966), and has an inhibitory effect on mixtures of cytochrome
_c and dehydrated succinate oxidase from beef heart (Heymann and Falser 1966) .
1,4-Naphthoquinone inhibited ATPase and nerve activity in the (American)
•j
cockroach. (Baker and Norris 1971, Baker 1972).
V. AQUATIC TOXICITY
Very little information was available. For 1,4-naphthoquiaone, a
median threshold limit value (TLM:24-28 hr) of 0.3-0.6 mg/L was listed for
an unspecified species of fish (Verschueren 1977).
VI. GUIDELINES
No guidelines for exposure to 1,4-naphthoquinone were located.
-------
References
Baker JE. 1972. Effects of feeding-inhibitory quiripnes on the nervous
system of Periplaneta. Experientia. 28(l):31-32.
Baker JE, Norris DM. 1971. Neurophysiological and biochemical effects
of naphthoquinones on the central nervous system, of Periplaneta.
J. Insect Physiol. 17:2383-2394.
Hawley GG. 1971. Condensed Chemical Dictionary, 8th edition. Van Nostrand
Reinhold Co.
Heymaan H, Feiser LF. 1948. Naphthoquinone antimalarials. XXI. Anti-
succinate oxidase activity. Jour. Biol. Chem. 176(3):1359-1369.
Kahnt FW, Neher R. 1966. Biosynthesis of adrenal steroids in vitro. II.
Importance of steroids as inhibitors. Helv. Chim. Acta 49(1):123-133. (Ger.)
Kotsifopoulos PN. 1975. In vitro effect of oxidizing and analgesic agents
on the erythrocyte membrane protein electrophoretic pattern. Nouv. Rev.
Fr. Hematol. 15(1) -.141-146. (Abstract in Chemical Abstracts, 83,72709Z).
Kryzhanovskaya MV, et al. 1966. Allergenic activity of some atmospheric
pollutants of a chemical nature. Gig. Sanit. 31(3):8-11.
National Institute of Occupational Safety and Health. Registry of Toxic
Effects of Chemical Substances. 1975. . -
Nieweg HO, et al. 1973. Drugs and thrombocytes. Proc. Eur. Soc. Study
Drug Toxic. 14:101-109.
Pakrashi A. 1963. Endocrinological studies of plant products. IV. Effect
of certain coumarins upon the biological potency of human chorionic gonado-
tropin. Ann. Biochem. Exptl. Med. (Calcutta) 23:357-370.
Slyusar MP, et al. 1964. Data on the toxicology of alpha-naphthoquinones:
and its permissible concentration in a working area. Gigiena 95-100.
(Abstract in Zh. Farmakol. Toksikol. 11.54.373, 1965).
Talakin YN. 1965. The experimental determination of the maximum permissible
concentration of alpha-naphthoquinone in water resources. Hyg. and Sanit.
30:184.
Thirtle JR. 1965. Quinones. In: Kirk-Othmer Encyclopedia of Chemical
Technology. 2nd Edition. John Wiley and Sons, -Inc., New York.
U.S. EPA 1975. Microbial degradation and accumulation of pesticides in
aquatic systems. EPA 660/3-75-007, PB 241 293.
»
U.S. EPA 1979. Toxic Substances Control Act Chemical Substance Inventory,
Production. Statistics for Chemicals on the Non-Confidential TSCA Inventory.
-------
Verschueren, K. 1977. Handbook of Environmental Data on Organic Chemicals, -
Van Nostrand Reinhold Co.
, M. .1. 1976. The Merc, Index, Here. . Co., lac., Rahway, «e» Jersey.
m-7
-------
No. 133
Nickel
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C. 20460
APRIL 30, 1980
/33-/
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
nickel and has found sufficient evidence to indicate that
this compound is carcinogenic.
-------
NICKEL
Summary
Nickel is a ubiquitous multi-media environmental contaminant. Al-
though nickel is toxic and appears to be a carcinogen to man, there is an
increasingly strong indication that nickel is an essential element. The
route of exposure to nickel is very important, since oral intake of nickel
metal is comparatively nontoxic. However, exposure to nickel by inhalation
or parenteral administration as well as cutaneous contact can produce toxic
• •
affects. In terms of human health effects, probably the most acutely toxic
nickel compound is nickel carbonyl. Nickel in several chemical forms has
been associated with lung cancer in_ man and experimental animals upon
inhalation; carcinogenic effects, however, are not indicated by the oral
route. The acceptable daily intake (ADI) of nickel is 254 ug per day for a
70 kg man.
The toxicity of nickel to aquatic life is affected by water hardness.
In the aquatic environment nickel is acutely toxic to freshwater fishes at a
concentration of 2,480 jug/1 (26 mg/1 hardness). Chronic toxicity to fishes
has been reported at 527 jug/1 (210 mg/1 hardness). Nickel toxicity is
affected by water hardness. Algae appears to be more sensitive to nickel
than fish. Based on the limited number of studies performed, the biocon-
centration factor for fish is 61, for algae the factor is 9.8, and the
weighted average bioconcentration factor is 11 for fish and shellfish.
-------
NICKEL
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Docu-
ment for Nickel (U.S. EPA, 1979).
Nickel (Ni; atomic weight 58.71), a bright, silver metal of the iron-
cobalt-nickel triad, is a hard and malleable metal with a high tensile
strength used in virtually all areas of metallurgy. Nickel does not readily
form chloro-complexes under environmental conditions and would not be ex-
pected to form significant amounts of sulfate complexes (U.S. EPA, 1979).
In 1972, U.S. consumption of nickel, exclusive of scrap, was estimated
to total about 160,000 tons (Reno, 1974). The estimate consisted mainly of
commercially pure nickel (about 110,000 tons) which is used in stainless
steel, electroplating, and various other alloys. *
II. EXPOSURE
The route by which most people in the general population receive the
largest portion of daily nickel intake is through foods. Total daily di-
etary intake values may range up to 900 ;jg nickel, depending on the nature
of the diet, with average values of 300 to 500 ug daily (NAS, 1975). The
U.S. EPA (1979) has estimated a weighted average bioconcentration factor for
nickel to be 11 for the edible portions of fish and shellfish consumed by
Americans. This estimate is based on measured steady-state bioconcentration
studies in fathead minnow larvae (Pimephales promelas) (Lind, et al. Manu-
script). The values for nickel levels in 969 U.S., public water supplies for
1969-1970 was 4.8 pg/1, with only 11 systems of this" total exceeding 25 pg/1
(NAS, 1975). The levels of nickel in the air are also low, with a 1974
»
arithmetic mean level for urban air of 9 ng/m3 (U.S. EPA, 1976).
-------
III. PHARMACOKINETICS
A. Absorption
The major routes of nickel absorption are inhalation and ingestion
via the diet. Percutaneous absorption is a less significant factor for
nickel's systemic effects but important in the allergenic responses to nick-
el. Collectively the data of Tedeschi and Sunderman (1957), Perry and Perry
(1959), Nomoto and Sunderman (1970), Nodiya (1972), and Horak and Sunderman
(1973) indicate that 1 to 10 percent of dietary nickel is absorbed. Skin
penetration of nickel has been- demonstrated with, nickel entering at sweat-
duct °and hair-follicle ostia (Wells, 1956). The extent to which nickel en-
ters the bloodstream by way of the skin cannot be stated at the present time
(U.S. EPA, 1979).
Respiratory absorption of various forms of nickel is probably the
«
major route of nickel entry into man under conditions of occupational expo-
sure. Pulmonary absorption into the bloodstream is probably greatest for
nickel carbonyl vapor, with animal studies suggesting that as much as half
of the inhaled .amount is absorbed (Sunderman and Selin, 1963). Nickel in
particulate matter is absorbed from the pulmonary tract to a lesser degree
than nickel carbonyl (Leslie, et al. 1976). Based on animal studies, nickel
appears to have a half-life cf several days in the body, yet there is little
evidence for tissue accumulation.
B. Distribution
Blood is the main vehicle for transport of absorbed nickel, with
serum albumin being the main carrier protein, although a specific nickelrich
metalloprotein has been identified in man (NAS, 1975). Tissue distribution
»
of absorbed nickel appears to be dependent on the route of intake. Inhaled
nickel carbonyl leads to highest levels in the lung, brain, kidney, liver,
-------
and adrenals (Armit, 1908; Sunderman and Selin, 1968; Mikheyev, 1971). Par--
enteral administration of nickel salts usually results in highest levels in
the kidney, with significant uptake shown by endocrine glands, liver and
lung (Wase, -et al. 1954; Smith and Hackley, 1968).
C. Metabolism
A number of disease states and other physiological stresses are
reported to alter the movement and tissue distribution of nickel in man as
well as experimental animals. In man, increased levels of serum nickel are
seen in cases of acute myocardial infarction (D'Alonzo and Pell, 1963; Sun-
derman, et al. 1972), acute stroke and extensive burn injury (McNeely, et
al. 1971). Reduction is seen in hepatic cirrhosis or uremia, possibly sec-
ondary to hypoalbuminemia.
Nickel appears to be an essential element, at least in experimental
animals. Nickel deficient diets have produced decreased growth rates and
impaired reproduction in swine (Anke, et al. 1974) and rats (Schnegg and
Kirchgessner, 1975). •
D. Excretion
The routes of elimination for nickel in man and animals depend in
part on the chemical forms of nickel and the mode of nickel intake. Dietary
nickel, due to the low extent of gastrointestinal absorption, is simply lost
in the feces (U.S. EPA, 1979). Urinary excretion in man and animals is usu-
ally the major clearance route for absorbed nickel. In some instances sweat
can constitute a major route of nickel elimination (Hohnadel, et al. 1973).
Nodiya (1972) reported a fecal excretion average of 258 jjg in Russian stu-
dents. Horak and Sunderman (1973) determined fecal excretion of nickel in
*
10 healthy subjects and arrived at a value identical to that found in the
Russian study.
-------
IV. EFFECTS
A. Carcinogenicity
A carcinogenic response to"'various nickel compounds upon injection
has deen observed in a number of animal studies (Lau, et al. 1972; Stoner,
et al. 1976; IARC, 1976). In nickel refinery workers, an excess risk of
nasal and lung cancer has been demonstrated (IARC, 1976). However, there is
no evidence at present to indicate that orally ingested nickel is tumori-
genic.
The qualitative and ..quantitative character of the carcinogenic effects
of nickel as seen in experimental animal models has been shown to vary with
the chemical form of the nickel, the route of exposure, the animal model em-
ployed, and the amounts of the substance administered (U.S. EPA, 1979).
3. Mutagenicity
Pertinent information could not be located in the available litera-
ture.
C. Teratogenicity
While Ferm (1972) has claimed unspecified malformations in surviv-
ing hamster embryos when mothers were exposed to parenteral nickel (0.7 to
10.0 mg/kg), Sunderman, et al. (1978) found no teratogenic effects from oral
administration of either nickel chloride (16 mg/kg) or nickel subsulfide (80
mg/kg) in rats. Exposure of pregnant rats by inhalation to nickel carbonyl
on days 7 or 8 of gestation frequently caused the progeny to develop ocular
anomalies, including anophthalmia and microphthaimia. The incidence of ex-
traocular anomalies is very low. The specificity of nickel carbonyl for in-
duction of ocular anomalies in rats appears to be unique among known terato-
genic agents (Sunderman, et al. 1979).
-------
D. Other Reproductive Effects
Schroeder and Mitchner (1971) have demonstrated adverse affects in
a three generation study with rats at a level of 5 mg/1 (5 ppm) nickel in
drinking water. In each of the generations, increased numbers of runts and
enhanced neonatal mortality were seen. A significant reduction in litter
size and a .reduced proportion of males in the third generation were also
observed. Nickel sulfate (25 mg/kg) has been demonstrated to be gametotoxic
in rats, with complete obliteration of spermatozoa following exposure for
120 days (Hoey, 1966; Waltschewa, et al. 1972).
E. Chronic Toxicity
Chronic exposure to nickel has resulted in injury to both the upper
and lower respiratory tract in man (Tolot, et al. 1956; McConnell, et al.
1973). Inhalation of nickel particulate matter is likely to play a role in
chronic, respiratory infections by effects on alveolar macrophages. Contact
dermatitis in man with nickel sulfate has been observed (Fregert, et al.
1969; Brun, 1975). Also, dietary nickel can elicit a dermatitic response
(Kaaber, et al. 1978).
F. Other Relevant Information
There are experimental data that demonstrate that nickel has a syn-
ergistic effect on the carcinogenicities of polycyclic hydrocarbons (Toda,
1962; Maenza, et al. 1971; Kasprzak, et al. 1973). Nickel and other ele-
ments are known to be present in asbestos and may possibly be a factor in
asbestos carcinogenicity (Cralley, 1971). Also,., a synergistic action be-
tween nickel and viruses has been suggested (Treagon'and Furst, 1970).
V. AQUATIC TOXICITY
»
A. Acute Toxicity
Water hardness significantly influences the acute toxicity of nick-
el to freshwater fish. For fish, observed LC5Q values range from 2,480
-------
/jg/1 for the rock bass (Ambloohites ruoestris) (hardness = 26 mg/1) to
110,385 jug/1 for the bluegill (Lsoomis macrochirus) (hardness = 42 mg/1).
At a hardness of 20-29 mg/1, six freshwater species .have LC_Q values of
between 2,916 and 5,360 ug/1 (Pickering and Henderson, 1966; Lind et al.,
manuscript). At a hardness of 360 ug/1, values range from 39,600 to 44,500
/jg/1. In comparison, acute tests with freshwater invertebrate species have
a greater range of LC-- values at a fixed hardness. The stonefly (Aero-
neuria lycorias) exhibited the highest LC5Q of 33,500 jug/1 (Warnick and
Bell, 1969) and Daphnia maqna gave the lowest value of 510 ug/1 (Biesinger
and Christensen, 1972). LLnd, et al. (1979) provide the only data obtained
under relatively high hardness conditions (244 mg/1), an LC5Q value of
2409 jug/1 for Daphnia pulicaria.
Data on the acute toxicity of nickel to saltwater fishes is limit-
ed. The LC.Q values range from 29,000 jug/1 for the Atlantic Silverside
(Menidia menidia) to 350,000 ug/1 for the mummichog (Fundulus heteroclitus)
(Eisler and Hennekey, 1977). The invertebrate acute toxicity data base con-
sists of 14 results, with a range of LC-- values from- 310 ug/1 for larvae
>u
of the hard clam (Mercenaria mercenaria) (Calabrese and Nelson, 1974) to
500,000 ug/1 for adults of the cockle Cardium edule (Portmann, 1963).
B. Chronic Toxicity
A life cycle test (Pickering, 1974) and an embryo-larval test
(Lind, at al., manuscript) have been conducted with the fathead minnow
(Pimeohales oromelas). The chronic values are 527 ug/L (210 mg/1 hardness)
and 109 jug/1 (44 mg/1 hardness) respectively, aiesinger and Christensen
(1972) conducted a life cycle test with Daohnia manna resulting in a chronic
»
value of 53 ug/1 at a hardness of 45 mg/1. There are no chronic saltwater
data available (U.S. SPA, 1979).
-------
C. Plant Effects
Hutchinson (1973) and Hutchinson and Stokes (1975) observed reduced
growth of several algae species at concentrations ranging from 100 to 700
jjg/1. A decrease in diatom diversity was observed by Patrick, et al. (1975)
to occur at concentrations as low as 2 ug/1.
D. Residues
Bioconcentration data is limited to the fathead minnow, Pimephales
promelas, (Lind, et al., manuscript) and the alga, Scenedesmes acuminata
(Hutchinson and Stokes, 1975). The bioconcentration factor for the whole
body of the fathead minnow is 61 and for the alga the factor is 9.8.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the_ aquatic criteria derived by U.S. EPA
(1979a), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed.'
A. Human
The American Conference of Governmental Industrial Hygienists
(ACGIH, 1971) has adopted a threshold limit value (TLV) for a workday expo-
sure of 1 ppb. The acceptable daily intake (ADI) for man has been determin-
ed to be 294 jjg/day (U.S. EPA, 1979). The U.S. EPA (1979) draft water qual-
ity criterion for nickel is 133 ug/1.
B. Aquatic
For nickel, the draft criterion (U.S. EPA, 1979) to protect fresh-
water aquatic life is:
(1.01 . In (hardness) - 1.02)
e
»<
as a 24-hour average, and the concentration should not exceed at any time:
(0.47 . In (hardness) + 4.19)
Q *
The draft criterion to protect saltwater aquatic life is 220 ug/1
as a 24-hour average, not to exceed 510 ug/1 at any time (U.S. EPA, 1979).
-------
NICKEL
REFERENCES
American Conference of Governmental Industrial Hygienists.
Threshold- limit values for chemical substances and physical
agents in the workroom environment with intended changes for
1978. 94 pp.
Anke, M. , et al. 1974. Low nickel rations for growth and
reproduction in pigs. In; Trace Element Metabolism in Ani-
mals- 2. W.G. Hoekstra, J.W. Suttie, H.S. Ganther and W.
Mertz (eds.). University Park Press, Baltimore, MD., pp.
715.'
Armit, H.W_ 1908. The toxicology of nickel carbonyl. Part
II. Jour. Hygiene 8: 565.
0
Biesinger, K.E., and G.M. Christensen. 1972. Effects of
various metals on survival, growth, reproduction, and metabo-
lism of Daphnia magna. Jour. Fish. Res. Board Can.. 29:
1691.
Brun, R. 1975. Epidemiology of contact dermatitis in Geneva-
(1,000 cases). Dermatol. 150: 193. (French)
Calabrese, A., and D.A. Nelson. 1974. Inhibition of embry-
onic development of the hard shell clam, Mercenaria mercen-
aria, bv heavy metals. Bull. Environ. Contain. Toxicol. 2:
Cralley, L.J. 1971. Electromotive phenomenon in metal and
mineral particulate exposures. Relevance to exposure to as-
bestos and occurrence of cancer. Am. Ind. Hyg. Assoc. Jour.
32: 653.
D'Alonzo, C.A., and S. Pell. 1963. A study of trace metals
in myocardial infarction. Arch. Environ. Health 6: 381.
Sisler, R, , and R.J. Hennekey. 1977. Acute toxicities of
Cd2"*", Cr2*, Ni2"*". amd Zn2* to estaurine macro fauna.
Arch. Environ. Contam. Toxicol. 6: 315.
Perm, v.H. 1972. The teratogenic effects of metals on mam-
malian embryos. In: Advances in Teratology, Vol. 5. D.H.M.
Wollam (ed. ) Academic Press, New York. pp. 51-75.
Fregert, S., et al. 1969. Epidemiology of contact dermati-
tis. Trans. St. Johns Hosp. Derm. Soc. 55: 71.
Hoey, M.J. 1966. The effects of metallic salts on the his-
tologv and functioning of the rat testes. Jour. Reprod.
Fertil. 12: 461.
-------
Hohnadel, D.C., et al. 1973. Atomic absorption spectrometry
of nickel, copper, zinc, and lead in sweat collected from
health subjects during sauna bathing. Clin. Chem. 19:
1288.
Horak, E., and F.W. Sunderman. 1973. Fecal nickel excretion
by healthy adults. Clin. Chem. 29: 429.
Hutchinson, T.C. 1973. Comparative studies of the toxicity
of heavy metals to phytoplankton and their synergistic inter-
actions. Water .Pollut. Res. (Canada) 8: 68.
Hutchinson, T.C., and P.M. Stokes. 1975. Heavy metal toxi-
city and algal bioassays. ASTM STP 573, Am. Soc. Test.
Mater. pp. 320-343.
International Agency for Research on Cancer. 1976. Nickel
and nickel compounds. In; Evaluation of Carcinogenic Risk of
Chemicals to Man (International Agency for Research on Cancer
Monographs, 11) IARC, Lyon, p. 111.
Kaaber, K., et al. 1978. Low nickel diet in the treatment
of patients with chronic nickel-dermatitis. Brit.. Jour.
Derm.. 98: 197.
Kasprzak, K.S., et al. 1973. Pathological reactions in rat
lungs following intratracheal injection of nickel subsulfide
and 3,4-benzpyrene. Res. Comm. Chem. Pathol. Pharmacol. 6:
237.
Lau, T.J., et al. 1972. The carcinogenicity of intravenous
nickel carbonyl in rats. Cancer Res. 32: 2253.
Leslie, A.C.D., et al. 1976. Prediction of health effect of
pollution aerosols. In; Trace Substances in Environmental
Health - X. D.D. Hemphill (ed.), University of Missouri,
Columbia, Mo. pp. 497-504.
Lind, D., et al. Regional copper-nickel study, Aquatic Tox-
icology Study, Minnesota Environmental Quality Board, State
of Minnesota (Manuscript).
Maenza, R.M. et al. 1971. Rapid induction of sarcomas in
cats by combination of nickel sulfide and 3,4-benzypyrene.
Cancer Res. 31: 2067.
M.cConnell, L.H., et al. 1973. Asthma caused by nickel sen-
sitivity. Ann. Ind. Med. 78: 888.
McNeely, M.D., et al. 1971. Abnormal concentrations of
nickel in serum in cases of myocardial infarction, stroke,
burns, hepatic cirrhosis, and uremia. Clin. Chem. 17:
1123.
J
-------
Mikheyev, M.I. 1971. Distribution and excretion of nickel
carbonyl. Gig. Tr. Prof. Zabol. 15: 35.
National Academy of Sciences. 1975. Nickel. National Acad-
emy of Sciences Committee of Medical and Biological Effects
of Environmental Pollutants. Washington, DC.
Nodiya, P.I. 1972. Cobalt and nickel balance in students of
an occupational technical school. Gig. Sanit. 37: 108.
Nomoto, S., and F.W. Sunderman, Jr. 1970. Atomic absorption
spectrometry of nickel in serum, urine, and other biological
materials. Clim. Chem. 16: 477.
Patrick, R., st al. 1975. The role of trace elements in
management of nuisance growths. U.S. Environ. Prot. Agency,
EPA 660/2-75-008, 250 p.
Perry, H.M., Jr.,. and E.P. Perry. 1959. Normal concentra-
tions of some trace metals in human urine: Changes produced
by ethylenediametetracetate. Jour. Clin. Invest. 38: 1452.
Pickering, Q.H. 1974. Chronic toxicity of- nickel to the
fathead minnow. Jour. Water Pollut. Control Fed. 46: 760.
Pickering, Q.H., and C. Henderson. 1966. The acute toxicity
of some heavy metals to different species of warmwater
fishes. Air Water Pollut. Int. Jour. 10: 453.
Portmann, J.E. 1968. Progress report on a program of
insecticide analysis and toxicity testing in relation to the
marine environment. Helgolander wiss. Meeresunters 17:
247.
Reno, H.T. 1974. Nickel. In: Minerals Yearbook 1972, Vol.
I. Metals, Minerals and Fuels. Washington, DC, U.S. Gov-
ernment Printing Office, pp. 871.
Schnegg, A., and M. Kirchgessner. 1975. The essentiality of
nickel for the growth of animals. Z. Tierphysiol., Tierer
naehr. Futtermittelkd. 36: 63.
Schroeder, H.A., and M. Mitchner. 1971. Toxic effects of
trace elements on the reproduction of mice and rats. Arch.
Environ. Health 23: 102.
Smith, J.C. , and 3. Hackley. 1968. Distribution and excre-
tion of nickel-63 administered intravenously to rats. Jour.
Nutr. 95: 541.
»
Stoner, G.D., at al. 1976. Test for carcinogenicity of me-
tallic compounds by the pulmonary tumor response in strain A
mice. Cancer Res. 36: 1744.
-------
Sunderraan, F.W., et al. 1978. Embryotoxicity and fetal
toxicity of nickel in rats. Toxicol. Appl. Pharmacol. 43:
381.
Sunderman, F.W., Jr. 1978. Carcinogenic effects of metals.
Fed. Proc. 37: 40.
Sunderman, F.W., Jr., and C.E. Selin. 1968. The metabolism
of nickel-63 carbonyl Toxicol. Appl. Pharmacol. 12: 207.
Sunderraan, F.W., Jr., et al. 1972. Nickel metabolism in
health and disease. Ann. N ,.Y. Acad. Sci. 199: 300.
Sunderman, F.W.,- Jr., -et al. - 1979. Eye. malformation in
rats: Induction by prenatal exposure to nickel carbonyl.
Science 203: 550.
s
Tedeschi, R.E., and F.W. Sunderman. 1957. Nickel poisoning.
V. The metabolism of nickel under normal conditions and
after exposure to nickel carbonyl. Arch. Ind. Health 16:
486.
Toda, M. 1962. Experimental studies of occupational lung
cancer. Bull. Tokoya Med.. Dentr Univ. 9: 441.
Tolot, F. , et al.. 1956.. Asthmatic forms of lung disease in
workers exposed to chromium, nickel and aniline inhalation.
Arch. Mol. Prof. Med.. Tran.. Secur. Soc. 18: 288.
Treagon, L., and A. Furst. 1970. Inhibition of interferon
synthesis in mammalian cell cultures after nickel treatment.
Res. Comm.- Chem. Pathol. Pharmacol. 1: 395.
U.S. EPA. 1976 (August). Air quality data for metals 1970
through 1974 from the national air surveillance network.
EPA-600/4-76-041, U.S. Environ. Prot. Agency, Research
Triangle Park, NC.
U.S. EPA, 1979. Nickel: Ambient Water Quality Criteria.
Waltschewa, V.W. et al. 1972. Hodenveranderungen bei
weissen Ratten durch chronische Verabreichung von Nickel sul-
fate. (Testicular changes due to long-term administration of
nickel sulphate in rats.) Exp.. Pathol. 6: 116. In German
with Engl. abstr.
Warnick, S.L., and H.L. Bell. 1969. The acute toxicity of
some heavy metals to different species of aquatic insects.
Jour. Water Pollut. Control Fed. 40: 280.
»
Wase, A.W., et al. 1954. The metabolism of nickel. I.
Spatial and temporal distribution of Ni^3 ^n the mouse.
Arch. Biochem. Biophys. 51: 1.
-------
Wells, G.C. 1956. Effects of nickel on the skin. Brit.
Jour. Dernatol. 68: 237.
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No. 134
Nitrobenzene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy»
-------
NITROB5NZENE
Summary
Nitrobenzene is a. pale yellow oily liquid with an almond-like odor.
There is little or no information available on its teratogenic, mutagenic or
carcinogenic effects. Nitrobenzene yielded negative results in the Ames
assay for mutagenicity. Gross abnormalities were observed in 4 fetuses of
30 rats administered nitrobenzene.
Chronic exposure to nitrobenzene produces cyanosis, methemoglobinemia,
jaundice, anemia, and sulfhemoglobinemia in man.
Static tests with the bluegill, sunfish, Daphnia maqna, and an alga,
Selenestrum capricomutum, indicates little difference in sensitivity with
no 50 percent effective concentration lower than 27,000 ug/1. An embryo-
^
larval test with the fathead minnow demonstrated no adverse chronic effects
at the highest concentration tested (32,000 ug/1). Static tests with salt-
water fish, shrimp, and alga gave repeated 96-hour LC_Q or EC5Q values
of 58,538 jjg/1, 6,676 ug/1 and 9,600 jug/1, respectively.
-------
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Nitrobenzene (U.S. EPA, 1979). The principal uses of nitrobenzene are
for reduction to aniline (97 percent), solvent for Friedel-Crafts reaction,
metal polishes, shoe black, perfume, dye intermediates, crystallizing sol-
vent for some substances, and as a combustible propellant (Dorigan and
Hushon, 1976).
Nitrobenzene (CJHJOJ is a pale yellow oily liquid with an
almond-like odor. Its physical properties include: melting point, 6°C;
vapor pressure, 0.340 mm Hg at 25°C; and solubility in water of 1000 mg/1
at 20°C (U.S. EPA, 1979). Nitrobenzene is miscible with most organic sol-
vents, a fairly strong oxidizing agent, and undergoes photoreduction when
irradiated with ultraviolet light in organic solvents that contain abstraci-
table hydrogen atoms.
II. EXPOSURE
i
A. Water
Levels of nitrobenzene in wastewater are monitored by plants pro-
ducing and using the chemical, but nitrobenzene levels in city water systems
are usually too low to measure (Pierce, 1979).
3. Food
Nitrobenzene is not an approved food additive (Oorigan and Hushon,
1976). There have been reports of nitrobenzene poisoning resulting from its
contamination of alcoholic drinks and food (Nabarfo, 1948).
The U.S. EPA (1979) has estimated the weighted average bioconcentration
factor for nitrobenzene to be 4.3 for the edible portions of fish and.shell-
fish consumed by Americans. This estimate was based on octanol/water par-
tition coefficients.
-------
C. Inhalation
Atmospheric nitrobenzene levels outside a plant are not monitored
by industry. Since inner plant levels are below the Threshold Limit Value
(TLV) of 5 mg/m and nitrobenzene vapors accumulate at the floor level due
to their high density, the external concentrations are expected to be very
low (Dorigan and Hushon, 1976).
III. PHARMACOKINETICS
A. -Absorption
• Nitrobenzene absorption can occur by all possible routes, but it
takes place mainly through the respiratory tract and skin. On the average,
80 percent of the nitrobenzene vapors are retained in the human respiratory
tract (Piotrowski, 1977).
Nitrobenzene, as liquid and vapor, will pass directly through the
skin. The rate of vapor absorption depends on the air concentration, rang-
ing from 1 mg/hr at 5 mg/m concentration to 9 mg/hr at 20 mg/m . Maxi-
2
mal cutaneous absorption of liquid nitrobenzene is 0.2 to 3 mg/cm /hr de-
pending on skin temperature.
3. Distribution
Upon' entry into the body, nitrobenzene enters the bloodstream.
Nitrobenzene is a very lipid soluble with an oil to water coefficient of
800. In a rat study, the ratio of concentration of nitrobenzene in adipose
tissue versus blood in internal organs and muscle was approximately 10:1 one
hour after an intravenous injection (Piotrowski, -1977). Oorigan and HusHon
(1976) found that 50 percent of the nitrobenzene administered to rabbits
accumulated unchanged in tissues within two days after intubation.
-------
C. Metabolism
There are two main pathways for the metabolism of nitrobenzene: 1)
reduction to aniline followed by hydroxylation to aminophenols, and 2)
direct hydroxylation of nitrobenzene to form nitrophenols. Further reduc-
tion of nitrophenols to- aminophenols may also occur (Piotrowski, 1977). The
first pathway proceeds via the unstable intermediates, nitrosobenzene and
phenylhydroxylamine, both of which are toxic and have pronounced methemo-
globinemic capacity. These reactions occur in the cytoplasmic and micro-
somal fractions of liver cells by the nitro-reductase enzyme system (Fouts
and Brodie, 1957). The aniline is then excreted as an acetyl derivative, or
hydroxylated and excreted as an aminophenol. The second pathway does not
occur in the microsomal fraction. This .reaction proceeds via peroxidase in
the presence of oxygen (Piotrowski, 1977). ;
Robinson, at al. (1951) found p-aminophenol to be the main metabol-
ic product of nitrobenzene metabolism in rabbits. Little unchanged nitro-
benzene was excreted in the urine and only 1 percent was expired as carbon
dioxide. Together with nitrophenols and nitrocatechol, p-aminophenol con-
stituted 55 percent of the urinary metabolites. Metabolites were detected
in the urine up to one week after dosing.
D. Excretion
In man, the primary known excretion products of nitrobenzene are
p-aminophenol and p-nitrophenol which appear in the urine after chronic or
acute exposure. In experimental inhalation exposure -to nitrobenzene,
p-nitrophenol was formed with the efficiency of 6 to 21 percent. The
efficiency of p-aminophenol formation is estimated from acute poisorjing
-------
cases where the molar ratio of excreted p-nitrophenol to p-aminophenol is'
two to one, since p-aminophenol is not formed at a detectable level in short
subacute exposure (Piotrowski, 1977).
Ikeda and Kita' (1964) found the rate of excretion of these two
metabolites to parallel the level of methemoglobin in the blood.
Nitrobenzene remains in the human body for a prolonged period of
time. The excretion coefficient of urinary p-nitrophenol (followed for
three weeks) in man is about 0.008 per hour. The extended systemic reten-
tion and slow excretion of metabolites in man is determined by the low rates
of metabolic transformation "(reduction and hydroxylation) of the nitroben-
zene itself. The conjugation and excretion of the metabolites, p.-nitrophe-
nol and p-aminophenol, is rapid (Piotrowski, 1977). The urinary metabolites
in man account for only 20 to 30 percent of the nitrobenzene dose; the fate
of the rest of the metabolites is not known (Piotrowski, 1977).
IV. EFFECTS
A. Carcinogenicity
The available literature does not demonstrate the Carcinogenicity
of nitrobenzene, although it is suspect (Dorigan and Hushon, 1976).
Some nitrobenzene derivatives have demonstrated carcinogenic capa-
cities. Pentachloronitrobenzene (PCN8)'induced hepatomas and papillomas in
mice (Courtney, et al. 1976).
l-Fluoro-2,4-dinitrobenzene (ONFB) was found to be a promoter of
skin tumors in mice, although it does not induce them when administered
alone (Bock, et al 1969).
B. Teratogenicity
»
There is a paucity of information on the teratogenic effects of
nitrobenzene. In one study, 125 mg/kg was administered to pregnant rats
J*
-------
during preimplantation and placentation periods (Kazanina, 1963). Delay of
embryogensis, alteration of normal placentation, and abnormalities in the
fetuses were observed. Gross morphogenic defects were seen in 4 of 30
fetuses examined.
C, Mutagenicity .
Nitrobenzene was not found to be mutagenic in the Ames Salmonella
assay (Chiu, et al., 1978). Trinitrobenzene and 'other nitrobenzene deriva-
tives have demonstrated mutagenicity in the Ames Salmonella microsome assay
and the mitotic recombination assay in yeast (Simmon, et al. 1977), thus
raising questions concerning the mutagenicity of nitrobenzene.
0. Other Reproductive Effects
Changes in the tissues of the chorion and placenta of pregnant
women who worked in the production of a rubber catalyst that used nitro-
benzene were observed. No mention was made of the effects on fetal develop-
ment or viability (Dorigan and Hushon, 1976). Menstrual disturbances after
chronic nitrobenzene exposure have been reported.
Garg, at-al. (1976) tested substituted nitrobenzene derivatives for
their ability to inhibit pregnancy in albino rats. Two of the compounds
tested (p-methoxy and p-ethoxy derivatives) inhibited implantation and preg-
nancy 100 percent when administered on days 1 through 7 after impregnation.
E. Chronic Toxicity
Symptoms of chronic occupational nitrobenzene absorption are cyan-
osis, methemoglobinemia, jaundice, anemia, sulfhemoglobinemia, presence of
Heinz bodies in the erythrocytes, dark colored urine, and the presence of
nitrobenzene metabolites (e.g., nitrophenol) in the urine (Pacseri and
9
Magos, 1958; Hamilton, 1919; Wuertz, et al. 1964; Browning, 1950; Maiden,
1907; Piotrowski, 1967).
-------
Chronic exposure of laboratory animals to nitrobenzene (via inhala-
tion, ingestion or subcutaneous injection) produced symptoms similar to
those mentioned above for humans as well as tissue degeneration of the
heart, liver, and kidney, and reductions in erythrocytes and hemoglobin
levels in the blood (U.S. EPA, 1979).
F. Other Relevant Information
Alcohol ingestion has been found to act synergistically with nitro-
benzene in man and animals (Dorigan and Hushon, 1976; Smyth, et al., 1969).
Kaplan, et al. (1974) showed that caffeine, an inducer of microsom-
al enzymes, increases the rate of metabolism and' excretion of nitrobenzene
thus causing a rapid decline in nitrobenzene induced methemoglobin levels-
Metabolism and excretion of nitrobenzene in humans is slower by an
order of magnitude than in rats or rabbits (Piotrowski, 1977). .
V. AQUATIC TOXICITY
A. • Acute Toxicity
The 96-hour LC5Q reported value for the bluegill (Lepomis macro-
chirus) is 42,600 ug/1 and the observed 48-hour LC^n for Daohnia magna is
—•«-^• ^ ' J\J —•••••••••••_ i^HHMBMBM-
27,000 ug/1. Saltwater species tested are the sheepshead minnow, Cyprinodon
varieqatus, which has a reported 96-hour LC5Q of 58,539 jug/1 and the mysid
shrimp, Mysidopsis bahia, with a reported 96-hour LC5_. of 6',676 jug/1 (U.S.
EPA, 1979).
8. Chronic Toxicity
In the only chronic data available, .,no adverse effects were
observed during an embryo-larval test with the fathead minnow (Pimephales
promelas) at nitrobenzene test concentrations as high as 32,000 pg/1 (U.S.
»
EPA, 1978).
-------
C. Plant Effect
Based on cell numbers and chlorophyll a concentration, reported
EC5Q values for the freshwater alga, Selenastrum capricornutum. are 42,000
and 44,100 ug/1; and for the marine alga, Skeletonema costatum, there are
reported £C.Q values of-9,600 and 10,300 ug/1 (U.S. EPA, 1979).
0. Residues
_A bioconcentration factor of 15 was estimated for aquatic organisms
that contain 8 percent lipids.
VI. EXISTING GUIDELINES'AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed. ^
A. Human.
The TLV for nitrobenzene is 5 mg/m . This is the OSHA Federal
standard, the value set by the ILO/WHO committee on Occupational Health, and
the TLV suggested by the American Conference of Governmental and Industrial
Hygienists (Goldstein, 1975, ACGIH, 1977).
The draft water quality criteria for nitrobenzene is 30 ug/1 (U.S.
EPA, 1979). This value is based on the TLV and organoleptic level (minimum
detectable odor limit in water) of nitrobenzene.
S. Aquatic
For nitrobenzene the drafted criterion to.-protect freshwater aquat-
ic life is 480 ug/1 as a 24-hour average concentration not to exceed 1,100
ug/1 at any time. To protect saltwater aquatic life, the 24-hour average is
•
53 ug/1 and this concentration should not exceed 120 ug/1 at any time (U.S.
EPA, 1979).
-------
NITROBENZENE
REFERENCES
American Conference of Governmental Industrial Hygiensts. 1977. Docu-
mentation of the threshold limit value for substances in workroom air.
Cincinnati, Ohio.
Bock, A.G., et al. 1969. Tumor promotion by 1-fluoro-2, 4-dinitrobenzene,
a potent skin sensitizer. Cancer-Res. 29: 179.
Browning, E. 1950. Occupational jaundice and anemia. Practitioner
164: 397.
Chiu, C.W., et al. 1978. Mutagenicity of some commercially available nitro
compounds for Salmonella typhinurium. Mut. Res. 58: 11.
Courtney, K.D., et al. 1976. The effects of pentachloronitrobenzene, hexa-
chlorobenzene, and related compounds on fetal development. Toxicol. Appl.
Pharmacol. 35: 239-
Dorigan, J., and J. Hushon. 1976. Air pollution assessment of nitro-
benzene. U.S. Environ. Prot. Agency.
Fouts, J.R., and B.B. Brodie, 1957. The enzymatic reduction of cloram-
phenicol, p-nitrobenzoic acid and other aromatic nitro compounds in
mamma]*. Jour. Pharaiacol. Exp. Ther. 119: 197.
Garg, S.X., et al. 1976. Potent female antifertility agents. Indian Jour.
Med. Res. 64: 244.
Goldstein, I. 1975. Studies on MAC values of nitro and amino-derivatives
of aromatic hydrocarbons. Adverse Effects Environ. Chem. Psychotropic
Drugs 1: 153.
Hamilton, A. 1919. Industrial poisoning by compounds of the aromatic
series. Jour. Industr. Hyg. 1: 200.
Ikeda, M., and A. Kita. 1964. Excretion of p-nitrophenol and p-aminophenol
in the urine of a patient exposed to nitrobenzene. Br. Jour. Ind. Med.
21: 210.
Kaplan, A.M., et al. 1974. Methemoglobinemia and metabolism of nitro com-
pounds. Toxicol. Appl. Pharmacol. 29: 113-
Kazanina, S.S. 1968. Morphology and histochemistry -of hemochorial placen-
tas of white rats during poisoning of the maternal organisms by nitro-
benzene. Bull. Exp. Biol. Med. (U.S.S.R.) 65: 93-
*
Maiden, W. 1907. Some observations on the condition of the blood in men
engaged in aniline dyeing and the manufacture of nitrobenzene and its com-
pounds. Jour. Hyg. 7: 672.
_/ ^£a
1J U >
-------
Nabarro, J.D.N. 1948. A case of acute mononitrobenzene poisoning. 3r.
Med. Jour. 1: 929.
Pacseri, I., and L. Magos. 1953. Determination of the measure of exposure
to aromatic nitro and amino compounds. Jour. Hyg. Epidemiol. Microbiol.
Lnmunol. 2: 92.
Pierce, M. 1979. Personal communication. Quality Control Dep.,
Philadelphia Water Treatment Div., Philadelphia, ?a.
Piotrowski, J. 1967. Further investigations on the evaluation of exposure
to nitrobenzene. 3r. Jour. Ind. Med. 24: 60.
Piotrowksi, J. 1977. Exposure tests for organic compounds in industrial
toxicology. NIOSH 77-144. U.S. Dep. Health, Edu. Welfare.
Robinson, D., et al. 1951. Studies in detoxication. 40. The metabolism
of nitrobenzene in the rabbit, o-, o-, and p-aitrophenols, o-, m-, and
p-aminophenols and 4-nitrocatechol as metabolites of nitrobenzene.
Biochem. Jour. 50: 228.
Simmon, V.F.r et al. 1977. Munitions wastewater treatments: Does chlori-
nation or ozonation of individual components produce microbial mutagens?
Toxicol. Appl. Pharmacol. 41: 197.
Smyth, H.F., Jr., et al. 1969. An exploration of joint toxic action:
Twenty-seven industrial chemicals intubated in rats in all possible pairs.
Toxicol. Appl. Phannacol. 14: 340.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646.
U.S. SPA. 1979. Mitrobenzenes. Ambient Water Quality Criteria (Draft).
Wuertz, R.L., et al. 1964. Chemical cyanosis - anemia syndrome. Diag-
nosis, treatment, and recovery. Arch. Environ. Health 9: 478.
-------
No. 135
•4-Nitrophenol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
/ -3 ff-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents..
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
4-NITROPHSNOL
SUMMARY
There is-no evidence to indicate that 4-nitrophenol is carcin-
ogenic.
Weak mutagenic effects in Saccharomyces and in Proteus have
been observed. Results from the Ames assay, the E. coli, and
the dominant lethal assay failed to show mutagenic effects from
4-nitrophenol.
No information on the teratogenic or adverse reproductive
effects of 4-nitrophenol is available.
A single animal study indicates cumulative chronic .toxicity;
the methodology of this study was not available for review.
For freshwater organisms, acute values for the toxic effects
of 4-nitrophenol ranged from 8,280 to 60,500 pg/1, and 7,170
to 27,100 ug/1 for marine organisms. Effective concentrations
for aquatic plants fall within these ranges of concentrations.
-------
4-NITROPHENOL
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Nitrophenols (U.S. EPA, 1979).
The raononitrophenols are a family of compounds composed
of the isomers resulting from nitro group substitution at the
2,3, and 4 position of phenol (the ortho, meta, and para isomers,
respectively). The -para isomer, 4-nitrophenol, has a molecular
weight of 139.11, a boiling point of 279°C, a' melting point of
113-114°C, a density of 1.479 g/ml; it is soluble in water (U.S.
EPA, 1979).
Uses of the mononitrophenols include the following: produc-
tion of dyes, pigments, Pharmaceuticals, rubber chemicals, lumber
preservatives, photographic chemicals, and pesticidal and fungici-
dal agents (U.S. EPA, 1979). 'Production was 17.5 x 10 tons
per year in 1975 (Chem. Market. Reporter, 1976).
The nitrophenols may be formed via microbial degradation
or photodegradation of pesticides (e.g., parathion) containing
the nitrophenol moiety. 4-Nitrophenol may be produced in the
atmosphere through the photochemical reaction between benzene
and nitrogen monoxide (U.S. EPA, 1979). Partial microbial degrada-
tion of certain nitrophenols has been shown, particularly • by
acclimated microorganisms. Mononitrophenols appear to be effi-
ciently degraded by unacclimated microorganisms (Haller, 1978).
II. EXPOSURE
»
The lack of monitoring data on the mononitrophenols makes
it difficult to assess exposure from water, inhalation, and foods.
-------
Mononitrophenols in water have been detected in the effluents
of chemical plants (U.S. EPA, 1976, 1979). 4-Nitrophenol has
been shown to penetrate the skin and to produce damage at thres-
hold concentrations of 0.8 and 0.9 percent (w/v) , respectively
(U.S. EPA, 1979) .
Exposure to nitrophenols appears, to be primarily through
occupational contact (chemical plants, pesticide applications) .
Contaminated water may result in isolated poisoning incidents.
The U.S. EPA (1979) has estimated the weighted average bio-
concentration factor for 4-nitrophenol to be 4.9 for the edible
portions of fish and shellfish consumed by Americans. This esti-
mate is based on the octanol/water partition coefficient.
III. PHARMACOKINETICS
A. Absorption and Distribution
Pertinent data could not be located in the available
literature regarding absorption or distribution.
B. Metabolism
Metabolism of the mononitrophenols occurs primarily
by conjugation. Other possible routes are reduction of the nitro
group to an amino group or oxidation to dihydric-nitrophenols
(U.S. EPA, 1979). These reactions are mediated primarily by
liver enzyme systems, although other tissues show lower metaboliz-
ing activity (U.S. EPA, 1979).
3. Excretion
An animal study has indicated that- oral or intraperi-
•
toneal administration of 4-nitrophenol leads to rapid elimination
in all species tested, and that the total elimination period
is not likely to exceed one week (Lawford, et al. 1954) .
-------
IV. EFFECTS
A. Carcinogenicity
There is no evidence available regarding the carcinogeni-
city of raononitrophenols.
B. Mutagenicity_
A weak rautagenic effect was detected in Saccharomyces
cerevisiae by 4-nitrophenol (Fahrig, 1974); this was also indi-
cated .by testing 4-nitrophenol for growth inhibition in a DNA
repair deficient strain of Proteus mirabilis (Adler, et al. ,
1976). This compound has also induced chromosome breaks in plants
(U.S. EPA, 1979). 4-Nitrophenol has failed to show mutagenic
effects in the Ames assay, in E. coli, or in the dominant lethal
assay (U.S. EPA, 1979).
C. Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the available
literature regarding teratogenicity and other reproductive effects.
D-. Chronic Toxicity
A single Russian study (Makhinya, 1969) reported that
chronic administration of mononitrophenol to mammals produced
hepatitis, splenic hyperplasia, and neurological symptoms. Method-
ology of this study was not available for review.
V. AQUATIC TOXICITY
A. Acute Toxicity
L<~50 va^-ues have been obtained for two species of fresh-
water fish: 8,280 ug/1 for bluegills, Lepomis macrochirus, in
»
a 96-hour static assay (U.S. SPA, 1973), and 60,510 ug/1 for
the fathead minnow, Pimephales oromelas, in a 96-hour flow-through
assay (Phipps, et al. unpublished manuscript). For the fresh-
-------
water invertebrate, Daphnia magna, determined LCen values range
from 8,396 to 21,900 ug/1 (U.S. EPA, 1979). The marine fish,
sheepshead minnow, Cyprinodon variegatus, has produced deter-
mined LCjQ va'lue of 27,100 816 ug/1 in a 96-hour static assay,
while the marine mysid shrimp, Mysidopis bahia, was more sensi-
tive^ with a reported LCen value of 7,170 pg/1.
B. Chronic Toxicity
No chronic studies on freshwater organisms are available.
In an embryo-larval test of the marine fish, sheepshead minnow,
a chronic value of 6,325 ug/1 was obtained. No chronic testing
for marine invertebrates was available.
C. Plant Effects
Four species of freshwater plants have been tested
with 4-nitrophenol. The algae, Selenastrum capricornutum and
Chlorella vulgar is, and the duckweed, Lemna minor , were most
sensitive with effective concentrations of 4,190, 6,950, and
9,452 pg/1, respectively; while the alga, Chlorella pyrenoidosa,
was much more resistant, with an effective concentration of 25,000
ug/1. The marine alga, Skeletonema costatum, provided effective
concentrations of 7,370 to 7,570 pg/1 (U.S. EPA, 1979).
D. Residues
No bioconcentration factors for either freshwater • or
marine species were available.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived by
9
U.S. EPA (1979), which are summarized below, have gone through
the process of review; therefore, there is a possibility that
these criteria will be changed.
/3S-7
-------
A. Human
Available data pertaining to 4-nitrophenol is insuffi-
cient for deriving a criterion to protect human health.
B. Aquatic
A criterion for protecting freshwater organisms has
been drafted as 240 ug/1, for a 24-hour average concentration,
not to exceed 550 ug/1. For marine life, a criterion has been
drafted as 53 ug/1 for a 24-hour average, not to exceed 120 ug/1
•
(U.S. EPA, 1979).
-------
4-NITROPHENOL
REFERENCES
Adler, Bi", et al. 1976. Repair-defective mutants of Pro-
teus mirab'ilis as a prescreening system for the detection
of potential carcinogens. Biol. Zbl. 95: 463.
Chemical Marketing Reporter. 1976. Chemical profile:
p-nitrophenol. Chem. Market. Reporter p. 9.
Fahrig, R. 1974. Comparative mutagenicity studies with
Pesticides. Pages 161-181 In: R. Montesano and L. Tomatis
eds. Chemical carcinogenesls" essays. Proc. workshop on
approaches to assess the significance of experimental chemi-
cal carcinogenesis data for man organized by IARC and the
Catholic University of Louvain, Brussels, Belgium. IARC
Sci. Publ. No. 10. Int. Agency Res. Cancer, World Health
Organization.
Haller, H.D. 1978. Degradation of mono-substituted ben-
zoates and phenols by wastewater. Jour. Water Pollut. Con-
trol Fed; 50: 2771.
Lawford, D.J., et al. 1954.. On the metabolism of some
aromatic nitro-compounds by different species of animals.
Jour. Pharm. Pharmacol. 6: 619.
Makhinya, A.P. 1969. Comparative hygienic and sanitary-
toxicological studies of nitrophenol isomers in relation
to their normalization in reservoir waters. Prom Zagryazneniya
Vodoemov. 9: 84.
Phipps, G.L., et al. The acute toxicity of phenol and sub-
stituted phenols to the fathead minnow. (Manuscript).
U.S. EPA. 1976. Frequency of organic compounds identified
in water. U.S. Environ. Prot. Agency. Contract No. EPA
600/4-76-062.
U.S. EPA. 1978. In-depth studies on health and environ-
mental impacts of selected water pollutants. Contract No.
68-01-4646..
U.S. EPA. 1979. Nitrophenols: Ambient Water Quality Cri-
teria (Draft) .
-------
No. 136
Nitrophenols
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
J36'l
-------
DISCLAIMER
This report represents a survey of- the potential health
and environmental hazards from exposure to the subject chemi-
cal.. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
.. ( f f\L
" f ]} V I
-------
NITROPHENOLS
SUMMARY
None of the nitrophenols have shown carcinogenic activity.
Mutagenicity testing has indicated positive effects
of: 2,4-dinitrophenol in mouse bone marrow cells and E.
coli; 2,4,6-trinitrophenol in E. coli and Salmonella; and
4,6-dinitro-ortho-cresol in Proteus. Weak mutagenic effects
of 4-nitrophenol have been reported in Saccharomyces and
in Proteus. Other mutagenic test assays have shown negative
results for these compounds.
Teratogenic effects have been reported in the develop-
ing chick embryo following administration of 2,4-dinitro-
phenol. This compound did" not produce teratogenic effects
in mammalian studies. Adverse reproductive effects (embryo
toxicity) were seen- in rats exposed to 2,4-dinitrophenol.
{The chronic effects of 2,4-dinitrophenol ingestion
have included cases of agranulocytosis, neuritis, functional
heart damage, and cataract formation. Ingestion of 4,6-
dinitro-ortho-cresol has also produced cataracts in humans.
One Russian study has reported cumulative toxic effects
in animals produced by the mononitrophenols; methodology
of this study was not available for review.
Freshwater fish appeared to be the most sensitive or- •
ganism to the action of nitrophenols, wi'th acute values
ranging from 230 to 167,000 ug/1. The reactivities of vari-
ous nitrophenols in order of decreasing toxicity are, in .
general: 2,4-dinitro-6-methylphenol, 2,4-dinitrophenol,
2-nitrophenol, 4-nitrophenol, and 2,4,6-trinitrophenol.
-------
NITROPHENOLS
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Nitrophenols (U.S. EPA, 1979).
The nitrophenols are a family of compounds which, de-
pending on the extent and position of nitro group substituents,
include the mononitrophenols, dinitrophenols, and trinitro-
phenols. Dinitrocresols are related compounds bearing an
additional 2-position methyl group. The mononitrophenols
(molecular weight 139.11) show boiling points from 194-279°C
(depending on the isoraeric form) and melting points of 44—
114°C. They have a density of 1.485 and are soluble in
water. The dinitrophenols (molecular weight 184.11) have
melting points from 63.5-144°C and show a density of 1.67
to 1.70. Water solubility is from 0.42 to 2.3 g/1. Tri-
nitrophenols (molecular weight 229.11) have melting points
from 96-123°C; they are slightly soluble in water. 2,4,6-
Trinitrophenol, the most widely used isomer, has a density
of 1.763 g/ml and a solubility of 1.28 g/1. Of the six
isomers of dinitrocresol, 4,6-dinitro-o-cresol is the only
one of any commercial importance. The physical properties
of 4,6-dinitro-o-cresol, hereafter referred to as dinitro-
ortho-cresol, include a molecular weight of 198.13, a melt-
ing point of 85.8°C and a solubility of 100,mg/l in water
(U.S. EPA, 1979).
Uses of the mononitrophenols include the following:
production of dyes, pigments, Pharmaceuticals, rubber chemi-
-------
cals, lumber preservatives, photographic chemicals, and
pesticidal and fungicidal agents. The dinitrophenols are •
used as chemical intermediates for sulfur dyes, azo dyes,
photochemicals, pest control agents, wood preservatives,
and explosives. 2,4,6-Trinitrophenol (picric, acid) is used
for dye intermediates, germicides, tanning agents, fungi-
cides, tissue fixative, photochemicals, Pharmaceuticals,
and for the etching of metal surfaces. Dinitro-ortho-cresol
is used primarily as a blossom-thinning agent on fruit trees
and as a fungicide, insecticide, and miticide on fruit trees
during the dormant season (U.S. EPA, 1979).
Current Production: 2-nitrophehol 5-. 7.5x10 tons/year .(1976)
4-nitrophenol 17.5x10 tons/year (1976)
2
2,4-dinitrophenol 4.3x10 tons/year (1968)
The nitrophenols may be formed via microbial degrada-
tion or photodegradation of pesticides (e.g., parathion)
containing the nitrophenol moiety (U.S. EPA, 1979). Partial
microbial degradation of certain nitrophenols has been shown,
particularly by acclimated microorganisms. Mononitrophenols
appear to be efficiently degraded by unacclimated microorgan-
isms (Haller, 1978).
II. EXPOSURE
The lack of monitoring data on the nitrophenols makes
it difficult to assess exposure from water, inhalation,
and foods. Nitrophenols in water have been detected in
•a-
-V 6 W "
-------
effluents from chemical plants (U.S. EPA, 1976; 1979) or
following dumping of explosives (Harris, et al. 1946).
Dermal absorption of mononitrophenols, dinitrophenols, tri-
nitrophenols (picric acid), and dinitro-ortho-cresol (DNOC)
has been detected .(U.S. EPA, 1979).
Exposure to nitrophenols appears to be primarily through
occupational contact (chemical plants, pesticide applica-
tion) . Contaminated water may result in isolated poisoning
incidents.
•
The U.S. EPA (1979) has estimated weighted average
bioconcentration factors for the following nitrophenols:
2-nitrophenol, 4.0; 4-nitrophenoJL, 4.9; 2,4-dinitrophenol,
2.4; 2,4,6-trinitrophenol, 6.0; and 4 ,6-dinitrocresol, 7.5
for fish and shellfish consumed by Americans. This estimate
is based on octanol/water partition coefficients.
III. PHARMACOKINETICS
A. Absorption
Specific data on the absorption of the mononitro-
phenols is not available. The dinitrophenols are readily
absorbed following oral, inhalation, or dermal administra-
tion. Data on the absorption of trinitrophenols is not
available. Animal studies with oral administration of 2,4,6-
trinitrophenol indicate that it is readil-y absorbed from
the gastrointestinal tract. Dinitro-ortho-cresol is readily
absorbed through the skin, the respiratory tract, and the
»
gastrointestinal tract in humans (NIOSH, 1978).
-------
B. Distribution
No information on the distribution of the raono-
nitrophenols is available. Dinitrophenol blood levels rise
rapidly af-ter absorption, with little subsequent distribu-
tion or storage at tissue sites (U.S. 2PA, 1979) . 2,4,6-
Trinitrophenol and dinitro-ortho-cresol have been found
to stain several body tissues; however, the compounds may
be bound to serum proteins, thus producing non-specific
organ distribution (U.S. SPA, 1979).
C. Metabolism
Metabolism of the nitrophenols occurs through
conjugation, reduction of nitro groups to amino groups,
or oxidation to dihydric-nitrophenols (U.S. EPA, 1979) .
These reactions are mediated primarily by liver enzyme systems,
although other tissues show lower metabolizing activity
(U.S. EPA, 1979) . The metabolism of dinitro-ortho-cresol
is very slow in man as compared to that observed in animal
studies (King and Harvey, 1953) .
Q. Excretion
Evidence from human poisoning with parathion indi-
cates that excretion of 4-nitrophenol in the urine is quite
rapid (Arteberry, at al. 1961). Experiments with urinary
clearance of dinitrophenols in several animal species indi-
cate rapid elimination of these compounds (Harvey, 1959) .
2,4,6-Trinitrophenol has been detected in the urine of ex-
posed human subjects indicating at least partial urinary
elimination (Harris, et al. 1946). The experiments of Parker
136-7
-------
and coworkers (1951) in several animal species indicate
that dinitro-ortho-cresol is rapidly excreted following
injection; however, Harvey, et al. (1951) have shown slow
excretion 'of dinitro-ortho-cresol in human volunteers given
the compound orally.
IV.. EFFECTS
A. Carcinogenicity
There are no available data to indicate that the
mononitrophenols are carcinogenic. Both 2- and 4-nitrophenol
failed to show promoting activity for mouse skin tumors
(Boutwell and Bosch, 1959); this same study failed to show
promoting activity for 2,4-dinitrophenol. No evidence is
available to indicate that dinitrophenols, trinitrophenols,
or dinitro-ortho-cresol produce any carcinogenic effects
(U.S. EPA, 1979).
B. Mutagenicity
A weak mutagenic effect was detected in Saccharo-
myces cerevisiae for 4-nitrophenol (Fahrig, 1974); this
was also indicated by testing 4-nitrophenol for growth in-
hibition in a DNA repair deficient strain of Proteus mirabilis
(Adler, et al. 1976). This compound has also induced chromo-
some breaks in plants (U.S. EPA, 1979). 4-Nitrophenol has
failed to show mutagenic effects in the Ames assay, in E.
coli, or in the dominant lethal assay (U.S.,EPA, 1979).
Testing of 2,4-dinitrophenol has indicated muta-
genic effects in E. coli (Demerec, et al. 1951) and damage'
in murine bone marrow cells (chromatid breaks) (Mitra and
iManna, 1971) . Tn vitro assays of unscheduled DNA synthesis
-------
(Friedman and Staub, 1976) and DNA damage induced during
call culture (Swenberg, et ai. 1976) failed to show positive
results with this compound.
'2,4,6-Trinitrophenol has produced mutations in
E. coli and Salmonella assays (Demerec, et al. 1951; Yoshikawa,
et al. 1976) . Testing in Drosop'nila has failed to indicate
mutagenic activity.
Adler, et al. (1976) have reported that dinitro-
ortho-cresol shows some evidence of producing DNA damage
in Proteus mirabilis. Testing of this compound in the Ames
Salmonella system (Anderson, et al. 1972) or in E. coli
(Nagy, et al. 1975) failed to show any mutagenic effects.
C. Teratogenicity
No information is available to indicate that mono-
nitrophenols, 2,4,6-trinitrophenol, or dinitro-ortho-cresol
produce teratogenic effects.
2,4-Dinitrophenol has produced developmental abnor-
malities in the chick embryo (Bowman, 1967; Miyamoto, et
al. 1975). No teratogenic effects were observed following
intragastric administration to rats (Wulff, et al. 1935)
or intraperitoneal administration to mice (Gibson, 1973).
D. Other Reproductive Effects
Feeding of 2,4-dinitrophenol to. pregnant rats
produced an increased mortality in offspring (Wulff, et
al. 1935); similarly, intraperitoneal administration of
the compound to mice induced embryotoxicity (Gibson, 1973) '
-------
Influence of the compound on maternal health may have contri-
buted to these effects (U.S. EPA, 1979).
E. Chronic Toxicity
• Chronic administration of mononitrophenols to
mammals has been reported to produce hepatitis, splenic
hyperplasia, and neurological symptoms in a single Russian
study (Makhinya, 1969). Methodology of this study was not
available for review.
Use of 2,4-dinitrophenol as a human dieting aid
has produced some cases of agranulocytosis, neuritis, func-
tional heart damage, and a large number of cases of cataracts
(Homer, 1942). Cataracts have also been reported in patients
poisoned with dinitro-ortho-cresol (NIOSH, 1978).
Human effects resulting from 2,4,6-trinitrophenol
exposure have been reported as temporary impairment of speech,
memory, walking, and reflexes (Dennie, et al. 1929).
F. Other Relevant Information
A synergistic action in producing teratogenic
effects in the developing chick embryo has been reported
with a combination of 2,4-dinitrophenol and insulin (Landauer
and Clark, 1964).
The combination of 2,4,6-trinitrophenol and opioids
or minor analgesics produced an increase in analgesia (Huidobro,
1971).
2,4-Dinitrophenol is a classical uncoupler of
oxidative phosphorylation, which accounts for its marked
acute toxicity. Dinitro-ortho-cresol is also well known
for its activity as an uncoupler.
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
Freshwater fish LC values reported for the blue-
gill (Lepomis macrochinus) ranged from 230 to 167,000 ug/1
and for the juvenile fathead minnow (Pimephales promelas),
from 2,040 to 60,510 ug/1. The order of decreasing toxicity
for five nitrophenols examined was: 2,4-dinitro-6-methyl
phenol, 2,4-dinitrophenol, 2-nitrophenol, 4-nitrophenol,
•
2,4,5-trinitrophenol (U.S. EPA, 1979). For three of the
phenols tested with both the bluegill and fathead minnow,
»
the bluegill appeared more sensitive. In static bioassays
with the freshwater invertebrate, Daphnia magna, 48-hour
LC5Q values of 4,090 to 4,710; 8,396 to 21,900; and 84,700
ug/1 were reported for 2,4-dinitrophenol, 4-nitrophenol
and 2,4,6-trinitrophenol, respectively (U.S. ,SPA, 1979).
The marine fish, sheepshead minnow (Cyprinodon variegatus),
was the only fish species acutely tested for three nitro-
phenols, with reported LC5Q values of 29,400; 27,100 and
134,000 ug/1 being obtained for 2,4-dinitrophenol, 4-nitro-
phenol, and 2,4,6-trinitrophenol. Observed LC.-Q values
of 4,350; 7,170 and 19,700 ug/1 were reported for the mysid
shrimp (Mysidopsis bahia) for the same three formulations,
respectively.
3. Chronic Toxicity
Pertinent information on the chronic effects on
freshwater species could not be located in the available
literature searches. The only chronic test on a marine
-------
species was an embryo-larval assay of the sheepshead minnow
that produced a chronic value of 6,325 ug/1 (U.S. EPA, 1978).
Pertinent information relative to chronic effects on marine
invertebrates could not be located in the available literature.
C. Plant Effects
The effects of various nitrophenols vary widely
among species of freshwater plants and according to the
formulation of nitrophenol tested. The duckweed, Lemna
minor, was the most sensitive plant tested with 2,4-dinitro-
phenol and was the most resistant with 2-nitrophenol, hav-
ing effective concentrations (50 percent growth reduction,
time unspecified)ranging from 1,472 to 62,550 ug/1 for the
two respective formulations. The marine alga, Skeletonema
costatum, appeared to be slightly more resistant than fresh-
water species tested, with effective concentrations ranging
from 7,370 to 141,000 ug/1 for 4-nitrophenol and 2,4,6-tri-
nitrophenol, respectively.
D. Residues
Bioconcentration factors were not determined for
any freshwater or marine species. However, based on octanol/
water partition coefficients, bioconcentration factors were
estimated as 8.1, 21, and 26 for 2,4-dinitrophenol, 2,4,5-
trinitrophenol, and 2,4-dinitro-6-dimethylphenol, respectively.
VI. EXISTING GUIDELINES AND STANDARDS
The human health and aquatic criteria derived by U.S.
EPA (1979), which are summarized below, have not yet gone
through the process of public review; therefore, there is
a possibility that these criteria may be changed.
/ 3 6-
-------
A. Human
Eight-hour TWA exposures for 2,4,6-trinitrophenol
(0.1 mg/m ) and 4,6-dinitro-ortho-cresol (0.2 rag/m ) have
been established by the ACGIH (1971).
Draft, water quality criteria for the following
nitrophenols have been estimated, by U.S. SPA (1979) based
on adverse effects data: dinitrophenols - 63.6 pg/1; tri-
nitrophenols - 10 /ig/1; and dinitrocresols - 12.3 }ig/l.
B. Aquatic
Criteria drafted to protect freshwater life from
nitrophenols follow: 57 ^g/1 as a 24-hour average concen-
tration, not to exceed 130 ug/1, for 2,4-dinitro-6-methyl-
phenol; 79 jug/1, not to exceed 180 ug/1, for 2,4-dinitro-
phenol; 240 ug/1, not to exceed 550 ug/1, for 4-nitrophenol;
2,700 pg/1, not to exceed 6,200 pg/1, for 2-nitrophenol;
and 1,508 ug/1, not to exceed 3,400 ug/1, for 2,4,6-trinitro-
phenol. For marine life the following criteria have been
drafted as 24-hour average concentrations: 37 ug/1, not
to exceed 84 ug/1, for 2,4-dinitrophenol; 53 pg/1, not to
exceed 120 pg/1, for 4-nitrophenol; and 150 ug/1, not to
exceed 340 g/1, for 2,4,6-trinitrophenol.
if (11
J U I B^
I36-/3
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NITROPHENOLS
REFERENCES
Adler, B., et al. 1976. Repair-defective mutants of Proteus
mirabilis as a prescreening system for the detection of po-
tential carcinogens. Biol. Zbl. 95: 463.
American Conference of Governmental Industrial Hygienists.
1971. Documentation of the threshold limit values for sub-
stances in workroom air. Vol. 1. 3rd ed. Cincinnati, Ohio.
Anderson, K.J., et al. 1972. Evaluation of herbicides for
possible mutagenic properties. Jour. Agric. Food Chem. 20:
649.
Arterberry, J.D., et al. 1961. Exposure to parathion: Mea-
surement by blood cholinesterase level and urinary p-nitro-
phenol excretion. Arch. Environ. Health 3: 476.
Boutwell, R.K., and O.K. Bosch. 1959. The tumor-promoting
action of phenol and related compounds for mouse skin.
Cancer Res. 19: 413.
Bowman, P. 1967. The effect of 2,4-dinitrophenol on the
development of early chick embryos. Jour. Embryol. Exp..
Morphol. 17: 425.
Demerec, M., et al. 1951. A survey of chemicals for muta-
genic action on E_. coli. Am. Natur. 85: 119.
Dennie, C.C., et al. 1929. Toxic reactions produced by the
application of trinitrophenol (picric acid). Arch. Dermatol.
Sypnilol. 20: 698.
Fahrig, R. 1974. Comparative mutagenicity studies with Pes-
ticides. Pages 161-181 In; R. Montesano and L. Tomatis.
(eds.) Chemical carcinogenesis essays. Proc. workshop on
approaches to assess the significance of experimental chemi-
cal carcinogenesis data for man. Organized by IARC and the
Catholic University of Louvain, Brussels, Belgium. IARC Sci.
Publ. No. 10. Int. Agency Res. Cancer, World Health Organi-
zation.
Friedman, M.A., and J. Staub. 1976. Inhibition of mouse
testicular DMA synthesis by mutagens and carcinogens as a po-
tential simple mammalian assay for mutagenesis. Mutat. Res.
37: 67.
Gibson, J.E. 1973. Teratology studies in mice with 2-sac-
butyl-4, 6-dinitrophenol (dinoseb). Food Cosmet. Toxicol.'
11: 31.
-------
Haller, H.D, 1978. Degradation of mono-substituted benzo-
ates and ohenols by wastewater. Jour. Water Pollut. Control
Fed. 50: 2771.
Harris, A.H., et al. 1946. Hematuria due to picric acid
poisoning at a naval anchorage in Japan. Am. Jour. Pub.
Health 3.6: 727.
Harvey, D.G. 1959. On the metabolism of some aromatic nitro
compounds by different species of animal. Part III. The
toxicity of the dinitrophenols, with a note on the effects of
high environmental temperatures. Jour. Pharm. Pharmacol.
11: 462. »•
Harvey, D.G., et al. 1951. Poisoning by dinitro-ortho-cre-
sol. Some observations on the effects of dinitro-ortho-cre-
sol administration by mouth to human vplunteers. 3r. Med.
Jour. 2: 13.
Horner, W.D. 1942. Dinitrophenol and its relation to forma-
tion to cataracts. Arch. Ophthal. 27: 1097.
Huidobro, F. 1971. Action of picric acid on the effects of
some drugs acting on the central nervous system, with special
reference to opiods. Arch. Int. Pharmacodyn Ther. 192:.
362.
Xing, E., and D.G. Harvey. 1353. Some observations on the
absorption and excretion of 4,6-dinitro-o-creosol .(DNOC). I.
Blood dinitro-o-cresol levels in the cat and rabbit following
different methods of absorption. Biochem. Jour. 53: 185.
Landauer, W. , and E. Clark. 1964. Uncouplers of oxidative
ohosphorylation and teratogenic activity of insulin. Nature
204: 285.
Makhinya, A.P. 1969. Comparative hygienic and sanitary
toxicological studies of nitrophenol isomers in relation to
their normalization in reservoir waters. Prom. Zagryazneniya
Vodoemov. 9: 84. (Translation).
Mitra, A.B., and G.K. Manna. 1971. Effect of some phenolic
compounds on chromosomes of bone marrow cells of mice. In-
dian Jour. Med. Res. 59: 1442.
Miyamoto, K., et al. 1975. Deficient myelination by 2,4-
dinitrophenol administration in early stage of development.
Teratology 12: 204.
Nagy, A., et al. 1975. The correct mutagenic affect of pes-
ticides on Escherichia coli WP2 strain. Acta. Microbiol. '
Acad. Sci. Hung.22: 309.
-------
National Institute for Occupational Safety and Health. 1978.
Criteria for a recommended standard: Occupational exposure to
dinitro-ortho-creosol. Dep.. Health Edu. Welfare, Washing-
ton, D.C.
Parker, V.H., et al. 1951. Some observations on the toxic
properties of 3,5-dinitro-ortho-cresol. Br. Jour. Ind. .Med.
9: 226.
Swenberg,' J.A., et al. 1976. In vitro DNA damage/akaline
elution assay for predicting carcinogenic potential.
Biochem. Biophys. Res. Cbiranun. 72: 732.
U.S. EPA. 1976. Frequency of organic compounds identified
in water. U.S. Environ. Prot. Agency. Contract No. EPA
600/4-76-062.
U.S. EPA. 1978. In-depth studies on health and environmen-
tal impacts of selected water pollutants. Contract No.
6801-4646.
U.S. EPA. 1979. Nitrophenols: Ambient Water Quality Cri-
teria. (Draft).
Wulff, L.M.B., et al. 1935. Some effects of alpha-dinitro-
phenol on pregnancy in the white rat. Proc. Soc. Exp. Biol.
Med. 32: 678.
Yoshikawa, K., et al. 1976. Studies on the mutagenicity of
hair-dye. Kokurltsu Eisei Shikenjo 94: 28.
-------
No. 137
NItrosamines
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
nitrosamines and has found sufficient evidence to indicate
that this compound is carcinogenic.
-------
NITROSAMINE5
Summary
Nitrosamines and nitrosamides are widespread in the environment and can
also be produced end.ogenously by nitrosation of constituents of food. Ni-
trosamines and nitrosamides are considered to be among the most potent of
all carcinogenic, mutagenic, and teratogenic agents known. The livers of
rats chronically exposed to nitrosamines exhibit pathological changes.
Toxicity data examining the effects of nitrosamines on aquatic organ-
isms is scant. For freshwater life forms, acute toxicity levels of 5,850 to
7,760 ug/1 were reported, while for marine fish an acute value of nearly
3,300,000 ug/1 was reported (both values for N-nitrosodiphenylamine). N-ni-
trosodimethylamine has been shown to induce hepatocellular carcinoma .in
rainbow trout.
i / i &
*~) v> I
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NITROSAMINES
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Nitrosamines (U.S. EPA, 1979).
The nitrosamines _(and nitrosamides) belong to a large group of chemi-
cals generally called N-nitroso compounds. Because they frequently coexist
with N-nitrosamines in the environment and are structurally related to ni-
trosamines, nitrosamides .are also included in the U.S. EPA (1979) document
and in .this profile.
The nitrosamines vary widely in their physical properties and may exist
as solids, liquids or gases. Nitrosamines of low molecular weight are vola-
tile at room temperature, while those of high molecular weight are steam
* ' •
volatile. Nitrosamines are soluble in water and organic solvents (U.S. SPft,
1976) .
Synthetic production of nitrosamines is limited" to small quantities.
The only nitrosamine produced in quantities greater than 450 kg per year is
N-nitrosodiphenylamine, which is used in rubber processing and in the manu-
facture of pesticides. Other N-nitroso compounds are produced primarily as
research chemicals (U.S. EPA,. 1976).
Nitrosamines are rapidly decomposed by sunlight and thus do not persist
in ambient air or water illuminated by sunlight (U.S. EPA, 1979; Fine, at
al. 1977a). Some nitrosamines have been found to persist for extended peri-
ads of time in the aquatic environment (Fine, at. al. 1977a; Tate and Alex-
ander, 1975).
II. EXPOSURE
»
Nitrosamines are widespread in the environment. The most probable
source of environmental nitrosamines is nitrosation of amine and amide ' pre-
cursors which are ubiquitous in the environment (Bogovsxi, et.al. 1972).
Y
-------
It has been estimated that air, diet, and smoking all play a roughly
equivalent role in human exposure to preformed nitrosamines, contributing a
few micrograms per day; intake from drinking water is probably much less
than 1 ug per day (U.S. EPA, 1976).
A. Water
Significant concentrations of nitrosamines have been reported for a
limited number of samples of ocean water, river water, and waste treatment
plant effluent (3 to 4 ug dimethylnitrosamine/1) adjacent to or receiving
wastewater from industries using nitrosamines or secondary amines in produc-
tion operations (Fine, et al. 1977b). Well water with high nitrate levels
and coliform counts had nitrosamine concentrations of less than 0.015 ug/1
(U.S. EPA, 1977). Non-volatile nitrpsamines have been tentatively identi-
fied in New Orleans drinking water at levels of 0.1 to 0.5 ug/1 (Fine, .-.at
al. 1976).
Contamination of water can occur both from industrial wastewater
and from agricultural runoff.
3. Food
Nitrosamines have been found in foods, particularly in meats such
as sausages, ham, and bacon which have been cured with nitrite. N-nitroso-
dimethylamine was present in a variety of foods in the 1 to 10 ug/kg range
and occasionally at levels up to 100 ug/kg (Montesano and Bartsch, 1976).
N-nitrosopyrrolidine has been consistently found in cooked bacon in the
range of 10-50 ug/kg (Fine, et al. 1977a).
Many food constituents can either be converted directly to N-nitro-
so compounds or give rise to nitrosatable products after a metabolic inter-
#
mediate step which can be involved directly or indirectly in such reactions.
,. / / o^L^
7 0 ^
*
137-6
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Constituents include nitrate, nitrite, some amino acids, choline, phospholi- •
pids, purines, pyrimidines, some vitamins, caffeine, and some pesticides
(Walters, 1977; Elsperu and Lijinsky, 1973).
Nitrate and nitrite are well supplied in the diet. Eighty-six per-
cent of the nitrate ingested comes from vegetables; 9 percent comes from.
cured meats. Only 2 percent of the nitrite ingested comes from vegetables,
while 21 percent comes from cured meat (White, 1975).
The U.S. EPA (1979) has estimated the weighted average bioconcen-
tration factor to be 500 for N-nitrosodiphenylamine in the edible portions
of fish and shellfish consumed by Americans. This estimate is based on mea-
sured steady-state bioconcentration studies with bluegills. Based on the
octanol/water partition coefficient for. each compound, the U.S. EPA (1979)
has estimated weighted average bioconcentration factors for the following-.
compounds in the edible portions of fish and shellfish consumed by Ameri-
cans: N-nitrosodimethylamine, 0.06; N-nitrosodiethylamine, 0.39; N-nitroso-
di-n-butylamine, 4.9; and N-nitrosopyrrolidine, 0.12.
C. Inhalation
Due to the photolabile nature of nitrosamines, concentrations in
• ambient air are very low, except near sources of direct emissions of nitros-
amines (i.e. chemical plants) (Fine, at al. 1977a). Nitrosamines were de-
tected only twice at 40 collection points in New Jersey and New York City,
and then only below the 0.01 ug/m level.
Tobacco and tobacco smoke contain both secondary amines and nitros-
amines (Hoffman, st al. 1974). The intake of nitrosamines from smoking 20
cigarettes per day has been estimated at approximately 6 pg/day (U.S. EPA,
1979).
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III. PHARMACOKINETICS
A. Absorption
Pertinent data could not be located in the available literature.
B. Distribution
Following intravenous injection into rats, nitrosamides and nitros-
amines are rapidly and fairly uniformly distributed throughout the body
(Magee, 1972; Stewart, et al. 1974). Both nitrosamides and nitiosamines ap-
pear to cross the placenta since they induce neoplasms in offspring if ad-
ministered maternally to rats in late pregnancy (Magee, et al. 1976).
C. Metabolism and Excretion
Nitrosamides are rapidly metabolized in animals and excreted in the
urine within 24 hours (Magee, et al. 1976)..
Nitrosamines are metabolized less rapidly and persist in the body
unchanged for a longer period. The rate of metabolism depends upon the
chemical structure (U.S. EPA, 1979).
After administration of C-labeled dimethylnitrosamine, diethyl-
nitrosamine, or nitrosomorpholine, the amount of isotope appearing as
14
C02 within 12 hours is 60, 45, and 3 percent, respectively, while the
corresponding urinary excretions are 4, 14, and 80 percent. Urinary metabo-
lites include other nitroso compounds formed by oxidation of the alkyl
groups to the alcohols and carboxylic acids (Magee, et al. 1976). Dimethyl-
nitrosamine is excreted in the milk of female rats (Schoental, et al. 1974).
The liver appears to be the major site for' metabolism of nitrosa-
mines; kidney and lung also metabolize nitrosamines ('Magee, et al. 1976).
The metabolites of nitrosamines are thought to be the active teratogenic,
»
mutagenic and carcinogenic forms (U.S. EPA, 1979).
-------
IV. EFFECTS
A. Carcinogenicity
The epidemiological studies conducted to date have been inadequate
to establish any correlation between exposure to N-nitroso compounds or
their precursors and human cancer (U.S. EPA, 1979).
In animals, nitrosamines and nitrosamides are potent carcinogens,
inducing tumors in essentially all vital organs via all routes of admini-
stration (Montesano and Bartsch, 1976; Druckrey, at al. 1967).
Many of the N-nitroso compounds which have been tested are carcino-
genic. There is a strong relationship between chemical structure and type
of tumors produced. Symmetrically substituted dialkylnitrosamines and some
cyclic nitrosamines produced carcinomas.of the liver. Asymmetrical dialkyl-
nitrosamines produced carcinomas of the esophagus (Druckrey, et al. 1967)r<
Apparently all N,N-dialkylnitrosamines containing a tert-butyl group are
noncarcinogenic (Heath and Magee, 1962).
There are large differences in species response to carcinogenic
nitrosamines and nitrosamides, both in type of tumor produced and in suscep-
tibility, but all animal species tested are vulnerable. The late fetus and
neonate appear to be highly susceptible (U.S. EPA, 1979). Exposure to
nitrosamides during pregnancy may result in a risk not only to the immediate
offspring, but also for at least two more generations of animals (Montasano
and Sartsch, 1976). There is no evidence to indicate that nitrosamines pose
a similar threat (U.S. EPA, 1979).
Daily oral doses of N-nitroso compounds 'of 2.5 percent of the
LDjQ values were sufficient to induce cancer in rats (Druckrey, et al.
1967).
3 7-
-------
8. Mutagenicity
The N-nitroso compounds include some of the most powerful mutagens
known. Nitrosamides are mutagenic in almost all test systems, due to non-
i
enzymic formation of active degradation products. Nitrosamines must be
metabolically activated to be mutagenic in microbial assays (U.S. EPA, 1979).
Oimethylnitrosamine and diethylnitrosamine have been reported to
induce forward and reverse mutations in §_._ typhimurium, E^ coli, Neurospora
crassa and other organisms; gene recombination and conversion in Saccharo-
myces cerevisiae; "recessive lethal mutations" in Drosophila; and chromosome
aberrations in mammalian cells (Montesano and Bartsch, 1976). Negative re-
sults were obtained in the mouse dominant lethal test.
C. Teratogenicity
N-nitroso compounds can be potent teratogens (U.S. EPA, 1979.).
Nitrosamides are teratogenic over an extended period of gestation, whereas
nitrosamines are active only when administered late in pregnancy (Druckrey,
1973) probably because of the inability of the embryonic tissue to metabo-
lize nitrosamines during early pregnancy (Magee, 1973).
0. Other Reproductive Effects
Nitrosamines and nitrosamides are embryotoxic (Druckrey, 1973).
E. Chronic Toxicity
The livers of rats and other species chronically exposed to nitros-
amines exhibit pathological changes including biliary hyperplasia, fibrosis,
nodular parenchymal hyperplasia, and the formation of enlarged hepatic par-
enchymal cells with large nuclei (Magee, et al. 1976).
137-1°
-------
F. Other Relevant Information
Unlike nitrosamines , nitrosamides cause tissue injury at the site
of contact (Magee, et al. 1976). This is thought to be due to the nonenzy-
matic decomposition of nitrosamides into active products upon contact with
tissues.
Aminoacetonitrile , which inhibits the metabolism of dimethylnitros-
amine, prevented the toxic and carcinogenic effects of dimethylnitrosamine
in rat- liver (Magee, et al. 1976).
Ferric oxide, cigarette smoke, volatile acids, aldehydes, methyl
nitrite, and benzo(a)pyrene have been suggested to act in a cocarcinogenic
manner with dimethylnitrosamine (Stenback, et al. 1973; Magee, et al. 1976).
V. AQUATIC TOXICITY
A. Acute Toxicity
The LC5Q value of 5,850 ug/1 for bluegill sunfish (Lsoomis macro-
chirus) exposed to N-oitrosodiphenyiamine represents the sole acute toxicity
data for freshwater fish, while an LCCQ value of 7,760 ,ug/l was obtained j
for the freshwater invertebrate, Daohnia maqna (U.S. EPA, 1978). The marine
mummichog (Fundulus heteroclitus) was relatively resistant to N-nitrosodi-
methyiamine in a 96-hour static test, where an adjusted LC5Q value of
3,300,000 ug/i was reported (Ferraro, et al. 1977). NO additional data con-
cerning marine organisms was presented in the Ambient Water Quality Criteria
Document (U.S. EPA, 1979).
3. Chronic Toxicity
The chronic effects of M-nitrosodiphenyl anrine have been examinee
in Daohnia maqna, with no adverse effects being reported at a concentration
•
of 48 ug/1. NO chronic data concerning marine organisms were found in the
available literature.
-LL 1 / -
^^^^^^^^^^
?
137-U
-------
C. Plant Effects
Pertinent data could not be located in the available literature.
D. Residues
A bioconcentration factor of 217 was reported, as was.a biological
half-life of less than .one day in the freshwater bluegill sunfish (U.S. EPA,
1978). No data on residues in marine life were found in the available lit-
erature.
E. Miscellaneous
Shasta strain rainbow trout (Salmo gairdneri) fed N-nitrosodi-
methylamine in their diet for 52 weeks developed a dose-response occurrence
of hepatocellular carcinoma at doses of 200, 400, and 800 mg N-nitrosodi-
methylamine per kg body weight (Grieco, et al. 1978).
VI. EXISTING GUIDELINES AND STANDARDS ^
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed.
A. Human
Using the "one-hit" model, the U.S. EPA (1979) has estimated the
following levels of nitrosamines in ambient water which will result in spe-
cified risk levels of human cancer.
The water concentration of dimethylnitrosamine corresponding to a
lifetime cancer risk for humans of 10~ is 0.026.-ug/l, based on the induc-
tion of liver tumors in rats (Druckrey, 1967).
The water concentration of dibutylnitrosamine corresponding to a
c •
lifetime cancer risk for humans of 10 is 0.013 ug/1, based on induction
of tumors of the bladder and esophagus in mice (Bertram and Craig, 1970).
-M&r-
13
-------
The water concentration of N-nitroso-pyrrolidine corresponding to a •
lifetime cancer risk for humans of 10 is 0.11 ,ug/l, based on the induc-
tion of hepatocellular carcinomas in rats (Preussman, et al. 1977).
NO other guidelines or standards are available.
B. Aquatic
No criteria for freshwater or marine life have been drafted (U.S.
EPA, 1979).
-------
NITROSAMINES
REFERENCES
Bertram, J-.S., and A.W. Craig. 1970. Induction of bladder
tumours in mice with dibutylnitrosamine. Br. Jour. Cancer
24: 352.
Bogovski, P., et al. 1972. N-nitroso compounds, analysis
and formation. IARC Sci. Pub. No. 3. Int. Agency Res.
Cancer, Lyon, France.
Druckr.ey, H., et al. 1967. Organotropic carcinogenic action.
of 65 different N-nitroso compounds in BD rats. Z. Krebs-
forsch. 69: 103.
Druckrey, H. 1973.* , Specific carcinogenic and teratogenic
effects of "indirect" alkylating methyl and ethyl compounds,
and their dependency on stages of oncogenic development.
Xenobiotica 3: 271.
Elsperu, R., and W. Lijinsky. 1973. The formation of N-
nitroso compounds from nitrite and some agricultural, chemi-
cals. Food Cosmet. Toxicol. 11: 807.
Ferraro-, A.F., et al. 1977. Acute toxicity of water-borne
dimethylnitrosamine (DMN) to Fundulus heteroclitus (L).
Jour.- Fish. Biol. 10: 203.
Fine, D.H., et al. 1976. N-Nitroso compounds in air and
water. IARC Sci. Publ. No. 14. Int. Agency Res. Cancer,
Lyon, France.
• «•»
Fine, D.H., et al. 1977a. Human exposure to N-nitroso
compounds in the environment. In: H.H. Hiatt, et al.,
eds. Origins of human cancer. Cold Spring Harbor Lab.,
Cold Spring Harbor, New York.
Fine, D.H., et al. 1977b. Determination of dimethylnitro-
samine in air, water and soil by thermal energy analysis:
measurements in Baltimore, Md. Environ. Sci. Technol. 11:
581.
Grieco, M.P., et al. 1978, Carcinogenicity and acute toxi-
city of dimethylnitrosamine in rainbow trout (Salmo gaird-
neri). Jour. Natl. Cancer Inst. 60: 1127.
Heath, D.F., and P.N. Magee. 1962. Toxic properties of
dialkylnitrosamines and some related compounds. Br. Jour!
Ind. Med. 19: 276.
-------
N1.TSOSAM1NES
REFEBENC2S
Bertram, 3.S., and A.W. Craig. 1970. Induction of bladder
tumours in mica with dibutylnitrosamine. Br. Jour. Cancer
24: 352..
Bogovski, P., et al. 1972. N-nitroso compounds, analysis
and formation. IARC Sci. Pub. Ho. 3. Int. Agency Res.
Cancer, Lyon, France.
Druckrey, H., et al. 1967- Qrganotropic carcinogenic action.
of 65 different N-nitroso compounds in 3D rats. 2. Krebs-
forsch. 69: 103.'
Druckrey> H. 1973.* Specific carcinogenic and teratogenic
effects of "indirect" alkylating methyl and ethyl compounds,
and their dependency on stages of oncogenic development..
Xenobiotica 3: 271.
Slsperu, R., and W. Lijinsky. L973. The formation of N-
nitroso compounds from nitrite and some agricultural, chemi-
cals. Food Cosmet. Toxicol. 11: 807.
Ferrara,'A.F., at al. 1977. Acute toxicity of water-borne
dimethylnitrosamine (DMN) to Fundulus heteroclitus (L).
Jour.- Fish. Biol. 10: 203.
Fine, D.H., et al. 1976. N-Nitroso compounds in air and
water. IARC Sci. Publ. No. 14. Int. Agency Res. Cancer,
Lyon, France.
> <»
Fine, D.H., et al. 1977a. Human exposure to N-nitroso
compounds in the environment. In: H.H. Hiatt, et al.,
eds. Origins of human cancer. ~"£old Spring Harbor Lab.,
Cold Spring Harbor, New York.
Fine, D.H., et al. 1977b. Determination of dimethylnitro-
samine in air, water and soil by thermal energy analysis:
measurements in Baltimore, Md. Environ. Sci. Technol. 11:
581.
Grieco, M.P., et al. 1978. Carcinogenicity and acute toxi-
city of dimethylnitrosamine in rainbow trout (Salmo gaird-
neri). Jour. Natl. Cancer Inst. 50: 1127. "
Heath, D.F., and P.N. Magee. 1962. Toxic properties of
dialkyinitrosamines and some related compounds. Br. Jour'
Ind. Jled. 19: 276.
-------
Hoffman, D., et al. 1974. Chemical studies on tobacco
smoke. XXVI. On the isolation and identification of vola-
tile and non-volatile N-nitrosamines and hydrazines in ciga-
rette smoke. In; N-Nitroso compounds in the environment.
IARC Sci. Pub. No. 9. Int. Agency Res. Cancer, Lyon, France.
Magee, P.N. 1972. Possible mechanisms of carcinogenesis
and mutagenesis by nitrosamines. In; W. Nakahara, et al.,
eds. Topics in chemical carcinogenesis. University of
Tokyo Press, Tokyo.
Magee, P.N. 1973. Mechanisms of transplacental carcino-
genesis by nitroso compounds. In; L.. Tomatis and U. Mohr,
eds. Transplacental carcinogenesis, IARC Sci. Pub. No. .
4. Int. Agency Res. Cancer, Lyon, France.
Magee, P.N., et al. 1976. N-Nitroso compounds and related
carcinogens. In; C.S. Searle, ed. Chemical Carcinogens.
ACS Monograph No. 173. Am. Chem. Soc., Washington, D.C.
Montesano, R., and H. Bartsch. 1976. Mutagenic and carcino-
genic N-nitroso compounds: Possible environmental hazards.
Mutat. Res. 32: 179.
Preussmann, R., et al. 1977. Carcinogenicity of N-nitroso-
oyrrolidine: Dose-response study in rats. Z. Krebsforsch.
90: 161. " ..
Schoental, R., et al. 1974. Carcinogens in milk: Transfer
of ingested diethylnitrosamine into milk by lactating rats.
Br. Jour. Cancer 30: 238.
Stenback, ?., et al. 1973. Synergistic effect of ferric
oxide on dimethylnitrosamine carcinogenesis in the Syrian
golden hamster. Z. Krebsforsch. 79: 31.
Stewart, 3.W., et al. 1974. Cellular injury and carcino-
genesis.. Evidence for the alkylation of rat liver nucleic
acids in vivo by N-nitrosomorpholine. Z. Krebsforsch. 82:
1.
Tate, R.L., and M. Alexander. 1975. Stability of nitro-
samines in samples of lake water, soil and sewage. Jour.
Natl. Cancer Inst. 54: 327.
U.S. EPA. 1976. Assessment of scientific information on
nitrosamines. A report of an ad hoc study group of the
U.S. Environ. Prot. Agency Sci. Advis. Board Executive Comm.
Washington, D.C.
U.S. EPA. 1977. Scientific and assessment report on nitro-
samines. EPA 600/6-77-001. Off. Res. Dev. U.S. Environ.
Prot. Agency, Washington, D.C.
• • i / si i
**/ uj>
-------
U.S. EPA. 1978. In-depth studies on health and environ-
mental impacts of selected water pollutants. Contract No.
68-01-4646. U.S. Environ. Prot. Agency.
U.S. EPA. 1979. Nitrosamines: Ambient Water Quality Cri-
teria (Draft) .
Walters/ C.L. 1977. Nitrosamines - environmental carcinogens?
Chem. Br. 13: 140. '
White, J.W,, Jr. 1975. Relative significance of" dietary
sources of nitrate and nitrite. Jour. Agric. Food Chem.
23: 886. " ~"
-------
No. 138
N-Nitrosodiphenylamina
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
- i / '
-------
N-NITROSODIPHENYLAMINE
SUMMARY
Formation of N-nitrosodiphenylamine (NDPhA) has been shown
experimentally in the stomachs of individuals receiving nitrite
and diphenylamine. N-nitrosodiphenylamine undergoes photochemi-
cal decomposition in -solution or in the atmosphere in the
presence of sunlight. Bacterial degradation of NDPhA has been
demonstrated in soil.
Prior to the release of recent findings from the NCI bio-
assay program, NDPhA was considered a non-carcinogenic nitros-
amine. In the NCI lifetime rat feeding study, however, NDPhA was
found to induce a significant incidence of urinary bladder tumors
in both males and females. Few urinary bladder tumors were
observed in mice in a similar experiment, although there was a
high incidence of non-neoplastic bladder lesions.
N-nitrosodiphenylamine has consistently been found negative
in a variety of mutagenicity assays.
I. INTRODUCTION
This document is based on the Ambient Water Quality Criteria
Document on Nitrosamines (U.S. EPA, 1979b),..the Scientific and
Technical Assessment Report on Nitrosamines (U.S. EPA, 1977), and
other selected references. The term "N-nitrosodiphenylamine"
»
(NDPhA) in this report refers specifically to that compound; the
term "nitrosamine" when used in this report refers to nitrosa-
mines in general.
-------
• N-nitrosodiphenylamine (NDPhA; molecular weight 198.23;
molecular formula C]_2H10N2°^ ^s a yellow to brown or orange
powder or flakes. It has the following physical/chemical
properties (Hawley, 1977):
Melting Point: 64-66°C
Solubility: insoluble in water;
soluble in organic ~
•
solvents.
NDPhA is used as a vulcanization retarder in the rubber
industry (Hawley, 1977).
A review of the production range (includes importation)
statistics for N-nitrosodiphenylamine (CAS No. 86-30-6) which is
listed in the initial TSCA Inventory (1979a) has shown that
between 400,000 and 900,000 pounds of this chemical were pro-
duced/imported in 1977.-!/
II. EXPOSURE
A. Formation
The chemistry of formation of nitrosamines is quite complex,
however, they are in general formed by the combination of amines
(Rj_R2N-) with some nitrosating agent. Formation has been shown
to occur with primary, secondary, and tertiary amines, as well as
This production range information does not include any produc-
tion/importation data claimed as confidential by the person(s)
reporting for the TSCA Inventory, nor does it include any*
information which would compromise Confidential Business
Information. The data submitted for the TSCA Inventory,
including production range information, are subject to the
limitations contained in the Inventory Reporting Regulations
(40 CFR 710).
Tlf ' "7 ' —
^ ) U -J u
-------
other amino compounds. The nitrosating agent can be derived from
nitric oxides (NO, NO2, ^2°3' or N2°4^ or inor9anic nitrite (U.S.
EPA, 1977)'.
The in vivo formation of nitrosamines following ingestion of
precursors has been demonstrated in human and animal studies
(U.S. EPA, 1977) Sander and Seif (1969) showed the formation of
NDPhA in the stomachs of humans given- nitrite and diphenylamine.
B. Environmental Fate
In the absence of light, nitrosamines are quite stable and
will decompose hydrolytically only following prolonged contact
with strong acid. There is no evidence of thermal instability of
nitrosamines in the gas phase? however, they do undergo photo-
chemical decomposition in solution or in the atmosphere in the
presence of sunlight or ultra-violet light (U.S. EPA, 1977).
Transnitrosation reactions involving direct transfer of the
nitroso group from NDPhA to other amines have been demonstrated
(Challis and Osborn, 1972). Such a reaction yields-a new
N-nitroso compound and diphenylamine.
In unattended soil, 70% of added NDPhA was lost within 30
days. In soil amended with bacteria, added NDPhA had disappeared
completely at the end of day 10 (Mallik, 1979).
C. Bioconcentration
See Section V.C.
-------
III. PHARMACOKINETICS
Intestinal bacteria common in the gastrointestinal tract of
many animals and humans have been shown capable of degrading
NDPhA (Rowland and Grasso, 1975).
IV. HEALTH EFFECTS IN MAMMALS
A. Carcinogenicity
In a one-year study, Argus and Hoch-Ligeti (1961) adminis-
tered NDPhA by gavage to 25 male rats for 45 weeks (total dose
• •
244 mg/rat). So tumors were observed. In other studies (Boyland
.et^jal.', 1968) no tumors were seen when 20 rats were given the
test compound in the diet for 100 weeks at daily doses of 120
mg/kg, or when 24 male rats were administered DNPhA by intra-
peritoneal injection once per week for 6 months at a dose of 2.5
rag/week. Both tests were terminated after 2 years. When two
groups of mice (18 male and 18 female per group) were admin-
istered NDPhA by gavage daily for 3 weeks at 1,000 mg/kg', then in
diet at 3,769 ppm for 18 months, no significant incidences of
tumors were observed. However, in another assay reticulum cell
sarcomas were observed in the mice when the chemical was injected
subcutaneously (NCI, 1968; Innes jst_ _al>., 1969). Druckrey et al.
(1967) reported a lack of tumorigenicity in rats administered 120
mg/kg/day of NDPhA for 700 days, for a tota"! dose of 65 g/kg.
Taken together, these studies were viewed as a demonstration of
the non-carcinogenicity of NDPhA.
Recent results from the NCI bioassay program, however, have
demonstrated that NDPhA is a carcinogen in rats (NCI, 1979; Cardy
y
-------
^t_ jal_. / 1979). In these studies NDPhA was administered in the
diet to rats and mice at two doses, the "maximum tolerated dose"
for each species and one-half that amount. Groups of 50 animals
of each sex were tested at each dose for approximately 100
weeks. The study found that dietary exposure to NDPhA gave rise
to a significant incidence of urinary bladder tumors in both male
(40%) and female (90%) rats. Pew urinary bladder tumors.were
observed in the mice, although there was a high incidence of non-
neoplastic bladder lesions. The authors (Cardy _et_ ^1_. , 1979)
ascribed the strong carcinogenic effect seen in rats in this
study to the higher doses used; they estimated that the maximum
daily intake of NDPhA was 320 mg/kg in females and 240 mg/kg in
males. These levels are somewhat higher than those used by
Druckrey ^t_ ^1_. (1967) in the only other known chronic feeding
study done in rats.
B. Mutagenicity
NDPhA has consistently been reported negative in a variety
of mutagenicity assays: S. typhimurium (Ames test), with and
without activation (Yahagi e-t^ al_. , 1977; Bartsch _et_ _al_. , 1976;
Simmon, 1979a; Rosenkranz and Poirier, 1979); E. coli, with
activation- (Nakajima _et_ _al_., 1974); (Pol A~) E. coli (Rosenkranz
and Poirier, 1979); N. crassa (Marquardt £t^-_al_., 1963); Chinese
hamster V79 (lung) cell line, with and without activation (Kuroki
et al., 1977); Saccharomyces cerevisiae D3, with activation
•
(Simmon, 1979b); host mediated assay (tester strains: S.
typhimurium and S. cerevisiae D3) (Simmon et al., 1979); in vivo
mouse testicular DNA synthesis assay (Friedman and Staub, 1976).
-------
C. Other Toxicity
The oral LD50 in rats is 1650 rag/kg; in mice the oral LD50
is 3,850 mg/kg (NIOSH, 1978).
V. AQUATIC EFFECTS
A. Acute
The 96-hour LC^Q for NDPhA in bluegill sunfish under static
test conditions is 5.9 mg/1 (nominal concentration). The-48-hour
ECcQ (static conditions) in Daphnia magna is 7.7 rag/1 (nominal
concentration). The adjusted 96-hour LCgg for the mummichog (a
marine fish) under static conditions is 3,300 mg/1 (nominal con-
centration) (U.S. EPA, 1979b).
B. Chronic
No adverse effects were reported at any test concentration
in a chronic toxicity study in Daphnia magna at concentrations
below 0.048 mg/1 (U.S. EPA, 1979b).
C. Other
Bioconcentration of NDPhA by bluegill sunfish reached equi-
librium within 14 days; the bioconcentration factor was 217. The
half-life of the compound in bluegill sunfish was less than one
'day (U.S. EPA, 1979b).
VI. EXISTING GUIDELINES
Criteria for the protection of aquatic species from excess
»
NDPhA exposure have not been established (U.S. EPA, 1979b).
-------
REFERENCES
Argus, M.F., and Hoch-Ligeti, C. 1961. Comparative study of the
carcinogenic activity of nitrosamines. J. Natl. Cancer Inst. 27,
695.
Bartsch, H., C. Mala-veille, and R. Montesano. 1976. The predic-
tive value of tissue-mediated mutagenicity assays to assess the
carcinogenic risk of chemicals. IARC Scientific Publications
(Lyon), No. 12, 467.
Boyland, E. , R..L. Carter, J.W. Gorrod, and F.J.C. Roe. 1968.
Carcinogenic properties of certain rubber additives. Europ. J.
Cancer 4_, 233. (as cited in NCI, 1979).
Cardy, R.H., W. Lijinsky, P.K. Hilderbrandt. 1979. Neoplastic
and non-plastic urinary bladder lesions induced in Fischer 344
rats and B6C3F, hybrid mice by N-nitrosodiphenylamine. Ectotox-
icol. Env. Safety, J_(D, 29.
Challis, B.C. and M.R. Osborn. 1972. Chemistry of nitroso
compounds. The reaction of N-nitrosodiphenylamine with N-methyl-
aniline—a direct transnitrosation. Chem. Comm. 518
Druckrey, H., R. Preussmann, S. Ivankovic, and D. Schmahl. 1967.
Organotrope carcinogene Wirkungen bei 65 verschiedenen N-Nitroso-
Verbindungen an BD-Ratten. Z. Krebsforsch. 69, 103. (as cited
in NCI, 1979 and Cardy _et_ _al_., 1-979).
Friedman, M.A., J. Staub. 1976. Inhibition of mouse testicular
DNA synthesis by mutagens and carcinogens as a potential simple
mammalian assay for mutagenesis. Mutat. Res., 37(1), 67-76.
Hawley, G.G. 1977. The Condensed Chemical Dictionary, 9th ed.,
Van Nostrand Reinhold Co.
Innes, J.R.M., B.M. Ulland, M.G. Valerio, L. Petrucelli,
L. Fishbein, E.R. Hart, A.J. Pallotta. R.R. Bates, H.L. Falk,
J.J. Gart, M. Klein, I. Mitchell, and J. Peters. 1969. Bioassay
of pesticides and industrial chemicals for tumorigenicity in
mice: a preliminary note. J. Natl. Cancer Inst. 42_(6), 1101-
1106. (as cited in NCI, 1979).
Kuroki, T., C. Drevon, and R. Montesano. 1977. Microsome-
mediated mutagenesis in V79 Chinese hamster cells by various
nitrosamines. Cancer Res. 37, 1044-1050.
Mallik, M.A. 1979. Microbial contribution to nitrosamine
formation in soil. Smithsonian Scientific Information Exchange
No. GY 70884 2.
Marquardt, H., R. Schwaier, 'and F. Zimmerman. 1963. Nicht-
Mutagenitat von Nitrosamininen bei Neurospora Crassa. Natur-
wissenschaften _50_, 135. (as cited in Cardy _et_ al_. , 1979).
-------
Nakajima, T., A. Tanaka, and K.I. Tojyo. 1974. The effect of
metabolic activation with rat liver preparations on the mutagen-
icity of aeveral N-nitrosamines on a streptomycin-dependent
strain of Escherichia coli. Mutat. Res. 26, 361-366.
National Cancer Institute. 1968. Evaluation of Carcinogenic,
Teratogenic, and Mutagenic Activities of Selected Pesticides and
Industrial Chemicals'. Vol. I. Carcinogenic Study. (as cited in
NCI, 1979).
National Cancer Institute. 1979. Bioassay of N-Nitrosodiphenyl-
amine for Possible Carcinogenicity. NIH Publication No. 79-1720.
National Institute for Occupational Safety and Health. 1978.
Registry of Toxic Effects of Chemical Substances.
Rosenkranz, H.S. and L.A. Poirier. 1979. Evaluation of the
mutagenicity and DNA-modifying activity of carcinogens and non-
carcinogens in microbial systems. J. Natl. Cancer Inst. 62, 873-
892.
Rowland, I.R. and P. Grasso. 1975. Degradation of N-nitros-
amines by intestinal bacteria. Appl. Microbiol. ^9.(1), 7-12.
(Abstract only).
Sander, J. and P. Seif. 1969. Bakterielle reduction von nitrat
in Magen des Menschen als Ursoche einer nitrosaminbildung.
Arnz.-Forsch 19, 1091.- (as cited in U.S. EPA, 1977).
Simmon, V.F. 1979a. In vitro mutagenicity assays of chemical
carcinogens and related compounds with Salmonella typhimurium.
J. Natl. Cancer Inst. 62, 893-899.
Simmon, V.F. 1979b. In vitro assays for recombinogenic activity
of chemical carcinogens and related compounds with Saccharomyces
cerevisiae D3. J. Natl. Cancer Inst. 62, 901-909.
Simmon, V.F., H.S. Rosenkranz, E. Zeiger _et_ _al_. 1979. Mutagenic
activity of chemical carcinogens and related compounds in the
intraperitoneal host-mediated assay. J. Natl. Cancer Inst. 62,
911-918.
U.S. EPA. 1977. Scientific and Technical Assessment Report on
Nitrosamines, EPA-600/6-77-001.
U.S. EPA. 1979a. Toxic Substances Control Act Chemical Sub-
stances Inventory, Production Statistics for Chemicals on the
Non-Confidential Initial TSCA Inventory.
»
U.S. EPA. 1979b. Ambient Water Quality Criteria: Nitrosamines.
PB 292 438.'
Yahagi, T., M. Nagao, Y. Seino, T, Matsushima, T. Sugimura, and
M. Okada. 1977. Mutagenicities of N-nitrosamines on Salmonella.
Mutat. Res. 48, 121.
/ 3
-------
No. 139
N-Nitrosodi-n-propylamine
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA1s Carcinogen Assessment Group (CAG) has evaluated
n-nitrosodi-n-p^opj^ylamine and has found sufficient evidence
to indicate that this compound is carcinogenic.
/3?-3
-------
N-NITROSODI-n-PROPYLAMINE
SUMMARY
The International Agency for Research on Cancer has con-
cluded that "N-nitrosodi-n-propylamine should be regarded for
practical purposes as if it were carcinogenic in humans." The
conclusion is based on positive findings in several long-term
animal studies with the compound. It has also been found muta-
genic in several test systems with activation.
The chemistry of formation of nitrosamines is quite complex,
however, they are formed in general by the combination of amines
with some nitrosating agent. Nitrates, nitrites, and amines
(primary, secondary, and tertiary), the precursors in the
formation of nitrosamines, are ubiquitous in the environment.
Significant quantities of the precursors are also produced'
through human activities.
The in vivo formation of nitrosamines following ingestion of
precursors has been demonstrated in humans and animals.
Nitrosamines degrade in the presence of sunlight; however,
in the dark they are quite stable. Microorganisms can function
both in the formation and degradation of nitrosamines. The half-
life of aliphatic nitrosamines in the environment ranges from one
hour in the atmosphere in sunlight to more'than 40 days in soils
and water (in the absence of light).
I. INTRODUCTION
This document is based on the Ambient Water Quality Criteria
Document for Nitrosamines (U.S. EPA, 1979a), Volume 17 of the
-------
IARC Monographs on the Evaluation of the Carcinogenic Risk of
Chemicals to Humans (IARC, 1978), the Scientific and Technical
Assessment Report on Nitrosamines (U.S. EPA, 1977), and. other
selected references.. The term "N-nitrosodi-n-propylamine" (NDPA)
in this report refers specifically to that compound; the term
"nitrosamine" when used in this report refers in general to
'simple aliphatic nitrosamines.
N-nitrosodi-n-propylamine (NDPA; CgH^NjO; molecular weight
130.2) is a yellow liquid having the following physical chemical
properties (IARC, 1978).
Boiling Point: 81°C
Density: d|° 0.9160
Solubility: soluble in water, organic
solvents, and lipids.
Volatility: can be steam distilled
quantitatively.
A review of the production range (includes importation)
statistics for NDPA (CAS No. 621-64-7) which is listed in the
initial TSCA Inventory (1979b) has shown that between zero and
900 pounds of this chemical were intentionally produced/imported
in 1977.I/
*/
—' This production range information does not include any pro-
duction/importation data claimed as confidential by the per-
son(s) reporting for the TSCA Inventory, nor does it include
any information which would compromise Confidential Business
Information. The data submitted for the TSCA Inventory,
including production range information, are subject to the
limitations contained in the Inventory Reporting Regulations
(40 CFR 710).
-------
No information on the commercial uses of NDPA was Located,
however, it appears likely that most, if not all, of that pro-
duced is used solely in the laboratory.
II. EXPOSURE
Nitrates, nitrites, and amines (in this case the propyl-
amines), which are precursors in the formation of nitrosamines,
are ubiquitous in the environment and occur in food, water, soil,
and air. The natural occurrence of nitrates, nitrites, and
secondary and tertiary amines results from their formation during
the nitrogen cycle. In addition to the naturally formed precur-
sors , significant quantities are produced through human activi-
ties (U.S. SPA, 1977). Some of the major man-made sources of the
precursors are listed in Table 1.
A. Formation
The chemistry of formation of nitrosamines is quite complex,
however, they are formed in general by the combination of amines
(R,R~N-) with some nitrosating agent. Formation has been shown
to occur with primary, secondary, and tertiary amines, as well as
other amino compounds. The nitrosating agent can be derived from
nitric oxides (NO, N02, ^2°3' or N2°4^ or inor
-------
Table 1. Man-Made Sources of Nitrosamine Precursors (U.S. EPA, 1977)
Nitric Oxides Amines
Transportation
Motor vehicles
Aircraft
Railroads
Fuel combustion in stationary sources
. .Coal
Fuel Oil
Natural gas
Wood
Industrial processes
Solid waste disposal
Miscellaneous
Forest fires
Structural fires
Coal refuse
Agricultural
Feedlots
Rendering plants
Antioxidants
Vulcanization
accelerators
Pharmaceuticals
Self-polishing waxes
Synthetic detergents
Pesticides
Solvents
Corrosion inhibitors
Animal glues
Photographic products
Leather tanning
Primary amine
production
The in vivo formation of nitrosamines following the inges-
tion of precursors has been demonstrated in human and animal
studies (U.S. EPA, 1976,').
Nitrosamines can be formed in soil, water, and sewage under
appropriate conditions (Ayanaba jt_ ^_1_., 1973a, b; Ayanaba and
Alexander, 1974? Kohl ^t_ ^1_. , 1971). Microorganisms in soil and
water can participate in the formation of nitrosamines (Ayanaba
.et_ .al_. , 1973b; Mills and Alexander, 1976), although microbial
involvement in such formation reactions is not essential (Mills,
1976; Mills and Alexander, 1976).
B. Environmental Fate
In the absence of light, nitrosamines are quite stable and
will decompose hydrolytically only following prolonged contact
with strong acid. There is no evidence of thermal instability of
nitrosamines in the gas phase; however, they do undergo photo-
1.3.9-7
-------
chemical decomposition in solution or in the atmosphere in the
presence of sunlight or ultra-violet light. There are very few
quantitative studies on the rate of photochemical degradation of
nitrosamines or on the rate effects of other factors (U.S. EPA,
1977; IARC, 1978). Nonetheless, it has been shown that N-nitro-
sodimethylamine has an atmospheric half-life (during ambient
atmospheric conditions) of between 30 minutes and one hour in
sunlight (Hanst _et_ _al_., 1977). The atmospheric half-life of NDPA
should be similar (U.S. EPA, 1979a).
N-nitrosodi-n-propylamine appears to be fairly resistant to
microbial attack under environmental conditions. The soil half-
life of NDPA under varying conditions has been reported as rang-
ing between 10 and 40 days (Tate and Alexander, 1975; Saunders et
al., 1979; Oliver et_ _al_., 1978). In lake water under laboratory
conditions, NDPA persisted for more than 4 months (Tate and
Alexander, 1975).
A laboratory soil leaching study (Saunders _et_ _al>., 1979) has
indicated that NDPA (which is about 1% soluble in water) will
leach under heavy simulated rainfall conditions. In a field
study, however, NDPA did not leach below a depth of 20 cm. The
authors suggest that under field conditions, NDPA is dissipated
due to volatilization and degradation.
C. Bioconcentration
No information on the bioaccumulation potential of NDPA was
located, although it should be fairly low. •
D. Environmental Occurrence
NDPA has been detected in food, alcoholic beverages,and
s.everal pesticides (IARC, 1978). It has also been detected in
'"/ 13 J (!)'
-------
the waste-water from several chemical plants (Cohen and Bachman,
1978).
III. PHARMACOKINETICS
A. Absorption'
In goats, one hour after oral administration, NDPA was found
in milk and blood, indicating fairly rapid uptake. Only traces
were found in the milk after 24 hours (Juszkiewicz and Kowalski,
1974).
B. Distribution
No information was located on the distribution of NDPA;
however, simple aliphatic nitrosamines tend to distribute rapidly
and fairly uniformly in the body (U.S. EPA, 1979a).
C. Metabolism
Available evidence suggests that NDPA must be metabolically
activated to exert its toxic and carcinogenic effects. Urine
collected during the 43 hours after oral administration of an
LD^g dose of NDPA to rats contained the following compounds:
N-nitroso-3-hydroxy-n-propyl-n-propylamine, N-nitroso-2-carboxy-
ethyl-n-propylamine, and to a lesser extent, N-nitrosocarboxy-
methyl-n-propylamine, and N-nitroso-2-hydroxy-n-propyl-n-
propylamine (Blattman and Preussmann, 1973). The last named
metabolite, N-nitroso-2-hydroxy-n-propyl-n-propylamine, has been
found carcinogenic in rats (Reznik et al., 1975) and hamsters
(Pour _et_ ^1_., 1974a,b) , thus it may be the active carcinogenic
metabolite (proximate and/or ultimate carcinogen) of NDPA.
-------
IV. HUMAN HEALTH EFFECTS
A. Carcinogenicity
Groups of rats were given NDPA in the drinking water at
doses of 4, 8, 15, or 30 mg/kg day. Of the 48 animals on test,
45 developed liver carcinomas, 8 developed papillomas or car-
cinomas of the esophagus, and 6 showed carcinomas of the tongue
(Druckrey _et_ _al/ , 1967).
Groups of rats were injected subcutaneously with 1/5, 1/10,
or 1/20 the LD5Q of NDPA (LD5Q: 487 mg/kg) once weekly for
life. The average total dose of NDPA ranged between 0.93 and 2.7
g/kg. A high incidence of neoplasms was observed in the nasal
cavities. In addition, tumors of the liver, lung, kidney, and
esophagus were observed (Althoff et al., 1973a; Reznik et al.,
1975).
Groups of Syrian golden hamsters were injected
subcutaneously with 1.2% NDPA in olive oil once weekly for life
at 5 dose levels (highest dose was 60 rag/kg). Tumors were
observed in the nasal cavities, laryngobronchial tract, lungs,
and a variety of other organs (Althoff e_t_ £l_., 1973br Pour et
al., 1973).
The International Agency for Research on Cancer (1978) has
concluded:
There is sufficient evidence of a carcinogenic effect of
N-nitrosodi-n-propylamine in two experimental animal
species. Although no epidemiological data were avail-
able. ..N-nitrosodi-n-propylamine should be regarded for
practical purposes as if it were carcinogenic to humans,
B. Mutagenicity
NDPA was positive in the Ames test (S. typhimurium strains
TA 1530, TA 1535, and TA 100) with activation (Barstch et al.,
~1 / ^ ^
* ] US
-------
1976? Camus et_ &1_., 1976; Olajos and Cornish, 1976; Sugimura et
al., 1976). NDPA was also mutagenic in E. coli (Nakajima et al.,
1974) and in Chinese hamster V79 cells (Kuroki £t_ al_., 1977), in
both cases with activation.
C. Other Toxic Effects
The acute oral LD5Q of NDPA was 480 rag/kg in rats (Druckrey
et_ _al_., 1967); the subcutaneous LD5Q was 487 mg/kg in rats and
600 mg/kg in hamsters (Pour _et_ ^1_. , 1973; Reznik ^t_ _al_. , 1975).
V. AQUATIC EFFECTS
No data on the aquatic effects of NDPA were located.
VI. EXISTING GUIDELINES
The class of compounds "nitrosamines" was included in.the
American Conference of Governmental Industrial Hygienists (1977)
list of "Industrial Substances Suspected of Carcinogenic Poten-
tial for Man." No threshold limit value (TLV) was given.
As noted in Section IV.A, the International Agency for
Research on Cancer (1978) has concluded that "N-nitrosodi-n-
propylamine should be regarded for practical purposes as if it
were carcinogenic to humans."
-------
REFERENCES
Althoff, J., F.W. Kruger, J. Hilfrich, D. Schmahl, and U. Mohr.
1973a. Carcinogenicity of B-hydroxylated dipropylnitrosamine.
Naturwissenschaften, 60, 55 (as cited in IARC, 1978).
Althoff, J., F.W. Kruger, and U. Mohr. 1973b. Carcinogenic
effect of dipropylnitroaamine and compounds related by B-oxida-
tion. J. Nat. Cancer Inst.., 51, 287-288 (as cited in IARC,
1978).
American Conference of Governmental Industrial Hygienists,
Threshold Limit Values for Chemical Substances and Physical
Agents in the Workroom Environment, 1977.
Ayanaba, A., W. Verstraete, and M. Alexander. 1973a. Formation
of dimethylnitrosamine, a carcinogen and mutagen in soils treated
with nitrogen compounds. Soil Sci. Soc. Amer. Proc. 37, 565-568.
(as cited in U.S. EPA, 1977).
Ayanaba, A., W. Verstraete, and M. Alexander. 1973b. Possible
microbial contribution to nitrosamine formation in sewage and
soils. J. Nat. Cancer Inst. 50, 811-813. (as cited in U.S. EPA,
1977).
Ayanaba, A. and M. Alexander. Transformation of methylamines and
formation of a hazardous product, dimethylnitrosamine, in samples
of treated sewage and lake water. J. Environ. Qual. _3_, 83-89.
(as cited in U.S. EPA, 1979). t
Bartsch, H., C. Malaveille, and R. Montesano. 1976. The predic-
tive value of tissue-mediated mutagenicity assays to assess the
carcinogenic risk of chemicals. In: Montesano, R., Bartsch, H.
and Tomatis, L., eds. Screening Tests in Chemical Carcinogen-
esis, Lyon (IARC Scientific Publications No.12), pp. 467-491.
(as cited in IARC, 1978).
Blattman, L. and R. Preussmann. 1973. Struktur von metaboliten
carcinogener dialkylnitrosamine im rattenurin. Z. Krebsforsch.,
79, 3-5. (as cited in IARC, 1978).
Camus, A., B. Bertram, Kruger, F.W., C. Malaveille, and
H. Bartsch. 1976. Mutagenicity of 3-oxidized N,N-di-n-propyl-
nitrosamine derivatives in S. typhimurium.. mediated by rat and
hamster tissues. Z. Krebsforsch., 86, 293-302 (as cited in IARC,
1978).
Cohen, J.B. and J.D. Bachman. 1978. Measurement of environ-
mental nitrosamines. In: Walker, E.A., Castegnaro, M.,
Gricuite, L. and Lyle, R.E., eds., Environmental Aspects of
ET-Mitroso Compounds, Lyon (IARC Scientific Publications No. 19) .
(as cited in IARC, 1978).
Druckrey, H., R. Preussmann, S. Ivankovic, D. Schmahl. 1967.
Organotrope carcinogene Wirkungen bei 65 verschiedenen N-nitroso-
verbindungen an BD-ratten. 2. Krebsforsch., 69, 103-201. (as
cited in IARC, 1978).
-------
Hanst, P.L., J.W. Spence, and M. Miller. 1977. Atmospheric
chemistry of N-nitroso dimethylamine. Env. Sci. Tech., 11(4),
403.
Juskiewicz, T. and B. Kowalski, 1974. Passage of nitrosamines
from rumen into milk in goats. In: Bogavski, P. and E.A. Walker,
eds., N-Nitroso Compounds in the Environment, Lyon (as cited in
IARC, 1978).
International Agency for Research on Cancer. 1978. IARC Mono-
graphs on the Evaluation ..of the Carcinogenic Risk of Chemicals to
Humans, Vol. 17.
Juskiewicz, T. and B. Kowalski, 1974. Passage of nitrosomines
from rumen into milk in goats. In: bogaski, P. and E. A. Walker,
eds., n-Nitroso Compounds in the Environment, Lyon (as cited in
IARC, 1978).
Kuroki, T., C. Drevon, and R. Montesano. 1977. Microsome-
mediated mutagenesis in V79 Chinese hamster cells by various
nitrosamines. Cancer Res., 37, 1044-1050. (as cited in IARC,
1978).
Mills, A.L. 1976. Nitrosation of secondary amines by axenic
cultures of microorganisms and in samples of natural ecosystems.
Ph.D. Thesis. Cornell University, Ithaca, New York. 95 pp. (as
cited in U.S. EPA, 1977).
Mills, A.L. and M. Alexander. 1976. Factors affecting dimethyl-
nitrosamine formation in samples of soil and water. J. Environ.
Qual. , _5_(4), 437.
Mirvish, S.S. 1977. N-Nitroso compounds: Their chemical and in
vivo formation and possible importance as environmental carcino-
gens. J. Toxicol. Env. Hlth. , 2_, 1267.
Nakajima, T., A. Tanaka, and K.I. Tojyo. 1974. The effect of
metabolic activation with rat liver preparations on the mutagen-
icity of several N-nitrosamines on a streptomycin-dependent
strain of Escherichia coli. Mutat. Res., 26, 361-366. (as cited
in IARC, 1978).
Olajos, E.J. and H.H. Cornish. 1976. Mutagenicity of
dialkylnitrosamines: metabolites and derivatives (Abstract No.
43). Toxicol. Appl. Pharmacol., 37, 109-110. (as cited in IARC,
1978).
Oliver, J.E., P.C. Kearney, and A. Kontson. 1978. Abstract
presented at the 175th National Meeting of the American Chemical
Society, Paper No. 80, Pesticide Division. (as cited by Saunders
et_al_., 1979).
Pour, P., F.W. Kruger, A. Cardesa, J. Althoff, and U. Mohr.
1973. Carcinogenic effect of di-n-propylnitrosamine in Syrian
golden hamsters. J. Nat.:Cancer Inst., 51, 1019-1027. (as cited
in IARC, 1978).
-------
Pour, P., F.W. Kruger, A. Cardesa, J. Althoff, and U. Mohr.
1974a. Effect of beta-oxidized nitrosamines on Syrian golden
hamsters. I. 2-Hydroxypropyl-n-propylnitrosamine. J. Nat.
Cancer Inst., 52, 1245-1249. (as cited in IARC, 1978).
Pour, P., J. Althoff, A. Cardesa, F.W. Kruger, and U. Mohr.
1974b. Effect of beta-oxidized nitrosamines on Syrian golden
hamsters. II. 2-Oxopropyl-n-propylnitrosamine. J. Nat. Cancer
Inst., 52, 1869-1874. (as cited in IARC, 1978).
Reznik, G., U. Mohr, F.W. Kruger. 1975. Carcinogenic effect of
di-n-propylnitrosamine, B-hydroxypropyl-n-proylnitrosamine, and
methyl-n-propylnitrosamine on Sprague-Dawley rats. J. Nat.
Cancer Inst., 54, 937-943. (as cited in IARC, 1978).
Saunders, D.G., J.W. Mosier, J.E. Gray, and A. Loh. 1979. Dis-
tribution and movement of N-nitrosodipropylamine in soil. J.
Agric. Fd. Chem., ^7J3), 584.
Sugimura, T., T. Yahagi, M. .Nagao, M. Takeuchi, T,. Kawachi,
K. Hara, E. Yamakaki, T. Matsushima, Y. Hashimoto, and M. Okada.
1976. Validity of mutagenicity tests using microbes as a rapid
screening method for environmental carcinogens. In: Montesano,
R., Bartsch, H. and Tomatis, L., eds., Screening Tests in Chemi-
cal Carcinogenesis, Lyon (IARC Scientific Publication No. 12),
pp. 81-101. (as cited in IARC,. 1978).
Tate, R.L. and M. Alexander. 1975. Stability of N-nitrosamines
in samples of lake water, soil, and sewage. J. Nat. Cancer Inst.
54, 327-330. (as cited in U.S. EPA, 1977).
U.S. EPA. 1977. Scientific and Technical Assessment Report on
Nitrosamines. EPA-600/6-77-001.
U.S. EPA. 1979a. Ambient Water Quality Criteria: Nitrosamines.
PB 292 438.
U.S. EPA. 1979b. Toxic Substances Control Act Chemical Sub-
stances Inventory, Production Statistics for Chemicals on the
Non-Confidential Initial TSCA Inventory.
-------
No. 140
Paraldehyde
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect .all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
PARALDEHYDE
Summary
There is no evidence in the available literature to indicate that
paraldehyde, a central nervous system depressant, is carcinogenic, muta-
genic, or teratogenic.
In low doses (4-8 ml) paraldehyde has a hypnotic effect on the central
nervous system. Following chronic and acute exposures at higher concen-
trations, paraldehyde affects the respiratory and circulatory systems.
Data concerning the effects of paraldehyde on aquatic organisms were
not found in the available literature.
Guidelines or standards concerning air or water exposures were not
found in the available literature.
If 0
-------
PARALDEHYDE
I. INTRODUCTION
ParaJdehyde, 2,4,6-trimethyl-l,3,5-trioxane, also known as para-
acetaldehyde, is a colorless liquid with a molecular weight of 132.2. This
compound melts at D°C and boils at 125°C. It has a specific gravity of
0.994 at. 20°C, and its solubility in water is 120,000 mg/1 at D°C and
58,000 mg/r'at 100°C (Verschueren, 1577). The odor of paraldehyde is not
pungent or unpleasant, but it is characterized by a disagreeable taste
„ r
(Wilson,, .et al. 1577).
Paraldehyde was introduced into medicine by Ceruello in 1882 as
the second synthetic organic compound to be used as a sedative hypnotic
(Wilson, et al. 1577). It is used frequently in delirium tremens and in
treatment pf psychiatric states characterized by excitement when drugs must
be given over a 'long period of time (Wilson, et al. 1577). It also is ad-
ministered for intractable pain which does not respond to opiates and for
basal and obstetrical anaesthesia (Goodman and Oilman, 1570). It is
effective against experimentally induced convulsions and has been used in
emergency therapy of tetanus, eclampsia, status epilepticus, and poisoning
by convulsant drugs (Goodman and Oilman, 1970).
It is used primarily in medicine, and therefore, the chance of
accidental human exposure or environmental contamination is low. However,
paraldehyde decomposes to acetaldehyde and acetic acid (Gosselin, et al.
1576); these compounds have been found to be toxic-." In this sense, occupa-
tional exposure or environmental contamination is possible. Since paral-
dehyde is prepared from acetaldehyde by polymerization in the presence of an
»
acid catalyst, there exists a potential for adverse effects, although none
have been reported in the available literature.
X
JtJO'1/
-------
II. EXPOSURE
No monitoring data are available to indicate ambient air or water
levels of the compound. Human exposure to par aldehyde from ingestion cannot
be assessed, due to a lack of monitoring data. No data on dermal exposure
of humans were found in the available literature.
III. PHARMACOKINETICS
Paraldehyde is rapidly absorbed from the gastrointestinal tract
and parenteral sites. Following oral administration to rats, the maximum
concentration in the brain is reached within 30 -minutes (Figot, et al.
1953). A significant percentage is excreted unchanged through the lungs.
Lang, et al. (1969) reported that human-subjects given unspecified oral
doses exhaled 7 percent of the administered dose within 4 hours. Only
traces are observed in the urine; the rest is metabolized by the liver.
There is indirect evidence that paraldehyde is depolymerized to acetaldehyde
in the liver, then oxidized by aldehyde dehydrogenase to acetic acid which,
in turn, is ultimately metabolized to carbon dioxide and water in mice
(Hitchcock and Nelson, 1943).
No data on bio accumulation of paraldehyde were found in the
available literature. Based on the evidence of metabolism above, however,
significant bio accumulation would appear unlikely.
IV. EFFECTS
A. Carcinogenicity
Paraldehyde has been designated a "suspect carcinogen" (NIOSH,
1978), although no increase in neoplasms was observed in the mouse-skin
painting study (Row and Salaman, 1955), which was cited by NIOSH.
8. Mutagenicity, Teratogenicity and Other Reproductive Effects.
Pertinent data could not be located in the available literature.
s
+}$t^~
/V0-J
-------
' C. Chronic Toxicity
In low doses (4-8 ml), par aldehyde has found use as a therapeutic
agent. However, if used for a prolonged period of time, intoxication
results in tolerance and dependence. Paraldehyde addiction resembles alco-
holism; withdrawal may result in delirium tremens and vivid hallucinations
(Goodman and Gilman, 1570).
Acidosis, bleeding gastritis, muscular irritability, azotemia,
oliguria, albuminuria, leukocytosis, fatty changes in the liver and kidney
with toxic hepatitis and nephrosis, pulmonary hemorrhages, edema, and dila-
tion of the right heart have all been observed in cases of chronic paral-
*
dehyde poisoning. Metabolic acidosis is a manifestation of paraldehyde in-
toxication in the paraldehyde addict. The etiology of the acidosis is un-
certain (Beier, et al. 1963).
0. Acute Toxicity , .
Figot, et al. (1953) reported an oral LD50 Qf 1.55 g/t
-------
Toxic doses of unspecified amounts, given intravenously, cause
diffuse, massive pulmonary hemorrhages and edema, as well as dilation of the
right heart. Adverse effects, as seen in cases of severe acute paraldehyde
intoxication, resemble those seen in chronically exposed individuals, e.g.,
addicts.
Metabolic acidosis. is., also found in the severe acute cases. Hay-
ward and Boshell (1957) produced metabolic acidosis and other toxic effects,
including pulmonary edema in dogs, by administering unspecified amounts of
deteriorated paraldehyde through gastric tubes over a period of 18 hours.
In this case it is uncertain whether the paraldehyde or the deteriorated
product was the cause of the observed effects. The sane is true in another
study where a deteriorated product (40 percent acetic acid) produced sudden
death with intense corrosion of buccal mucosa and upper air passages.
Rectal administration (a common route in therapeutic settings) in another
poisoning victim caused great pain and sloughing of rectal mucosa (Gosselin,
i
et al. 1976).
High concentrations (unspecified) depressed cholinergic junctions
in frogs, apparently by reducing the amount of acetyleneline liberated from
nerve endings (Nicholls and Quillam, 1956; Quillam, 1959).
The lethal dose in humans is disputable. Less than one ounce by
mouth has been shown to be lethal in some cases, while others have tolerated
four ounces. Death results from respiratory failure preceded by prolonged
and profound coma (Goodman and Gilman, 1970).
Paraldehyde has been used in obstetrics; "however, it readily
crosses the placental barrier and appears in the fetal circulation. Unde-
*
sirable effects, including delay in respiratory movements, have been
-7
-------
observed in neonates following administration to the mother during labor
(Goodman and Gilman, 1970). Consequently, paraldehyde finds little or no
use in obstetrics today.
The lowest dose of paraldehyde reported to produce any toxic
effect (unspecified) in tiumsns is 121 mg/kg. Oral LD50 values have been
reported for the following species: rats, 1530 mg/kg; r^Dbits, 3304 mg/kg;
• and dogs, 3500 mg/kg. NIOSH (1978) has reported the lowest lethal inhala-
tion concentration to be 2000 ppm.
V. AQUATIC TOXICITY
Data concerning the effects of paraldehyde on aquatic organisms
were not found in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
NO exposure limits or standards were found in the available liter-
ature to exist for air or water. .
-------
References
Beier, L.*, et al. 1963. Metabolic acidosis occurring during paraldehyde
intoxication. Chem. Abst. 59: 1022.
Figot, P., et al. 1953. Estimation and significance of paraldehyde levels
in blood and brain. Chem. Abst. 47: 660.
Goodman, L. and A. Oilman. 1970. The Pharmacological Basis of Thera-
peutics. 4th ed. MacMillan Co., New York.
Gosselin, R.E., et al. 1976. Clinical Toxicology of Commercial Products.
Williams and Wilkins Co., Baltimore, Maryland.
Hayward, J. and B. Boshell. 1957. Paraldehyde intoxication with metabolic
acidosis. Am. Jour. Med. 23: 965.
Hitchcock, P. and E. Nelson. 1943. The metabolism of paraldehyde: II.
Jour. Pharmac. Exp. Ther. 79: 286.
Kirk, R.E. and D.F. Othmer. 1979. Encyclopedia of Chemical Technology.
John Wiley and Sons, New York.
Lang, 0., et al. 1969. Data of pulmonary excretion of paraldehyde in man.
Chem. Abst. 71: 202.
Nicholls, J. and J. Quillam. 1956. Mechanism of action of paraldehyde and
methyIpentyno1 on neuromuscular transmission in the frog. Chem. Abst.
50: D295. I
National Institute for Occupational Safety and Health. 1978. Suspected
Carcinogens. A Subfile on the Registry of Toxic Effects of Chemical Sub-
stance. U.S. Department of Health, Education and Welfare, Cincinnati, Ohio.
Quillam, J. 1959. Paraldehyde and methy Ipentyno 1 and ganglionic trans-
mission. Chem. Abst. 53: 20562.
f
Row, .F.J.C, and M.H. Salaman. 1955. Further studies on incomplete carcin-
ogenesis: Triethylene melanine (TEM), 1,2-benzanthracene, and g-propiolac-
tone as initiators of skin tumor formation in the mouse. Brit. Jour. Cancer
(London). 9: 177.
Verschueren, K. 1977. Handbook of Environmental Data on Organic Chemicals.
Van Nostrand Reinhold Company, New York.
Wilson, C., et al. (ed.) 1977. Textbook of Organic Medicinal and Pharma-
ceutical Chemistry. J.B. Lippincott Co., Philadelphia, Pa.
-------
No. 141
Pentachlorobenzene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report'represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
**jout
-------
PENTACHLOROBENZEIC
Summary
Oral feeding of pentachlorobenzene to pregnant rats has produced devel-
opmental effects and decreased body weights in fetuses. No adverse repro-
ductive or developmental effects were seen in mice following maternal admin-
istration of the compound orally.
There is no information available on the mutagenic effects of penta-
chlorobenzene.
•
A single study has alluded to carcinogenic effects of pentachloroben-
zene in mice and lack of carcinogenic effects in dogs and rats. The details
of this study were not available for evaluation.
Reported 96-hour IC50 values for the bluegill, mysid shrimp, and
sheepshead minnow range from 250 to 830 ,ug/l. Oaphnia is considerably less
sensitive. Studies with algae, with 96-hour EC_Q values based on chloro-
phyll a_ concentration, have reported values ranging from 2,000 to 7,000
jug/1. The steady-state bioconcentration factor for the bluegill is 1,800.
-------
I. INTRODUCTION
Pentachlorobenzene, CAS registry number 608-93-5, is a colorless crys-
talline solid with a pleasant aroma. It is produced mainly as a byproduct
of other chlorobenzenes and has the following physical and chemical proper-
ties (Windnolz, 1976; We.ast, 1972; Hawley, 1971):
Formula: C6HC15
Molecular. Weight: 250.34
Melting Point: 86°c
Boiling Point: 277°c
Density: . 1.S34216-5
Solubility: Soluble in carbon disulfide,
chloroform, and hot alcohol,
insoluble in water
Pentachlorobenzene is used primarily as a precursor in the synthesis of
the fungicide pentachloronitrobenzene, and as a flame retardant.
II. EXPOSURE
A. Water
Burlingame (1977) has identified pentachlorobenzene in the efflu-
ent from a wastewater treatment plant in southern California. Access to
water can occur by industrial discharge or from the degradation of other
organochlorine compounds.
8. Food
Pentachlorobenzene has been detected in plants (Balba and Sana,
1974; Kohli, et al. 1976a) and in animal fat (Stijve, 1971; Saha and Bur-
rage, 1976; Greve, 1973), and was shown to arise from the metabolic break-
down of lindane or other organochlorine compounds. The U.S. EPA (1979) has
estimated the weighted average bioconcentration factor for pentachloroben-
zene to be 7,800 for the edible portions of fish and shellfish consumed by
Americans. This estimate is based on steady-state bioconcentration studies
in bluegills.
-------
C. Inhalation
The primary site for inhalation exposure could be the workplace in
industries utilizing or producing pentachlorobenzene.
0. Oential
Pertinent data could not be located in the available literature.
III. PHARMACOKINETICS
•A. Absorption
From studies with rabbits it would appear that pentachlorobenzene
«
is very poorly absorbed from the gastrointestinal tract (Parke and Williams,
1960).
3. Distribution
The distribution of pentachlorobenzene favors retention in the fat
(Parke and Williams, 1560). Khera and villeneuve (1575) have found wide-
spread tissue distribution of the compound following oral administration to
pregnant rats and accumulation in fetal tissues.-
C. Metabolism
There appear to be some qualitative and quantitative differences
between species in the metabolism of pentachlorobenzene. In the rat and
rabbit, pentachlorobenzene was shown to be metabolized to a variety of iso-
mers of tetrachlorophenol, with the amount of unchanged pentachlorobenzene
excreted in the urine of the rabbit being one percent (Kohli, et al. 1576b),
and in the rat being nine percent (Koss and Koransky, 1577). Kohli and co-
workers (1576b) suggest that the dechlorination hydroxylation step to the
tetrachlorophenol derivative proceeds through an arene oxide intermediate.
0. Excretion
In rats and rabbits urinary excretion of metabolites or unchanged
pentachlorobenzene predominated. Rozman, et al. (1578) found the biological
half-life of pentachlorobenzene to be two to three months in rhesus monkeys.
4
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After 40 days, ten percent of the total dose was secreted in the urine; of
this, 58 percent was pentachlorophenol. After the same period, about 40
percent of the dose was excreted in the feces, 99 percent as pentachloroben-
zene. The authors suggest that biliary excretion was occurring.
IV. EFFECTS
A. Carcinogenicity
There is ane report, which could not be critically evaluated,
which alludes to pentachlorobenzene being carcinogenic in mice but not in
rats or dogs (Preussman, 1975).
9. Mutagenicity
Pertinent data could not be located in the available literature.
C. Teratogenicity
Rats receiving 50, 100, and 200 mg/kg pentachlorobenzene on days 6
to 15 of gestation had pups with increased suprauni ribs at all doses (Khera
and Villeneuve, 1975). The high dose also produced sternal defects consist-
ing of unossified or nonaligned sternabrae with cartilagenous precursors
present. The authors did not consider these defects to be teratogenic.
0. Other Reproductive Effects
Oral administration of pentachlorobenzene (50 or 100 mg/kg) to
pregnant mice on days 6 to 15 of gestation produced no teratogenic or ad-
verse reproductive effects (Courtney, et al. 1977).
E. Chronic Toxicity
Pertinent data could not be located in-the available literature.
V. AQUATIC TOXICITY
A. Acute
»
The U.S. EPA (1978) reported 96-hour LC5Q values for the blue-
gill (Lepomis macrochirus) exposed to pentachlorobenzene to be 250 ug/1.
y
^
*
-------
The 48-hour EC5Q value reported for Daphnia magna is 5,280 ug/1 (U.S. EPA,
1978). For the saltwater species, sheepshead minnow (Cyprinodon variegatus)
and mysid shrimp (Mysidoosis bahia),. the determined 96-hour LC5Q values
are 830 and 160/ug/l, respectively.
9. Chronic
Pertinent data could not be located in the available literature.
C. Plant Effects
The reported 96-hour £C5Q vaj.ue f0r selenastrum caoricornatum
based on chlorophyll a_ concentration is 6,780 jjg/1 (U.S. EPA, 1978).- For
the marine alga Skeletonema costatum, a 96-hour EC5Q value on the same
basis is 1,980 ug/1 (U.S. EPA, 1978).
0. Residue
After a 28-day exposure, the steady-state bioconcentration factor
for the bluegill for pentachlcrocenzene is 1,800. The half-life is greater
than seven days (U.S. EPA, 1973).
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The U.S. EPA (1979) has drafted a criterion of O.S^ug/l for the
protection of human health.
8. Aquatic
No criteria have been developed or proposed to protect aquatic
organisms from pentachlorobenzsne toxicity due to the lack of pertinent data.
ift-7
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REFERENCES
Balba, M.H. and J.G. Saha. 1974. Metabolism of l_indane~14c by wheat
plants grown from treated seed. Environ. Let. 7: 181.
Burlingame, A.L. 1977. Assessment of the trace organic molecular composi-
tion of industrial and municipal wastewater effluents by capillary gas
chromatography/real time high resolution mass spectrometry: a preliminary
report. Ecotoxicol. Environ. Saf_ 1: 111.
Courtney, K.D., et al. 1977. Teratology study of pentachlorobenzene in
mice: no teratogenic effect at 50 or 100 mg/kg/day from day 6 to day 15 of
gestation. IRCS Med. Sci. 5: 587.
Greve, P.A. 1973. Pentachlorobenzene as a contaminant of animal feed.
Meded. Fac. lanbouwwet Rijksuniv Gent. 38: 775.
Hawley, G.G. (ed.) 1971. The Condensed Chemical Dictionary. 8th ed., Van
Nostrand Reinhold Co., New York.
Khera, K.S. and O.C. Villeneuve. 1975. Teratogenicity studies on haloge-
nated benzenes (pentachloro-, pentachloronitro-, and hexabromo-) in rats.
Toxicology. 5: 117.
Kohli, J., et al. 1976a. Balance of conversion of carbon-14 labeled lin-
danes in lettuce in hydroponic culture. Pestic. Biochem. Physiol. 6: 91.
Kohli, J., et al. 1976b. The metabolism of higher chlorinated benzene iso-
mers. Can Jour. Biochem. 54: 203.
Koss, G. and W. Koransky. 1977. Pentachlorophenol in different species of
vertebrates after administration of hexachlorobenzene and pentachloroben-
zene. Pentachlorophenol, K.R. Rao, (ed.), Plenum Press, New York. p. 131.
Parke, D.V. and R.T. Williams. 1960. Studies in detoxification LXXXI.
Metabolism of halobenzenes: (a) Penta- and hexachlorobenzene: (b) Further
observations of 1,3,5-trichlorobenzene. Biochem. Jour. 74: 1.
Preussman, R. 1975. Chemical carcinogens in the human environment. Hand.
Allg. Pathol. 6: 421.
Rozman, K., et al. 1978. Metabolism and body distribution of pentachloro-
benzene after single oral dose in rhesus monkeys. Toxicol. Appl. Pharmacol.
45: 283.
Saha, J.G. and R.H. Burrage. 1976. Residues of lindane and its metabolites
in eggs, chicks and body tissues of hen pheasants after ingestion of Lindane
carbon-14 via treated wheat seed or gelatin capsules. Jour. Environ. Sci.
Health Bull. 67.
»
Stijve, T. 1971. Determination and occurrence of hexachlorobenzene resi- .
dues. Mitt. Geb. Lebenmittelunters. Hyg. 62: 406.
-------
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646, U.S. Environ. Prot.
Agency.
U.S. EPfl. 1579. Chlorinated Benzenes: Ambient Water Quality Criteria.
(Draft)
Weast, B.C. 1971. Handbook of Chemistry and Physics. 53rd ed., Chemical
Rubber Company, Cleveland, Ohio.
windnolz, M. (ad.) 1976. The Merck Index. 9th ed., Merck and Co., Inc.,
Pahway, New Jersey.
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No. 142
Pentachloronitrobenzene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-7 II) 7f'
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DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-^ ( "T '
I \y ,)T
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (GAG) has evaluated
pentachloronitrobenzene and has found sufficient evidence
to indicate that this compound is carcinogenic.
- 3
-------
DISCLAIMER
The mention of company trade names or products does not constitute
endorsement by the U.S. EPA or the Federal government.
'-77/T-
-------
PENTACHLORONITROBENZENE
Summary
Increased'incidence of hepatoma formation was reported in hybrid mice
treated with pentachlorobenzene (PCNB). PCNB was found to be mutagenic in
the hcr-strain of Escherichia coli ochre, but not in another §_._ coli strain.
PCNB containing a number of contaminants produced renal agenesis and
cleft palate in C57B1/6 mice, cleft palate in CD-I mice, but was not terato-
genic in CD rats. Purified PCNB (less than 20 ppnv. hexachlorobenzene) re-
sulted in fewer cleft palates in the fetuses. No significant teratogenic
effects in rats were detected at dosages as high as 1,563 ppm. In a three
generation study using doses as high as 500 ppm, PCNB had no significant ef-
fects on the reproduction of rats.
Acute toxicity data for fish were: a 96-hour LCCg in bluegill from
0.29 to 0.38 ppm and a 96-hour LC5Q Of 0.31 pprn in rainbow trout.
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I. INTRODUCTION
This profile is based on the Initial Scientific Review of Pentachloro-
nitrobenzene, PCNB, plus relevant scientific research articles published
subsequent to that document (U.S. EPA, 1976).
Pentachloronitrobenzsne (molecular weight, 255.34) is a pale yellow-to-
white solid, depending on purity, that melts between 142° and 146°C, has
a boiling point of 328°C at 760 mm Hg, and a density of 1.718 g/crn3 at
25°C. Reported vapor pressure values for PCNB are: 1.16 x 10~5 mm Hg
at 10°C, 5.0 x lO-5 mm Hg at 20°C, and 11.3 x 1Q-5 mm Hg at 25°C
(U.S. EPA, 1976). PCNB has. a relative vapor density (air = 1) of 10.2
(verschueren, 1977). Water solubility of PCNB is 0.44 mg/1 at 20°C and 2
mg PCNB will dissolve in one liter ethanol at 25°C. PCNB is freely sol-
uble in carbon disulfide, benzene, chloroform, ketones, and aromatic and
chlorinated hydrocarbons, and slightly soluble in alkanols (U.S. EPA, 1976).
PNC3 is primarily registered as a soil fungicide for a wide variety of
crops and is also used as a seed-treatment fungicide. It is effective
against bunt of wheat, Botrytis, Rhizoctonia, and Sclerotinia spp. There
are no current nonagricultural uses of PCNB (U.S. EPA, 1976). PGNB is manu-
factured domestically under the trade name TerraclorS) with an estimated
annual production in 1971 of 3 million pounds (U.S. EPA, 1972). According
to the Olin Corporation (1974), 60 to 70 percent of the PCNB produced will
be used in the United States. The United States has imported from 20,000 to
132,000 Ibs. between 1966 and 1969 (U.S. EPA, 1976).. PCNB manufactured in
Europe is marketed under the common name Quintozene (Dejonckheere, et al.
-------
1976). It may be worth noting that commercial PCNB fungicides contain im-
purities such as hexachlorobenzene, pentachlorobenzene and tetrachloronitro-
benzene, which may be more hazardous than PCNB itself (Dunn, et al. 1978;
Simon, et al. 1979).
No data are available for the disassociation' of PCNB in aqueous sys-
tems. Crosby and Hamadmad (1971) studied the photoreduction of PCNB. The
compound remained unchanged in sunlight, probably excluding photolysis as a
major route of environmental degradation. At temperatures above 328°C,
some decomposition of PCNB has been noted (U.S. EPA, -1976).
PCNB can be biodegraded by pure cultures of actinomycetes and filamen-
tous fungi during their active growth phase (Chacko, et al. 1966).
II. EXPOSURE
PCNB is prepared by either chlorination or nitration reactions. The
reaction temperature for the chlorination process is 60 to 70°C. Although
this reaction is well below the boiling point of PCNB, atmospheric emissions
are possible because of PCNB's relatively high vapor pressure. Furthermore,
there exists a potential for environmental release via wastewater effluents
at the manufacturing sites. No monitoring data are available for ambient
air or water levels of the compound. The major source of environmental con-
tamination is through its application as a fungicide. In the United States,
PCNB is used primarily on cotton and peanut crops. Geographic use distribu-
tion is mainly concentrated west of the Mississippi River (U.S. EPA, 1976).
Carey,'et al. (1979) in their study of pesticide residues in the soil detec-
ted PCNB in only three of the 1,483 sample sites. The .detected residue con-
centration was from 0.22 to 2.61 ppm. It should be noted, however, that
their study was primarily confined to the eastern United States.
-------
Routes of human exposure to PCN8 include water, air, contaminated
foods, and fish. Casanova and Oubroca (1973) studied the residues of PCNB
found in lettuce grown in soil treated with the fungicide. Residue values
were 0.73 ppm '(15 kg PCNB/ha) and 1.56 ppm (45 kg PCN8/ha). Gcursaud, et
al. (1972) detected PGNB.contamination in endive roots. Since the main ob-
jective of their study was the uptake of hexachlorobenzene, actual PCNB
concentrations were not noted. However, in a subsequent experiment
Goursaud,'-et al. (1972) fed cows endive roots containing 2.16 ppm PCNB.
PCNB residues found in the cows' milk were negligible. Bioaccumulation of
PCNB in White Leghorn cockerels (Dunn, et al. 1978) was also found to be
negligible (accumulation ratio 0.001 = tissue concentration/dietary
concentration). Broiler chickens (Reed, et al. 1977) did not accumulate
PGNB or its metabolites to any appreciable extent (0.002 ppm). NO
additional information on the levels of PCNB in foods is available.
Bioaccumulation data on PCNB were not found in the literature for aqua-
tic organisms, Ko and Lockwood (1963) resorted that the mycelium of fungi
had accumulated a concentration of PCNB seven times that of the surrounding
soil.
III. PHARMACOKINETICS
A. Absorption
Absorption data on PCNB were restricted to oral administration in-
volving three test species. Betts, et al. (1955) reported that 60 percent
of the oral dosage was not absorbed from the gastrointestinal tract in rab-
bits. Two subsequent studies, however, report that PCNB is readily absorbed
from the gastrointestinal tract and/or metabolized by gut flora to another
»
compound and then almost fully absorbed. Kogel, et al. (1979). found that
PGNB was readily and almost completely absorbed from the gastrointestinal
i .- n ] -"
•*7 b I <*•
-------
tract of Rhesus monkeys. After a single dose of 2 mg/kg given in methyl
cellulose suspension, only 7.4 percent of the administered amount was ex-
creted as unmetabolized FCNB in the feces. When 91 mg/kg PCNB was given in
sesame oil, only 4.3 percent of the dose was excreted unmetabolized. Uptake
occurs mainly by the portal venous route, with little involvement of the
lymphatic system, bringing the absorbed PCNB directly to the liver where
biotransformation can begin. Studies of Comet Red and White Leghorn chick-
ens yielded similar results. Chickens fed 300 ppm PCNB in laying mash for
sixteen weeks excreted only 1.1 ppm PCNB (Simon, et ai. 1979).
B. Distribution
Several studies have been conducted on the distribution and stor-
age of ingested PCNB. Due to rapid metabolism and elimination, this com-
pound shows very little accumulation in body tissues. Betts, et al. (1955)
used rabbits and Borzelleca, et al. (1971) employed beagles and rats. In
neither experiment was PCNB detected in liver, kidney, muscle, or adipose
tissue. Othe'r studies have indicated very low concentrations of PCNB in
various tissues. Simon, et al. (1979) found PCNB at concentrations of 0.85
ppm in fat and 0.005 ppm in egg whites of chickens fed 300 ppm PCNB for six-
teen weeks. Other tissues examined contained no detectable levels of PCNB.
Dunn, et al. (1978) found the highest tissue residues of PCNB in adipose
tissue (1.14 and 1.87 ppm) and the gizzard (1.60 and 0.84 ppm) in chickens
given 100 ppm and 1,000 ppm PCNB in feed, respectively. Leg and breast mus-
cles and heart, kidney, and liver contained very low (0.16 to 0.07 ppm) or
trace amounts of PCNB.
Concentrations of PCNB in various organs of Rhesus monkeys after
chronic feeding of 2 ppm PCNB in the daily diet were (in ppm): blood, O.D7;
muscle, 0.01; brain, 0.03; liver, 0.19; kidney, 0.14; adrenal cortex, 0.08;
-------
thymus, 0.20; lymph nodes (large intestine), 0.12; bone marrow, 0.13; and
omental fat, 0.21 (Mueller, et al. 1978). Kogel, et al. (1979) found the
highest concentration of PCNB and/or its metabolites occurring in bile (7.73
> 0.2 ppm in males and 3.72 +_ 0.05 in females) after feeding of 2 ppm PCNB
for 70 days.
C. Metabolism
PCNB metabolism has been studied in rats, dogs, cows, and rabbits.
Pentachloroaniline and methyl pentachlorophenyl sulfide are the major metab-
olites. Tissue retention of these compounds is found primarily in body fat
with minimal concentrations found in muscle (U.S. EPA, 1976). Two major
•
pathways for the. biotransformation of PCNB in Rhesus monkeys are: 1) the
reduction of the hitro-moeity to the corresponding aniline, and 2) the clea-
vage of the C-N bond, presumably via conjugation with sulfur-containing
amino acids (Kogel, et al. 1979).
0. Excretion
PCNB and its metabolites ar.e excreted mainly in the urine and
feces. Mueller, et al. (1978) reported that Rhesus monkeys excreted almost
80 percent of the ingested PCNB within 5 days; of the excreted radio-
activity, 91.2 percent was in the form of metabolites.
IV. EFFECTS
A. Carcinogenicity
Very little information on possible carcinogenic effects of PCNB
was found in the available literature. Courtney, et al. (1976) cite one
study which found PCNB to be carcinogenic in a hybrid mouse with an in-
creased incidence of hepatoma formation. Levels of exposure were not given.
-------
8. Mutagenicity
PCNB was found to be mutagenic in the hcr-strain of Escherichia
coli B/r ochre, but not in another £_._ coli strain. In the host-mediated as-
say in mice, no significant increase in mutation rates in Salmonella
typhimurium and Serratia morcescens was observed after subcutaneous injec-
tion of PCNB. The compound also gave negative results in spot tests (U.S.
EPA, 1976).
C. Teratogenicity and Other Reproductive Effects
PCNB was administered to pregnant rats by intubation on days 6 and
15 of gestation at dosages from 100 to 1,563 ppm. Fetuses were examined for
gross malformations. No significant effects on the number of corpora lutae,
the position and numbers of dead or resorbed fetuses, or the fetal weights
and sex ratios were observed at any dose level. No significant skeletal or
soft tissue anomalies were reported in the fetuses (U.S. EPA, 1976).
A three-generation study with groups of rats fed diets containing
0, 5, 50 or 500.ppm (Olin technical PCNB) showed no significant effects on
fertility, gestation, viability, lactation, rats born per litter, or rats
weaned per litter or their average weaning weights (U.S. EPA, 1976).
PCNB containing a number of contaminants, however, produced renal
agenesis and cleft palate in C56B1/6 mice and cleft palate in CD-I mice, but
was not teratogenic in CD rats. Purified PCNB (less than 20 ppm hexachloro-
benzene) resulted in few cleft palates in fetuses (Courtney, et al. 1976).
D. Chronic Toxicity
PCNB does not appear to be chronically toxic,when administered in
feeding studies. Rhesus monkeys given 2 ppm or 91 ppm PCNB in their diet
for 70 days were monitored for clinical chemistry and hematology parameters
throughout the study. These parameters remained unchanged, indicating that
l/JL-lf
-------
organ function and hematopoiesis was not affected by PCNB or its metabolites
(Kogel, et al. 1979).
White Leghorn chickens fed PCNB at concentrations up to 1,000 ppm
for the first 8 weeks of life did not develop tissue lesions and hens fed up
to 1,000 ppm for 35 weeks- failed to develop histopathological changes (Dunn,
et al. 1978).
Kogel, et al. (1979) cite--studies which -report that the toxic ef-
fect of Terraclor^ in rats and dogs is limited to liver enlargement due to
. •* s
hepatocellular hypertrophy. Also, cats had increased methemoglobin levels
after moderate and high doses of Terraclor^ and dogs fed a very high dose
(5,000 ppm) of PCNB of undetermined purity for two years were found to have
reduced hematopoiesis. These effects, however, may be due to the presence
of hexachlorobenzene as a contaminant (Kogel, et al. 1979).
E. Acute Toxicity
Cholakis, under contract with the U.S. EPA, administered single
doses of pentachloronitrobenzene by gavage to several species of microtine
rodents (voles) (U.S. EPA, 1978). The acute oral LD5Q values in male and
female M^ montanus were 4,194 mg/kg and 5,717 mg/kg, respectively. In M^
ochrogaster, M^ canicaudus, and M^ pennsylvanicus, values were greater than
5,000 mg/kg for both sexes. Toxicologic signs observed were some piloerec-
tion, loss of righting reflex and lachrymation. Most signs disappeared
after 24 hours. Most deaths occurred within two to six days of dosing.
V. AQUATIC TOXICITY .:
A. Acute Toxicity
In static, acute toxicity bioassays using various PCNB formula-
»
tions, bluegill (Lspomis macrochirus) had 96-hour median lethal concentra-
tion (LC5Q) values ranging from 0.29 to 0.38 ppm. Rainbow trout (Salmo
-i / P /.
"7" u o
-------
gairdneri) had a 96-hour LC5Q value of 0.31 ppm (U.S. EPA, 1976).
B. Chronic Toxicity, Plant Effects and Residues
Pertinent data could not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
No guidelines or standards were located in the available literature for
humans or aquatic life.
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REFERENCES
Betts, J.J., et al. 1955. The metabolism of PCN8 and 2,3,4,6-tetrachloro-
nitrobenzene and the formulation of meriapturic acids in rabbit. Biochem.
Jour. 61: 611.
Borzelleca, J.F., et al. 1971. Toxicologic and metabolic studies on PCNB.
Toxicol. Appl. Pharmacol.. 18: 522.
Carey, A.E., et al. 1979. Pesticide residue levels in soils and crops from
37 states, 1972. Pest. Monit. Jour. 12: 209.
Casanova, M. and 3. Oubroca. 1973. Etude des residues de divers fongicides
utilises dans le traitement des cultures de laitures en serre. Ann. Phyto-
pathoi. 5: 65.
*.
Chacko, C.I., et al. 1966. Chlorinated hydrocarbon pesticides: degradation
by mirobes. Science 154: 393.
Courtney, K.D., et al. 1976. The effects of pentachloronitrobenzene, hexa-
chlorobenzene, and related compounds on fetal development. Toxicol. Appl.
Pharmacol. 35: 239.
Crosby, O.G. and N. Hamadmad. 1971. The photoreduction of pentachloroben-
zenes. Jour. Agr. Food Chem. 19: 1171.
Oejonckheere, w.f et al. 1976. Residues of Quinotozene. Pest. Monit.
Jour. 10: 68. . ,
Dunn, J.S., et al. 1978. The accumulation and elimination of tissue resi-
dues after feeding PCNB to White Leghorn cockerels. Poultry Sci. 57: 1533.
Goursaud, J., et al. 1972. Sur la pollution du lait par les residues HC3.
Industries Alimientoires et Agr. 89: 31.
Ko, W.H. and J.L. Lockwood. 1968. Accumulation and concentration of chlor-
inated hydrocarbon pesticides by microorganisms in soil. Can. Jour. Micro-
biol. 14: 1075.
Kogel, W., et al. 1979. Biotransformation of PCNB - 14c in Rhesus mon-
keys after single and chronic oral administration. Chemosphere 8: 97.
Mueller, W.F., et al. 1978. Comparative metabolism of HC3 and PCNB in
plants, rats', and Rhesus monkeys. Ecotoxicol. Environ. Safety. 2: 437.
Olin Corporation. 1974. Agricultural Products Division, Little Rock, Ark.
Personal communication to Scon. Branch, Criteria and Evaluation Division,
Office of Pesticide Programs, U.S. EPA.
Reed, E.L., et al. 1977. Tissue residues from feeding PCNB to broiler
chickens. Toxicol. Appl. Pharmacol. 42: 433.
-------
Simon, G.S., et al. 1979. Distribution and clearance of pentachloronitro-
benzene in chickens. Toxicol. Appl. Pharmacol. 50: 401.
U.S. EPA. 1972. The pollution potential in pesticide manufacturing. Mid-
west Research Institute. EPA Rep. No. OWP-TS-00-72-04. NTIS PB-213 782.
U.S. EPA. 1976. Initial Scientific Review of PCNB. Office of Pesticide
Programs, Washington, D.C. EPA-540/1-75-016.
U.S. EPA. 1978. Study of the chemical and behavioral toxicology of
substitute chemicals in microtine rodents. EPA-600/3-78-082. Midwest
Research Institute, Kansas City, MO.
•Verschueren, K. 1977. Handbook of Environmental Data on Organic Chemicals.
Van Nostrand Reinhold Co., New York.
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No. 143
Pentachlorophenol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C.. 20460
APRIL 30, 1980
'{ / 0 ^
') V I v
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
PENTACHLOROPHENOL
SUMMARY
Pentachlotophenol has shown no evidence of carcinogenicity.
Evidence for mutagenicity is equivocal. Pentachlorophenoi is
teratogenic in experimental animals at levels which produce mater-
nal or fetal toxicity. Adverse health effects have been minimal
in workers chronically exposed to pentachlorophenol. Relatively
k
high levels of continous exposure produce muscle weakness, head-
ache, anorexia, abdominal- pain, weight loss, and irritation of
skin, eyes, and respiratory tract. Pentachlorophenol is a strong
uncoupler of oxidative phosphorylation.
Pentachlorophenol has been demonstrated to be acutely toxic
to freshwater salmonids at levels as low as 37 ug/1. Comparable
levels of toxicity were' observed for marine fish. . Freshwater
plants were also highly susceptible to the action of this chemi-
cal- with effective concentrations_as low as 7.5 ug/1.
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PENTACHLOROPHENOL
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Pentachlorophenol (U.S. EPA, 1979).
Pentachlorophenol. (PCP; CgCl5OH; molecular weight 266.35)
has the following physical and chemical properties (Stecher,
1966;_-Natl.. Fire .Prot. Assoc., 1973; Sax, 1975; Spector, 1956;
Weast, 1975-76):
Melting 'point Range 190 - 191° C
Boiling Point Range 309 - 310 (decomposes)
' Vapor Pressure 0.12 mm Hg at 100 C
Solubility ' Water: 14 mg/1 at 20° C
Commercial preparations of pentachlorophenol contain
"caustic insolubles" or "nonphenolic. neutral impurities" such
as octachlorodibenzofurans and tetra-, penta-, hexa-, hepta-,
and octachldrodibenzo-p-dioxins (Johnson, et al. 1973; Schwetz,
et al. 1974). In addition, commercial pentachlorophenol contains
three to ten percent tetrachlorophenol (Goldstein, et al. 1977;
Schwetz, et al. 1978).
Pentachlorophenol is a commercially produced bactericide,
fungicide, and slimicide used primarily for the preservation
of wood, wood products, and other materials. As a chlorinated
hydrocarbon, PCP is also used as a herbicide, insecticide, and
molluscicide (U.S. EPA, 1979).
Pentachlorophenol and its sodium salt are widely dissemi-
nated in the environment (U.S. EPA, 1979). Pentachlorophenol
undergoes photochemical degradation in solution in the presence
of sunlight (Mitchell, 1961; Hanadmad, 1967; Wong and Crosby,
1977) and is reported to persist in warm moist soils for a period
X
-, i J- Q 1 -
^ U I U •
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of 12 months (Harvey and Crafts, 1952). in laboratory experiments,
some microorganisms have been reported to metabolize pentachloro-
phenol and its sodium salt (Watanabe, 1973; Suzuki and Nose,
1971; Cserjesi, 1967; Reiner, et al. 1977).
II. EXPOSURE
Residues of pentachlorophenol have been found in food,
water and human tissues. Pentachlorophenol levels of 0,06 ug/1
in finished drinking water prepared from untreated water contain-
ing 0.17 ug/1 have been reported (Buhler, et al. 1973). Penta-
chlorophenol has been detected in 13 of 240 food composites at
levels of 0.01 to 0.04 mg/kg (Johnson and Manske, 1977). The
calculated daily dietary exposure is one to six pg/person/day
(Duggan and Corneliusen, 1972).
The U.S. EPA (1979) has estimated the weighted average
bioconcentration factor of pentachlorophenol at 58 for the edible
portion of fish and shellfish consumed by Americans. This esti-
mate is based on measured steady-state bioconcentration studies
in goldfish (Carassius auratus) , bluegill (Lapomis macrochirus),
eastern oyster (Crassostrea virginica) , and sheepshead minnow
(Cyprinodon variegatus).
Inhalation and dermal exposure data for the general popula-
tion are not available (U.S. EPA, 1979). These routes of expo-
sure are more likely to occur occupationally. :
Total body exposures, based on reported' urine levels of
pentachlorophenol, appear to be in the range of 10-17 /ig/person/
•
day for the general population and 1500-4400 pg/person/day for
occupational exposures (U.S. EPA, 1979). These values may be
-------
due not only to direct exposure to pentachlorophenol, but also
to exposure to hexachlorobenzene (pesticide, fungicide) and lin-
dane (pesticide) , which are degraded in part to pentachlorophenol
(Yang, et al.' 1975; Lui and Sweeney, 1975; Mehendale, et al.
1975; Koss and Koransky, 1978; Karapally, et al. 1973; Engst,
et al. 1976) .
III. PHARMACOKINETICS.
A. Absorption
The half-life for absorption in humans after oral
ingestion of pentachlorophenol is 1.3 + 0.4 hr. In humans, a
,'
peak plasma concentration of 0.248 mg/1 was observed four hours
after ingestion of a 0.1 mg/kg dose (Braun, et al. 1978). Absorp-
tion in rats is similar to that found in humans (Braun, et al.
1977).
Pentachlorophenol is readily absorbed through the skin
as indicated by its lethality after dermal exposure (Deichmann,
*
et'al. 1942; Armstrong, et al. 1969).
B. Distribution
In humans (fatal pentachlorophenol intoxication) and
in rats (non-lethal exposure), the highest levels of pentachloro-
phenol are found in liver, kidney, and blood, with the lowest
levels in brain, spleen, and fat (Cretney, 1976; Armstrong, et
al. 1969; Braun, et al. 1977; Larsen, et al. 1975).
C. Metabolism
In four male volunteers ingesting 0.1 mg pentachloro-
phenol/kg, approximately 74 percent of the dose was elimina'ted
in the urine as pentachlorophenol (PCP) and 12 percent as PCP
glucuronide; four percent was eliminated in feces as pentachloro-
* fu r?
-------
phenol and PCP glucuronide (Braun, et al. 1973) . Rats excrete
75 percent of administered pentachlorophenol as the unchanged
PCP, 16 percent as tetrachlorohydroquinone, and nine percent
as PCP glucuroriide (Braun, et al. 1977). In another study (Ahlborg,
1978) , trichloro-£-hydroquinone was found as an additional metabo-
lite of pentachlorophenol in rats. Mice also metabolize penta-
chlorophenol to tetrachlorohydroquinone (Jakobson and Yllner,
1971).
D. Excretion
In humans and in experimental animals, the primary
mode of excretion for pentachlorophenol is in the urine (Diechmann,
et al. 1942; Braun, et al. 1977, 1978; Larsen, et al. 1975; Jakobson
and Yllner, 1971) .
In humans, the plasma pentachlorophenol half-life
is 30.2 + 4.0 hours. -The half-lives for elimination of penta-
chlorophenol and PCP glucuronide from urine are 33.1 + 4.5 and
12^7 + 5.4 hours, respectively (Braun, et al. 1978) . Elimination
of pentachlorophenol by the rat is similar to elimination by
humans (Braun, et al. 1977) .
The available literature indicates that pentachloro-
phenol does not accumulate in body tissues to any significant
extent (U.S. EPA, 1979). Long term, low level tissue binding
has not been adequately studied.
IV. EFFECTS
A. Carcinogenicity
Pentachlorophenol has not shown evidence of carci'no-
genicity. Pentachlorophenol did not promote papillomas or car-
cinomas when applied repeatedly to the skin at high concentra-
//J-7
-------
tions after initiation with dimethylbenzanthracene (Boutwell
and Bosch, 1959). Mice receiving commercial pentachlorophenol
in the diet throughout their lifespans (about 18 months) did
not have a significant incidence of tumors (Innes, et al. 1969) .
Pentachlorophenol, with low levels of nonphenolic contaminants,
was non-carcinogenic when fed to rats for 22 to 24 months (Schwetz,
et al. 1978). - -
B. Mutagenicity
• * A
Pentachlorophenol has been shown to be mutagenic in
a few test systems. Recrystallized pentachlorophenol increased
the frequency of mutations and mitotic gene conversion in Sac-
charomyces cerevisiae when used at a level (400 mg/1) which re-
sulted in a 59 percent survival rate of test organisms (Fahrig,
et al. 1978). Four of the 473 offspring of- female mice injected
with a single high dose of pure pentachlorophenol during gesta-
tion were reported to have changes in hair, coat color (spots)
of genetic significance (Fahrig, et al. 1978).
No mutagenic activity was detected in male germ cells
of Drosophila (Vogel and Chandler, 1974) , in the mouse host-mediated
assay, in in vitro spot tests (Buselmaier, et al. 1973), or in
histidine-required mutants of Salmonella typhimurium (Anderson,
et al. 1972).
C. Teratogenicity
Information suggesting pentachlorophenol is a human
teratogen was not encountered. Pentachlorophenol of both com-
»
mercial and purified grades produced fetal anomalies in rats
at levels considered to be toxic either to the maternal rat or
•3"
-------
to the fetus (Larsen, et al. 1975; Schwetz, et al. 1974? 1978).
Abnormalities included subcutaneous edema, dilated ureters, de-
layed ossification of the skull, skeletal anomalies, dwarfism,
exencephaly, macropthalmia, and taillessness.
D. Other Reproductive Effects
In a study in which male and female rats were fed
3 or 30 mg/kg pentachlorophenol continuously starting 62 days
before mating, no adverse effects were observed at the 3 mg/kg
level. At 30 mg/kg, the following indices were decreased: maternal
body weight; percent liveborn pups; 7, 14, 21 day survival; 1,
7, 14, 21 day body weight-pups; 7, 14, 21 day litter size. Selected
abnormalities were also seen at this dose.(Schwetz, et al. 1978).
E. Chronic Toxicity
Adverse health effects have been minimal in workers
chronically exposed to pentachlorophenol (JClemmer, 1972; Takahashi,
et al. 1976). Increased levels of serum enzymes SCOT, SGPT,
»
and- LDH, and elevated levels of total bilirubin and creatine
phosphokinase were noted, but all levels were still within normal
limits. A significantly higher prevalence of gamma mobility
C-reactive protein (CRP) was detected in the sera of chronically
exposed workers. CUP levels are often elevated in acute states
of various inflammatory disorders or tissue damage (Takahashi,
et al. 1976). A chronic health effect which has been associated
with human exposure to certain types of commercial PCP is chlor-
acne (Saader and Bauer, 1951; Nomura, 1953). Chloracne could
have resulted from impurities in the pentachlorophenol; commercial
PCP containing high levels of chlorodioxins produced chloracne
in the rabbit ear test, while pure pentachlorophenol or penta-
d^^^^^^Q: -
~ / t> / 0
-------
chlorophenol with reduced dioxin content did not (Johnson, et
al. 1973).
Chronic intoxication in humans results from relatively
high levels of continuous exposure. Symptoms include muscle
weakness, headache, anorexia, abdominal pain, and weight loss
in addition to skin, eye, and respiratory tract irritation (U.S.
EPA, 1979) .
Rats fed pentachlorophenol containing low levels of
nonphenolic contaminants at daily levels of 1 to 30 mg/kg for
eight months (Goldstein, et al. 1977) and 22 to 24 months (Schwetz,
et al. 1978) had decreased body weight gains at dosage levels
of 30 and 10 mg/kg, respectively. In the 22 to 24 month study,
the 30 mg/kg dose resulted in increased serum enzyme SGPT levels
and increased specific gravity of the urine.
F. Other Relevant Information
Pentachlorophenol is a strong uncoupler of oxidative
phdsphorylation (Weinbach and Garbus, 1965; Mitsuda, et al. 1963).
V. AQUATIC TOXICITY
A. Acute Toxicity
The results of 38 freshwater flow-through bioassays
reveal a range of 96-hour LC5Q values of from 63 ug/1 for the
sockeye salmon (Oncorhynchus nerka) (Webb and Brett, 1973) to
340 ug/1 for the fathead minnow (Pimephalea- promelas) (Ruesink
and Smith, 1975). In 19 static assays, LCcn values ranged from
37 ug/1 for the coho salmon (0. kisutch) to 600 pg/1 for the
#
fathead minnow. Five species of salmonids were more sensitive
than 4 other species of minnows or centrachids. Freshwater in-
vertebrates displayed LC5Cj values ranging from 310 ug/1 to 1,400
-------
ug/1 for the tubificid worm (Tubifex tubifex) and were affected
by increasing the PH from 7.5 to 9.5. The acute toxicity of
pentachlorophenol to saltwater fish ranged from 38 ug/1 in a
96-hour static pinfish (prolarvae) (Lagodon rhomboides) assay
(Borthwick and Schimme,!, 1978) to 442 ug/1 for juvenile sheeps-
head minnows (Cyprinodon variegatus) (Parrish, et al. 1978).
For three marine invertebrate species tested, LC5Q values ranged
from 40 to 5,600 ug/1, with the eastern oyster (Crassostrea vir-
ginica) being the most sensitive marine invertebrate.
B. Chronic Toxicity
Freshwater chronic studies for fish or invertebrates
were not available. A life-cycle chronic test of 151 days in
the marine sheepshead minnow produced a chronic value of 64 ug/1•
(Parrish, et al. 1973). Data for marine invertebrates was not
available (U.S. EPA, 1979).
C. Plant Effects '
For freshwater plants,_ the lowest affective concentra-
tion was 7.5 ug/1, which resulted in the total destruction of
chlorophyll in the alga Chlorella pyrenoidosa after 72 hours.
A drastic decrease in cell numbers of the marine alga Monochrysis
lutheri was observed after 12 days of exposure to 293 ug/1 (Woelke,
1965) , and 50 percent inactivation of photosynthesis was seen
in kelp (Macrocystis pyrifera) exposed for .4 days to 300 ug/1
(Clendenning and North, 1960).
D. Residues
r
. Equilibrium levels of PCP in water and tissues of
aquatic organisms are attainable within four days; and when pre-
viously exposed marine eastern oysters (Crassostrea virginica)
-------
or freshwater bluegills (Lepomis macrochirus) were held in PCP-
free water, a rapid loss- of PC? from the organism occurred (Schim-
mel, et al. 1978; Pruitt, et al. 1977). Bioconcentration factors
in marine organisms ranged from 0.26 for the juvenile brown shrimp
(Penaeus aztecus) to 78 for the eastern oyster. In freshwater
fish, bioconcentration factors of 1,000 for the whole body of
the goldfish (Carassius auratus) and of 13 for the muscle tissue
of the bluegill have been reported (Kobayashi and Akitake, 1975;
Pruitt, et al. 1977) .
VI. EXISTING GUIDELINES AND STANDARDS
A. Human.
The U.S. EPA (19.79) draft criterion for pentachioro-
phenol in ambient water is 680 ug/1.
The maximum air concentration established by the Ameri-
can Industrial Hygiene Association (1970) is 0.5 rag pentachloro-
phenol or 0.5 mg sodium pentachlorophenate/mj for an 8-hour expo-
sur'e (TLV) . The code of Federal Regulations 21, part 121, para-
graph 12±:2556 allows up to 50 ppm pentachlorophenol in treated
wood which will come in contact with food.
A NOEL in drinking water of 0.021 mg pentachlorophenol/1
is suggested by the National Research Council (1977) , based on
a NOEL of 3 mg/kg in 90 day and 8 month rat studies and an uncer-
tainty factor of 1,000.
B. Aquatic
The draft criterion to protect marine life is 6.2
ug/1 as a 24-hour average, not to exceed 14 ug/1 at any time.
The draft criterion to protect marine life is 3.7 ug/1 for a
24-hour average, not to exceed 8.5 ug/1 at any time (U.S. EPA,
1979) .
If 3-
-------
PENTACHLOROPHENOL
REFERENCES
Ahlborg, U.O. 1978. Dechlorination of pentachiorophenol in vivo and in
vitro, pp. 115-130. In: K.R. Rao (ad.), Pentachlorophenol: Chemistry,
pharmacology and environmental toxicology. Plenum Press, New York.
American Industrial Hygiene Association. 1970. Hygienic Guide Series:
Pentachlorophenol and sodium pentachlorophenate. Am. Ind. Assoc. Jcur.
31: 521..
Anderson, K.J., et al. 1972. Evaluation of herbicides for possible muta-
genic properties. Jour. Agri. Food Chem. 20: 649-.
Armstrong, R.W., et al. 1969. Pentachlorophenol poisoning in a nursery for
newborn infants. II. Epidemiologic and toxicologic studies. Jour.
Pediatr. 75: 317.
Baader, E.w. and H.J. Bauer. 1951. Industrial intoxication due to penta-
chlorophenol. Industr. Med. 4 Surg. 20: 286.
Borthwick, P.W., and S.C. Schimmmel. 1978. Toxicity of Pentachlorophenol
and related compounds to early life stages of selected estuarine animals.
Pages 141-146 In: K.R. Rao (ed.), Pentachlorophenol: Chemistry, pharma-
cology and environmental toxicology. Plenum Press, N,Y.
Boutwell, R.K. and K.K. Bosch. 1959. The tumor-promoting action of phenol
and related compounds for mouse skin. Cancer Res. 19: 413.
Braun, W.H., et al. 1977. The pharmacokinetics and metabolism of penta-
chlorophenol in rats. Toxicol. Appl. Pharmacol. 41: 395.
s_.
Braun, W.H., et al. 1978. The metabolism/pharmacokinetics of pentachloro-
phenol in man, and a comparison with the rat and monkey model. Toxicol.
Appl. Pharmacol. 45: 135.
Buhler, D.R., et al. 1973. Occurrence of hexachlorophene and Pentachloro-
phenol in sewage and water. Environ. Sci. Technol. 7: 929.
Buselmaier, et al. 1973. Comparative investigations of the mutagenicity of
pesticides in mammalian test systems. Mutat. Res. 21: 25.
Clendenning, K.A. and W.J. North. 1960. Effects of wastes on the giant
kelp, Macrocystis pyrifera. Pages 82-91 In: Proc. 1st Conf. on waste dis-
posal in the marine environment. Pergamon Press, New York•
Cretney, M.J. 1976. Psntachlorophenol death. Bull. T.I.A.F.T. 12 10.
In: T.J. Haley, 1977. Human poisoning with Pentachlorophenol and its
treatment. Ecotoxicol. Environ. Safety (In press).
Cserjesi, A.J. 1967. The adaptation of fungi to pentachloroohenol and its
biodegradation. Can. Jour. Microbiol. 13: 1234.
-------
Deichmann, W., et al. 1942. Acute and chronic effects of pentachlorophenol
and sodium pentachlorophenate upon experimental animals. Jour. Pharm. Exp.
Therap. 76: 104.
Ouagan, R.E., and P.E. Corneliussen. 1972. Dietary intake of pesticide
chemicals in - the United States (III), June 1968-April 1970. Pestic.
Monitor. Jour. 5: 331.
Engst, R., et al. 1976. The metabolism of lindane and its metabolites
gamma-2,3,4,5,6-pentachlorocyclohexene, pentachlorobenzene and pentachloro-
phenol in rats and the pathways of lindane metabolism. Jour. Environ. Sci.
Health 2: 95.
Fahrig, R., et al. 1978. Genetic activity of chlorophenols and chloro-
phenol impurities. Pages 325-338' In: K.R. Rao (ed.), Pentachlorophenol:
Chemistry, pharmacology and environmental toxicology. Plenum Press, New
York.
Goldstein, J.A., et al. 1977. Effects of pentachlorophenol on hepatic
drug-metabolizing enzymes and porphyria related to contamination with chlor-
inated dibenxo-p-dioxins and dibenzofurans. Biochem. Pharmacol. 26: 1549.
Hanadmad, N. 1967. Photolysis of pentachloronitrobenzene, 2,3,5,6-tetra-
chloronitrobenzene and pentachlorophenol. Ph.D. dissertation. University
of California, Davis.
Harvey, W.A. and A.S. Crafts. 1952. Toxicity of pentachlorophenol and its
sodium salt in three yolo soils. Hilgardia 21: 487.
Innes, J.R.M., et al. 1969. Bioassay of pesticides and industrial chem-
icals for tumorigenicity in mice. A preliminary note. Jour. Natl. Cancer
Inst. 42: 1101.
Jakobson, I. and S. Yllner. 1971. Metabolism of *C -pentachlorophenol in
the mouse. Acta. Pharmacol. Toxicol. 29: 513.
Johnson, R.D. and D.D. Manske. 1977.' Pesticides in food and- feed: Pes-
ticide and other chemical residues in total diet samples (XI). Pestic.
Monitor. Jour. 11: 116.
Johnson, R.L., et al. 1973. Chlorinated dibenzodioxins and pentachloro-
phenol. Environ. Health Perspec. Exp. Issue 5: 171.
Karapally, J.C., et al. 1973. Metabolism of lindane-1 ^C in the rabbit:
ether-soluble urinary metabolites. Jour. Agric. Food Chem. 21: 311
Klemmer, H.w. 1972. Human Health and Pesticides •- community pesticide
studies. Residue Rev. 41: 55.
Kobayashi, K. and H. Akitake. 1975. Studies on the metabolism of chlaro-
phenols in fish. I. Absorption and excretion of PCP by goldfish. Bull.
Jap. Soc. Sci. Fish. 41: 87.
-------
Koss, G. and w. Koransky. 1978. Pentachlorophenol in different species of
vertebrates after administration of hexachlorobenzene and pentachloro-
benzene. Pages 131-137 In: K.R. Rao (ed.), Pentachiorophenol: Chemistry,
pharmacology and environmental toxicology. Plenum Press, New York.
Larsen, R.V.;- et al. 1975. Placental transfer and teratology of penta-
chlorophenol in rats. Environ. Lett. 10: 121.
Lui, H., and C.D. Sweeney. 1975. Hepatic metabolism of hexachlorobenzene
in rats. FE3S Lett.' 51:'225.
Mehendale, H.M., et al. 1975, Metabolism and effects of hexachlorobenzene
on hepatic microsomal enzymes in the rat. Agric. Food Chem. 23: 261.
Mitchell, L.C. 1961. Effect of ultraviolet light (2537A) on 141 pesticide
chemicals by paper chromatography. Jour. Off. Anal. Chem. 44: 643.
Mitsuda, W., et al. 1963. Effect of chlorophenol analogues on the oxida-
tive phosphorylation in rat liver mitochondria. Agric. Biol. Chem. 27: 366.
National Fire Protection Assoc. 1973. Fire protection guide on hazardous
materials. 5th ed. Natl. Fire Prot. Assoc. Int., Boston.
National Research Council. 1977. Drinking water and health. Natl. Acad..
of Sci. Washington, O.C.
Nomura, S. 1953. Studies on chlorophenol poisoning. Podo Kaguku Jour.
Sci. Labor 29: 474.
Parrish, P.R., et al. 1978. Chronic toxicity of chlordane, trifluralin,
.and pentachloroohenol to sheepshead minnows, Cyprinoden variegatus. Report
No. EPA 60013-78-010:1.
Pruitt, G.W., et al. 1977. Accumulation and eliminatrion of pentachloro-
ohenol by the bluegill, Leoomis macrochirus. Trans. Am. Fish. Soc.
106: 462.
Reiner, E.A., et al. 1977. Microbial metabolism of pentachlorophenol.
Proc. Symp. on Pentachlorophenol, June 27-29. U.S. Environ. Prot. Agency
and Univ. West Florida.
Ruesink, R.G. and L.L. Smith, Jr. 1975. The relationship of the 96-hour
LCso to the lethal threshold concentration of hexavalent chromium, phenol,
and sodium pentachlorophenate for fathead minnows, Pimeohales oromelas
rafinesoue. Trans. Am. Fish. Soc. 104: 567.
Sax, N.I. 1975. Dangerous properties of industrial materials. 4th ed.
Van Nostrand Reinhold Co., New York.
Schimmel, S.C., et al. 1978. Effects of sodium pentachlorophenoL on
several estuarine animals: toxicity, uptake, and depuration. Pages 147-155
In: K.R. Rao (ed.), Pentachlorophenol: Chemistry, pharmacology and
environmental toxicology. Plenum Press, N.Y.
-------
Schwetz, B.A., at al. 1974. The effect of purified and commercial grade
pentachlorophenol on rat embryonal and fetal development. Toxicol. Appl.
Pharmacol. 28: 151.
Schwetz, B.A., et al. 1978. Results of two-year toxicity and reproduction
studies on pentachlorophenol in rats. In: K.R. Rao (ed.), Pentachloro-
phenol: Chemistry, pharmacology and environmental toxicology. Plenum
Press, New York.
Spector, U.S. 1956. ' Handbook of toxicology. W.B. Saunders Co.,
Philadelphia.
Stecher, P.G. (ed.). 1968. The Merck Index. 8th ed. Merck and Co., Inc.,
Rahway, N.J.
Suzuki, T. and K. Nose. 1971. Decomposition of PCP in farm soil. Part
II. PCP metabolism by a microorganism isolated from soil. Moyaku Seisan
Gijutsi (Japan) 26: 21.
Takahashi, W., et al. 1976. Acute phase proteins and pesticide exposure.
Life Sci. 19: 1645.
U.S. EPA. 1979. Pentachlorophenol: Ambient Water Quality Criteria (Draft).
Vogel, E. and J.L.R. Chandler. 1974. Mutagenicity testing of cyclamate and-
some pesticides in Drosoohila melanooaster. Experientia 30: 621.
Watanabe, I. 1973. Decomposition of pesticides by soil microorganisms.
Jap. Agric. Res. Q. 7: 15.
Weast, R.C. (ed.O. 1975-1976. Handbook of chemistry and physics. 5th ed.
CRC Press, Cleveland, Ohio.
Webb, P.W. and J.R. Brett. 1973. -Effects of sublethal concentrations of
sodium pentachlorophenate on growth rate, food conversion efficiency, and
swimming performance in underyearling sockeye salmon (Oncorhynchus nerka).
Jour. Fish. Res. Board Can. 30: 499.
Weinbach, E.C. and J. Garbus. 1965. The interaction of uncoupling phenols
with Mitochondria and with Mitochondrial protein. Jour. Biol. Chem.
240: 1811.
Woelke, C.E. 1965. Development of a bioassay method using the marine
algae, Monochrysis lutheri. Wash. Dep. Fish. Shellfish Progress Rep. 9p.
Wong, A.S. and D.G. Crosby. 1977. Photodecomposition of pentachlorophenol
(PCP). Proc. Symp. on Pentachlorophenol, June 27-29., U.S. Environ. Prot.
Agency and Univ. West Florida.
Yang, R.S.H., et al. 1975. Chromatographic methods for the analysis, of
hexachlorobenzene and possible metabolites in monkey fecal samples. Jour.
Assoc. of Anal. Chem. 58: 1197.
r.' Yf f*
S ) / I) $
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No. 144
Phenol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
- /Y/7 /-
<^V ) V U
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
PHENOL
SUMMARY
Insufficient data exist to indicate that phenol is a
carcinogenic agent. In skin painting studies, phenol appears
to function primarily as a nonspecific irritant. Information
on the mutagenicity of phenol is equivocal. Phenol does not
appear to be teratogenic. Chronic exposure to phenol at rel-
atively high levels causes liver damage in humans and ani-
•
mals, and kidney damage in animals. Exposure to acutely tox-
ic levels of phenol causes CNS depression.
The toxic effects of phenol have been extensively exam-
ined in freshwater organisms by acute studies in 13 fish and -
13 invertebrate species. Considerable interspecies and intra
species variation were described, with acute values ranging
from 5,020 to 780,000 ug/1. Only three marine species were
examined in acute tests, and LC5Q values ranged from
5,200 to 58,250 ug/1.
i «-t*,i 7-
^ / U
-------
PHENOL
I. INTRODUCTION
This profile is based on the Ambient Water Quality Cri-
teria Document for Phenol (U.S. EPA, 1979).
Phenol (CgH^OH; molecular weight 94.11) is a clear,
colorless (light pink when impurities are present) hygro-
scopic, crystalline solid at 25° C with the following physi-
cal and chemical properties (Manufacturing Chemist Assoc. ,
1974; Kirk and Othmer, 1963; Weast, 1974).
Melting Point 43° C
Boiling Point 182° C at 760 mm Hg
Flash Point open cup 85° C
closed cup 79° C
Vapor Pressure 0.35 mm Hg at 25° C
Solubility Water:- 6.7 g/100 ml at 16° C and
is soluble at all proportions at
66° C. Also soluble in e.ther, al-
cohol, acetic acid, glycerol, liq-
uid sulfur dioxide, benzene, and
oils.
Industrial capacity for production is 1.44 to 10*> tons
per year (Chem. Eng. News, 1975). About 90 percent of the
phenol produced is used in the production of phenolic resins,
caprolactam, bisphenol-A, alkylphenols, and adipic acid
(Chemical Profiles, 1972).
Phenol may be biochemically hydroxylated to ortho- and
para-dihydroxybenzenes and readily oxidized to the corres-
ponding benzoquinones. These may in turn react with numer-
ous components of industrial waters or sewage such as mercap-
tans, amines, or the -SH or -NH groups of proteins (Stom,
1975). When ambient water containing phenols is chlorinaced,
various chlorinated phenols may be produced in sufficient
yyy-y
-------
quantities to produce an objectionable taste and odor (Aly,
1968; Barnhart and Campbell, 1972; Jolley, 1973; Jolley, at
al. 1975).
II. EXPOSURE
A. Water -
There have been no market basket surveys of free
and conjugated phenols with which to estimate the average
daily dietary intake of phenols. The National Organic Moni-
toring Survey (U.S. EPA, 1977) reported finding unspecified
•
concentrations of phenol in 2 out of 110 raw water supplies.
The Survey found no phenol in any finished water supplies.
The National Commission on Water Quality (1975) reported an
annual mean concentration of 1.5 ug phenol/1 in raw water
from the lower Mississippi River.
B. ?ood
Phenol is produced endogenously in the mammalian
intestinal tract through microbial metabolism (Harborrie,
1964) and free and conjugated phenol is a normal constituent
of animal matter (U.S. SPA, 1979). Phenol concentrations of
7 mg/kg in smoked summer sausage and 28.6 mg/kg in smoked
pork belly have been reported (Lustre and Issenberg, 1970).
Several mouthwashes and lozenges contain phenol in amounts of
up to 32.5 mg total phenol/lozenge.
The U.S. EPA (1979) has estimated the-weighted average
bioconcentration factor for phenol to be 2.3 in the edible
#
portions of fish and shellfish consumed by Americans. This
estimate is based on the octanol/water partition coefficient
of phenol.
-------
C. Inhalation
The inhalation of. phenol vapor appears to be large-
• ly restricted to the occupational environment (U.S. EPA,
1979). Dermal exposures, can be from a number of medicinal
preparations for skin application (lotions, powders, oint-
ments) containing up to 4.75 percent phenol, or from certain
feminine hygiene products, and hemorrhoidal products (U.S.
EPA, 1979) .
III. PHARMACOKINETICS
A. Absorption
Phenol is readily absorbed by all routes. This is
illustrated by the fact that acutely toxic doses of phenol
can produce symptoms within minutes of administration regard-'
less of the route of entry (U.S. EPA, 1979). Sixty to 80
percent of inhaled phenol is retained in the lungs. Piotrow-
ski (1971) found that phenol vapor could be readily absorbed
by intact human skin. The rate of dermal absorption for
phenol, vapor can be represented by the formula A=(0.35)C,
when A is the amount of phenol absorbed in mg/hour and C is
the phenol concentration in mg/m3 (Piotrowski, 1971; recal-
culation of data of Ohtsuji and Ikeda, 1972 by U.S. EPA,
1979).
B. Distribution
Free and conjugated phenol appear to be normal
trace constituents in humans and other mammals (Harborne,
1964). Values reported for free and conjugated phenol in'
normal human blood vary greatly due in part to the specifi-
city of the analytical methods used in and in part to the
-------
amount of the dietary protein which increases urinary phenol
excretion. Recent values in normal human blood are between
0.04 to 0.56 mg/1 for the free phenol and 1.06 to 5.18 rag/1
for conjugated phenols (Dirmikis and Darbre, 1974). For the
total phenol (free and conjugated) a range between 2 and 18
mg/1 has been reported (Van Haaften and Sie, 1965).
Upon absorption, phenol is rapidly distributed to
all organ systems, followed by relatively rapid metabolism
and excretion. Within 15 minutes of an oral dose, the high-
• ^
est concentrations are found in the liver, followed by heart,
kidneys, lungs, brain and blood (Deichmann, 1944).
C. Metabolism
The major metabolites "of phenol are sulfate and
glucuronic acid conjugates of phenol and 1,4-dihydroxyben-
zene. There are, however, species differences in'the excre-
tion pattern of these metabolites (Capel, et al. 1972). The
cat, which is sensitive to phenol, in addition to sulfate
conjugated phenols, excretes also, as a major metabolite,
1,4-dihydroxybenzene (Miller, et al. 1976). The metabolic
pattern is also dose dependent. Other agents, which are nor-
mally metabolized to phenol, such as benzene or phenylsalicy-
late, produce increased urinary excretion of phenol metabo-
lites (Kociba, et al. 1976).
D. Excretion
In humans and in all mammals that have been tested,
nearly all of the phenol and its metabolites are excreted .in
the urine within 24 hours (U.S. EPA, 1979; Piotrowski, 1971;
Deichmann and Keplinger, 1963). Reported normal background
. I **, 1 ^
*•• } > I U~ >
-------
values for human urinary phenol range from 1.5 to 5 mg/1
(Fishbeck, et al. 1975? U.S. EPA, 1979). Urinary excretion
levels of phenol metabolites in workers exposed to phenylsal-
icylate ranged from 150 to 1,371 mg/1. Upon ingestion of
eight chloraseptic lozenges at the recommended dosing sched-
ule, the total phenol and the free phenol concentrations in
the urine peaked at 270 and 10 mg/1, respectively. When dogs
were fed 125 mg phenylsalicylate/kg/day for 41 days, the peak
urinary phenol concentration was 6,144 mg/1 and the treatment
was not associated with ill effects (Kociba, et al. 1976).
The half-life of phenol in man is approximately 3.5 hours
(U.S. EPA, 1979).
IV. EFFECTS
A. Carcinogenicity
There is no convincing evidence that phenol acts as
a carcinogen, particularly at concentrations within normal
physiologic limits. Phenol appears to function primarily as
a nonspecific irritant (NIOSH, 1976). Only one case of human
cancer associated with exposure to phenol was found in the
literature. A 12-year old man who had applied a salve of
phenol and ergot to his back daily for 20 years developed an
invasive squammous cell epithelioma (Stevens and Callaway,
1940).
Phenol produced papillomas but not "carcinomas when ap-
plied to the skin of some strains of mice. Phenol has car-
cinogenic activity when applied repeatedly to the skin of a
specially bred strain of Sutter mice at concentrations which
produce repeated skin damage (Boutwell and Bosch, 1959; Sala-
-------
man and Glendenning, 1956) . Phenol promotes skin cancer in
mice when repeatedly applied after initiation with known car-
cinogens (Boutwell and Bosch, 1959; Salaman and Glendenning,
1956; Van' Duuren, et al. 1971). Tumorigenesis is highest at
dose levels of phenol, which have some sclerosing activity.
Phenol has no cocarcinogenic activity when applied simultane-
ously and repeatedly with benzo(a)pyrene to mouse skin (Van
Duuren, et al. 1973).
.8. Mutagenicity
Phenol was found to be mutagenic in Drosphila (Ha-
dorn and Niggli, 1946) and also reported to be nonmutagenic
for Neurosoora (Dickey, et al. 1.949). Phenol produced back
mutations in E. coli from streptomycin dependence to non-de-
pendence at phenol concentrations high enough that the
survival of bacteria was only '0.5 to 1.7 percent (Demerec, et
al. 1951).
C. Teratogenicity
Studies dealing directly with teratogenicity were
not reported in the O.S. EPA (1979) or NIOSH (1976) docu-
ments. In a study, not designed specifically as a teratogen-
icity study, rats were given phenol at concentrations of 100
to 12,000 mg/1 in their drinking water over three to five
generations. Specific teratogenic effects were not noted
(Heller and Pursell, 1938).
D. Other Reproductive Effects
#
In the study mentioned under teratogenicity, higher
concentrations of phenol in the drinking water (7,000 mg/1)
produced stunted growth in the young, death of the offspring
-------
at birth (10,000 mg/1), and failure to reproduce (12,000
mg/1) (Heller and Pursell, 1938).
E. Chronic Toxicity
Repeated exposures to phenol at high concentrations
have resulted in chronic liver damage in humans (Merliss,
1972). In unpublished studies by Dow Chemical Company.
(1976), rats received 135 doses of 100 mg phenol/kg or 50 mg
phenol/kg by gavage over a six month period. The growth of
the rats was comparable to that of controls» Very slight
liver changes and slight to moderate kidney damage were seen.
at the higher dose of phenol. The lower dose of phenol pro-
duced only slight kidney damage;
Rats given phenol in their drinking water at 300,
1,200, 1,600, 2,000, and 2,400 mg/1 had corresponding average
intakes of 21, 30, 49, 56, and 55 mg phenol per rat per day
based on actual water consumption data. The rats at the
three lower dosage levels showed no overt symptoms of toxic-
ity. The weight gain of the rats at the two highest dose
levels was depressed (Deichmann and Oesper, 1940).
F. Other Relevant Information
The primary effect of exposure to acutely toxic
levels of phenol is CNS depression. Significant evidence
could not be found to support the occurrence of synergistic
or antagonistic actions of phenol with other compounds in
mammals (U.S. EPA, 1979).
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
Acute toxicity data for phenol display a wide range
of interspecific variability and intraspecific sensitivity.
The range of LCgQ values for 13 species of freshwater
fish is 5,020 ug/1"for the rainbow trout (Salmo gairdneri) to
200,000 ug/1 for the goldfish (Carassius auratus) (Cairns, et
al. 1978). Several studies have indicated an inverse rela-
tionship between survival time and temperature for rainbow .
r
trout, golden shiner (Notemigonius crysoleueus) (U.S. EPA,
1979). Similar intraspecific sensitivity and interspecific
variability was demonstrated by bioassays with freshwater in-
vertebrates as test, organisms. The cladbcerans, Daphnia
magna and _D. lonqispina, displayed the greatest sensitivity
to phenol with LC5Q values as low as 7,000 ug/1 reported.
The freshwater clam, Sphaerium corneum, was the most resis-
tant species with an LC50 value of 780,000 ug/1 (U.S.
EPA, 1979).
Data for the acute toxicity of phenol to marine or-
ganisms is not nearly as extensive as that for freshwater
species. For marine fish, LC$Q values of 5,200 and 6,014
ug/1 were obtained for rainbow trout in saline waters and
mountain bass (Kuhlia sandvicensis), respectively (U.S. EPA,
1979). Eastern oyster embryos (Crassostrea virginica) and
hardclam embryos (Mercenaria mercenaria) were much more re-
sistant with LC5Q values of 58,250 and 52,630 ug/1,
respectively (Davis and Hidu, 1969).
jar
-------
B. Chronic
Data for the chronic effects of phenol on fresh-
water fish are not available. In a life cycle chronic test,
a chronic•value of 3,074 ug/1 was obtained for the freshwater
cladoceran, Daphnia magna (U.S. EPA, 1978). Chronic data
for marine organisms were not available..
C. Plant Effects
Plants are relatively insensitive to phenol expo-
sure with effective concentrations ranging from 20,000 to
1/504,000 ug/1 for three species of algae, one species of
diatom, and duckweed. Marine plants species have not been
examined for toxic effects of phenol.
D. Residues
Measured bioconcentration factors of 1.2 to 2.3
have been determined for goldfish (Kobayashi, et al. 1976;
Kobayashi and Akitake, 1975). Bioconcentration factors have
not been determined for freshwater invertebrates or plants,
or for any marine species.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria de-
rived by U.S. EPA (1979), which are summarized below, have
gone through the process of public review; therefore, there
is a possibility that these criteria will be changed.
A. Human
On the basis of chronic toxicity data for rats and
an uncertainity factor of 500, the U.S. EPA (1979) has de-
rived a draft criterion of 3.4 mg/1 for phenol in ambient
water corresponding to the calculated acceptable daily intake
-------
of 0.7 rag. The draft criterion for phenol is 1.0 ug/1 in
those instances where chlorination of phenol may take place
during water purification processes.
:The 1974 Federal standard and the ACGIH (1977)
recommendation foe phenol in air in the workplace is 19
mg/m^ (5 ppm) as a time-weighted average.
The NIOSH (1976) criterion for a recommended stand-
ard for occupational exposure to phenol is 20 mg/m^ in air
as a time weighted average for.up,to a 10-hour work day and a
40-hour work week, with .a ceiling concentration of 60 mg/rn^
for any 15-rainute sampling period.
The U.S. EPA interim drinking water limit for
phenol is 1 ug/1, which is largely an organoleptic standard
based on the objectionable taste and odor produced by chlori-
nated phenols. In response to a phenol spill, in southern
Wisconsin, the "J.S_ EPA proposed on November 26, 1974 an
emergency standard of 0.1 rag phenol/1 as being temporarily
acceptable for human consumption.
B. Aquatic
The draft criterion for protecting freshwater or-
ganisms is 600 ug/1, not to exceed 3,400 ug/1. No criterion
for marine organisms was derived (U.S. SPA, 1979).
I l-r "*-
•7l) i h
-------
PHENOL
REFERENCES
Aly, O.M. • 1968. Separation of phenols in waters by thin-layer chromato-
graphy. Water Res. 2: 287.
American Council for Governmental Industrial Hygienists. 1977. Threshold
limit values for chemical substances and physical agents in workroom envi-
ronment with intended changes for 1977.
Barnhart, E.L. and G.R. Campbell. 1972. The effect of chlorination on
selected organic chemicals. U.S. Environ. Prot. Agency.
Boutwell, R.K. and O.K. Bosch. 1959. The tumor-promoting action .of phenol
and related compounds. Cancer Res. 19: 413.
a
Cairns, J., Jr., et al. 1978. Effects of temperature on aquatic organisms
sensitivity to selected chemicals. Project B-084-VA. Bull. 106. Virginia
Polytechnic Inst. State University.
Capel, I.D., et al. 1972. Species variations in the metabolism of phenol.
Biochem. Jour. 127: 25.
Chemical and Engineering News. July 28, 1975.
Chemical Profiles. 1972. Phenol. Schnell Publishing Co., New York.
Davis, H.C. and H. Hidu. 1969. Effects of pesticides on embryonic devel-
opment of clams and oysters and on survival and growth of the larvae. Fish
Wildl. Fish. Bull. 67: 393. U.S.. Oep. Inter.
Deichmann, W.B. 1944. Phenol studies. V. The distribution, detoxifica-
tion, and excretion of phenol in the mammalian body. Arch. Biochem. 3: 345.
Deichmann, W.B. and M.L. Keplinger. 1963. Phenols and -phenolic compounds.
Page 1363 In: F.A. Patty (Ed.), Industrial hygiene and toxicology. Inter-
science Publishers, New York.
Deichmann, W.B. and P. Oesper. 1940. Ingestion of phenol — Effects on the
albino rat. Ind. Med. 9: 296.
Demerec, M., et al. 1951. A survey of chemicals for mutagenic action on E.
coli. Am. Natur. 85: 119.
Dickey, F.H., et al. 1949. The role of organic peroxides in the induction
of mutations. Proc. Natl. Acad. Sci. 35: 581.
Dirmikis, S.M. and A. Darbre. 1974. Gas-liquid chromatography of "simple
phenols for urinalysis. Jour. Chromatogr. 94: 169.
-------
Oow Chemical Co. 1976. References and literature review pertaining to
toxicological properties of phenol. Toxicol. Res. Lad. Unpubl. Manuscript.
Fishbeck, W.A., et al. 1975. Elevated urinary phenol levels not related to
benzene exposure. Am. Ind. Hyg. Jour. 36: 820.
Hadom, E. and H. Niggli. 1946. Mutations in Orosophila after chemical
treatment of gonads in vitro. Nature 157: 162.
Harborne, J.B. 1964. Biochemistry of phenolic compounds. Academic Press,
New York.
Heller, V.G. and L. Pursell. 1938. Phenol'-contaminated waters and their
physiological action. Jour. Pharmacol.. Exp. Ther. 63: 99.
Jolley, R.L. 1973. Chlorination effects on organic constituents in efflu-
ents from domestic sanitary sewage treatment plants. Ph.D. dissertation,
University of Tennessee, Knoxville.
Jolley, R.L.., et al. 1975. Chlorination of cooling water: a source of
envi- ronmentally significant chlorine-containing organic compounds. Proc.
4th Natl. Symp. Radioecology. Corvallis, Ore.
Kirk, R.E. and O.F. Othmer. 1963. Kirk-Qthmer encyclopedia of chemical
technology. 2nd ed. John Wiley and Sons, Inc., New York. ;
Xobayashi, K. and H. Akitake. 1975. Metabolism• of chlorophenols in fish.
IV. Absorption and excretion of phenol by goldfish. Nippon Suisan
Gakkaishi. 41: 1271.
Kobayasni, K., at al. 1976. Studies on the metabolism of chlorophenols in
fish. VI. Turnover of absorbed phenol in goldfish. Bull. Jap. Soc. Sci.
Fish. 42: 45.
Xociba, R.J., et al. 1976. Elevated urinary phenol levels in beagle dogs
treated with salol. Am. Ind. Hyg. Jour. 37: 183.
Lustra, A.O. and P. Issenberg. 1970. Phenolic components of smoked meat
products. Jour. Agric. Food Chem. 18: 1056.
Manufacturing Chemists Assoc. 1974. Chemical safety data sheet SD-4;
Phenol. Washington, O.C..
Merliss, R.R. 1972. Phenol moras. Mus. Jour. Occup. Med. 14: 55.
Miller, J.J., et al. 1976. The toxicity of dimethylphenol and related com-
pounds on the cat. Toxicol. Appl. Pharmacol. 38: 47.
National Commission on Water Quality. 1975. Water quality and environ-
mental assessment and predictions to 1985 for the lower Mississippi River
and Barataria Bay. Vol. 1. Contract WQ5AC062.
National Institute for Occuoational Safety and Health. 1976. Criteria for
a recommenced standard...Occupational exposure to phenol. NIOSH 76-196.
-------
Ohtsuji, J. and M. Ikeda. '1972. Quantitative relationship between atmos-
pheric phenol vapor and phenol in the' urine of workers in bakelite fac-
tories. Br. Jour. Ind. Med. 29: 70.
Piotrowski,, J.K. 1971. Evaluation of exposure to phenol: absorption of
phenol vapour in the lungs and through the skin and excretion of phenol in
urine. Br. Jour. Ind. Med. 28: 172.
Salaman, M.H. and O.M. Glendenning. 1956. Tumor promotion in mouse skin by
sclerosing agents. Br. Jour. Cancer 11: 434.
Stevens, J.B. and J.L. Callaway. 1940. Mixed epithelioma of the back
arising from daily applicaton of a phenl and ergot ointment. Am. Jour.
Cancer. 38: 364.
Stom, O.J. 1975. Use of thin-layer and paper chromatography for detection
of ortho- and para- quinones formed in the course of phenol oxidation.
Acata Hydrochim. Hydrobiol. 3: 39.
U.S. EPA. 1977. National Organic Monitoring Survey. General review of
results and methodology: phases I-III. Water Supply Res. Oiv.
U.S. EPA. 1978. In-depth studies on" health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646. ;
U.S. EPA. 1979. Phenol: Ambient Water Quality Criteria. (Draft)
Van Duuren, B.L., et ai. 1971. Cccarcinogenesis studies on mouse skin and
inhibition of tumor production. Jour. Natl. Cancer Inst. 46: 1039.
Van Duuren, B.L., et al. 1973. Cocarcinogenic agents in tobacco carcino-
genesis. Jour. Natl. Cancer Inst. 51: 703.
Van Haaften, A.B. and S.T. Sie. 1965. The measurement of phenol in urine
by gas chromatography as a check on benzene exposure. Am. Ind. Hyg. Assoc.
Jour. 26: 52.
Weast, R.C. (Ed.) 1974. Handbook of chemistry and physics. 55th ed. CRC
Press, Cleveland, Ohio.
-li
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No. 145
Phorate
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
MS-1
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DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented, by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
Disclaimer Notice
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.
-------
PHORATE
Summary
Phorate is an organophosphorous insecticide used on a variety of crops,
mainly in south-central states. Phorate is readily absorbed through inhala-
tion and skin contact and'is highly toxic to humans and other animals. Pri-
marily, it affects the central and peripheral nervous systems by inhibiting
cholinesterase activity. Information concerning carcinogenic and mutagenic
effects was not located in the available literature. The threshold limit
value for phorate is 50 ug/m3, based on dermal contact. Additionally,
phorate has been classified for restrictive use by the U.S. EPA.
Although phorate is highly toxic to certain aquatic organisms, no ap-
parent adverse effects have been observed in the aquatic environment.
-------
I. INTRODUCTION
Phorate is a highly toxic organophosphorous insecticide used on a vari-
ety of agricultural crops. It was introduced in 1954 by the American Cyana-
mid Co. under the trade name Thin.iiS) (Martin and worthing, 1974). Phorate
is prepared by the reaction of phosphorous pentasulfide vdth ethanol, for-
maldehyde, and ethyl mercapton. Production in the U.S. totaled 3400 tonnes
in 1977 (NAS, 1977). Virtually all of the phorate is used on root and field
cropsoils to control sucking insects and nematodes (NAS, 1975). Phorate is
slightly soluble in water and hydrolyzes in moisture. It has an overall
degradation rate constant of 0.02/d'ay and a bioconcentration factor of 5.2.
Other properties are listed in Table 1.
II. EXPOSURE
A. Mater
Phorate is produced in the United States by the American Cyanamid
Co. at Hannibal, Mo. (SRI, 1977). Available information on an annual U.S.
production shows that 1900 tonnes were produced in 1971, 3600 tonnes in
i
1974, and 3400 tonnes in 1977 (NAS, 1975, 1977). Berg, et ai. (1972) noted
an application rate of 1 pound of actual material per acre (1.1 kg/ha; in
this case, to control corn borers). Application rates vary according'to use.
Phorate has found increasing use on croplands in the south-central
states to protect cotton, hops, alfalfa, barley, sorghum, peanuts, sugar
beets, sugar cane, potatoes, rice, and tomatoes. Only small amounts are
used in the southeastern and northeastern U.S. American Cyanamid Co. re-
ported that phorate may fill the void left by the removal from the market of
chlorinated hydrocarbons and projected a strong demand for phorate in the
corn rootworm market (Berg, et al. 1977).
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TABLE 1. PHYSICAL AND CHEMICAL PROPERTIES OF PHORATE
Synonyms: 0,0-diethyl-S-(ethyIthiomethyl)phosphorodithioate;
0,0-diethyl-S-ethylmercaptomethyl dithiophosphate;
THIMET American Cyanamid (3911): timet (USSR);
CAS Registry No. (298-02-2); Dranutox; Rampart; Vergfru
Structural Formula: (C2H50)2(P=S)SCH2SC2H5
Molecular Weight: 260.4
Description: Clear liquid
Miscible with: CQ4, dioxan, vegetable oils, xylene, alco-
hols, ethers, esters
Soil Attenuation: Kd approx. 5 x 1Q2; KOC = 3199
Specific Gravity and/or Density: d25 - 1.167
Melting and/or Boiling Points: bp 118 to 12QOC at 0.8 mm
mp less than -150C
Stability: Stable at room temperature
Hydrolyzed in the presence of moisture
Overall degradation rate constant (0.02/day)
Soil half-life: 1-4 weeks
Bacterial/Hydrolysis: constant = 8 x
Solubility (water): 50 ppm at room temp.
sediment . 4.5
H20 * 1
Vapor Pressure: 8.4 x 10-4 mm Hg at 20°C
Bioconcentration Factor (BCF) and/or
Octanol/water partition coefficient (KQW): KOW = 18
BCF =5.2
Source: Martin and Worthing, 1974; Fairchild, 1977; Windholz, 1976;
U.S. EPA, 1980
-------
Little information was found on phorate production processes.
Lawless, et al. (1977) noted that in the production, crude phorate was wash-
ed and filtered. No information was given on the treatment of the waste
water or filter cake associated with this process. No information on waste
sludge or landfill disposal was found in the available literature.
Phorate can enter water by runoff or by ground water drainage
after application. Phorate is relatively stable in ground water. Only 10
percent decomposition was estimated in a river environment in 5 days (50 to
250 mile transport; 80-400 km). Also, estimates show that less than 90 per-
cent decomposition per year occurs in a lake environment- (U.S. EPA, 1980).
There are no estimates on the amount of phorate entering the environment or
on the levels of phorate in ambient water. Menzie (1974) noted that phorate
decomposes to phorate sulfoxide and phorate sulfone and the sulfoxide and
sulfone of the oxygen analog.
Walter-Echols and Lichtenstein (1977) showed that some oxidation
products of phorate (phorate sulfoxide) reduce to phorate in lake mud under
certain conditions. Using a flooded phorate sulfoxide-treated loam soil,
they noticed the production of only small amounts of phorate. After lake
mud was added, the reduction of phorate sulfoxide to phorate increased dra-
matically and, after two weeks' incubation, accounted for 44 percent of the
recovered residues. They related the reduction process to the activity of
microorganisms in an environment of organic nutrients.
f
B. Food
Information available in the open literature does' not quantify the
amount of phorate detected on foods. In a study reported by Menzie (1974),
phorate was applied to bermuda grass and com at the rate of 2 pounds per
-------
acre (2.2 kg/ha). Fourteen days after treatment, less than 1 ppm phorate
residue was noted on the corn; after 21 days less than 1 ppm was found on
bermuda grass.
C. Inhalation and Dermal
Data are not available indicating the number of people subject to
inhalation or dermal exposure to phorate. The primary human exposure would
appear to occur during production and application.. The-.U.S. EPA (1976) list-
ed by occupational group the frequency of illness caused by exposure to or-
ganophosphorous pesticides. Of 1157 reported cases, most illnesses occurred
among ground applicators (229) and mixer/loaders (142); the lack of, or re-
fusal to use, safety equipment was a major factor of this contamination.
Other groups affected were gardeners (101), field workers exposed to pesti-
cide residues (117), nursery and greenhouse workers (75), soil fumigators in
agriculture (29), equipment cleaners and mechanics (28), tractor drivers and
irrigators (23), workers exposed to pesticide drift (22), pilots (crop dust-
ers) (17), and flaggers for aerial application (6). Most illnesses were a
result of carelessness, lack of knowledge of the hazards, and/or lack of
safety equipment. Under dry, hot conditions, workers tended not to wear
protective clothing. Such conditions also tended to increase pesticide
levels and dust on the workers.
III. PHARMACOKINETICS
A. Absorption
Newell and Dilley (1978) exposed four different groups of rats to
phorate via four routes of administration. They compared LD-Q an(j \_£5Q
values and found that inhalation was the most toxic route, followed, in de-
creasing order, by intravenous, oral, and dermal routes. The phorate ae.ro-
-------
sol generated in the laboratory had a particle size range of 0.3-3.0 \m dia-
meter, a size small enough to enter the gas exchange regions of the lung.
Young, et al. (1979) reported on two occupational exposure inci-
dents that suggested absorption in the lungs was the most effective -route of
entry. In both cases, the individuals wore protective clothing, goggles,
and respirators while working in the dust house where technical grade phor-
ate was produced. Gas chromatographic analyses of air samples from the dust
house showed phorate levels ranging from 0.7 to 14.6 mg/nP. NO estimate
of particle size was reported by the authors.
B. Distribution
Phorate would be expected to distribute in the body like organo-
phosphorous pesticides of similar solubility. A report by Pugh and Forest
(1975) described the distribution in calves exposed to phorate in a manger
containing 1200 ppm. Phorate concentrations in the liver ranged from 0.004-
0.26 ppm; in the kidney, O.CQ2-Q.021. ppm; and in the brain, 0.025-0.19 ppm.
C.. Metabolism
The major phorate metabolites found in blood after oral admini-
stration to rats are phorate sulfoxide, phorate sulfone, and phoratoxon sul-
fone (NAS, 1977). Bowman and Casida (1958) showed that phorate hydrolyzes
in rats to produce urinary diethylphosphorodithioic acid, diethylphosphoro-
thioic acid, and diethylphosphoric acid. Oxidative metabolites are not
found as components of excretory products of animals treated with phorate
(NAS, 1977). However, DuBois, et al. (1950) showed that in rat liver
slices, phorate was converted to its oxidative products.
D. Excretion
The previous section notes that phorate is eliminated primarily
through the urinary system.
-------
IV. EFFECTS
A. Carcinogenicity and Mutagenicity
Pertinent data could not be located in the available literature on
the carcinogenicity or mutagenicity of phorate. Formaldehyde, a suspected
carcinogen, and other contaminants may be present in technical grade phorate.
B. Teratogenicity
In a study described in the absorption section of this report,
Newell and Oilley (1978) did not find dose-related teratogenesis in rats ex-
posed to phorate via inhalation, intravenous, dermal, or oral routes. In
the chick embryo test, Richert and Prahlad (1972) injected 1.5 or 2.0 ppm in
a peanut oil medium into eggs on the tenth day of incubation. Controls re-
ceived only peanut oil. Hatchability of the eggs decreased in a dose-depen-
dent manner. Malformations were produced, but these did not seem to be
dose-related. The relevance of these studies to mammalian teratology is
unclear (NAS, 1977).
C. Other Reproductive Effects
In a study in which CFI mice were fed diets containing 98.7 per-
cent phorate at 0.6, 1.5, and 3.0 ppm, the no-adverse-effect level for re-
productive performance was 1.5 ppm (NAS, 1977).
0. Chronic Toxicity and Other Relevant Information
Pertinent data on chronic toxicity could not be located in the
available literature. Several subchronic studies have been reported. In
subchronic feeding studies of 1, 5, and 25 ppm phorate for 28 days, choli-
nesterase in the 1 ppm group was not decreased (Tusing, 1955). In a second
rat study, Tusing (1956) fed groups of 50 males and females 92 percent phor-
ate for 13 weeks at 0.22, 0.66, 2.0, 6.0, 12.0, and 18.0 ppm. He noted a
no-adverse-effect dosage at 0.66 ppm.
-------
Tusing (1956) fed three dogs 92 percent phorate at 0.01, 0.05,
0.25 and 1.24 mg/kg 6 days per week for 13-15 weeks. The no-adverse-effect
dosage was judged to be 0.01 mg/kg; even at this level, a very slight de-
crease in plasma cholinesterase resulted. Higher dosages, caused significant
depression of cholinesterase, culminating in death at the two highest
dosages.
Rat feeding studies showed higher subchronic toxicities on phorate
oxidative metabolites than on phorate, according to Rombunski, et al.
(1958). Others have also noted that phorate metabolites are more potent
cholinesterase inhibitors than phorate (Curry, et al. 1961).
Young, et al. (1979) reported on acute exposures to high levels of
phorate (up to 14.6 mg/m5) in a production facility (see absorption sec-
tion). The symptoms accompanying the exposures were confusion, dizziness,
nausea, vomiting, pupil constriction, respiratory distress, cardiac arrhyth-
mia, and unconsciousness. Treatment involved a regime of RAM and atropine.
According to Gleason (1969), the symptoms produced by a sub-lethal dose are
typical of central and peripheral nervous system toxicity. EPA's accident
files contain reports of 21 episodes of poisoning involving phorate for
1971-1973. Eleven were agriculturally related. There are no controlled
studies in humans from which no-adverse-effect dosages could be derived.
For humans, the lowest published lethal (UD^) value is estimat-
ed to be 5 mgAg. The following studies list acute phorate rtoxicity levels
for human and nonhuman species, reported by Fairchild (1977):
Hf-ll
-------
Species Exposure LDgn (mg/kg)
Rat Oral. 1.1
Rat Skin 2.5
Rat Intravenous 1.2
Mouse Oral 11
Guinea pig Oral 20
Guinea pig Skin 20
Duck Oral 2.55
Duck Skin 203
Wild Bird Oral 1
V. AQUATIC TOXICITY
A. Acute and Chronic Toxicity
Phorate is highly toxic to certain species of fish, crustaceans,
and terrestrial wildlife .(NAS, 1977). NAS noted that there were no reported
killings of these species in the environment.
B. Plant Effects and Residues
Pertinent data could not be located in the available literature.
VI. EXISTING GUIDELINES
A. Human
The threshold limit value for phorate is 50 jUg/nP, based on skin
contact (Fairchild, 1977). An 8-hour time-weighted average of 50 mg/m?
was adapted for phorate by the Tennessee Department of Health (Young, et al.
1979). In addition,, phorate is classified for restrictive use by the U.S.
EPA for liquid formulations containing 65 percent and greater active ingre-
dients. The restriction was influenced by the acute dermal toxicity of
phorate and by residue effects on avian species (applicable to foliar appj.i-
cations only).
-------
8. Aquatic
Pertinent data could not be located in the available literature.
-------
REFERENCES
Berg, G.L., et al. (ed.) 1977. Farm Chemicals Handbook. Meister Publish-
ing Company, willoughby, Ohio.
Bowman, J.s. and J.E. Casida. 1958. Further studies on the metabolism of
Thimet by plants, insects and mammals. Jour. Econ. Entomol. 51: 838.
Curry, A.M., et al. 1961. Determination of residue of phorate and its in-
secticidally active metabolites by cholinesterase inhibition. Jour. Agric.
Food Chem. 9: 469.
DuBois, K.P., et al. 1950. Studies on toxicity and pharmacological action
of octamethyl pyrophosphoramide. Jour. Pharmacol. Exp. Ther. 99: 376.
Fairchild, E.J. (ed.) 1977. Agricultural Chemicals and Pesticides. A Sub-
file of the NIOSH Registry of Toxic Effects of Chemical Substances. U.S.
DHEW.
Gleason, M.N., et al. 1969. Clinical Toxicology of Commercial Products.
Acute Poisoning. 3rd ed.
Lawless, E.W., et al. 1972. The Pollution Potential in Pesticide Manufac-
turing. U.S. EPA, Office of Water Programs, Technical Studies Report TS-00-
72-04.
Martin, H. and C.R. Worthing (eds.) .1974. Pesticide Manual. 4th ed.
Menzie, C.M. 1974. Metabolism of Pesticides: An Update. U.S. Dept. of the
Interior Special Scientific Report - Wildlife No. 184, Washington, O.C.
National Academy of Sciences. 1975. Pest Control: An Assessment of Pre-
sent and Alternative Technologies, Vol. I.
National Academy of Sciences. 1977. Drinking Water and Health. Natl.
Acad. Sci., Washington, D.C.
Newell, G.W. and J,.V. Dilley. 1978. Teratology and Acute Toxicology of
Selected Chemical Pesticides Administered by Inhalation. U.S. NTIS, PB Rep.
PB-277077, 66 pp.
Pugh, W.S. and O.N.T. Forest. 1975. Outbreak of organophosphate poisoning
(Thimet) in cattle. Can. Vet. Jour. 16: 56.
Richert, E.P. and K.V. Prahlad. 1972. The effect- of the organophosphate
0,0 diethyl S-C(ethylthio)methyl]phosphorodithioate on the chick. Poultry
Sci. 51: 613..
Rombunski, et al. 1958. Cited in National Academy of Sciences, 1977.
»
Stanford Research Institute. 1977. Directory of Chemical Producers. Stan-
ford Research Institute, Menlo Park, California.
-------
Tusing, T.w. 1955. Unpublished report of American Cyanamid. Cited in U.S.
EPA Initial Scientific and Minieconomic Review of Phorate, 1974.
Tusing, T.W. 1956. Unpublished report of American Cyanamid. Cited in U.S.
EPA Initial Scientific and Minieconomic Review of Phorate, 1974.
U.S. Environmental Protection Agency. 1976. Organophosphate Exposure from
Agricultural Usage, EPA 600/1-76-025.
U.S. Environmental Protection Agency. 1980. Aquatic Fate and Transport Esti-
mates for Hazardous Chemical Exposure Assessments. Environmental Research
Laboratory, Athens, Georgia.
Walter-Echols, G. and E.P. Lichtenstein. 1977. Microbial reduction of phor-
ate sulfoxide to phorate in a soil-lake mud-water microcosm. Jour. Econ.
Entomol. 70: 505.
Windholz, M. (ed.) 1976. The Merck Index, 9th ed. Merck Co., Inc., Rahway,
New Jersey.
Young, R.J., et al. 1979. Phorate intoxication at an insecticide formulating
plant. Am. Ind. Hyg. Assoc. Jour. 40: 1013.
-------
No. 146
Phthalate Esters
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey oz the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
^^^^^^^^^^J^i
~ / J 0 "
-------
PHTHALATE ESTERS
Summary
Certain' phthalates (dimethyl phthalate, diethyl phthalate, mono-2-
ethyl-hexyl phthalate and dimethoxyethyl phthalate), have shown mutagenic
effects in both bacterial systems and the dominant lethal assay.
All eight phthalates tested by injection in pregnant rats produced
teratogenic effects. These effects were not noted when DEHP or dibutyl
phthalate were administered orally to pregnant rats. Additional reproduc-
tive effects produced include impaired implantation, parturition and de-
creased fertility in rats. Testicular damage has been reported following
intraperitoneal (i.p.) or oral administration of DEHP, or oral administra-
tion of dibutyl phthalate. No evidence of carcinogenic effects produced, by"
«
phthalates is available.
Chronic toxicity includes toxic polyneuritis in workers exposed primar-
ily to dibutyl phthalate. DEHP animal studies show induced liver and kidney
changes while dimethyl phthalate induced only kidney effects. Following in-
jection dibutoxyethyl phthalate, di-(2-methoxyethyl) phthalate, and octyli-
sodecyl phthalate have caused damage to the developing chick embryo nervous
system.
Toxicity of the phthalate esters to aquatic organisms varies within
this group of chemicals. Freshwater organisms have appeared somewhat more
sensitive than marine species. The data is insufficient to allow for the
drafting of criteria to protect aquatic life for any of the phthalates.
-J
-------
PHTHALATE ESTERS
I. INTRODUCTION
This profile is based primarily on the draft Ambient Water Quality Cri-
teria Document for Phthalate Esters (U.S. EPA, 1979).
The phthalate esters are esters of the benzenedicarboxylic acid ortho
form. Esters of the parent compound meta and para forms will not be review-
ed in this profile. The phthalate esters are colorless liquids of low vola-
tility, poorly soluble in water and soluble in organic solvents and oils.
Some physical and chemical properties of the phthalate esters are indicated
in Table.. 1.on the following page (U.S. EPA, 1979).
The phthalate esters are widely used as placticizers, and through this
application are incorporated into wire and cable covering, floor tiles,
swimming pool liners, upholstery and seat covers, footwear, and in food and.^
medical packaging materials. Non-plasticizer uses include incorporation
into pesticide carriers, cosmetics, fragrances, munitions, industrial oils,
and insect repellants (U.S. Int. Trade Commission, 1978). The most current
production figure is 6 xlO5 tons/year in 1977 (U.S. EPA, 1979).
Phthalate esters are ubiquitous. Monitoring surveys have detected
phthalates in soil, air, water, animal and human tissues, and certain vege-
tation. Some plants and animal, tissues may synthesize phthalic acid esters
(Peakall, 1975). From in vitro studies indications, certain bacterial flora
may be capable of metabolizing phthalates to the monoester form (Englehardt,
at al. 1975).
II. EXPOSURE
Phthalate esters appear in all areas of the environment. Environmental
release of the phthalates may occur through leaching of plasticizers 'from
polyvinyl chloride (PVC) materials, volatilization of phthalates from PVC
-------
materials, and the incineration of PVC items. Human exposure to phthalates
includes contaminated foods and fish, dermal application of phthalates in
cosmetics and insect repellants, and parenteral administration by use of PVC
blood bags, tubings, and infusion devices (U.S. EPA, 1979).
TABLE 1
PHYSICAL AND CHEMICAL PROPERTIES OF FHTHALATE ESTERS
Phthalate
Compounds
Dimethyl
Diethyl
Oiallyl
Oiisobutyl
Dibutyl
Oimethoxyethyl
Oicyclohexyl
Butyl octyl
Oihexyl
Butylphthayl
butyl glycolate
Dibutoxyethyl
sthyl
Di-2-ethylhexyl
Diisooctyl
Di-n-octyl
Dinonyl
Molecular
Weight
194.18
222.23
246.27
278.30
278.34
282.00
330.00
334.00
334.00
336.37
366.00
391.00
391.00
391.00
419.00
Specific
Gravity
1.189 (25/25)
1.123 (25/4)
1.120 (20720)
1.040
1.047 (21)
1.171 (20)
1.200 (25/25)
—
0.990
1.097 (25/25)
1.063
0.985 (20/20)
0.981
0.978
0.965
Bp, Percent
OC Solubilitv in
H20, g/100 ml
282
296.1
290
327
340
190-210
. 220-228
340
—
219/5 mm
210
386.9/5 mm
239/5 mm
220/5 mm
413
0.5
Insoluble
0.01
Insoluble
0.45 (25°C)
0.85
Insoluble
—
Insoluble
0.012
0.03
Insoluble
Insoluble
Insoluble
Insoluble,
Source: U.S. EPA, 1979
rifts
-------
Monitoring studies have indicated that most water phthalate concentra-
tions are in the ppm range, approximately 1-2 ug/1 (U.S. EPA, 1979). Air
levels of pnthalates in closed PVC tiled rooms have been reported to be from
0.15 to 0.26 mg/m (Peakall, 1975), while industrial monitoring has mea-
sured air levels of phthalates from 1.7 to 66 mg/m (Milkov, et al. 1973).
Phthalate levels in various foods have ranged from non-detectable to 82 ppm
(Tomita, et al. 1977). Cheeses, milk, fish and shellfish present potential
sources of high phthalate intake (U.S. EPA, 1979). Estimates of patient
parenteral exposure to di-2-ethylhexyl phthalate (DEHP) during use of PVC
m
medical appliances have indicated approximately 150'mg OEHP exposure from a
single hemodialysis course. Through application of certain cosmetics and
insect repellants dermal exposure to phthalates is possible (U.S. EPA, 1979).
Using average human fish and shellfish consumption data, the U.S. EHA
(1979) has derived the following bioconcentration factors for the edible
portions of fish and shellfish consumed by Americans - diethyl phthalate,
270; dibutylphthalate, 1500; OEHP, 95; dimethyl phthalate, 130. OMP,. DEP
and 8BP are based on the steady-stata bioconcentrations in bluegills and in
fathead minnows for OEHP. A weighted average bioconcsntration factor of 26
was calculated for dibutyl phthalate utilizing the octanoi water partition
coefficient (U.S. EPA, 1979).
III. PHARMACOKINETICS
A. Absorption
The phthalic acid asters and/or their metabolites are readily ab-
sorbed from the intestinal tract, the peritoneal cavity, and the lungs (U.S.
EPA, 1979). Daniel and Bratt (1974) found that seven days following admin-
»
istration of radiolabelled-OEHP, &2 percent of the dose is recovered in the
urine and 57 percent recovered in the faces of rats. 3iliarv excretion of
/•ft.- 6
-------
orally administered CEHP has been noted by Wallin, et al. (1974). Limited
human studies indicate that 2 to 4.5 percent of orally administered OEHP is
recovered in the urine within 24 hours (Shaffer, et al. 1945). Lake, et al.
(1975) suggest orally administered phthalates are absorbed after metabolic
conversion to the monoester form in the gut.
Dermal absorption of OEHP in rabbits has been reported at 16 to 20
percent of the initial dose within three days following administration
(Autian, 1973).
B. Distribution
Studies in rats injected with radiolabelled-OEHP have shown that
from 60 to 70 percent of the administered dose was detected in the liver and
lungs within 2 hours after injection (Daniel and Bratt, 1974). Wadell, et
al. (1977) have reported rapid accumulation of radiolabelled-OEHP in the
kidney and liver of rats after intravenous (i.v.) injection, followed by
*.
rapid excretion into the urine, bile, and intestine. Seven days after i.v.
administration of radiolabelled-OEHP to mice, levels of the compound were
found preferentially in the lungs and to a lesser extent in the brain, fat,
heart, and blood (Autian, 1973).
An examination of tissue samples from two deceased patients, recip-
ients of large volumes of transfused blood, detected. OEHP in the spleen,
liver, lungs, and abdominal fat (Jaeger and Rubin, 1970). Daniel and Bratt
(1974) have suggested phthalates achieve a steady-state concentration, after
which the compounds or metabolites are rapidly eliminated by various routes.
Injection of radiolabelled-OEHP and diethyl phthalate in pregnant
rats has shown the phthalates may cross the placental barrier (Singh, et al.
1975).
-------
C. Metabolism
Various metabolites of OEHP have been identified following oral
feeding of rats (Albro, et al. 1973). These results indicate that OEHP is
initially converted from the diester to the monoester, followed by the oxi-
dation of the monoester'side chain forming two different alcohols. The al-
cohols are then oxidized to the corresponding carboxylic acid or ketone.
Enzymatic clearance of phthalates to the monoester form may take place in
the liver or in the gut (Lake, et al. 1977). This enzymatic conversion has
been observed' in stored whole blood .indicating widespread distribution ' of
a
this metabolic activity (Rock, et al. 1978).
0. Excretion
Elimination of orally administratered OEHP is virtually completed
within four days in the rat (Lake, et al. 1975). Major excretion is through;
the urine and faces, with biliary excretion increasing the content of DEHP
(or metabolites) in the intestine (U.S. EPA, 1979). Schulz and Rubin (1973)
have noted a progressive increase in total water soluble metabolites in the
first 24 hours fallowing injection of radiolabelled OEHP to rats. Within
one hour, eight percent of the OEHP was found in the liver, intestine and
urine. After 24 hours, 54.6 percent DEHP was recovered in the intestinal
tract, excreted feces and urine, and only 20.5 percent OEHP was recovered in
organic extractable form.
The half-life of phthalate elimination from the tissues and total
body is short (U.S. EPA, 1979). Siphasic elimination of OEHP from the blood
of rats showed half-life values of 9 minutes and 22-'minutes, respectively
(Schulz and Rubin, 1973).
-------
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not be found in the available literature.
8. Mutagenicity
Testing of several phthalates in the Ames Salmonella assay has
shown that diethyl phthalate has some mutagenic activity (Rubin, et al.
1979). Oibutyl, mono-2-ethylhexyl, di-(2-ethylhexyl) and butylbenzyl phtha-
late all produced negative effects in this test system. Yagi, et al.
(1978) have reported mutagenic effects of mono-2-ethylhexyl phthalate in a
Bacillus subtillus recombinant assay system.
Results of a dominant lethal assay in mice have indicated DEHP and
dimethoxyethyl phthalate showed some mutagenic activity (Singh, et al. 1974).
C. Teratogenicity ;
The teratogenic effects of a number of phthalate esters (DEHP, di-
methyl, dimethoxyethyl, diethyl, diisobutyl, butylcarbobutoxymethyl, and di-
octyl phthalates) have been reported in rats (Singh, et al. 1972). Terato-
genic effects were not seen following oral administration of DEHP and dibu-
tyl phthalate to rats (Nikonorow, et al. 1973). Damage to the nervous sys-
tem or developing chick embryos has been produced by injection of dibutoxy-
ethyl phthalate, di-(2-methoxy-ethyl) phthalate, and octyl-isodecyl phtha-
late (Bower, et al. 1970).
0. Other Reproductive Effects
Effects on implantation and parturition have been observed in preg-
nant rats injected intraparenteneally with OEHP, dibutyl phthalate, and di-
methyl phthalate (Peters and Cook, 1973). A three generation rat reproduc-
»
tion study has indicated decreased fertility following maternal OEHP treat-
ment (Industrial Bio-Test, 1978).
-------
Testicular damage has been reported in rats administered OEHP in-
traparenteneally or orally. Seth, at al. (1976) found degeneration of the
seminiferous tubules and changes in spermatagonia; testicular atrophy and
morphological damage was noted in rats fed OEHP or dibutyl phthalate (Car-
ter, et al. 1977).
E. Chronic Toxicity
An increase in toxic polyneuritis has been reported by Milkov, et
al. (1973) in workers exposed primarily to dibutyl phthalate. Lasser levels
>
of exposure to dioctyl, diisooctyl, benzylbutyl phthalates, and tricresyl
phosphate were also noted. Neurological symptoms have been observed in sev-
eral phthalate plasticizer workers (Gilioli, 1978). Animal studies have
shown central nervous system degeneration and ancephalopathy in rats admin-
istered large oral or intiaperitoneal doses of butylbenzyl phthalate (Mai-
lette and Von Hamm, 1952).
Oral OEHP feeding has produced liver and kidney weight increases in
i
several animal studies (U.S. EPfl, 1979). Chronic exposure to transfused
blood containing OEHP has produced liver damage in monkeys (Kevy, et al.
1973). Lake, at al. (1975) have produced liver damage in rats by adminis-
tration of mono-2-ethylhexyl phthalate.
Two-year feeding studies with female rats have shown some kidney
effects produced by dimethyl phthalate (Draize, et al. 1948).
F. Other Relevant Information
Several animal studies have demonstrated- that OEHP pretreatment of
rats resulted in increased hexobaroital sleeping times (Daniel and 9ratt,
1974; Rubin and Jaeger, 1973; Swinyard, at al. 1976).
_-^a/A/ —
' I / " 8"
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
Acute values for freshwater fish were derived from eight 96-hour
bioassays for four phthalate esters. LC5Q values ranged from 730 ug/1 for
di-n-butyl phthalate in the bluegill sunfish (Lepomis macrochirus) (Mayer
and Sanders, 1973) to 98,200 ug/1 in diethyl phthalate for the bluegill,
Lepomis macrochirus. Butylbenzyl and dimethyl phthalates were intermediate
in their toxicity in bluegill assays with LC5Q values of 43,300 to 49,500
ug/1 respectively (U.S. EPA, 1978). The scud, Gammarus pseudolimnaeus, was
the most sensitive of freshwater species tested, producing a static 48-hour
adjusted LC-Q value of 765 ug/1 (Mayer and Sanders, 1973). In 48-hour
static Daphnia magna assays, the adjusted LC-Q values for butylbenzyl, di-
ethyl dimethyl, and di-n-ethylhexyl phthalates were 92,300, 52,100, 33,QOOn
and 11,100 ug/1, respectively. Among marine fish, juvenile sheepshead min-
nows, Cyorinodon variegatus, were most susceptible to diethyl phthalate,
producing a static 96-hour LC__ value of 29,600 jug/1. In similar assays,
the LC_Q values for butylbenzyl and dimethyl phthalate were 445,000 ug/1
and 58,000 ug/1 respectively. The marine mysid shrimp, Mysidopsis bahia,
was tested with diethyl phthalate, and produced a 96-hour LC_Q value of
7,590 ug/1. LC5Q values of 9,630 and 73,700 ug/1 were reported for butyl-
benzyl and dimethyl phthalates, respectively, in mysid shrimp assays.
B. Chronic Toxicity
The only chronic studies available are for one species of fresh-
water fish and one species of freshwater invertebrate (Mehrle and Mayer,
1976; Mayer and Sanders, 1973). A chronic value of 4.2 ug/1 was obtained in
»
a rainbow trout, Salmo gairdneri, embryo-larval study of di-(2-ethylhexyl)
If I'll
-------
phthalate. In Oaphnia maqna significant reproductive impairment was observ-
ed for di-2(-ethylhexyl) phthalate at 3.0 ug/1, the lowest concentration
tested. Chronic marine data was not available.
C. Plant Effects
In the freshwater algae, Selenastrum capricomutum, effective con-
centration ranges of 110 to 130 ug/1; 85,600 to 90,300 ug/1 and 39,300 to
42,700 ug/1 were obtained for butylbenzyl, diethyl and dimethyl phthalates
respectively. Effective concentrations were based on chlorophyll a content
and cell number.
0. Residues
Bioconcentration factors have been obtained for five of the phtha-
lates. In the scud, bioconcentration factors of 1400 were reported for di-
n-butyl phthalate, and 54,2680 for di-(2-ethylhexyl) phthalate. In the.'
bluegill, bioconcentration factors of 57, 117, and 663 were obtained for di-
methyl, diethyl, and butylbenzyl phthalates, respectively. For di-(2-ethyl-
hexyi) phthalate bioconcentration factors were reported from 24 to 150 for
'the sowbug, Ascellus brevicaudus, 42 to 113 for the rainbow trout, and 155
to 386 for the fathead minnow.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed.
A. Human ' ,
3ased on "no effect" levels observed in chronic feeding studies of
rats or dogs, the U.S. EPA calculated acceptable daily intake (ADI) levels
for several phthalates, and established recommended water quality criteria
-------
levels to protect human health for dimethyl phthalate, diethyl phthalate,
dibutyl phthalate, and OEHP. These levels are listed in Table 2 (U.S. EPA,
1979)
8. Aquatic
Data are insufficient to derive draft criteria for any of the
phthalate esters in either freshwater or marine environments (U.S. EPA,
1979).
TABLE 2
CALCULATED ALLOWABLE DAILY INTAKE IN WATER AND
FISH FOR VARIOUS PHTHALATE ESTERS (U.S. EPA, 1979)
Ester NO Effect Species Days
Dose
(mg/kg/day)
Dimethyl
Diethyl
Dibutyl
Dicyclohexyl
Methyl phthayl
ethyl glycolate
Ethyl phthayl
ethyl glycolate
Butyl phthayl
ethyl glycolate
Oi-2-ethyhexyl
1000
625
18
14
750
250
140
60
Rat
Dog
Dog.
Dog
Rat
Rat
Dog
Dog
104
52
52
52
104
104
104
52
ADI**- F*** Recommended
(mg/day) Criteria
(mg/1)
700.
438
12.6
9.8
525
175
98
42
130
270
26
Not
Established
Not
Established
Not
Established
Not
Established
95
160
60
5
10
**Allowable Daily Intake for 70 kg person (100 safety factor)
***F = Biomagnification factor
XT
-------
PHTHALATE ESTERS
REFERENCES
Albro, P.W., et al. 1973. Metabolism of diethhexyll phtha-
late by rats. Isolation and characterization of the urinary
metabolies. Jour. Chromatogr. 76: 321.
Autian, J. 1973. .Toxicity and health threats of phthalate
esters: Review of the literature. Environ. Health Perspect.
June 3. ...
Bower, R.K., et al. 1970. Teratogenic affects in the chick
embryo caused by esters of phthalic acid. Jour. Pharmacol.
Exp. Therap. 171: 314.
Carter, B.R., et al. 1977. Studies on dibutyl phthalate-
induced testicular atrophy in the rat: Effect on zinc metabo-
lism. Toxicol. Appl. Pharmacol. 41: 609.
Daniel, J.W., and H. Bratt. 1974. The absorption, metabo-
lism and tissue distribution of di(2-ethylhexyl) phthalate
in rats. Toxicology 2: 51.
Draize, J.H., et al. 1948. Toxicological investigations
of compounds proposed for use as insect repellents. Jour.
Pharmacol. Sxp. Ther. 93: 26.
Engelhardt, G. et al. 1975. The microbial metabolism of .
di-n-butyl phthalate and related dialkyl phthalates. Bull.
Environ. Contain. Toxicol. 13: 342.
Gilioli, R. et ai. 1978. A neurological electromyographic
and electroneurographic .study in subjects working at the
production of phthalate plasticizers: Preliminary results.
Med. Law. 69^ 631.
Industrial Bio-Test. 1978. Three generation reproduction
study with di-2-ethyl hexyl phthalate in-albino rats. Plas-
tic Industry News, 24^, 201-203.
Jaeger, R.J., and R.J. Rubin. 1970. Plasticizers from
plastic devices: Extraction, metabolism, and accumulation
by biological systems. Science 170: 460.
Kevy, S.V., et al. 1978. Toxicology of "plastic devices
having contact with blood. Rep. N01 HB 5-2906, Natl. Heart,
Lung and Blood Inst. Bethesda, Md.
Lake, E.G., et al. 1975. Studies on the hepatic effects '
of orally administered di-(2-ethylhexyl) phthaiate in the
rat. Toxicol. Appl. Pharmacol. 32: 355.
JJl-lf ,
-------
Lake, B.C., et al. 1977. The in vitro hydrolysis of some
phthalate diesters by hepatic and intestinal preparations
from various species. Toxicol. Appl. Pharmacol. 39: 239.
Mallette, F.S., and E. Von Haam. 1952. The toxicity and
skin effects of compounds used in the rubber and plastics
industries. II. Plasticizers. Arch. Ind. Hyg. Occup.
Med. 5: 231.
Mayer, F.L. Jr., and H.O. Sanders. 1973. Toxicology of
phthalic acid esters in aquatic organisms. Environ. Health
Perspect. 3: 153.
Mehrle, P.M., and F.L. Mayer. 1976. Di-2-ethylhexylphtha-
late: Residue dynamics and biological effects in rainbow
trout and fathead minnows. Pages 519-524. In, Trace sub-
stances in. environmental health. University of Missouri
Press, Columbia.
Milkov, L.E.., et al. 1973. Health status of workers ex-
posed to phthalate plasticizers in the manufacture of artifi-
cial leather and films based on PVC resins. Environ. Health
Perspect. Jan.. 175.
Nikonorow, M., et al. 1973. Effect of orally administered
plasticizers and polyvinyl chloride stabilizers in the rat.
Toxicol. Appl. Pharmacol. 26: 253.
Peakall, D.3. 1975. Phthalate esters: Occurrence and
biological effects. Residue Rev. 54: 1.
Peters, J.W., and R.M. Cook. 1973. Effects of phthalate
esters on reproduction of rats. Environ. Health Perspect.
Jan. 91.
Rock, G. et al. 1978. The accumulation of mono-2-ethyl
hexyl phthalate (MEHP) during storage of whole blood and
plasm. Transfusion 18_ 553.
Rubin, R.J., and R.J. Jaeger. 1973. Some pharmacologic
and toxicologic effects of di-2-ethylhexyl phthalate (DEHP)
and other plasticizers. Environ. Health Perspect. Jan. 53.
Rubin, R.J., et al. 1979. Ames mutagenic assay of a series
of phthalic acid esters: positive response of the dimethyl
and diethyl esters in TA 100. Abstract. Soc. Toxicol. Annu.
Meet.. New Orleans, March 11.
Schulz, C.O., and R.J. Rubin. 1973. Distribution, metabo-
lism and excretion of di-2-ethylhexyl phthalate in the rat.
Environ. Health Perspect. Jan. 123..
-------
Seth, P.K., et al. 1976. Biochemical changes induced by
di-2-ethylhexyl phthalate in rat liver. Page 423 in Environ-
mental biology. Interprint Publications, New OelhIT India.
Shaffer, C.B., et al. 1945. Acute and subacute toxicity
of di(2-ethyhexyl) phthalate with note upon its metabolism.
Jour. Ind.- Hyg. Toxicol. 27: 130.
Singh, A. et al. .1972. Teratogenicity of phthaiate esters
in rats. J. Pharm". Sci. 61, 51 (1972).
Singh, A.R., et al'. 1974. Mutagenic and antifertility
sensitivities of mice to di-2-ethylhexyl phthalate (DEEP)
and dimethoxyethyl phthalate (DMEP). Toxicol. Appl. Pharm-
acol. 29: 35. .
L4
Singh, A.R., et al. 1975. Maternal-fetal transfer of C-
di-2-ethylhexyl phthalate and C-diethyl phthalate in rats.
Jour. Pharm. Sci. 64: 1347.
Swinyard, E.A., et al. 1976. Nonspecific effect of bis(2-
ethylhexvl) ohthalate on hexobarbital sleep time. J. Pharm.
Sci. 65l 733.
Toraita, I., et al. 1977. Phthalic acid esters in various
foodstuffs anmd biological materials. Ecotoxicology and
Environmental Safety. 1: 275.
U.S. EPA. 1978. In-depth studies on health and environ-
mental impacts of selected water pollutants. U.S. Environ.
Prot. .Agency, Contract No. 63-01-4646.
U.S. EPA. 1979. Phthalate Esters: Ambient Water Quality
Criteria Document. (Draft).
U.S. International Trade Commission. 1978. Synthetic or-
ganic chemicals, U.S. production and sales. Washington,
D.C.
Waddell, W.M., et al. 1977. The distribution in mice of
intravenously administered C-di-2-ethylhexyl phthalate
determined by whole-body autoradiography. Toxicol. Appl.
Pharmacol. 39: 3"39.
Wallin, R.F., et al. 1974. Di(2-ethylhexyl) phthalate
(DEHP) metabolism in animals and post-transfusion tissue
levels in man. Bull. Parenteral Drug Assoc.' 28: 278.
'/agi, Y. at al. 1978. Smbryotoxicity of phthalate esters
in mouse. In: Proceedings of the First International Con- •
gress on Toxicology. Plaa, G. and Duncan. W. (ads.)
-------
No. 147
Phthalic Anhydride
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
• PHTHALIC ANHYDRIDE
Summary
Phthalic anhydride failed to produce carcinogenic effects in rats or
mice in a long term National Cancer Institute (NCI) feeding study (7,500
ppm; 15,000.ppm).
Information on the mutagenic effects of phthalic anhydride was not
found in the available literature.
The hydrolysis product of phthalic anhydride, phthalic acid, has shown
teratogenic effects in the developing chick embryo, but not in any mammalian
tests. Phthalic anhydride inhalation at high levels may produce repro-
ductive impairment in male rats.
4
Chronic occupational exposure to phthalic anhydride has been reported
to produce progressive respiratory damage in workers, including marked
fibrosis of the lungs.
Data concerning the effects of phthalic anhydride to aquatic organisms
was not found in the available literature.
-------
PHTHALIC ANHYDRIDE
I. INTRODUCTION
This profile is based on the Preliminary Environmental Hazard Assess-
ment of Chlorinated Naphthalenes, Silicones, Fluorocarbons, Benzene-
poly carboxylates, and-Chlorophenols (U.S. EPA, 1973).
Phthalic anhydride (molecular weight - 148.1) is a white, crystalline
solid that melts (sublimes) at 131°C, has a boiling point of 284.5°C, a
density of 1.527, and a solubility of 0.62 gms/100 gms water at 25°C
(Towle, et al. 1963). This compound is soluble in alcohol and sparingly
«
soluble in ether.
The major uses of phthalic anhydride are in the synthesis of plasti-
cizers, alkyd resins, unsaturated polyester resins, -and in the preparation
of various classes of chemical dyes (U.S. EPA, 1973). 4'
Production of phthalic anhydride in 1971 was 4 x 10 tons (Blackford,
1970).
Phthalic anhydride is in equilibrium with phthalic acid in aqueous sys-
tems. Under dry conditions, phthalic anhydride is relatively stable at am-
bient temperature (U.S. EPA, 1973). Elevated temperatures will produce oxi-
dative degradation of phthalic anhydride.
Phthalic anhydride is biodegraded by microorganisms (Ribbons and Evans,
1960; Saegar and Tucker, 1973).
II. EXPOSURE
Phthalic anhydride is used in large quantities and therefore has poten-
tial for industrial release and environmental contamination. NO monitoring
data are available to indicate ambient air or water levels of the compound.
Fawcett (1970) has determined 40-200 pprn by volume in phthalic anhydride
-------
off-gas process. Phthalic acid wastes have been noted in waste waters from
paint and varnish industries (Mirland and Sporykhina, 1968) and alkyd resin
plants (Minkovich, 1960).
Human exposure to phthalic anhydride from foods cannot be assessed, due
to a lack of monitoring data.
Release of phthalic acid from parenterally-used plastic medical devices
(blood bags, plastic tubings,, catheters, etc.) may occur since these mater-
ials have been treated with phthalate plasticizers; however, no data on this
type of release are available (U.S. EPA, 1973).
Bioaccumulation data on phthalic. anhydride were not found in the avail-
able literature.
III. PHARMACOKINETICS
Specific information on the metabolism, distribution, absorption, or
elimination of phthalic anhydride was not found in the available literature.
IV. EFFECTS
A. Carcinogenicity
A long-term carcinogenesis bioassay in rats and mice fed phthalic
anhydride (7,500 ppm; 15,000 ppm) has been conducted by the NCI (1979). The
results indicate that oral administration of these levels of the compound
produced no carcinogenic effects in either of the species used.
8. Mutagenicity
Information on the mutagenic effects of phthalic anhydride was not
found in the available literature.
C. Teratogenicity
Phthalic acid was shown to produce an increase in teratogenic
effects in the developing chick embryo following injection (Verrett, 'et al.
-------
1969). Mammalian testing of phthalic acid for teratogenicity failed to show
effects in mice (Koehler, et al. 1971).
0. Reproductive Effects
Inhalation exposure of rats to phthalic anhydride at high levels
(100-200 mg/1) has been reported to cause testicular changes and impaired
reproductive capability (Protsenko, 1970).
E. Chronic Toxicity . ...
Markman and Savinkina (1964) have reported progressive respiratory
. r
damage in workers exposed to phthalic anhydride for two years or more.
Workers exposed for six years evidenced marked fibrosis of the lungs.
F. Other Relevant Information
Phthalic anhydride has been implicated as a skin sensitizing agent
in some individuals exposed for prolonged periods of time (Amer. Ind. Hygi
Assoc., 1967).
V. AQUATIC TOXICITY
Data concerning the effects of phthalic anhydride to aquatic organisms
were not found in the available literature.
VI. EXISTING GUIDELINES
The 3-hour, TWA occupational exposure limit established for phthalic
anhydride is 1 ppm (ACGIH, 1977).
-------
PHTHALIC ANHYDRIDE
References
American Industrial Hygiene Association. 1967. Phthalic anhydride: Human
toxicity. Amer. Ind. Hyg. Assoc. J. 28: 395.
ACGIH. 1977. Threshold limit values for chemical substances in workroom
air.
Blackford, J.L. 1970. Isophthalic acid. Chemical economics handbook,
Stanford Research Institute.
Fawcett, R.L. 1970. Air pollution potential of phthalic anhydride. J. Air
Pollut. Contr. Assoc. 20: 461.
Koehler, F., et al. 1971. Teratogenicity of thalidomide metabolites.
Experientia. 27:. 1149.
Markman, G.I. and R.A. Savinkina. 1964. The condition of the lungs of
workers in phthalic anhydride production (an x-ray study). Kemerovo. 35.
Mirland, L.A. and V.A. Sporykhina. 1968. Polarographic determination of
phthalic acid in waste waters from the paint and varnish industry.
Lakokrasch.. Mater. Ikh. Primen. 1: 49.
Minkovich, O.A. 1960. The recovery of phthalic anhydride wastes in the
manufacture of alkyd resins. Lakokra. Mater, i ikh Primen. 1: 83.
NCI. 1979. Bioassay of phthalic anhydride for possible carcinogenicity.
NCI-CG-TR-159.
Protsenko, E.I. 1970. Gonadotropic action of phthalic anhydride. Gig.
Sanit. 35: 105.
Ribbons, D.W. and W.C. Evans. 1960. Oxidative metabolism of phthalic acid
by soil pseudomonads. Biochem. J. 76: 310.
Saegar, V.W. and E.S. Tucker. 1973. Biodegradation of phthalate esters.
In: Flexible vinyls and human safety: An objective analysis. Conference
or the Society of Plastics Engineers, Inc., March 20-22. Kiamesha Lake, N.Y.
Towle, P.H., et al. 1968. Phthalic acids and other benzenepolycarboxylic
acids. Vol. 15, p. 444. In: A Stauden (ed.)', Encyclopedia of chemical
technology. 2nd ed. J. Wiley & Sons, New York.
U.S. EPA. 1973. Preliminary hazard assessment of chlorinated naphthalenes,
silicones, fluorocarbons, benzenecarboxylates, and chlorophenols.
»
Verrett, M.J., et al. 1969. Teratogenic effects of captan and related com-
pounds in the developing chick embryo. Ann. N.Y. Acad. Sci. 160: 334.
IV7-7
-------
No. 148
2-Picoline
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal.. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone, scrutiny to
ensure its technical accuracy.
-------
2-PICOLINE
Summary
Pertinent data could not be found that defined 2-picoline as
a carcinogen or a omtagen. Studies on cats ' indicated that the
structure and composition of the liver and the structure and growth
pattern of the skin were disrupted in the offspring of tested rats
who were given 157 mg per kg body weight daily during their pregnancy.
2-picoline has been shown to produce biochemical and physical
changes in the liver, spleen, bone marrow, and lymph nodes.
-------
I. INTRODUCTION
2-picoline (alpha-picoline, 2-methylpyridine; CAS No.
109-06-8) is a colorless liquid possessing a strong unpleasant
odor. It has the following physical properties:
Formula: CgHyN
Molecular Weight: 93.12
Melting Point: -70°C
Boiling Point: 129°C
..Vapor Pressure: 8 mm Hg at 20°C
Vapor Density: 3.21
2-picoline is freely soluble in water and miscible with alcohol
and ether (Windholz, 1976). 2-picoline is used as an organic
solvent and intermediate in the dye and resins industries.
II. EXPOSURE"
A. Water
Pertinent data could not be located in the available
li terature.
B. Food
Pertinent data could not be located in the available
1i terature.
C. Inhalation
2-picoline occurs in the working environment of coke oven
workers (Naizer and Mashek, 1974) and is present in cigarette smoke
(Brennemann et. al., 1979).
D. Dermal
»
Pertinent data could not be located in the available
li terature.
-------
III. PHARMACOKINETICS
A.. Absorption
la racs, -2-picoline is rapidly absorbed and taken up by
the liver, heart, spleen, lungs, brain, and muscles during the
first .10 to 20 tninute-s after oral administration (Kupor, 1972).
• •»' •*
B. Distribution
Pertinent data could not be located in the available
literature.
C. Metabolism and -Excretion
o
Most of an administered dose in an acute toxicity study
was excreted in the urine within 48 hours (Kuper, 1972).
IV EFFECTS
A. Carcinogenic!ty
Pertinent data could not be found in the available
literature.
B. Mutagenicity
Pertinent' data could not be found in the available
li terature.
C. Teratogenicity
The structure and composition of the liver and the
structure and growth pattern of the skin were disrupted in the
offspring of treated rats who were administered 157 mg per kg body
weight of 2-picoline throughout their pregna-ncy (Hikiforova and
Taskaev, 1974).
D. Other Reproductive Effects
Glycolytic processes and protein formation in the liver
was disturbed during the pregnancy of rats inhaling 2-picoline at
-J'
-------
the maximum permissable concentration for 4 months. The pregnancy
complicated toxicosis which without pregnancy was successfully
compensated by the liver (Taskaev, 1979).
E. Chronic Toxicity ,,
The following biochemical and physical changes ha'v« been .
observed in rats after the administration of 2-picoline; changes
occurred in the liver carbohydrate metabolism (Taskaev, 1979; Kuper
and Gruzdeva, 1974) and changes occurred in protein synthesis of the
liver noted after chronic o.ral (Kuper and Gruzdeva, 1974) and
inhalation (Taskaev, 1979) exposure. Administration of low doses
results in changes in LDH isoenzyme distribution and activity
(Gruzdeva, 1976). The major chronic effects of 2-picoline are
injury to the liver (Ovchinnikova, 1978; Taskaev, 1979; Ovchinnikova,
1977) and spleen, bone marrow, and lymph nodes (Semchenko, 1973 and
1972).
F. Other Relevant Information
Pertinent data could not be found in the available
li terature.
V. AQUATIC TOXICITY
A. Acute Toxicity
Pertinent information could not be found in the available
li terature.
B. Chronic Toxicity, Plant Effects and Residues
Pertinent information could not be found in the available
1i terature. ,
C. Other Relevant Information
Pertinent information could not be found in the available
li terature.
!<+
-------
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The 8-hour, time-weighted average occupational exposure
limit for alpha-picoline has been set in .Russia at 5 cag/m^
(Verschueren, 1977). Maximum allowable concentration in Class I
waters for the production of drinking waters has been set in the
Netherlands at 0.05 mg/1 (Verschueren, 1977).
3. Aquatic
Pertinent information could not be found in the available
literature. "
-------
REFERENCES
Brunnemann, K.D., and at. al., 1978. Chemical Studies on Tobacco
Smoke: LXI. -Volatile Pyridines: Quantitative Analysis in Mainstream
and Sidestream Smoke of Cigarettes and Cigars. Anal. Lett. 11(7):
545-560.
Gruzdeva. K.N., et. al. 1976. Use of Electrophoretic Methods for
Determining Lactate Dehydrogenase Isoenzymes in Studying Chronic
Poisoning with Pyridine Derivatives. Khromatogr. Elektroforeticheakia
Metody Issled. Biol. Aktiv. Soedin. 44-7.
Kuper, V.G. Distribution of alpha-Picoline in Rat Tissue During
Acute alpha-Picoline Intoxication. Vop. Patokhimii Biokhim.
Belkov. Drugikh Biol. Aktiv. Soedin. 51-2.
Kuper, V.G., and K.N. Gruzdeva. 1974. Concerning the Question of
Carbohydrate Metabolism After Chronic Poisoning with alpha-Picoline.
Narusheniya Metab., Tr. Naucha. Konf. Med. Inst. Zapadn., Sib.,
1st, 261-5.
Naizer , Y. , and
Its Homologs in
(5):76-78.
V. Mashek.. 1974.
the Environment of
Determination of Pyridine and
Coke Plant Workers. Gig. Sanit.
Nikiforova, A.A., and I.I. Taskaev. 1974. Liver and Skin Morpho-
genesis in Some Laboratory Animal Embryos Following Poisoning with
Pyridine Bases. Reakt. Plast. Epiteliya Soedin. Tkani Norm, Eksp.
Patol. Usloviyakh, Dokl. Mezhvuz, Gistol. Konf. 196-9.
Ovchinnikova,
in White Rats
2, 5-Lutidine.
L.S. 1977. Morpholgical and Histochemical Changes
Liver After Acute Poisoning with alpha-Picoline and
Gig. Aspekty Okhr. Zdorov'ya Naseleniya. 124-5.
Ovchinnikova, L.S., and Lambina. 1978. Morphohistochemical
Changes in Liver of White Rats with Subacute Poisoning with Products
of Synthetic Rubber Production. Deposited Doc., ISS. Viniti 2667-
78, 101-2.
Semchenko, V.V. 1972. Regenerative Processes in Blood-Forming
Organs of Experimental Animals During and After Chronic Intoxica-
tion by Methylpyridlne. Mater. Nauch. Sess., Posvyashch. 50-
Letiyu Obrazov. SSSR, Omsk, Cos. Med. Inst'. 896-8.
Semchenko, V.V. 1973. Histological and Histo'chemical Characteristics
of Spleen and Lymph Nodes of Rats During Chronic Intoxication with
alpha-Picoline and 2,5-Lutidine. Hezenkhima Tkanevya Proizvod. Evol.
Ontog., 56-8.
-------
REFERENCES
Taskaev, I.T. 1979. Histological and Cytological Changes in Rat
Liver During Experimental Poisoning and Subsequent Pregnancy.
Arkh. Anat. .-'Gistol. Smbriol. Vol. 76, ISS. 2, 49-54.
Verschueren, K. 1977. Handbook of Environmental Data on Organic
Chemicals. Van Nostrand Reinhold Company. New York.
Windholz, Martha et. al. (editors). 1976. The Merck Index. Merck
& Co., Inc. Rahway, N.J.
-------
No. 149
Polynuclear Aromatic Hydrocarbons (PAH)
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
polynuclear aromatic hydrocarbons and has found sufficient
evidence to indicate that this compound is carcinogenic.
-------
POLYNUCLEAR AROMATIC HYDROCARBONS'(PAH)
SUMMARY
The first chemicals ever shown to be involved in the development of
cancer belong to the polycyclic aromatic hydrocarbon (PAH) class. Several
PAH are well-known as animal carcinogens by all routes of administration.
Others are not carcinogenic alone, but in certain cases can enhance or in-
hibit the tumorigenic response of carcinogenic PAH. Numerous studies of
workers exposed to coal gas, coal tars, and coke oven emissions, all of
•which have large amounts of PAH, have demonstrated a positive association
between their exposures and lung cancer development. The carcinogenic risk
of ingested PAH in humans, however, has not been extensively studied.
NO standard toxicity data for aquatic organisms are available for
freshwater or marine life. Limited information concerning toxic responses
i
of freshwater fish reveals that concentrations of 1,000 juq/l for six months
produced an 37% mortality in one warm water species.
i
-------
I. INTRODUCTION
This profile is based primarily upon the Ambient Water Quality Criteria
Document for Polynuclear Aromatic Hydrocarbons (U.S. EPA, 1979a) and the
Multi-media Health Assessment Document for Polycyclic Organic Matter (U.S.
EPA, 1979b).
Polycyclic aromatic hydrocarbons (PAH) are a diverse class of compounds
consisting of substituted and unsubstituted polycyclic and heterocyclic aro-
• *
rnatic rings. PAH are formed as a result of incomplete combustion of organic
material (e.g., fossil fuels, wood, etc.). This leads to formation of C-H
free radicals which can polymerize to form various PAH. Among these PAH are.
compounds such as benzo(a)pyrene (BaP) and benz(a)anthracene (8aA), which
are ubiquitous in the environment an.d well-known for their carcinogenic
activity. The presence in ambient air of over one hundred individual PAH
has been reported, but quantitative data on only .26 PAH are available thus
far.
Most of the PAH are high melting-point, high boiling-point solids that
are very insoluble in water. As the ring size increases, the volatility de-
creases significantly. The PAH are strong absorbers of ultraviolet light,
and PAH fluoresce strongly; both of these, properties lead to analytical
methods for detection of trace quantities. Because of their high melting
points and low water solubilities and vapor pressures, most PAH are gener-
ally associated with particulate matter. In air, they are adsorbed on small
diameter particles that can be easily inhaled. In water, PAH appear to also
be primarily associated with particulate matter. Based upon water treat-
ability of PAH, the compounds appear to exist in equal proportions in three
»
forms; bound to large suspended particles; bound to finely dispersed par-
ticles, and as the dissolved form (U.S. EPA, 1979a).
-------
PAH adsorbed to airborne particulate matter appear to be fairly stable
in the environment. Nevertheless, some photooxidation occurs with atmos-
pheric PAH since quinone derivatives have been detected in the atmosphere,
and their concentrations increase during the summer when the light intensity
is greatest.
Considerable study on the microbial and chemical stability and degra-
dation of PAH in the aquatic environment has been conducted. In general,
the low .molecular weight molecules appear to biodegrade relatively rapidly
while PAH containing more than three rings appear to be extremely stable.
The first step in the microbial degradation process appears to be the forma-
tion of ortho-dihydrodiols which rapidly react to open the ring. PAH also
appear to be light sensitive in aquatic systems, but the rate of degradation
is difficult to determine experimentally since the vast majority of the cars-
pounds are adsorbed to particulate matter. Recent studies have shown that
adsorption of many PAH compounds to sediments is a major transport process
in aqueous systems. Studies in water treatment of municipal and industrial
sewage indicate that about two-thirds of the PAH can be eliminated by sedi-
mentation and biodegradation. If this secondary effluent is subjected to
chemical treatment (chlorination or ozonation) the remaining PAH can be
degraded.
II. EXPOSURE
A. Water
3ased upon work by Basu and Saxena (1978) the average concentra-
tions of BaP, carcinogenic PAH (BaP, benzo(j)fluoranthene, indeno(l,2,3-cd)-
pyrene), and total PAH (above 3 compounds plus benzo(g,h.i)perylene, benzo-
»
(b)fluoranthene, and fluoranthene) in U.S. drinking water are 0.55 ng/1, 2.1
ng/1, and 13.5 ng/1, respectively. NO drinking water monitoring data on
-------
other PAH compounds are available. The low con- centrations are somewhat a-
reflection of the extremely low water solu- bilities of PAH compounds.
Slightly higher drinking water values have been reported in Europe (e.g. 3-5
ng/1 carcinogenic PAH and 40-60 ng/1 total PAH), but these differences will
have relatively negligible effects on the calculated daily intake values
through drinking water compared to other sources (U.S. EPA, 1979a).
Assuming that a human consumes approximately 2 liters of water per day,, the
daily intake of PAH via drinking water would be:
0.55 ng/1 x 2 liters/day = 0.0011 jug/day (BaP)
2.1 ng/1 x 2 liters/day = 0.0042 jjg/day (carcinogenic PAH)
13.5 ng/1 x 2 liters/day = 0.0270 jug/day (total PAH)
8. Food
It is difficult to evaluate the human dietary intake of PAH through
foods since the amount not only depends on the food habits of the individual
and the style of cooking, but it also depends upon the origin of the foods.
In order to provide a reasonably accurate estimate of the PAH dietary 'in-
take, average concentrations of PAH in representative food items would have
to be available. Unfortunately, as of this date, these data have not been
generated. However, examination of the available food monitoring data does
suggest that a typical range of concentrations for PAH and BaP are 1.0-10.0
ppb and 0.1-1.0 ppb, respectively (U.S. EPA, 1979a). Combining these ranges
with average total daily food consumption by man from all types of foods of
1600 g/day, the following estimates of dietary PAH and BaP intake are poss-
ible:
0.1 - 1.0 ppb x 1600 g/day = 0.16 - 1.6jjg/day (BaP)
1.0 - 10 ppb x 1600 g/day = 1.6 - 16 jug/day"(PAH)
* / *} '/i -
111-TT
-------
The U.S. SPA (1979a) has estimated the weighted average bioconcen-
tration factors for the edible portion of all aquatic organisms consumed by
Americans. These range from 120 to 24,000, and are based on the octanol-
/water partition coefficients for each compound.
C. Ambient Air
It is not possible to determine the average intake of PAH from in-
halation of ambient air in the United States because the monitoring data
have focused mostly on BaP concentrations. However, by making some assump-
tions, it is possible to provide estimates that are reasonably close to
probable actual values. Using the 1974-1975 Los Angeles monitoring data
from Gordon (1976), the relative amounts to carcinogenic PAH and total PAH
compared to the average 3aP concentration are presented below.
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ »
Carcinogenic Total
BaP PAH . PAH
Ambient cone, ng/m5 0.5-2.9 2.0 10.9
Inhalation intake,
micrograms/daya O.C095-0.0435 0.038 0.207
aAssumed average air breathed per day was 19 m^
III. PHARMACQKINETICS
There are no data available concerning the pharmacokinetics of PAH in
humans. Nevertheless, it is possible to make limited assumptions based on
the results of animal studies conducted with several PAH, particularly BaP.
The metabolism of PAH in human and animal tissues has been especially well-
studied, and has contributed significantly to an .understanding of the
mechanisms of PAH-induced cancer.
/ 9 7 6 -"
-------
A. Absorption
Regardless of the route of exposure, it can be demonstrated in
laboratory animals that PAH are readily absorbed across all epithelia which
are in contact with the external environment (Rees, et al. 1971; Kotin, et
al. 1969; Vainio, et al. 1976). The fact that PAH are generallly high
lipid-soluble neutral molecules greatly facilitates their passage through
the predominantly lipid-like cell membranes of animals, including man.
•B. Distribution
Upon reaching the bloodstream, PAH are rapidly distributed to most
internal body organs (Kotin, et al. 1969; Bock and Dao, 1961; Oao, et al.
1959; Flesher, 1967). Under experimental conditions with laboratory
animals, the route of exposure has little apparent influence on the tissue
localization of PAH. Extensive localization in the fat and fatty tissues
(e.g., breast) is observed (Bock and Dao, 1961; Schlede, et al. 1970 a,b)
and suggests that these tissues may act as a chemical trap, creating a situ-
ation for sustained release of the unchanged substance. In pregnant rats,
it is apparent that BaP and 7,12-dimethylbenz(a)anthracene, but probably not
3-methylcholanthrene, are capable of transplacental passage and localization
in the fetus (Shendrikova and Aleksandrov, 1976).
C. Metabolism
PAH are metabolized by the microsomal mixed-function oxidase
system, also known as aryl hydrocarbon hydroxylase. This enzyme system is
readily inducible and is found in most mammalian tissues, although pre-
dominantly in the liver. In conjunction with various P-450 type cyto-
chromes, this enzyme complex is involved in detoxification of many xeno-
-------
biotics, but may also catalyze the formation of reactive epoxide metab-
olites, themselves leading to carcinogenesis. A second microsomal enzyme,
epoxide hydrase, converts epoxide metabolites of PAH to vicinal glycols, a
process which may also be of critical importance in the process of
carcinogenesis.
Because of the importance of metabolic activation for the ex-
pression of carcinogenic effects by PAH, the chemical fate of many reore-
sentative compounds in mammalian cells has been extensively explored (U.S.
EPA, 'i979a). By far the most widely studied of the PAH has been BaP, one of
the principal carcinogenic products from the combustion of organic
material. The metabolites of BaP (and all PAH) can be divided into a
water-soluble and an organic solvent-soluble fraction. Components of the
latter fraction are primarily ring-hydroxylated products, quinones, and
Labile spoxide intermediates, for BaP there are at least three dihydro-
diols, three quinones, and four phenols which can be detected as positional
isomers. The K-region (4,5-) and non-K-region (7,3-; 9,10-) epoxides are
precursors of the corresponding vicinal diols, which are formed by the
action of the epoxide hydrase enzyme. A subsequent oxidative attack by aryl
hydrocarbon hydroxylase may convert the non-X-region diols to vicinal diol
epoxides, one of which (7,8-diol-9,LQ-epoxide) is an ultimate carcinogenic
form of BaP.
In the water-soluble fraction containing BaP metabolites are mainly
conjugates of hydroxylated products with glutathione, glucuronic acid, and
sulfate. This group of metabolies is tentatively regarded to be composed of
non-toxic excretion oroducts.
-------
The general scheme of metabolism for unsubstituted PAH closely
parallels that for BaP, although several other major environmental PAH have
not been studied. It is also evident that K-region derivatives of PAH may
be preferred targets for conjugation and excretion, whereas non-K-region
epoxides undergo further reductions and oxidative attack to form
toxicologically important molecules. For PAH bearing alkyl substituents
(e.g., DMBA, MCA), the .primary metabolites formed are hydroxymethyl
derivatives. Nevertheless, epoxidation reactions at K-region and
non-K-region aromatic double bonds occur which are catalyzed by aryl
hydrocarbon hydroxylase. Removal of activated intermediates occurs by
conjugation with glutathione or glucuronic acid, or by further metabolism to
tetrahydrotetrols.
0. Excretion 4
Over forty years ago, researchers recognized that various PAH were
excreted primarily through the hepatobiliary system and the feces (Peacock,
1936; Chalmers and Kirby, 1940). However, the rate of disappearance of
various PAH from the body, and the principal routes of excretion are influ-
enced both by structure of the parent compound and the route of adminis-
tration (Heidelberger and Weiss, 1959; Aitio, 1974a,b). Moreover, the rate
of disappearance of a PAH (i.e., benzo(a)pyrene) from body tissues can be
stimulated markedly by prior treatment with inducers of microsomal enzymes
(e.g., benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene, 3-methylcholanthrene,
chrysene) (Schlede, et al. 1970a,b). Likewise, it has been shown that in-
hibitors of microsomal enzyme activity, such as parathion and paraoxon, can
decrease the rate of BaP metabolism in certain animal tissues (Weber, et al.
»
1976). From the available data concerning excretion of PAH in animals, it
is apparent extensive bioaccumulation is not likely to occur.
-------
IV. EFFECTS
A. Carcinogenicity
PAH were the first compounds ever shown to be associated with car-
cinogenesis. As of this date, carcinogenic PAH are still distinguished by
several unique features: (1) several of the PAH are among the most potent
carcinogens known to exist, producing tumors by single exposures to
microgram quantities; (2) they act both at the site of application and at
organs distant to the site of absorption; and (3) their effects have been
demonstrated in nearly every tissue and species tested, regardless of the
route of administration (U.S. EPA, 1979a). Among the more common PAH, at
least one, BaP, is ubiquitous in the environment. In animals, PAH produce
tumors which resemble human carcinomas. The demonstration that organic
extracts of particulate air pollutants are carcinogenic to animals has
raised concern over the involvement of PAH in human cancer formation
(Hoffmann and Wynder, 1976).
Oral administration of PAH to rodents can result in tumors of the
fore-stomach, mammary gland, ovary, lung, liver, and iymphoid and hemato-
poietic tissues (U.S. EPA, 1979a). Exoosure to very small doses of PAH by
inhalation or intratracheal instillation can also be an effective means of
producing tumors of the respiratory tract. However, for both oral and in-
tratracheal routes of administration, BaP is less effective than other PAH
(e.g., OM8A, MCA) in producing carcinomas. However, BaP has a remarkable
potency for the induction of skin tumors in mice-'that cannot be matched by
any other environmental PAH. Therefore, caution must be exercised in con-
sidering the carcinogenicity of PAH as a class, or in using BaP as a reore-
»
sentative example in evaluating the carcinogenic risk of PAH.
-------
The presence of PAH in the air, or as components of soot, tars, and
oils, have long been associated with an excess incidence of cancer in human
populations (U.S. EPA, 1979a,b). However, it has never been possible to
study a population having exposure to PAH in the absence of other potential
carcinogens, cocarcinqgens, tumor initiators, or tumor promoters.
Convincing evidence from air pollution studies indicates an excess
of lung cancer mortality among workers exposed to large amounts of PAH-
containing materials such as coal gas, tars, soot, and coke-oven emissions
(Kennaway, 1925; Kennaway and Kennaway, 1936, 1947; Henry, et al. 1931;
Kuroda, 1937; Reid and Buck, 1956; Doll, 1952; Doll, et al. 1965, 1972;
Redmond, et al. 1972, 1976; Mazumdar, et al. 1975; Hammond, et al. 1976;
Kawai, et al. 1967). However, no definite proof exists that the PAH present
in these materials are responsible for the cancers observed. Nevertheless,
our understanding of the characteristics of PAH-induced tumors in animals,
and their close resemblance to human carcinomas of the same target organs,
suggests PAH pose a carcinogenic threat to man, regardless of the route of
• exposure.
8. Mutagenicity
The demonstration of mutagenicity in bacterial and mammalian cells
by exposure to PAH is generally equated with the capability to induce tumor
formation. This assumption is based on the participation of a common elec-
trophilic metabolite in producing the carcinogenic/mutagenic event, and the
common target site in the cell (i.e., ONA or other components of the genome)
for the effect to be produced.
In recent years, considerable research effort has been directed at
determining the mutagenicity of various PAH derivatives as a means of ident-
ifying structural features associated with the biological effect produced.
-------
Working with bacterial mutants which can be reverted to histidine inde-
pendence by a chemically-induced mutation, epoxides of carcinogenic PAH were
shown to possess significant mutagenicity (U.S. EPA, 1979a). Further work
with cultured mammalian cells established that carcinogenic PAH can produce
forward mutations wheri a. drug metabolizing enzyme system is available
(Huberman and Sachs, 1974, 1976).
- .Numerous attempts have been made to correlate exposure to PAH with
the induction of chromosomal aberrations. Although variations in chromosome
number and structure" accompany PAH-induced tumors in rodents, it is not
clear whether these changes are consistently observable (U.S. EPA,
1979a,b). NO evidence in the published literature has been found to in-
dicate that PAH may produce somatic mutations in the absence of neoplastic
transformation. ' ^
C. Teratogenicity
PAH are not generally regarded to have significant teratogenic
activity. 3aP showed no effect on the developing embryo in several mam-
malian and non-mammalian species (Rigdon and Rennels, 196
-------
E. Chronic Toxicity
Little attention has been paid to the non-carcinogenic affects of
exposure to PAH. Nevertheless, it is known that tissues of the rapidly pro-
liferating type (e.g., intestinal epithelium, bone marrow, lymphoid organs,
testis) seem to be the preferred targets for PAH-induced cytotoxicity (U.S.
EPA, 1979). This action is probably due to a specific, attack on- DMA of
cells in the S phase of the mitotic cycle (Philips,, et al. 1972).
Acute and chronic exposure to various carcinogenic PAH has resulted
in selective destruction of hematopoietic and lymphoid elements, ovotoxicity
and anti-spermatogenic effects,, adrenal necrosis, and changes in the intes-
tinal and respiratory epithelia (U.S. EPA, 1979a).. For the most part, how-
ever, tissue damage occurs at dose levels that would also be expected to in-
duce carcinomas,, and thus the threat of malignancy predominates in evalu-
ating PAH toxicity* For the- non-carcinogenic PAH,, there is a shortage of
available data concerning- their involvement in toxic responses.•
V. AQUATIC TOXICITY'
A. Acute Toxicity
Standard toxicity determinations for freshwater or marine organisms
have not been conducted for any PAH. The marine worm,. Neanther
arenaceodenta, was exposed, to crude oil extracts, and LC_Q' values for
various PAH ranged from 300 to l.OOO^g/l (Neff, et al. 1976a,b). A 90 per-
cent lethality, -determined from photodynamic response, was obtained for the
protozoa, Paramecium caudatum at an for anthracene, concentration of 0-1 /ug/1
in one-hour exposures (Epstein, 1963). Bluegill sunfish (Leoomis
macrochirus) displayed an 87% mortality at concentration of 1,000 yug/1
benzo-a-anthracene. *
> ^n.^-
^ } / J J~
A
-------
a. Chronic
Standard toxicity studies using either freshwater or marine organ-
isms have, not been conducted on any PAH. A six-month study of benzo-
(a)pyrene on the bluegill sunfish (Leoomis macrochiras) produced 87 percent
mortality at a concentration of 1,000 ug/1 (Brown, et al. 1975).
C. Plants
Studies of the effects of PAH on freshwater or marine plants could
»
not be located in the available literature.
D. Residues
In short-term modeling of freshwater ecosystem studies, three-day
bioconcentration factors for benzo(a)pyrene of 930, 5,258, 11,536, 82,231,
and 134,248 were obtained for the mosquito-fish (Gamousia affinis), the
algae Oedoqonimi eardiacum, the mosquito Culex pipiens quinquefasciatus, the
snail Physa sp., and cladoceran Daonia puiex, respectively (Lu, et all
1977). For anthracene, a 1-hour bioconcentration factor of 200 was obtained
for Daphnia maqna (Herbes, 1976). For marine molluscs, bioconcentration
factor values ranged from 8.2 for the clam (Rangia cuneata) (Neff, et al..
1976a) to 242 for the eastern oyster (Crassostrea virginica) (Couch, et al.,
in press).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health and aquatic criteria derived by U.S. EPA
(1979a), which are summarized below, have not gone through the process of
public review; therefore, there is a possibility-'that these criteria may be
changed.
)*•
-------
A. Human
'TO date, one recommended standard for PAH as a class has been
developed. The World Health Organization (1970) recommends a concentration
of PAH in water not. to exceed 0.2/jg/l. This recommended standard is based .
on the composite analysis of six PAH in drinking water: (1) fluoranthene,
(2) benzo(a)pyrene, (3) benzo(g,h,i)perylene, (4) benzo(b)-fluoranthene, (5)
benzo(k)fluoranthene, and (6) indeno(l,2,3-cd)pyrene.
In the occupational environment, a Federal standard has been pro-
mulgated for coke oven emissions, based primarily on the presumed effects of
the carcinogenic PAH contained in the mixture as measured by the benzene
soluble fraction of total particulate matter. Similarly, the American Con-
ference of Governmental Industrial Hygiensists recommends a workplace expo-
sure limit for coal tar pitch volatiles, based .on the benzene-soluble frac-
*
tion containing carcinogenic PAH. The National Institute for Occupational
Safety and Health has also recommended a workplace criterion for coal tar
products (coal tar, creosote, and coal tar pitch), based on measurements of
the cyclohexane extractable fraction. These criteria are summarized below:
Substance Exposure Limit Agency
Coke Oven Emissions 0.150 mg/m3, 8-hr. U.S. Occupational Safety
time-weighted average and Health Administration
Coal Tar Products 0.1 mg/rn^, 10-hr. U.S. National Institute for
time-weighted average Occupational Safety and
Health
Coal Tar Pitch 0.2 mg/rn^, (benzene American Conference of
Volatiles soluble.fraction) 8-hr. Governmental Industrial
time-weighted average Hygienists
Based on animal bioassay data, and using the "one-hit" model, the
U.S. EPA (1979a) has set draft ambient water quality criteria for BaP and
»
dibenz(a,h)anthracene (DBA) which will result in specified risk levels of
human cancer as shown in the-table below.
-17
-------
Exposure Assumptions
(per day)
2 liters of drinking water
and consumption of 18.7
grams fish and shellfish.
Consumption of fish and
shellfish only.
Exposure-Assumptions
(per day)
2 liters of drinking water
and consumption of 18.7
grams fish and shellfish.
Consumption of fish and
shellfish only.
SaP
Risk Levels and Corresponding Draft Criteria
ng/1
0
0
10-7
0.275
1.25
10-6
2.75
12.5
10-5
27.5
125
DBA
Risk Levels and Corresponding-Draft Criteria
0
0
10-7
0.43
1.96
10-6
4.3
19.6
10-5
43
196
B. Aquatic
•
Criteria have not been proposed for the protection of aquatic
organisms (U.S. EPA, 1979a).
Ugt ft f
'/ / <3 y
-------
POLYNUCLEAR AROMATIC HYDROCARBONS
REFERENCES
Aitio, A. '1974a Different elimination and effect on mixed function oxidase
of 20-methylcholanthrene after intragastric and intraperitoneal adminis-
tration. Res. Commun. Chem. Path.. Phamacol. 9: 701.
Aitio, A. 1974b. Effect of chrysene and carbon tetrachloride adminis-
tration on rat hepatic microsomal monoxygenase and udglucuronsyltransferase
activity. FEBS Lett. 42: 46.
3asu O.K. and J. Saxena. 1978. Polynuclear aromatic hydrocarbons in selec-
ted U.S. drinking waters and their raw water sources. Environ. Sci.
Technol. 12: 75.
Bird, C.C., et al. 1970. Protection from the embryopathic effects of
7-hydroxymethyl-12-methylbenz(a) anthracene by 2-methyl-l,2-bis-(3
pyridyl)-l-propanone(metapirone ciba) and B-diethyl-aminoethyl-
diphenyl-n-propyl acetate (SKR 525-A). Br. Jour. Cancer 24: 548.
Bock, F.G., and T.L. Oao. 1961. Factors affecting the polynuclear hydro-
carbon level in rat mammary glands. Cancer Res. 21: 1024. ^
Brown, E.R., et al. 1975.- Tumors in fish caught in polluted waters: poss-
ible explanations. Comparative Leukemia Res. 1973, Laukemogenesis. Univ.
Tokyo Press/Karger, Basel, pp. 47-57.
Chalmers,. J.G., and A.H.M. Kirby. 1940. The elimination of 3,4-benzpyrene
from the animal body after subcutaneous injection. I. Unchanged benz-
pyrene.. Biochem. Jour. 34: 1191.
Couch, J.A. et al. The American oyster as an indicator of carcinogens in
the aquatic environment. Inj Pathobiology of environmental pollutants -
animal models and wildlife "or monitors. Storrs, Conn. National Academy of
Sciences. (In press).
Currie, A.R., at al. 1970. Embryopathic effects of 7,12-dimethyl-
benz(a)anthracene and its hydroxymethyl derivatives in the Sprague-Oawley
rat. Nature 226: 911.
Oao. T.L., et al. 1959. Level of 3-methylcholanthrene in mammary glands
of rats after intraaastric instillation of carcinogen. Proc. Soc. Exptl.
Biol. Med. 102: 635.
Doll. R. 1952. The causes of death among gas workers with special refer-
ence to cancer of the lung. Br. Jour. Ind. Med. 9: 180.
»
Doll. R., et al. 1965. Mortality of gas workers with special reference to
cancers of the lung and bladder, chronic bronchitis, and pneumoconiosis.
Br. Jour. Ind. Med. 22: 1.
Doll R. at al. 1972. Mortality of gas workers - final report of a pros-
pective study. Br. Jour. Ind. Med. 29: 394.
Epstein, S.S., et al. 1967. The photodynamic effect of the carcinogen,
3,4-benzoryene, on Paramecium caudatum. Cancer Res. 23: 35.
-------
Flesher, J.S. 1967. Distribution of radioactivity in the tissues of rats
after oral administration of 7,12-dimethyl-benz(a)anthracene~5H. Biochem.
Pharmacol. 16: 1821.
Gordon, R.J. 1976. Distribution of airborne polycyclic aromatic hydro-
carbons throughout Los Angeles. Environ. Sci. Technol. 10: 370.
Hammond, E.G., et al. 1976. Inhalation of benzpyrene and cancer in man.
Ann. N.Y. Acad. Sci. 271: 116..
Heidelberger, C., 'and S..M. Weiss. 1959. The distribution of radioactivity
in mice following administration of 3,4-benzpyrene-5Ci4 and 1,2,5,6-di-
benzanthracene-9, 10-C14. Cancer Res. 11: 885.
Henry, S.A. et al. 1931. The incidence of cancer of the bladder and pros-
tate in certain occupations. Jour. Hyg. 31: 125.
Herbes, S.E. 1976. Transport and bioaccumulation of polycyclic aromatic
hydrocarbons (PAH) in aquatic systems. In: Coal technology program
quarterly progress report for the period ending December 31, 1975. Oak
Ridge National Lab., Oak Ridge, TN. ORNL-5120. pp. 65-71.
Hoffmann 0. and E.L. Wynder. 1976. Re.spiratory carcinogenesis. In: chem-
ical carcinogens C.E. Searle (ed.) ACS Monograph 173, Amer. Chem. SocV
Washington, O.C- 4
Huberman, E., and L. Sachs. 1974. Cell-mediated mutagenesis of mammalian
cells with chemical carcinogens. Int. Jour. Cancer 13: 32.
Huberman, £., and L. Sachs. 1976, Mutability of different genetic loci in
mammalian cells by metabolically activated carcinogenic polycyclic hydro-
carbons. Proc. Natl. Acad. Sci. 73: 188.
Kawai, M., at al. 1967. Epidemiologic study of occupational lung cancer.
Arch. Environ. Health 14: 859.
Kennaway, E.L. 1925. The anatomical distribution of the occupational
cancers. Jour. Ind. Hyg. 7: 69.
Kennaway, E.L., and N.M. Kennaway. 1947. A further study of the incidence
of cancer of the lung and larynx. 3r. Jour. Cancer. 1: 260.
Kennaway, N.M., and E.L. Kennaway. 1936. A study of the incidence of can-
cer of the lung and larynx. Jour. Hyg. 36: 236.
Kotin, P., et al. 1969. Distribution, retention, and elimination of
C^4-3,4 benzpyrene after administration to mice and rats. Jour. Natl.
Cancer Inst. 23: 541.
Kuroda, S. 1937. Qccuoational pulmonary cancer of generator gas workers.
Ind. Med. Surg. 6: 304.
Lu, P. at ai. 1977. The environmental fate of three carcinogens; benzo-
(a)-oyrene, benzidine, and vinyl chloride evaluated in laboratory model eco-
systems. Arch. Environ. Contam. Toxicoi. 6: 125.
Mazumdar, S., et al. 1975. An eoidemiolcgicai study of exposure to coal
tar pitch volatiles among coke oven workers. APCA Jour. 25: 382.
f-JL*
-------
Neff, J.M., et al. 1976a. Effects of petroleum on survival, respiration
and growth of marine animals. In: Sources, Effects and Sinks of Hydro-
carbons in the Aquatic Environment. Proceedings of a symposium, American
University, Washington, O.C., American Institute of Biological Sciences, p.
520.
Neff, J.M., et al. 1976b. Accumulation and release of petroleum-derived
aromatic hydrocarbons by four species of marine animals. Mar. Siol.
38: 279.
Peacock, P.R.f 1936. Evidence regarding the-"mechanism of elimination of
1,2-benzpyrene, 1,2,5,6-dibenzanthracene, and anthracene from the blood-
stream of injected animals. Br. Jour. Exptl. Path. 17: 164.
Philips, E.F., et al. 1972. In vivo cytotoxicity of polycyclic hydro-
carbons., Vol. 2. p. 75 In: Pharmacology and the-Future of Man. Proc. 5th
Intl. Congr. Pharmacology,~T972, San Francisco..
Redmond, C.K.,. et al. 1972. Long term mortaility study of steelworkers.
Jour. Qccup. Med. 14: 621.
Redmond, C.K., et al. 1976. Cancer experience among coke- by-product
workers.. Ann. N.Y. Acad. Sci. p. 102.
Rees, E.O., et al. 1971. A study of the mechanism of intestinal absorption
of benzo(a)pyrene.. aiochem. Biophys. Act. 225: 96.
Reid, O.O., and C. Buck, 1956.. Cancer in coking plant workers. Br. .Jour.
Ind. Med. 13: 265.
Rigdon, R.H., and J. Neal. 1965. Effects of feeding benzo(a)pyrene on fer-
tility, embryos, and young mice. Jour. Natl. Cancer Inst. 34: 297.
Rigdon, R.H., and E.G. Rennels. 1964. Effect of feeding benzpyrene on re-
production in the rat. Experientia 20: 1291.
Schlede, E., et al. 1970a. Stimulatory effect of benzo(a)pyrene and pheno-
barbital pretreatment on the biliary excretion of benzo(a)pyrene metabolites
in.the rat. Cancer Res. 30: 2898.
Schlede, E. et al. 1970b. Effect of enzyme induction on the metabolism and
tissue distribution of benzo(a)pyrene.. Cancer Res. 30:2893.
Shendrikova, I.A., and V.A. Aleksandrov. 1974. Comparative characteristics
of penetration of polycyclic hydrocarbons through the placenta into the
fetus in rats. Byull.. Eksperiment. Biol. i Medit. -77: 169.
U.S. EPA. 1979a. Polynuclear Aromatic Hydrocarbons: Ambient Water Quality
Criteria (Draft).
U.S. EPA. 1979b. Multi-media Health Assessment of Polycyclic Organic
Matter. (Draft) prepared under contract to U.S. EPA by J. Santodonato, et
al., Syracuse Research Corp.
, *-r 0.0,
*) ' U )
-------
Vainio, H.-, et al. 1976. The fate of intratracheally installed benzo-
(a)pyrene in the isolated perfused rat lung of both control and 20-methyl-
cholanthrene pretreated rats. Res. Commun. Chem. Path. Pharmacol. 13: 259.
Weber, R.P., et al. 1976. Effect of the organophosphate insecticide para-
thion and its active metabolite paraoxon on the metabolism of benzo(a)pyrene
in the rat. 'Cancer. Res. 34: 947.
World Health Organization. 1970. European standards for drinking water.
2nd ed. Geneva.
- a-
-------
No. 150
Pyridine
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
PYRIDINE
Summary
Pyridine'has not shown carcinogenic effects following repeated subcuta-
neous administration to ,rats;-, the compound did not show mutagenic activity
in the Ames Salmonella assay.
A single study has indicated that pyridine produced developmental ab-
normalities when administered to chicken embryos.
Chronic exposure to. pyridine produces CNS disturbances and may produce
adverse hepatic and renal effects.
Pyridine has been shown to be toxic to freshwater fish at concentra-
tions ranging from 100,000 to 1,580,000 /jg/1. For freshwater invertebrates,
toxic concentrations of pyridine range from 575,000 to 2,470,000 >ig/l.
r-^ffl ^
' I > ) J*
I So-3
-------
I. INTRODUCTION
Pyridine (CAS number 110-86-1) is a colorless liquid possessing a
sharp, penetrating odor. It has the following physical properties:
Formula: C-H-N
Molecular Weight: 79.1
Melting Point: -42°C
Boiling Point: 115.3°c
Density: 0.982
Vapor Pressure: 10 mm Hg at 13.2°C
(Sax, 1975)
Solubility: misqible with water, alcohol,
ether, and other organic
solvents (Windholz, 1976)
Pyridine is a weak base and forms salts with strong acids. It is used
as a solvent for anhydrous mineral salts, in various organic synthetic pre-
parations, and in analytical chemistry (Windholz, 1976). The estimated an-
nual production of pyridine is in excess of 60 million pounds (Federal Reg-
ister 43:16638, April 19, 1978).
II. EXPOSURE
A. Water
Pertinent data could not be located in the available literature.
B. Food
Reported levels of pyridine in foods include: from 0.02 to 0.12
ppm, ice cream; 0.4 ppm, baked goods; 1.0 ppm, non-alcoholic beverages; 0.4
ppm, candy. Pyridine has also been found to occur naturally in coffee and
tobacco (Furia, 1975).
C. Inhalation
Pyridine may be produced and released during the combustion of
»
coke and as a combustion product in cigarette smoke (Graedel, 1978).
-------
The major release of pyridine is from emissions from manufacturing
and chemical processes. Based on total annual production, the U.S. EPA
(1976) has estimated a significant potential emission of pyridine during
manufacture. •
0. Dermal
Pertinent data could not be located in the available literature.
III.. PHARMACOKINETICS
A. Absorption
Absorption of pyridine occurs through the respiratory and gastro-
intestinal tracts, but probably not through the skin (Gosselin, et al. 1976).
B. Distribution
Pertinent data could not be located in the available literature.
C. Metabolism and Excretion
Pyridine may be partly excreted unchanged or may be methylated at
the N-position (Patty,. 1963) and excreted as N-methyl pyridinium hydroxide,
its chief metabolite (Browning,. 1965).- Methylation occurs in mice but not
in rats, and it may occur to some extent in man The fate of the majority
of absorbed pyridine is not known (Browning, 1965).
IV. EFFECTS
A. Carcinogenicity
Subcutaneous injection of pyridine at levels of 3 to 100 mg/kg
twice weekly for a year did not produce tumors in rats (Mason, et al. 1971).
B. Mutagenicity
Pyridine did not show mutagenic effects'with activation in the
Ames Salmonella assay (Commoner, 1976).
C. Teratogenicity
Pyridine caused chick embryo abnormalities in one limited study
(Federal Register 43:16688, April 197 1978).
-------
0. Other Reproductive Effects
Pertinent data could not be located in the available literature.
E. Chronic Toxicity
. Prolonged daily exposure to pyridine at levels from 6 to 12 ppm
causes mild central nervous system (CNS) disturbances in workers, while ex-
posure from 15 to 330 ppm causes insomnia, nervousness, and low-back or ab-
dominal pain accompanied by frequent urination (Gosselin, et al. 1976).
In animals, the major effects of repeated feeding of pyridine are
hepatic and renal injury (Patty, 1963). Chronic exposure to 10 or 50 ppm
pyridine vapors causes increased liver/body weight ratios in rats (ILQ,
1971).
F. Other Relevant Information
Symptoms in humans associated with inhalation or ingestion of
pyridine are CNS depression, arid liver and kidney damage (Federal Register
4:16688, April 19, 1978; Gosselin, et al. 1976; Sax, 1975; ILO, 1971).
Vapors are also irritating to eyes, skin, and nasal membranes (ACGIH, 1977;
Sax, 1975), Skin eruptions induced by pyridine may be provoked by exposure
to light (Arena, 1974). Ingestion of pyridine causes CNS depression, heart
and gastrointestinal distress, fever, and, at high doses, death; and may
stimulate bone marrow production of platelets in low doses (ACGIH, 1977;
Gosselin, et al. 1976). Death may be due to either hepatic or renal damage,
or from pulmonary injury (Gosselin, et al. 1976; ACGIH, 1977).
Exposure to vapors of pyridine from 1,250 to 10,000 ppm for 1 to 7
hours did not cause mortality in rats, but a 0.1 percent diet of pyridine
induced rapid weight loss and death in two weeks (ILO, 1971).
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
McKee and Wolf (1963) have reviewed the effects of pyridine on
several aquatic organisms. The freshwater minnow, bleak (Alburnus lucidus),
was the most sensitive sp.ecies tested with threshold toxicities ranging from
100,000 to 160,000 pg/1. Tests with the freshwater mosquitofish (Gambusia
affinis) revealed a 96-hour LC5Q value of 1,300,000 ug of pyridine per
liter of turbid water. Orange-spotted sunfish (Lepomis humilis) were killed
in one hour from exposure to pyridine at concentrations ranging from
1,480,000 to 1,580,000 ug/1, while goldfish (Carassius auratus) were killed
after 10 to 30 hours' exposure to pyridine. Verschueren (1979) has reported
a 24-hour LC5Q value of 1,350,000 ^ig/1 for mosquitofish exposed to pyri-
dine.
Oowden and Bennett (1965) demonstrated a 48-hour LC5Q value of
2,114,000 ;ug/l for Daphnia magna exposed to pyridine. McKee and Wolf (1963)
reported a threshold effect of 40,000 ug/1 for Daphnia sp. Canton and Adema
(1978) determined 48-hour LC5Q .values ranging from 1,130,000 to 1,755,000
'ug/1. for Daphnia magna, and 48-hour LC5Q values of 575,000 and 2,470,000
ug/1 for Daphnia pulex and Daphnia cucullata, respectively.
B. Chronic Toxicity, Plant Effects and Residues
Pertinent data could not be located in the available literature.
C. Other Relevant Information
Thomas (1973) reports that pyridine exposure levels of 5,000 jjg/1
impart an off-flavor to fish flesh.
>~rGrr
* I / ' /
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VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The 8-hour, time-weighted-average occupational exposure limit for
pyridine recommended by the American Conference of Governmental Industrial
Hygienists is 5 ppm (ACGIH, 1977).
8. Aquatic
Based on 96-hour LC5Q data, Hahn and Jensen (1974) have assigned
pyridine an aquatic toxicity rating of from 100,000 to 1,000,000 pg/1.
-------
REFERENCES
American Conference of Governmental Industrial Hygienists. 1977. Threshold
limit values for chemical substances and physical agents in the workroom
environment with intended changes for 1977, Cincinnati, Ohio.
Arena, J.M. 1974. Poisoning: Toxicology-Symptoms-Treatments. 3rd ed.,
Charles C. Thomas: Springfield, Illinois.
Browning, E. 1965.. Toxicity and Metabolism- of Industrial. Solvents. Ameri-
can Elsevier f • New York.
Canton, H.J., and D.D.M. Adema. 1978. Reproducibility of short-term and
reproduction toxicity experiments with Daphnia maqna and comparison of the
sensitivities of Daphnia magna with Daphnia pulex and Daphnia cucullata in
short-term experiments, Hydrobioligia. 59: 13T!
Commoner,. B. 1976. Reliability of bacterial mutagenesis techniques to
distinguish carcinogenic and non-carcinogenic chemicals. U.S. EPA, NTIS
PB-259 934.
Dowden, B. and H. Bennett. 1965. Toxicity of selected chemicals to certain
animals. Jour. Wat. Poll. Cont. Fed. 37: 1308.
Furia, T. 1975. Fenaroli's Handbook of Flavor Ingredients. 2nd ed. CRC
Press,. Boca Raton, Fla.
Gosselin, R.E., et ai. 1976. Clinical Toxicology of Commercial Products.
4th ed. Williams and Wilkins, Baltimore.
Graedel, T.. 1978. Chemical Compounds in the Atmosphere. Academic Press,
New York.
Hahn, R. and P. Jensen. 1974. Texas A and M University, College Station,
Texas. Water Quality Characteristics of Hazardous Materials. Prepared for
the National Oceanic and Atmospheric Administration. NOAA-78013001. NTIS
PB-285 946/OST.
International Labour Office. 1971. Encyclopedia of Occupational Safety and
Health, Vol. 2. McGraw-Hill Book Co., New York.
Mason, M., et al. 1971.. Toxicology and carcinogenesis of various chemicals
used in the preparation of vaccines. Clin. Toxicol. 4: 185.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria. The Resources
Agency of California. State Water Quality Control Boar.d Publication 3-A.
Patty, F.. 1963. Industrial Hygiene and Toxicology: Volume 2, Toxicology.
2nd ed. John Wiley and Sons, New York.
-------
Sax, N.I. 1975. Dangerous Properties of Industrial Materials. 4th ed.
Van Nostrand Reinhold Co., New York.
Thomas, N.A. 1973. Assessment of fish tainting substances. In: Biological
Methods for the Assessment of Water Quality. American Society for Testing
and Materials, ASTM-STP-528, p. 178.
U.S. EPA. 1976. Preliminary scoring of selected organic air pollutants.
U.S. Environ.. Prot.. Agency, EPA 450/3-77-008a.
Verschueren, K. 1979. Handbook of Environmental Data on Organic Chemicals.
Van Nostrand Reinhold Co., New York.
Windholz, M. (ed.) 1976. Merck Index. 9th ed- Merck and Co., Rahway, New
Jersey.
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No. 151
Qulnones
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
LJ^ ~ f
To v f
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
QUINONE
Summary
Quinone has been reported to produce neoplasms, but insufficient
data are available to assess its carcenogenic potential. Quinone
was not mutagenic to Orosophila melanogaster, human leukocytes,
nor Neurospora.
Quinone is very toxic to fish and plants. Exposure to humans
causes conjunctiyal irritation and, in some cases, corneal edema,
ulceration, and scarring; transient eye irritation was noted
above 0.1 ppm. Quinoae is highly toxic to mammals via the oral
and inhalation route.
-7***
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I. INTRODUCTION
Quinone (p-Benzoquinone; Gas No. 106-51-4) is a yellow,
crystalline•solid with chlorine-like irritating odor. It has the
following physical properties:
Formula:
Physical State: large, yellow, monoclinic
prisms
Molecular Weight: 108.09
Specific Gravity: 1.318 (20*C)
Melting Point: 112.9"C
Boiling Point: sublimes
Vapor Pressure: considerable; sublimes readily
upon gentle heating (Patty,1967)
Quinone is soluble in. alcohol, ether, and alkali; and slightly
soluble in hot water. Quinone can be prepared by oxidation starting
with aniline or by the reduction of hydroquinone with broaic acid. .
The compound has found wide application in the dye, textile, chemical,
tanning, photography, and cosmetic industries primarily because of
its ability to transform certin nitrogen-containing compounds into
a variety of colored substances (Patty, 1967).
II. EXPOSURE
A. Water
Pertinent data could not be located in the availabe
literature.
B. Food
Pertinent data could not be located in the available
literature.
-------
C. Inhalation
Because of its ability to sublime, quinone becomes an air
contaminant problem at Che production sice.
D. Dermal
Pertinent data could not be located in the available literature..
ILL PHARMACOKINETICS
A. Absorption
Quinone is readily abs.orbed from the gastroenteric trace
and subcutaneous tissues (Patty, 1967). Sax, 1979, reports quinine
as capable of causing death or permanent injury due Co Che exposures
of normal use via absorption through oral and inhalation routes.
Quinone affects the eyes (Procter, 1978).
B. Distribution
Pertinent data could not be located in the available literature.
C. Mebalolism. and Excretion
Quinone is partially excreted unchanged; but the bulk is
eliminated in conjugation with hexuronic, sulfuric, and other acids
(Patty, 1967).
IV. EFFECTS
A. Carcinogenicity
Quinone has been reported to produce neoplasms but upon
review by the International Agency for Research on Cancer, it was
determined that there was insufficient data to conclude that it-was
a carcinogen (IARC, 1977) '' ,
B. Mutagenlcity
Quinone did not produce mutagenic effects in studies with
-------
Orosophila melanogaster and human leukocytes (Lueers and Obe, 1972).
Another study reported quinone as nonmutagenic to Neurospora
(Reissig, 19'63).
C. Teratogenicity
Pertinent data could not be located in the available
literature.
D. Other Reproductive Effects
Pertinent data could not be located in the available literature.
E» Chronic Toxicity
Quinone has been reported to oxidize with the lens protein
SH groups in rabbits (Ikemota and Augusteyn, 1976). Chronic exposure
causes Che gradual development of changes characterized as follows:
brownish discoloration of the conjunctiva and cornea confined to
the intrapalpebral fissure; small opacities of the cornea; and
structural cornea! changes which result in loss of visual acuity
(Sterner, et al., 1947; Anderson and Oglesby, 1938).
F. Other Relevant Information
Acute exposure causes conjunctival irritation and, in
some cases, corneal edema, ulceration, and scarring; transient eye
irritation may be noted above 0.1 ppm and becomes marked at 1 to 2
ppm (AIHA, 1963). Ulceration of the cornea has resulted from one
brief exposure to a high concentration of the vapor of quinone, as
well as from repeated exposures to moderately .high concentrations
(Patty, 1967). Absorption of large doses of quinone from the gas
troenteric tract or from subcutaneous tissues of animals induces
chronic convulsions, respiratory difficulties, drop in blood pres-
sure, and death by paralysis of the medullary centers (Patty, 1967).
-------
Oral rat LDSOs have been reported for quinone ranging from
130 to 296 mg per kg body weight (Verschueren, 1977). Inhalation '
of quinone at concentrations ranging from 230 to 270 ng per cu.m.
for 2 hrs was lethal to 100 percent of the test population of
rats.
IV.. AQUATIC TOXICITY
A. Acute Toxicity
Quinone has been reported to be toxic to invertebrate
Daphnia at 0.4 ppm (Verschueren, 1977). Also, quinone has an LD50
for perch ranging from 5 to 10 mg/1 (Verschueren, 1977).
B. Chronic Toxicity, Plant Effects, and Residues
Quinone inhibits photosynthesis in the fresh water algae
S. capricornutum (Gidding, 1979), decreases chlorophyll flourescence
and cyclosis (protoplasmic streaming) of Nitella cells (Apartsin,
et al, 1979; Stom,. 1977; Stom and Kuzevania, 1976; Stom and Rogozina,
1976), and inhibits carbon metabolism in Ghloralla pyrenoidosa
(Printavu, 1975).
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The 8-hour, time-weighted average occupational exposure
limit for quinone has been set in the United States at a concentration
of 0.1 ppm and in the U.S.S.R. at a concentration of 0.01 ppm
(Verschueren, 1977).
/sf-7
-------
REFERENCES
Procter, M.H., and James Hughes. Chemical Hazards of the Workplace.
J.3. Lippincott Company. Philadelphia. 1978.
Reissig, J.L. 1963. Induction of Foward Mutants in the Pyr-3
Region of Neorospora. J. Gen. Microbial. 30:317-325.
Sterner,. J.H.t at al. 1947. Quinone Vapors and Their Harmful
Effects to Corneal and Conjunctival Injury. J. Ind. Hyg.
Toxicol. 29:60.
Stom, D.I. 1977. 'Influence of Polyphenols and Quinones on Aquatic
Plants and Their Blocking of Sulfhydryl Groups. Acta Hydrochim.
Hydrobiol. -Vol. 5, ISS. 3, 291-8.
Stom, D.I, and E.N. Kuzevanova. 1976. The Distribution of
Sulfhydryl Groups in Nitella Cells and the Effects on Them
of Polyphenols and p-Benzoquinone. Tsitologiya. Vol. 18,
ISS. 2, 230-2.
Stom, D.I., and N.A. Rogozina. 1976. Possible Mechanism of
Action of Quinone Pesticides on the Photoplasmic Streaming in
Marine Plants. Eksp. Vodn. Toksikol. Vol. 6, 111-118.
Verschueran, K. 1977. Handbook of Environmental Data on Organic
Chemicals. Van Nostrand Reinhold Co. New York.
AIHA. 1963 Hygenic Guide Series: Quinone. Am. Ind. Hyg. Assoc. J.
24:194. 1963.
Anderson, 3., and F. Oglesby. 1938. Corneal Changes from Quinone-
Hydroquinone Exposure. A.M.A. Arch. Opthalmol. 59:495.
Apartsin, M.S., et al. 1979. Mechamism of the Effect of
Pyrocatechol and p-Benzoquinone on Nitella cells. Dokl. Akad. Nauk.
S.S.S.R. Vol. 244, ISS. 2, 510-12.
Giddings, J. M. 1979. Acute Toxicity to Selenastrum capricornutum
of Aromatic Compounds from Coal Conversion. Bull. Environ. Coneam.
Toxicol. Vol. 23, ISS. 3, 360-4.
IARC. 1977. Monographs on the Evaluation of Carcinogenic Risk of
Chemicals to Man, Vol. 15. World Health Organization.
Ikemoto, F., and R.C. Augusteyn. 1976. The Reaction of Lens
Proteins and Amino Acids with 1,4-Benzoquinone. Jpn. J. Ophtnalmol.
(Japan). Vol. 20, ISS. 4, 457-65.
Lueers, H., and G. Obe. 1972. On the Possible Mutagenic Activity
of p-Benzoquinone. Mutut. Res. 15:77-80.
-------
Patty, F.A. 1967. Industrial Hygiene and Toxicology. Inter-
science Publishers. New York.
Pristavu, N. 1975. Action of p-Benoquinone on the Radioactive
Carbon Metabolism in Chlorella pyrenoidosa. Proc. Int. Congr
Photpsynth. ,' 3rd. Vol. 2. 1541-6.
IF/'?
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No. 152
Resorclnol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a. survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal* The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts, presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
RESORCINOL
Summary
Resorcinol, 1,3-dihydroxybenzene, is a phenolic compound. Resorcinol
is weakly antiseptic and resorcinol compounds are used in Pharmaceuticals
and hair dyes for human use. Major industrial uses are as adhesives in rub-
ber products and tires, wood adhesive resins, and as ultraviolet absorbers
in polyolefin plastics. Resorcinol is also a byproduct of coal, conversion
and is a component of cigarette smoke. Thus,, substantial opportunity exists
for human exposure.
Many phenolic compounds, including resorcinol, are strong mitotic spin-
dle poisons in plants. This, evidence of mutagenic activity and the strong
oncogenic activity in plants have not been adequately tested in animals to
provide an understanding of the processes. In animals the only cocarcino-
genic activity (in cigarette smoke condensate) demonstrated has been- as a
protective agent against benzo(a)pyrene carcinogenicity.'
Resorcinol has been demonstrated to result in chronic toxicity: reduc-
ing growth rate in an insect species and causing chronic health complaints
from workers in a tire manufacturing plant.
Acute toxicity through oral, eye, skin penetration, and skin irritation
has been demonstrated by all tests. Values vary in the literature and are
inadequate to draw a quantitative conclusion. Resorcinol has also been
shown to be acutely toxic to both freshwater and marine aquatic organisms in
96-hour LC5Q tests.
-------
No standards or guidelines exist for resorcinol. ACGIH's Committee on
Threshold Limits has proposed a TLV of 5 ppm but has not finalized that
recommendation. Industry has suggested this value is lower than is required
for safety, citing existing workplace levels of 9.6 ppm without worker com-
plaint or evidence of acute or chronic toxicity..
-------
I. INTRODUCTION
Resorcinol is a phenolic compound (molecular weight, 110.1; boiling
point, 276^0; melting point, 110.0°C). Synonyms are m-dihydroxybenzene,
1,3-benzenediol, 3-hydroxyphenol, and resorcin. Resorcinol occurs as white
or nearly white needle-shaped crystals or powder. It has a faint, charac-
teristic odor and a sweetish taste with a bitter aftertaste. One gram is
soluble in 1 ml of water and in 0.1 ml of alcohol. - ...
Resorcinol is a weak antiseptic and is used in antiseptics, keratolytic
disease treatments and fungicides (Wilson, et al. 1577). Major uses of re-
sorcinol are: in tires and other rubber products; wood adhesive resins; as
an ultraviolet absorber in polyolefin plastics; as an intermediate in dye
manufacture (especially hair dyes); and in the production of synthetic tan-
ning agents, explosives, and specialty adhesives. The tire and rubber in-
dustries accounted for 43 percent of the use of resorcinol in 1974, primar-
ily as adhesives in fabricating belting, rubberized hose, and rubberized
textile sheets (Stanford Research Institute, 1975).
Resorcinol is expected to be a. component of various waste streams from
coal conversion facilities. The potential for removal through existing
waste treatment processes is currently under assessment (Herbes and Beau-
champ', 1977).
II. EXPOSURE
Resorcinol is used in substantial quantities in industry and frequently
in small quantities in the home. Although the potential for human exposure
exists, very little exposure information is available. The Koppers Company,
Inc., Monroeville, Pennsylvania, is the major supplier of resorcinol in the
»
United States. They report substantial testing of the plant environment in-
dicating resorcinol concentration up to 9.6 ppm in ambient air (Flickinger,
197$). .
-------
Resorcinol is currently sold and transported as a solid, although the
Koppers Company reports increasing inquiries regarding bulk shipments of
molten resorcinol. They indicate that this would increase the opportunity
for industrial and public exposure to the compound (Flickinger, 1976).
In an epidemiological study of rubber workers at a hexamethylenetetra-
•mine-resorcinol (HR) resin system tire manufacturing plant, all environment-
al samples in the study were less than 1 mg/m3 (Gamble, et al. 1976)..
Resorcinol has been shown to be present in cigarette smoke and is a
component of the weakly acidic fraction of cigarette smoke condensate which
has been shown to have tumor-promoting capability (Schlotzhauer, et al..
1978).
III. PHARMACOKINETICS
_ Despite the presence of resorcinol and resorcinol compounds in numerous
pharmaceutical, preparations, no specific information on the metabolism, dis—
tribution, absorption,, or excretion of resorcinol was found in the available
literature.
IV.. EFFECTS
A. Carcinogenicity
The available data dealing with the potential carcinogenicity of
resorcinol are at this time inadequate to formulate, a clear understanding of
resorcinol's oncogenic potential. In a study of commonly used cutaneous
agents, Stenback (1977) showed no tumor induction in rabbits and mice from
topically applied resorcinol. Resorcinol was selected because of its pre-
sence in hair dyes.
Van Duuren and Goldschmidt (1976), in a study of 21 tobacco smoke
»
components, found that resorcinol reduced the carcinogenic potential of ben-
zo(a)pyrene (BaP) in dermal application to mice. Thus, fewer tumors were
-------
induced by BaP in1 the presence of resorcinol, indicating possible inhibition
of carcinogenic activity.
Substantial evidence appears to exist for the oncogenic activity
of resorcinoi in plants. Anderson (1573) reports that the "strong carcino-
genicity" of resorcinol, tested in Nicotiana hybrids suggests that "an onco-
genic reactivity of phenols is common to plant and animal tissues but with
differences in strength of reaction to a derivative in a given system".
B..- Mutagenicity
Dean .(1578) reports that most phenolic compounds including• resor-
cinol are mitotic spindle poisons in plant tissues. He further reports that
considering the severity of effects on plant chromosomes that it is surpris-
ing that ir^ vivo plant and animal tests have not been done to determine
their clastogenic properties.
By micronucleus test, Hossack and Richardson (1977) were unable to
find evidence of mutagenicity in resorcinol or a; number, of other hair dye
constituents tested.
The Ames assay for resorcinol was^negative in a test of commonly
used cutaneous agents (Stenback, 1977).
C- Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the available literature.
0. Chronic Toxicity
In a study of chronic toxicity effects on the black cutworm, Aqro-
tis epsilon, Reese and Beck (1976) found no significant correlation between
resorcinol concentration and pupation or survival but found correlation with
body weight at various stages of development. They report that resorcinol
is the only compound among those tested which had "no adverse effect on any
of the nutritional indices and yet reduced growth. It is also the only com-
IS
-------
pound which inhibited growth but did not inhibit pupation." They hypothe-
sized that resorcinol may act through a temporary inhibition of ingestion
but that the insects continued to eat. regularly, allowing pupation on a nor-
mal schedule (Reese and Beck, 1976).
In the epiderrcLological study of the HR resin system tire manufac-
turing plant, Gamble,, et al. (1976) reported that HR exposed workers consis-
tently showed an excess of respiratory symptoms and that there was a consis-
tent association of alcohol consumption with increased incidence- of symp-
toms. The reported symptoms included rash, itch,, difficult breathing at
work, cough,- chest tightness,, burning eyes, running nose, and burning sensa-
tion in the heart region.
E~ Acute Toxicity
with one exception, all acute toxicity data in the readily avail-
able literature are: supplied by Flickinger (1976) for the Koppers Company,
the primary manufacturer and supplier of resorcinol in the United States.
Lloyd, et al. (1977) independently reported the LD5Q for acute oral toxi-
city to be 370 mg/kg for resorcinol..
In a review of the industrial toxicology of the benzenediols,
Flickinger (1976) reports various acute toxicity data for resorcinol. A
summary of relevant results follows:
An acute oral LD5Q for resorcinol was reported by Flickinger
(1976) as 0.98 gm/kg in the rat.. Rats dying during the period showed hyper-
emia and distension of the stomach and intestines.. Surviving rats showed
normal weight and no gross lesions at necropsy.
The ^50 f°r derma-L application in the rat was 3.36 gm/kg. At
higher levels, resorcinol produced skin necrosis. At 1.0 gm/kg levels,
-------
moderate to severe irritation was followed in 24 hours by slight hyperkera-
tosis. Surviving rats snowed reduced, weight but no internal gross lesions
upon necropsy..
Flickinger (1576) reported that resorcinol is a severe eye irri-
tant (0.1 gm in eye of male, albino rabbits). No recovery was seen in the
14-day follow-up period with all exposed individuals exhibiting keratoconus
and pannus formation.
Resorcinol is a primary skin irritant. Contact with 0.5 gm of re-
sorcinol on intact and abraided skin produced moderate irritation on intact
skin and varying reactions including necrosis on abraided skiru
Inhalation of up to 2,800 mg/nP of resorcinol aerosol for 8
hours resulted in no observable toxic effects to the rats (Flickinger, 1576).
V. AQUATIC TOXICITY
The possibility that resorcinol may be present in some quantity in coal
conversion process effluents requires further investigation as to the feasi-
bility of control technology. Hertoes and Beauchamp (1577) compared toxic
interactions of two coal conversion effluents, resorcinol and 6-methylquina-
line. With Daphnia magna as a test species, they found mixtures of the two
compounds to be less toxic than either pure compound tested alone. They re-
port a 48-hour LC5Q for resorcinol alone to be 1.28 mg/1.
Curtis, et al. (1579) reported the acute toxicity of resorcinol to
freshwater and saltwater organisms. In freshwater, the LC5Q values for
fathead minnow are as follows: 24 hours, 88.6 mg/1; 48 hours, 72.6 mg/1;
and 96. hours, 53.4 mg/1. In saltwater, the LC5Q values for Palaemonetes
gugio or Penaeus setiferus are: 24 hours, 169.5 mg/1; 48 hours, 78.0 mg/1;
and 96 hours, 42.4 mg/1. Thus, resorcinol was found to be toxic to aquatic
life in both freshwater and saltwater.
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VI.. EXISTING GUIDELINES AND STANDARDS
There are no OSHA regulations, NIOSH recommendations, or other guide-
lines concerning resorcinol. In 1974, ACGIH's Committee on Threshold Limits
proposed a TLV for resorcinol of 5 ppm. Flickinger (1976) reports of cur-
rent industrial 8-hour workday exposures at 9.6 ppm "without.signs of intox-
ication or skin or respiratory irritation" and recommends TLV industrial ex-
posures of "at least 10 ppm, perhaps even 20 ppm or higher". ACGIH has not
issued a formal TLV for resorcinol.
Information regarding existing guidelines and standards to protect
aquatic life from the effects of resorcinol was not found in the available
literature.
-------
REFERENCES
Anderson, R.A. 1973. Carcinogenicity of phenols, alkylating agents, ure-
than, and a cigarette-smoke fraction in Nicotiana seedlings. Career Re-
search 33: 2,450.
Curtis, M.W., et al. 1979. Acute toxicity of 12 industrial chemicals to
freshwater and saltwater, organisms, water Research 13: D7.
Dean, 8.0. 1978. Genetic toxicology of benzene, toluene, hylenes, and phe-
nols. Mutation Research 47: 75.
Flickinger, C.W. 1976. The benzenediols: catechol, resorcinol and hydro-
quinone — a review of the industrial toxicology and current industrial ex-
posure limits. Am. Ind. Hyg. Assoc. Jour. 37: 596.
Gamble, J.F., et al. 1976. Respiratory function and symptoms: an environ-
mental - epidemiological study of rubber workers exposed to a phenol-formal-
dehyde type resin. Am. Ind. Hyg. Assoc. Jour. (September 1976): 499.
Heroes, S.E. and J.O. Beauchamp. 1977. Toxic interactions of mixtures of
two coal conversion effluent components, (resorcinol and 6-fliethylquinoline)
to Daohnia magna. Bull. Env. Contain. Toxicol.. 17: 25.
Hossack, O.O.N. and J.C. Richardson. . 1977. Examination of the potential
mutagenicity of hair dye constituents using the micronucleus test. Exper-
mentia 33: 377.
Lloyd, G.K.,. et al. 1977. Assessment of the acute toxicity of potential
irritancy of hair dye constituents. Food Cosmet. Toxicol. 15: 607.
Reese, J.C. and S.D. Beck. 1976. Effects of allelochemics on the black
cutworm, Aqrostis ipsilon: effects of resorcinpl, phloroglucinoal, and Gal-
lic acid on larval growth, development, and utilization of food. Ann. Ento-
mol. Soc. Am. 69: 999.
Schlotzhauer, W.S., et al. 1978. Characterization of catechols, resorci-
nols, and hydroquinones in an acidic fraction of cigarette smoke condensate.
Jour. Agric.. Food Chem. 26: 1277.
Stanford Research Institute. 1975. Chemical Economics Handbook- Stanford
Research Institute,"Menlo Park, California.
Stenback, F. 1977. Local and systemic effects of commonly used cutaneous
agents: lifetime studies of 16 compounds in mice and rabbits. Acta. Pharma-
col.. et Toxicol. 41: 417.
.van Ouuren, B.L. and 8.M. Goldschmidt. 1976. Cocarcinogenic and tumor-pro-
moting agents in tobacco carcinogenesis. Jour. Natl. Cancer Institute
56: 1237.
Wilson, C.Q., et al. (eds.) 1977. Textbook of Organic and Pharmaceutical
Chemistry. J.3. Lippincott Co., Philadelphia, Pennsylvania, pp. 72, 181,
194.
— f f?*] A -
^ If IA. •'
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No. 153
Selenium
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
1*3-1
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations'of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical.. This document has undergone scrutiny to
ensure its technical accuracy.
7/3-3k-
-------
SELENIUM
SUMMARY
Human daily intake of selenium has been estimated at 50
to 150 jag/day. While selenium is an. essential nutrient foe humans
and. other species, it is toxic in excessive amounts. Selenium
poisoning produces symptoms in man similar to those produced
by arsenic. Although it has been shown to produce tumors in
v
animals/ the Food and Drug Administration, the International
Agency for Research on Cancer and the National Academy of Science
have concluded that the available animal data are insufficient
to allow an evaluation of the carcinogenicity of selenium compounds.
The data base for selenium for aquatic life is quite limited.
No chronic data are available for marine fish. 'Selenium does
not bioconcentrate to a great extent in freshwater species, indi-
cating that tissue residues should not be a hazard to freshwater
organisms. This information is not available for marine organisms.
xl
•77*9-
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SELENIUM •
I. INTRODUCTION
This profile is based on the Ambient Wa.ter Quality Criteria
Document for Selenium (U.S. EPA, 1979).
Selenium (Se; atomic weight 78.96) is a naturally occurring
element which reacts with metals to form ionic selenides with
a valence of minus 2, and with most other chemials to form cova-
lent compounds. It may assume any of several valence states
ranging from minus 2 to plus 6. Selenium is used in photocopying,
the manufacture of glass, electronic devices, pigments, dyes
ana insecticides (Dept. Interior, 1974). It is also used in
veterinary medicine (U.S. EPA, 1979) and in antidandruff shampoos
(Cummings and Kimura, 1971). The major source of selenium in
the environment is the weathering of rocks and soils (Rosenfeld
and Beath, 1964) but human activities contribute about 3,500
metric tons per year (U.S. EPA, 1975a). Selenium is an essential
nutrient for humans and other species (Schroeder, 1970).
II. EXPOSURE
Selenium is not present in measurable quantities in most
U.S. drinking water supplies. Of 3,676 residences located in
33 geographically dispersed areas, only 9.96 percexit of the sam-
ples had selenium levels above the detection limits of 1 jug/1
(Craun, et al. 1977). However, in seleniferous areas of South
Dakota, levels of 50 to 330 ug/1 were measured in drinking waters
(Smith and Westfall, 1937). Sewage plant effluents may contribute
to tne selenium content of water; as much as 28U pg/1 have been
reported in caw sewage, 45 jag/1 in primary effluent, and 50 wg/1
-------
in secondary effluent. (Baird, et al. 1972). Selenium concentra-
tions in plants depend largely on the concentration in the soil
where the plants are grown. High selenium concentration in vegeta-
tion is transmitted to other food sources, e.g., meats and eggs.
The EPA (1979) has estimated the weighted average bioconcentration
factor for selenium to be 18 for consumed fish and shellfish.
Zoller and Reamer (1976) reported that most urban regions have
concentrations of particulate' selenium ranging from 0.1 to 10
ng/m .
III. PHARMACOKINETICS
A. Absorption
Selenium appears to be effectively absorbed by the
gastrointestinal tract. Thomson and Stewart (1974) reported
absorptions . of. 70, 64, and 44 percent for sodium selenite in
three young women. Data from rats are similar with absorptions
ranging from 81 to 97 percent for a number of organic selenium
compounds and sodium selenite (Thomson and Stewart, 1973; Thomson,
et al. 1975). The literature contains no information on absorp-
tion by inhalation or dermal exposures (National Research Council,
1976).
B. Distribution
The primary disposition sites for selenium in the body
are the liver, kidney, spleen, and middle, and lower sections
of the small intestine (U.S. EPA, 1979) . Based on the work of
Kincaid, et al. (1977) it is apparent that tissue concentration
levels of selenium can be affected both by dose and normal dietary
intake, although the primary deposition sites remain the same.
-------
C. Metabolism
Selenium is an essential element and at nutritional
levels it is incorporated into specific functional proteins;
at higher concentrations, it is substituted for sulfur in sulfur-
containing compounds. Selenium analogs are often less stable
than sulfur compounds, ana this lability may be the basis of.
toxicity (Stadtman, 1974). Selenite and selenate are methylated
by mammalian tissues in an apparent detoxification process.
Mouse liver, lung and kidney (Ganther, 1966)^are active in methyla-
tion, but muscle, spleen, and. heart have little activity.
0. Excretion
Thomson and Stewart (197<±) studied selenium excretion
by feeding three women selenite. It was apparent that the pri-
mary routes of excretion were in the feces ana urine, with little
loss through the skin or lungs.
IV. EFFECTS
A. Carcinogenicity
Only six studies have been performed to specifically
investigate whether selenium is carcinogenic. From these studies
there is no conclusive evidence that selenium has induced tumors
in the test animals. The Food .and Drug Administration has de-
clarea that selenium poses no carcinogenic risk (Food and Drug
Administration, 1973) .
B. Mutagenicity
Selenium has been shown to affect the genetic process
in barley (Walker and Ting, 1967) and in Drosophila melanog-aster
(Ting and Walker, 1969; Walker ana Braaley, 1969). However, these
/ ^3 -I
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ana other genotoxic effects are not true mutagenic effects.
There is no study in which a true mutagenic activity for selenium
has been demonstrated.
C.. Teratogenicity
The consumption ' of seleniferous diets interfered with
the normal, development of the. embryo in many mammalian species,
including rats, pigs, sheep and cattle (U.S. EPA, 1979) .. Robertson
(1970) suggested that selenium may be a teratogen in man from
the examination of the older literature whiqh correlated malformed
babies and the consumption of toxic grains by people in Columbia.
D. Other Reproductive Effects
Vesce (1947) noted changes in endocrine, glands, espe-
cially the ovaries, following oral administration of 5 to 12.5
mg sodium selenide to guinea pigs over two periods of 20 days.
E. Chronic Toxicity
Chronic effects from prolonged feeding of diets contain-
ing added selenium in amounts of 5 to 15 ug/g include liver damage
in the form of atrophy, necrosis, cirrhosis, and hemorrhage,
and marked and progressive anemia in some species (Fishbein,
1977). In man hepatic necrosis has not been observed following
chronic exposure; however, lassitude, loss of hair, discoloration
ana loss of fingernails were symptoms (Beath, 1962).
P. Other Relevant Information
The essentiality of selenium for several animals, has
been known since the 1950's (Ganther, 1970; Schwarz, 1961) with
•
selenium deficiency resulting in white muscle disease in ruminants,
hepatic degeneration and peridontal disease in other mammals.
-------
Synergism/antagonism exists between the actions of selenium and
other metals such as arsenic, mercury, cadmium, silver and thal-
lium (Diplock, 1976).
V. AQUATIC TOXICITY
A. Acute Toxicity
Cardwell, et al. (1976) exposed 6 species of freshwater
fish to selenium dioxide and observed the 96-hour LCcQ values
to range from 2,060 to 28,500 ug/1. The 96-hour LC5Q values
for fathead minnow fry and juveniles are 2,060 and 5,200 ug/1,
\
respectively, indicating an apparent decrease in toxicity with
age. With the invertebrates Daphnia magna and scud, the LC5Q
values are 430 and 313 ug/1 respectively (U.S. EPA, 1978; Adams,
1976) .
The 96-hour LCeg values for marine species are 6,710
pg/1 for the sheephead minnow (U.S. EPA, 1978) and 600 ug/1 for
mysid shrimp (U.S. EPA, 1978).
B. Chronic Toxicity
No pertinent data are available on the chronic toxicity
of selenium to freshwater organisms (U.S. EPA, 1979). The only
data available, in marine species is that of the mysid shrimp
(Mysidopsis oahia). It has been exposed to selenium for its
life cycle and the chronic value is 135 ug/1.
C. Plant Effects
Selenium is toxic, to two freshwater algal species,
Chlorella vulgaris and Haematoccus cupensis, with growth being
»
retarded at 50 ug/1 (Hutchinson and Stokes, 1975). For the salt-
water alga, Skeltonema costaturn, the 96-hour ECcQ values for
-------
chlorophyll a^ and cell numbers are 7,930 and 8,240 pg/1, respec-
tively (U.S. EPA, 1978).
0. Residues
Bioconcentration factors have been determined for the
rainbow trout, fathead minnow and bluegill. These factors range
from Z to 20 (Adams, 1976,- U.S. EPA, 1978). The tissue half-
life for the bluegill is between 1 and 7 days (U.S. EPA, 1978).
These results show that tissue accumulation of selenium should
not present a hazard to freshwater aquatic, organisms.
No residue data are available, for marine species (U.S.
EPA, 1979). •
VI. EXISTING GUIDELINES
A.. Human
The U.S. Environmental Protection Agency (1975b) has
established the maximum permissible, level of selenium at 0.01
mg/1 for U.S. drinking waters. A time-weighted average concentra-
tion threshold limit value (TLV) of 0.2 mg/m has been established
by the American Conference of Government Industrial. Hygienists
(ACGIH, 1977). The minimum toxic, dose for selenium has been
calculated to be 16.1 mg/day. The U.S. EPA (1979) draft water
criterion for selenium is 10 ug/1. As a result of public comments
received, additional review and consideration of the recommended
criterion is required.
B. Aquatic
For selenium in freshwater, the draft criterion* to
protect aquatic life is 9.7 ug/1 as a 24-hour average and the
concentration .should not exceed 22 pg/1 at any time (U.S. EPA,
"•»
1979) .. .In saltwater the criterion is 4.4 ug/1 as a 24-hour average
and the concentration should not exceed 10 ug/1 at any time.
-T&r-
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SELENIUM
REFERENCES
Adams, W.J. '1976. The toxicity and residue dynamics of selenium
in fish and aquatic invertebrates» Diss. Abstr. Int. p. 121.
American Conference of Industrial Hygienists. 1977. Threshold
limit values for chemical substances in workroom air adapted
by ACGIH for 1977..
Baird, R.B., et al. 1972.. Determination of trace amounts of
selenium in wastewaters by carbon rod atomization. Anal. Chem.
44: 1887.
Beath, O.A. 1962. The story of selenium in^ Wyoming. University
of Wyoming» Lararaie.
Cardwell, R.D., et al. 1976. Acute toxicity of selenium dioxide
to freshwater fishes. Arch. Environ. Contam. Toxicol. 4: 129.
Craun, G.F., et al. 1977. Preliminary report of an epidemio-
logic investigation of the relationship(s) between tap water
constituents and cardiovascular disease. Proc. Am. Water Works
Assoc. Meet.
Cummins, L.M. and E.T. Kimura. 1971. Safety evaluation of
selenium sulfide antidandruff shampoos. Toxicol. Appl. Pharmacol.
20: 89.
Department of Interior. 1974. Minerals yearbook, 1972. Bureau
of Mines, Washington, D.C.
Diplock, A.T. 1976. Metabolic aspects of selenium action and
toxicity. CRC Crit. Rev. Toxicol. 271.
Fishbein, L. 1977. Toxicology of selenium and tellurium. Adv.
Mod. Toxicol., Vol. 2, .1 ISS Trace Elem., 191.
Food and Drug Administration. 1973. Selenium in animal feed.
Federal Register, Vol. 38, No. 81.
Ganther, H.E. 1966. Enzymic synthesis of dimethyl selenide
from sodium selenite in mouse liver extracts. Biochemistry
5: 1089.
Ganther, H.E. 1970. In Trace element metabolism in animals,
ed. C.F. Mills, Edenburgh:Livingstone, 212.
Hutchison, T.C. and P.M. Stokes. 1975. Heavy metal toxicity
and algal bioassays. Water quality parameters. ASTM: 320.
Kincaid, R.L., et al. 1977. Effect of added dietary selenium
on metabolism and tissue distribution of radioactive and stable
selenium in calves. Jour. Anim. Sci. 44:1: 147.
J_
-------
National Research Council. 1976. Selenium. Comm. Meci. Biol.
Effects Environ. Pollut., Subcomm. Selenium. Natl. Acad. Sci.,
Washington, D.C.
Robertson, D.S.F. 1970. Selenium, a possible teratogen? Lancet
L: 518.
Rosenfeld, I. 1964. Excretion and retention of Se in relation
to modes of administration, toxicity and pregnancy in rats.
Metabolic effects and metabolism of selenium in animals. Part
IV, Bull.. 414.. Agric.. Exp. Sta., University of Wyoming.
Rosenfeld, I. and O.A. Beath. 1964. Selenium; geobotany, bio-
chemistry, toxicology and nutrition. Academic Press, New York.
Schroeder, H.A- 1974. Selenium. Page 101 in The poisons around
us.. Indiana University Press, Bloomington.,.
Schroeder, H.A., et al. 1970. Essential trace metals in man:
selenium. Joar. Chron. Dis. 23: 227.
Schwarz, K. 1961. Development and status of experimental work
of factor 3 selenium. Fed. Proc. 20.: 666.
Smith, M.I. and B.3. Westfall. 1937. Further field studies
on the selenium problem in relation to public, health. U.S. Pub.
Health Rep.. 52: 1375.
Stadtman, T.C. 1974. Selenium biochemistry. Proteins containing
selenium are essential components of certain bacterial and mamma-
lian enzyme systems. Science 133: 915-
Thomson, C.D. and R.D.H. Stewart. 1973. Metabolic studies of
( °Se) selenomethionine and ( Se) selenite in the rat. Br.
Jour. Nutr. 30: 139.
Thomson, C..D. and R.D.H. Stewart. 1974. The metabolism of ( Se)
selenite in young women. Br. Jour. Nutr. 32: 47.
Thomson, C.D-75et al. 1975. Metabolic studies of ( Se) seleno-
cystine and ( Se) selenomethionine in the rat. Br. Jour. Nutr.
34: 501.
Ting, K.P. and. G.W.R.. Walker. 1969.. The distributive effect
of selenoamino acid treatment on crossing-over in Drosophila
melanogaster. Genetics 61: 14iw
U.S. EPA. 1974. Safe drinking water act, puolic law 93-523,
93rd Congress, S. 433.
»•
U.S. EPA. 1975a. Preliminary investigation of effects on the
environment of boron, indium, nickel, selenium, tin, vanadium
and their compounds. Selenium. U.S. Environ. Proc. Agency,
Washington, D.C.
U.S. EPA. l975b. National interim primary drinking water regu-
lations. Fed. Reg. 40:248: 59566.
-------
U.S. EPA. 1978. In-depth studies on health and environment
impacts of selected water pollutants. -U.S. Environ. Prot. Agency.
Contract No. 68-01-4646.
U.S. EPA. 1979. Selenium: Ambient Water Quality Criteria.
Environmental Protection Agency, Washington, D.C.
Vesce, C.A. 1947. Intossicazione spermentale da.selenio. Intos-
sicazione Sperimentale da Selenio, Folia Med. (NAPOLI) 33: 209.
Walker, G.W.R- and A.M. Bradley. 1969. Interacting effects
of sodium monohydrogen arsenate and selenocystine on crossing-
over in Drosophila Melanogaster. Can. Jour. Genet. Cytol. 11: 677.
Walker, G.W.R. and K.P. Ting. 1967. Effects of selenium in
recombination in barley. Can. Jour. Genet. Cytol. 9: 314.
Windho
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No. 154
Silver
Health and Environmental Effects
U.S.. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
. /- * 4 ^
-/a J-'-
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DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SILVER
SUMMARY
While metallic silver in the zero valence state is not
considered to be toxic, most of its salts are toxic to a
large number of organisms. Silver salts can combine with
certain biological-molecules and subsequently alter their
properties. Upon ingestion, many silver salts are absorbed
in the human circulatory system and deposited in various body
tissues, resulting in generalized or sometimes localized gray
pigmentation of the skin and mucous membranes known as argy-
ria. Silver has not been shown to be a carcinogen (except by
the mechanism of solid state tumorigenisis); however, there
is some evidence that silver salts can effect the growth of
tumors.. The acceptable daily intake for silver has been de-
termined to be 1.6 mg per day for a 70 kg man..
Silver is acutely lethal to aquatic species in the ug/1
range. In terms of acute lethality, Daphnia magna appears to
be the most sensitive species, with a 48-hour EC5Q of 1.5
ug/1.. At levels as low as 0,17 ug/1/ silver caused premature
egg hatching and reduced, fry growth in fathead minnows.
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SILVER
I. INTRODUCTION
This .profile is based on the Ambient Water Quality Cri-
teria Document for Silver (U.S. EPA, 1979).
Silver (Ag; atomic weight 107.87) is a white ductile
metal occuring naturally in the pure form and in ores.
Silver can exist in two valence states, Ag"1" and Ag"1"*",
The solubility of common silver salts varies greatly, with
silver nitrate having a solubility of 2,,5-x 109 p.g/1 and
silver iodide having a solubility of 30 ug/1 (Windholz,
1976). Many silver salts are light-sensitive.. Water or
atmospheric oxygen have no effect on metallic silver; how-
ever, ozone, hydrogen sulfide, and sulfur react with it. The
principle uses of. silver are in photographic materials, elec-
troplating, dental alloys, solder and brazing alloys, paints,
jewelry, silverware, coinage, mirror production.
II. EXPOSURE
Exposure to silver is mainly through food and water
intake with only minimal contribution from ambient aerosols.
Concentrations of silver in.surface waters have been shown to
vary from 0-38 ug/1 with a mean of 2.6 ug/1 in samples
containing silver. High silver concentrations are obtained
in high silver mineralized areas or in waters* receiving
effluent from industries that use silver.
The average intake of silver from food has been calcu-»
lated to be 40 ug/day (Tipton, et al. 1966) to 88 ug/day
(Kehoe, et al. 1940) in the U.S. Although silver is detected
in neats and vegetables, the concentrations in fish, shell-
y-
-------
fish, .and Crustacea are greater. Marine animals accumulate
silver in concentrations which are higher than their environ-
ment. This is particularly significatnt in areas such as
sewage-sludge dumping sites, which contain high concentra-
tions of silver in "the sediment. The dead bodies of animals
in reducing environments wall contribute- their silver to sed-
iments,, a major factor in the geochemical cycle of silver
(Boyle, 1968).
Exposure to high levels of silver has also occurred by
inhalation in specific industries (e.g., silver smelting and
photography) and from mechanical uses of silver compounds.
Steel mills do not seem to contribute to ambient air concen-
trations of silver (Harrison, et al. 1971).
III.. P HARM AGO KINETICS
A. Absorption
Silver may enter the body via the respiratory
tract, the gastrointestinal tract, mucous membranes, or bro-
ken skin. The efficiency of absorption by any of these
routes is poor. Colloidal silver given orally to rats showed
two to five percent -absorption by the gastrointestinal tract
(U.S. EPA, 1979). Dogs receiving orally a tracer quantity of
silver nitrate absorbed ten percent. It was shown in hu-
mans who accidently inhaled silver that the biological half-
life of silver was about one day, pcobably due to rapid muco-
ciliary clearance, swallowing, and fecal excretion (Newton .
and Holmes, 1966). Some absocpotion did take place since
there was localization of silver in the liver, but quantifi-
cation was impossible. In human burn patients treated with
_ ;o i *r..
/ (J J>
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silver nitrate dressing, only 0.008 percent of the silver was
absorbed (U.S. EPA, 1979).
B. Distribution
The amount of silver, its chemical form, and the
route by which it is administered affects the tissue content
and distribution of silver within the body (Furchner, et al.
1968). Table 1 summarizes data on the distribution of silver
in rats.
Table 1: Distribution of Silver in the Rat and Day 6
Following Intramuscular Injections of Differ-
ent Doses of Silver (percent of dose per or-
gan) (Scott and Hamilton, 1950).
Percent of Dose
Absorbed
Absorbed
Heart and Lungs
Spleen
Blood
Liver
Kidney •
G.I. tract
Muscle
Bone
Skin
Urine
Feces
Unabsorbed
Carrier- Free
92.1
0.06
0.01
0.50
0.36
0.07
1.12
0.27
0.18
0.24
(1.64
96.56
7.9
Dose
0 .1 ng
63.7
0.13
0.13
0.95
2.24
0.92
4.22
0.56
0.35
0.67
0.88
88.95
36.3
1.0 ma
53.5
0.59
2.69
3.03
33.73
0.63
8.21
2.39
2.20
7.39
1.82
37.33
46.5
Silver administered to other species appears to generally
follow this distribution pattern.
C. Metabolism
Inhaled silver particles that are not removed from the
lungs by the mucociliary reflex and coughing are probably
^r
^^^Q <7 ft
iA JU
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phagocytized and transported via the protein fractions of the
blood plasma to the liver, from which they are eventually ex-
creted in the bile. Formation of silver selinide deposits in
the liver, as well as the formation of metallic silver,
silver sulfide, or silver complexes with sulfur amino acids
may be a method of detoxifying silver. -In the kidney, com-
plexation with metallothionein may be another detoxification
pathway (U.S. EPA, 1979).
D. Excretion
».
Regardless of route and chemical form of silver
administered, fecal excretion always predominates over uri-
nary excretion. Most absorbed silver is excreted into the
intestines by the liver via the bile.. Phalen and Morrow
(1973) exposed beagle dogs to an atmosphere containing silver
aerosols and showed the biological half-life to be 8.4 to
12.9 days..
IV. EFFECTS
A. Carcinogenicity
Implanted foils and disks and injected colloidal
suspensions of metallic silver have been found to produce
tumors or hyperplasia in several studies. These tumors may
be due to the particular physical form of the metal or to its
being an exogenous irritant. There is no evidence that
silver or its salts produce tumors by any'other mechanisms.
In one study, intratumoral injections of colloidal silver ap-
peared to stimulate cancer growth (Guyer and Mohs, 1933), and
in another study silver nitrate 'appeared to act as a promoter
with DMBA (7,12-dimethylbenz(a)anthracene) initiated mice
-------
(Saffrotti and Shubik, 1963). On the other hand, Taylor and
Carraichael (1953) showed a tumor growth inhibitor effect of •
silver chloride. The evidence for any carcinogenic effect of
silver is'very tenuous (U.S. EPA, 1979).
B. Mutagenicity
Silver nitrate (Demerec, et al. 1951), silver chlo-
ride (Nishioka, 1975), and silver sulfadiazine (Fox, et al.
1969) have been examined for rautagenicity in microorganisms
and shown to be nonmutagenic in these test systems.
C. • Teratogenicity
Few associations between silver and birth defects
have appeared in the literature and one is apparently erro-
neous. Kukizaki (1975) found only weak cytotoxic effects
when silver-tin alloy powder was incubated in seawater with
fertilized eggs or early embryos of the sea urchin Hemicen-
trotus pulcherrinus. Silver salts were tested for toxicity
to 4- and 8-day-old chick embryos but did not produce abnor-
malities in development (Ridgway and Karnofsky, 1952).
D. Other Reproductive Effects
Pertinent information could not be located in the
available literature concerning any other reproductive ef-
fects due to exposure to silver.
E. Chronic Toxicity
In rats, chronic exposure to 0.4 mg/1 of silver in
drinking water causes hemorrhages in the kidney. Larger
doses cause changes in conditioned-reflex activity, lowering
of immunological resistance (0.5 mg/1), and growth depression
(20 mg/1). In humans, the most common noticeable effect of
-------
chronic exposure to silver or silver compounds is generalized
argyria (generalized gray pigmentation).
F. Other Relevant Information
'Silver exhibits antagonism to selenium, vitamin E,
and copper, inducing deficiency symptoms in animals fed ade-
quate diets: or aggravating deficiency symptoms when the ani-
mal's diet lacks one- or more of the nutrients. The effects
have been described in dogs, sheep, pigs, rats, chicks, tur-
key, poults, and ducklings (U.S. EPA, 1979).
V. AOUATIC TOXICITY
A. Acute Toxicity
Davies, et al. (1978) conducted 96-hour tests with
rainbow trout in both hard (350 mg/1 as CaC03) and soft
water (26 mg/1 as CaCC>3) water. The LC50 values were
6.5 and 13 uq/1 for soft and hard water, respectively. There
are too few data" to assess the relative importance of hard-
ness and experimental variability on these nonreplicated re-
sults.
The 48-hour static EC5Q for Daphnia magna in
soft water (40 mg/1 as CaC03) is 1.3 ug/1 (U.S. EPA, 1978),
indicating that this species is the most sensitive freshwater
invertebrate species tested.
Acute toxicity data are available only for four
saltwater invertebrate species and range from 5.8 to 262 ug/1,
(Calabrese, et al. 1973; Calabrese and Nelson, 1974; nelson,
»
et al. 1976; Sosnowski and Gentile in; U.S. EPA, 1979). The
American oyster is the most sensitive saltwater species test-
ed, and the mysid shrimp is the most resistant.
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B.. Acute Toxicity
Davies, et al. (1978) conducted an 18-month mortal-
ity test with rainbow trout and found the no-effect concen-
tration of silver to be 0.09 - 0..17 ug/1 (17.2% mortality at
0.17 ug/1 and no mortality at 0.09 ug/1). There was also
premature hatching of eggs and reduced growth of fry at 0.17
ug/1.
The chronic toxicity of silver to mysid shrimp has
been determined, based on a flow-through, life-cycle exposure
«.
(Sosnowski and Gentile _in: U.S. EPA, 1979). No spawning
occurred at 103 ug/1- The time of spawning was delayed to
seven days at 33.3 ug/1. Brood size was statistically
smaller at 33.3 ug/1 when compared to the controls, although
larval survival was not affected. The highest concentration
of silver tested that had no effect on growth, reproduction,
or survival was 10.2 ug/1/ which is approximately 0.04 times
the 96-hour LCgg determined for adult shrimp.
C. Plant Effects
Hutchinson and Stokes (1975) observed growth retar-
dation in the freshwater alga, Chlorella vulgaris, at silver
concentrations, between 10 and 60 ug/l» A concentration of
2,000 ug/1 was determined to be toxic to six additional algal
species (Gratteau, 1970).
The only marine algal species tested, Skeltonema
costatum, showed growth inhibition after a 96-hour exposure
f
to 130 ug/1 (U.S. EPA, 1978).
D. Residues
Bioconcentration factors of 17 to 368 were deter-
mined for three species of insects exposed to silver
-------
(Nehring, 1973). Bluegills showed no bioconcentration of
silver at a water concentration of 0.03 ug/1 after a. 28-day
test (U.Sk EPA, 1978). Pertinent information on residues in
saltwater species could not be located in the available
Literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Humans
Both the U.S. standard for silver in drinking water
and in workplace air have been based on a'presumed 1 g mini-
mum dose of silver that has caused agryia.
The existing standards for silver are:
Existing Standards Regarding Silver
Medium Silver Concentration Authority
Drinking water 50 ug/1 U.S.. EPA (1976) Ra-
tional Academy of
, Sciences (1977)
Drinking water 0.5 ug/1 State of Illinois
(cited in National
Academy of Sci-
ences ,1977)
Drinking water 10 ug/1 State of California
(cited in National
Academy of Sciences,
1977)
Workplace air, thresh— 0.01 mg/m^ Occupational Safety
old limit value and Health Adminis-
time-weiahted tration (1974)
(39 FR 23541)
Short-tern exposure 0.03 mg/i?.3 .American Conference
limit (_>. 15 minutes) of Governmental In-
4 tines per day dustrial Hygiensts
(1977)
The acceptable daily intake (ADI) for silver is 1.6 mg/day. The
U.S.. EPA draft water criterion for silver is 10 ug/1 for the
protection of human health. This criterion is presently
-------
undergoing further evaluation and review before final recom-
mendation.
B. Aquatic
For silver the draft criterion to protect fresh-
water aquatic life-is 0.009 ug/1 as a 24-hour average; the
concentration should not exceed 1.9 ug/1 at any time (U.S.
EPA, 1979)..
To protect saltwater aquatic life, the draft cri-
terion is 0.26 ug/1 as a 24-hour average; the concentration
«.
should not exceed 0.58 ug/1 at any time (U.S. EPA, 1979).
-------
SILVER
REFERENCES
American Conference of Governmental Industrial Hygienists, 1977
TLV Airborne Contaminants Committee. 1977. TLVs threshold
limit values. for chemical substances and physical agents in the
workroom environment with intended changes for 1977. Am. Conf.
Govt. Ind.. Hyg., Cincinnati, Ohio.
Boyle, R.W. 1968. Geochemistry of silver and its deposits with
notes on geochemical prospecting for the element. Geol. Surv..
Can., Bull. No. 160. p. 1.
Calabrese, A., and D.A. Nelson. 1974. Inhibition of embryonic
development of the hard clam, Mercenaria mercenaria by heavy
metals* Bull. Environ. Con tarn. Toxicol. Lit- 92.
Calabrese, A., et al. 1973. The toxicity of heavy metals to
the embryos, of the American oyster (Crassostrea virginica).
Mar. Biol. 18t 162.
Davies. P.H., et al. 1978. Toxicity of silver to rainbow trout
(Salmo gairdneri). Water Res. 12: 113.
Demerec, M.., et al. 1951. A survey of chemicals for mutagenic
action on S. coli. Am. Nat. 85: 119»
Fox, C.L., et al. 1969. Control of Pseudomonas infection in
burns by silver sulfadiazine. Surg.. Gynecol.7 Obstet. 128: 1021.
Furchner, J.E., et al. 1968. Comparative metabolism of radio-
nuclides in mammals. IV. Retention of silver-llOm in the mouse,
rat, monkey and dog. Health Phys. 15: 505.
Gratteau, J.C. 1970. Potential algicides for the control of
algae. Ref. No.. 1970.. Water Sewage Works p. R-24.
Guyer, M.F. and F.E. Mohs. 1933. Rat carcinoma and injected
colloidal platinum. Arch. Pathol. 15: 796.
Harrison, P.R., et al. 1971. Areawide trace metal concentra-
tions measured by multielement neutron activation analysis:
A one day study in northwest Indiana. Jour. Air Pollut. Contro.
Assoc. 21: 563~
Hutchinson, T.C., and P.M. Stokes. 1975. Heavy metal toxicity
and algal bioassays. Water Quality Parameters. ASTM SPT 573: 320.
Kehoe, R.A., et al. 1940. A spectrochemical study of the normal
ranges of concentration of certain trace metals in biological
materials. Jour. Nutr. 19: 579.
AT/-/3
-------
Kukizaki, S. 1975. Studies on the effects of dental amalgam
upon the fertilization and early development of sea urchin eggs
(Hemicentrotus pulcherrimus). Jour. Jap. Soc. Dent. Appar. Mater.
16: 123.
National Academy of Sciences. 1977. Drinking water and health.
U.S. Environ. Prot.. Agency, Washington, D.C., PB-269 519. Natl.
Tech. Inf. Serv., Springfield, Va.
Nehring, R.V. 1973. Heavy metal toxicity in two species of
aquatic insects. Master's Thesis, Colorado- State Univ., Fort
Collins, Colorado. 82 p.
Nelson, D.A., et al. 1976. Biological effects of heavy metals
on juvenile bay scallops, Argopecten irradians, in short-term
exposures. Bull. Environ. Contain.. Toxicol. 16: 275.
Newton, D. and A. Holmes. 1966.. A case of accidental inhalation
of zinc-65 and silver-HOm. Radiat. Res. 29: 403.
Nishioka, H. 1975. Mutagenic activities of metal compounds
in bacteria. Mutat. REs. 31: 135.
Phalen, R.F. and P.E. Morrow. 1973. Experimental inhalation
of metallic silver. Health Phys. 24: 509.
Ridgway, L.D., and D.A. Karnofsky. 1952. The effects of metals
on the chick embryo: Toxicity and production of abnormalities
in development. Ann. N.Y. Acad. Sci. 55: 203.
Saffrotti, U. and P. Shubik. 1963. Studies on promoting action
in skin carcinogenesis. Natl. Cancer Inst. Monogr. 10: 489.
Scott, K.G. and J.G. Hamilton. 1950. The metabolism of silver
in the rat with radiosilver used as an indicator. Univ. Calif.
(Berkeley) Publ. Pharmacol. 2: 241.
Sosnowski, S.L. and J.H. Gentile. Chronic toxicity of copper
and silver to the raysid shrimp Mysidopsis bahia. EPA-Environ-
mental Research Lab., Narragansett, R.I.Manuscript.
Taylor, A. and N. Carmichael. 1953. The effect of metallic
chlorides on the growth of tumor and non-tumor tissue. Univ.
Texas Publ. No.. 5314, Biochem. Inst. Stud. 5, Cancer Stud. 2-
p. 36.
Tipton, I.H., et al. 1966. Trace elements in diets and excreta.
Health Phys. 12: 1683.
»
U.S. EPA. 1976. National interim primary drinking water regula-
tions. EPA-570/9-76-003. U.S. Environ. Prot. Agency, Off. of
Water Supply.
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of selected water pollutants. U.S. EPA Contract No.
68-01-4646. U.S. Environ. Prot. Agency, Washington, D.C.
-------
U.S. EPA. L979. Silver: Ambient Water Quality Criteria. Envi-
ronmental Protection Agency, Washington, D.C.
Windholz, M. (ed.) 1976. The Merck Index. 9th ed.' Merck
and Co., Inc., Rahway, N.J.
IS'H- If
-------
No. 155
TCDD
Health and Environmental Effects
a.S- ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This 'report, represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal fc The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical.. This document- has undergone scrutiny to
ensure, its. technical accuracy.:
Iff-*-
-------
2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD)
SUMMARY
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been
found to induce heptocellular carcinomas and tumors in two
rat feeding studies. TCDD has also produced fetotoxic and
teratogenic effects in laboratory animals. The positive
rautagenicity of TCDD has been, demonstrated in three bacte-
rial bioassay systems. TCDD is also a potent inducer of
hepatic and renal microsomal drug metabolizing enzymes.
v
No standard tests for acute or chronic toxicity in
aquatic life have been conducted_with TCDD. Other studies,
however, have shown adverse effects over a period of 96
hours to concentrations as low as 0.000056 jug/1. The weighted
average bioconcentration factor for TCDD for edible portion
of all aquatic organisms consumed by Americans has been
calculated to be 5,800.
-------
2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD)
I. INTRODUCTION
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a contami-
nant unintentionally formed during the production of 2,4,5-
trichlorophenol (TCP) from 1,2,4,5-tetrachlorobenzene.
TCDD is also found as a contaminant of 2,-4,5-trichlorophenoxy-
acetic acid. (2,4,5-T) (U.S. EPA, 1979).
Characteristically, TCDD (C^^C^f^) is a white crystal-
line solid with the. following physical properties: melting
point, 302-305°C; solubility in water, 0.2 to 0.6 ug/1;
lipiphilic, and non-volatile (U.S.. EPA, 1979) ..
TCDD is considered a relatively stable compound which
can: be degraded at temperatures in excess of. 500°C, or by
irradiation 'with UV light or sunlight under certain condi-
tions (U.S. EPA, 1979). It has. been shown to disappear
slowly from soil with residues persisting for ten years
after application. TCDD bio-accumulates in aquatic organisms.
II. EXPOSURE
A. Water
The amount of human exposure that can be directly
attributed to drinking water alone is difficult to determine
(U.S. EPA,. 1979). It has been stated that no TCDD has ever
been detected in drinking water, with limits of detection
in the parts per trillion range (National Research Council,
1977). Underground water supplies would probably not be
contaminated with TCDD under most conditions since vertical
movement of TCDD has not been demonstrated in soil (Kearney,
et al., 1972).
-------
B. Food
The occurence of TCDD in food could result from
(1) accidental spraying of plant crops; (2) contaminated
forage or (3) food chain magnification (U.S. EPA, 1979).
TCDO is neither absorbed by oat and soybean seeds
after spraying, nor taken up from the soil into the mature
plants (Isensee and Jones, 1971; Matsumura and Benezet,
1973). Aqueous solutions of pure TCDO exposed to either
artificial light or sun light, do not decompose, whereas
TCDD photodecomposes rapidly when applied to leaf surfaces
as a contaminant of the herbicides Agent Orange and Esteron
(Crosby, at al., 1971; Crosby and Wong, 1977).
TCDD has been detected in the adipose tissue of
cattle feeding on contaminated forage (Kocher, et al., 1978)
Studies conducted for the U.S. EPA also found TCDD in fat
of cattle previously exposed to 2,4,5-T (U.S. EPA, 1979).
No TCDD, however, was detected in liver samples.
The U.S. EPA (1979) has estimated the weighted
average bioconcentration factor of TCDD at 5,800. This
estimate is based on measured steady state bioconcentration
studies in channel catfish containing 3.2 percent lipids
(Isensee and Jones, 1975).
C. Inhalation
Pertinent information could not be located in
the available literature.
-------
III. PHARMACOKINETICS
A. Absorption
• Approximately 83-86 percent of the TCDD administered
in a single oral'dose, following activation with multiple
oral doses, is absorbed from the intestinal tract (Rose,
et al., 1976).
B. Distribution
The excretion of a single oral dose of TCDD in
rats occurred via the feces (53 percent), urine (13 percent),
and expired air (two percent) (Piper, et al., 1973). An-
alysis after three days showed the highest percent of the
administered dose per gram in the liver (3-18 percent) and
adipose (2.60 percent).
Rose, et al. (1976) found that 22 days, after a single
L4
oral dose of C labeled TCDD, 1.26 and 1.25 percent, of
14
the C was retained per gram of liver and adipose tissue,
respectively.. After repeated oral doses, however, the liver
was found to have five times as much radioactivity as adi-
pose tissue. Single oral doses of TCDD were excreted through
the feces, whereas significant amounts of radioactivity
were found both in the urine and the feces after repeated
oral doses -
C.. Metabolism
There is no complete agreement as to whether or
not TCDD is actually metabolized (U.S. EPA, 1979). Rose, •
et al. (1976) found unchanged 14C-labeled TCDD in the liver
after oral administration, but noted that most of the radio-
-------
activity in the feces came from compounds other than TCDD.
The slow elimination of TCDD from rats and monkeys suggests
that it is not readily metabolized (Van Miller, et al.,
1976).
0. Excretion
See also section B., Distribution.
Differences in TCDD elimination have been observed
between the sexes and between species. Rose, et al. (1976)
found male rats excreted 3.1 percent of the cumulative dose
in the urine while females excreted 12.5 percent in the
urine.
The half-life of. radioactive TCDD following a
single oral dose to rats was 31— 6 days, while that follow-
ing repeated oral doses was 23.7 days (Rose, et al., 1976).
IV. EFFECTS
A. Carcinogenicity
Three studies have reported data concerning the
carcinogenicity of TCDD. Van Miller, et al. (1977) fed rats
dietary levels of TCDD ranging from 0.001 to 1000 jug/kg
of diet for up to 78 weeks. In 50 animals receiving diets
ranging from 0.005 jug/kg to 5 jug/kg 13 benign and 15 malig-
nant tumors were observed~ No tumors were found in controls
or those fed a. dietary level of 0.0001 pg/kg. Animals fed
diets of 50 jug/kg or more died between the second and fourth
week of treatment.
Toth, et al. (1977) administered TCDD to mice
at levels of 0.007, 0.7, and 7 ,ug/kg per week for 12 months.
No tumors were noted at any dose.
-------
Kociba, et al. (in. press) administered 0.1, 0.01,
and 0.001 jug/kg ofTCDD per kg of body weight to male and
female rats. Males at the- 0.1 ;ug/kg dose exhibited a statis-
tically significant increased incidence of. squamous cell
carcinomas of the hard palate (4 out of 50) and of the tongue
(3 out of 50). Mo carcinomas were observed in the male
controls (0 .out of 35).. Females at the 0.1 jug/kg dose had
a statistically significant increase in incidence of car-
cinomas at three sites: -squamous cell carcinoma of the
hard palate (4 out of 49), squamous cell carcinoma of the
lung (7 out of 40), and hepatocellular carcinoma of the
liver (11 out of 49). Only one carcinoma of these three
sites occurred in the female controls (1 out of 86), and
that was hepatocellular carcinoma of the liver» Five sites,
pancreas., adrenal gland, pituitary gland, uterus,, and mam-
mary gland, had. a statistically significant, decrease in
their tumor incidence at certain dose levels (Kociba, et
al.., in press) .
B. Mutagenicity
Multiple, oral doses of TCDD over 5 weeks resulted
in vacuolization of liver cell nuclei, increased mitotic
rate, and a polyploid chromosome number (Vos, et al., 1974).
TCDD administered by intubation intraperitonealy,
or orally did not cause chromosomal aberrations in bone
marrow cells (Green and Moreland 1975). However, repeated
•
dosing of TCDD over 13 weeks produced an increase in chro-
mosomal breaks in rat bone marrow (Green, et al. 1977).
I
-------
Some studies have been conducted showing that
TCDD might be a dominant lethal inducing agent, while others
have found no evidence of this effect (U.S. EPA, 1979).
, Bacterial assays with E. coli, and S. typhimurium
have found TCDD to be mutagenic via intercalation with DNA
(Hussain, et al-, 1972). Some strains of Salmonella, how-
ever, have yielded negative mutagenic results when tested
(Seiler, 1973),
Tenchini, et al. (1977) found no significant differ-
ences in chromosome .number or chromosomal abnormalities
in maternal or abortive fetal samples from pregnant women
exposed to TCDD during the explosion of a 2,4,5-T factory
in Italy.
C. - Teratogenicity
Teratogenic effects from TCDD have been reported
in several studies. Both teratogenic and fetotoxic effects
were observed in mice and cats administered 2,4,5-T contain-
ing 30 ppra TCDD (Courtney, et al., 1970). Smith, et al.
(1976) found the incidence of cleft palate to be signifi-
cantly higher in mice receiving 1 /ag/kg and 3 /ag/kg per
day of TCDD for 10 days during gestation. At 3 jug/kg, the
incidence of bilateral dilated renal pelvis among fetuses
was also significantly greater. TCDD levels of 0.12S to
2.0 pg/kg/day given orally to cats, on days 6 to 15 of gesta-
tion produced dose-related increases in fetal mortality,
fetal intestinal hemorrhages, and early and late cesorptions
(Sparschu, et al., 1971).
AS1*--?
-------
D» Other Reproductive Effects
Pertinent information could not be located in
the available literature.
E. Chronic Toxicity
Chronic studies involving administration of TCDD
to rats> guinea, pigs and mice, have reported toxic effects.
to the liver and thymus (U.S. EPA, 1979). Female rhesus.
monkeys fed a diet containing 500 ppt TCDD for up to nine
months, exhibited symptoms of facial hair and eyelash loss,
edema, accentuated hair follicles, and dry scaly skin (Allen,
et al., 1977).
A large number of studies have reported the inci-
dence of chloracne among workers exposed to TCDD during
the production of 2,4,5-trichlorophenol (TCP,. 2,4-D or 2,4,5-
T) (U.S. EPA, 1979). Other chemical manifestations among
exposed workers include muscular weakness, loss of. appetite
'and weight, sleep disturbances, orthostatic hypotension,
abdominal pain, liver impairment, hyperpigmentation of the
skin,, hirsutism, and. psychopathological changes (U.S. EPA,
1979) ..
F. Other Relevant Information
No synergistic effect was detected when 2,4,5-
T and TCDD were administered to mice alone, or in combina-
tion with each other (U.S. EPA, 1979). Both compounds are
capable of producing cleft palates and kidney anomalies
in fetuses.
The International Agency for Research on Cancer
(1977) has reviewed the literature and concludes that TCDD
is a potent inducer of hepatic and renal microsomal drug
-------
metabolizing enzymes. TCDD intoxication results in a marked
increase in the cellular smooth endoplasmic reticulum con-
tent of hepatic and renal cells. This compound is also
capable of simultaneously activating and suppressing certain
microsome associated foreign compound and steroid-hormone-
metabolizing enzyme systems. It has' been found to increase
the activity of renal and hepatic glutathione-S-transferase,
*
and hepatic
-------
D. Residues
TCDD has a. high affinity for the tissues of aquatic
species. Isensee and Jones (1975) conducted a model fresh—
water ecosystem study'on TCDD and observed bioconcentration
factors between 3,600 and 26,000 over a 3 to 31 day period.
The highest bioconcentration factors were reported for. Dyphnia
maqna (26,000), the mosquito fish, Gambusia affinis (25,000),
and the snail,- Physa sp. (20,000).
VI. EXISTING GUIDELINES AND STANDARDS
A.. Human .
The calculated acceptable daily intake (ADI) for
-4
TCDD is 10 jug/kg/day. This ADI does not consider TCDD
to be a known or suspected carcinogen (NRC, 1977) .
The draft, ambient, water quality criterion has
been set by the U,S. EPA (1979) at levels intended to reduce
the human carcinogenic risk to rhe- range of 10"3, 10~ ,
and 10~ . The. corresponding draft criteria are 4.55 x 10~
7 jug/1, 4.55 x 10~8 ;ug/l, and 4.55 x. 10~9 pg/1, respectively.
B. Aquatic
No drafted criterion is available to protect fresh
and saltwater species from TCDD toxicity.
-------
TCDD
REFERENCES i
Allan, J.R., et al. 1977.. Morphological changes in monkeys
consuming a d-iet containing low levels of TGDD. Pood Cosrae-t.
Toxicol. " 15: 401.
Courtney, K. Diane,- -et al. 1970, Teratogenic evaluation of
2,4,5-T.. Science' 168: 864-.
Crosby, D.G., .and A.S.. Wong. 1977. Environmental degrada-
tion of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Science 195:
1337.
Crosby, D.G., et al. 1971. Photodecomposition of chlori-
nated dibenzo-p-dioxin. Science 173: 748-.
Green, S., and F.S. Morelandi 1975. Cytogenetic evaluation
of several dioxins in the rat- .Toxicol. Appl. Pharmacol.
33: 161. •
Green, S., et al. 1977.- Cytogenetic effect of
2,3,7,8tetrachlorodibenzo-p-diox_in on rat bone marrow cells.
FDA By-lines 7r 292.- Food. Drug Admin., Washington, D.C.
Hussain, S., et al. 1972. Mutagenic effects of TCDD on
bacterial systems. Ambico. 1:32.
International Agency for Research on Cancer, Chlorinated.
1977. Dibenzodioxins. IARC Monographs on The Evaluation of
Carcinogenic Chemicals to Man. Vol. 15, Lyon, France.
Isensee, A.R., and G.E. Jones. 1971. Absorption and trans-
location of coot and foliage applied 2,4-dichlorophenol, 2,7—
dichlorodibenzo-p-dioxin and TCDD. Jour. Agri. Food Chem.
19: 1210.
Isensee, A.R., and G.E. Jones. 1975. Distribution of
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in aquatic model
ecosystems. Environ. Sci. Technol. 9: 668.
Kearney, P.C., et al. 1972. Persistence and metabolism of
chlorodioxins in soils. Environ. Sci. Tech. 5: 1017.
Kocher, et al. 1978. A search for the presence of
2,3,7,8tetrachlorodibenzo-p-dioxin in beef fat. Bull.
Environ. Cont. Toxicol. 19: 229.
Kociba, et al. Toxic, and App. Pharm. In press.
Matsumura, F., and H.J. Senezet. 1973. Studies on the bio-
accumulation and microbial degradation of TCDD. Environ.
Health Perspect. 5: 253.
-------
Miller,. R.A., et al. 1973.. Toxicity of 2,3,7,8-tetrachloro-
dibenzo-p-diox in (TCDD) in aquatic organisms. Environ..
Health Perspect. 5: 177..
National'Research Council, Safe Drinking Water Committee.
1977. Drinking water and health: Part II. Natl. Acad. Sci.,
Washington, D.C.
Piper, W.N., et al. 1973. Excretion and tissue distribution
of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat. Environ.
Health Perspect.. 5: 241.
Rose., J.Q., et al.. 1976.. The. fate of 2,3,7,8-TCDD following
single and repeated oral doses to the rat. Toxicol. Appl.
Pharmacol. 36: 209.
Seiler, J.P. 1973. A survey on -the mutagenicity of various
pesticides. Experientia 29: 622.
Smith, F.A., et al. 1976. Teratogenicity of TCDD in DF-1
mice. Toxicol. Appl. Pharmacol^ 38: 519
Sparschu, G.L.., et al- 1971. Study of the teratogenicity of
TCDD in the rat.. Food Cosmet. Tech* 9: .405.
Tenchini, M..L., et al. 19.77.. Approaches to examination of
genetic damage after a major hazard in the chemical, industry:
Preliminary cytohenic findings on TCDD exposed subjects after
the Seveso accident. Presented at the Expert Conference on
Genetic Damage Caused by Environmental Factors, Oslor Norway,
May 11-13, 1977.
Toth, K., et al. 1977. Carcinogenic bioassay of the herbi-
cide 2,4,5-TCPE with different TCDD content in Swiss mice.
In: International Conference on Ecological Perspectives on
Carcinogens and Cancer Control, Cremona, 1976, Basel, Karger,
A.G..
U.S. EPA. 1979. 2,3,7,8-Tetrachlorodibenzo-p-dioxinr Am-
bient Water Quality Criteria. (Draft).
Van Miller,. J.P. , and J.R.. Allen. 1977. Chronic toxicity of
2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Fed. Proc. 35:
396.
Van Miller, J.P., et al.. 1976. Tissue distribution and ex-
cretion of tritiated tetrachlorodibenzo-p-dioxin in nonhuman
primates and rats. Food Cosmet. Toxicol. 14: 31.
vos, J.G., et al. 1974. Toxicity of 2,3,7,8-tetrachlorodi-
benzo-p-dioxin in C-57BL-6 mice. Toxicol. Appl. Pharmacol.
29: 229.
-------
No, 156
1,1,1,2-Tetrachloroethane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20A60
APRIL 30, 1980
-------
DISCLAIMER
This report, represents a survey of the- potential health
and environmental hazards from exposure to the subject chemi-
cal* The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short- profile-
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SUMMARY
1,1,1,2-Tetrachloroethane is potentially formed during chlqrination of
drinking water and has. been identified at a concentration of 0.11 /jg/1.
Although inhalation is the major route of exposure to chlorinated ethanes,
specific information on 1,1,1,2-tetrachloroethane inhalation is not avail-
able.
Literature reporting adverse occupational exposures to this chloro-
ethane cannot be found. Animal experiments measuring the acute and subacute
effects indicate, however, that chronic exposure may produce liver damage.
1,1,1,2-Tetrachloroethane is currently being tested by the National Cancer
Institute for possible carcinogenicity. The compound not mutagenic
according to one report. Data could not be located in the available
literature showing it to be teratogenic. • . . .
Pertinent information could not be found in the available literature
regarding the adverse effects of this compound on aquatic animals-or plants.
-------
1,1,1,2-TETRACHLOROETHANE
I. INTRODUCTION
This profile is based primarily on the Ambient Water Quality Criteria
Document for Chlorinated Ethanes (U.S. EPA, 1979a).
The chloroethanes- are hydrocarbons in which one or more of the hydrogen
atoms of ethane are replaced by chlorine atoms. In general, water solu-
bility and vapor pressure decrease with increasing chlorination, while dens-
ity and melting point increase. 1,1,1,2-Tetrachloroethane (molecular weight
167.9) is a liquid at room temperature with a boiling point of 129°C,. a
melting point of -68°c, a specific gravity of 1.553, and a solubility in
water of 2.85 mg/1 (U.S. EPA, 1979a).
1,1,1,2-Tetrachloroethane is used as a solvent and in the manufacture
of a number of widely used products, as are the other chloroethanes (U.S.
EPA, 1975). In general, these compounds form azeotropes with water (Kirk
and Othmer, 1963) and are very soluble in organic solvents (Lange, 1956).
Pearson and McConnell (1975) were unable to demonstrate microbial degrada-
tion of these compounds,, but did report chemical degradation. For a more
general, treatment of the chlorinated ethanes as a class, the reader is
referred to the EPA/ECAO Hazard. Profile on Chlorinated Ethanes (U.S.. EPA,
1979b)..
II. EXPOSURE
1,1,1,2-Tetrachloroethane is potentially formed during chlorination of
drinking water and has- been identified at a concentration of 0.11 jug/1 (U.S.
EPA, 1974). Information on the levels of 1,1,1,2-tetrachloroethane in food
are not available although other chloroethanes have been detected (U.S. EPA,
1979a). Inhalation is the major route of exposure to chlorinated ethanes.
However, specific information, on 1,1,1,2-tetrachloroethane exposure is not
-------
available (U.S. EPA, 1979a). As with most solvents, chloroethanes can be
absorbed through the skin. This is not, however, a major route of exposure
(U.S. EPA, 1979a).
The U.S. EPA (1979a) has estimated a weighted average bioconcentration
factor of 18 for .1,1,1,2-tetrachloroethane for the edible portions of fish
and shellfish consumed by Americans. This value was based on an estimated
steady-state bioconcentration factor of 62, which was determined from an
octanol/water partition coefficient of 457.
III. PHARMACOKINETICS
A. Absorption
Specific information on the absorption of 1,1,1,2-tetrachloro-
ethane is not available. In general, the chloroethanes are absorbed rapidly
following ingestion or inhalation (U.S. EPA, 1979a).
8. Distribution
Inhalation or ingestion of 1,1,1,2-tetrachloroethane results in
the presence of high levels of solvent in the fetuses of the exposed animals
(Truhaut, et al. 1974). Other studies indicate a widespread distribution of
chloroethanes throughout the body after administration (U.S. EPA, 1979a).
C. Metabolism
After oral administration to rats, guinea pigs, and rabbits,
1,1,1,2-tetrachloroethane underwent hydrolytic dehalogenation resulting in
formation of trichloroethanol, which was eliminated primarily in the urine
in the form of a conjugated glucuronic derivative, urochloralic acid. Oxi-
dation to trichloroacetic acid was considerable only in rats (Nguyen, et al.
1971; Truhaut and Nguyen, 1973). In the latter study monochloroacetic acid
and mercaptan derivatives were not found in the urine. The only halogenated
-------
compound found in the expired air was untransfarmed 1,1,1,2-tetrachlara-
ethane. Trichloroethanol. and trichloroacetic acid have also been identified
in the urine 'of rats following interperitoneal (i.p.) injection or vapor
inhalation of 1,1,1,2-tetrachloroethane (Ikeda and. Ohtsuji, 1972), and have
been identified in the urine of mice following i.p.. injection of the parent
compound (Yllner, 1571).
In general, the metabolism of chloroethanes involves both enzy-
matic dechlorination and hydroxylation and .non-enzymatic oxidation (U.S.
EPA, 1979a).. Oxidation reactions may produce unsaturated metabolites.which
are then transformed to the alcohol and ester (Yllner, 1971).
0. Excretion
Murine studies show that, after i.p. injection of 1,1,1,2-tetra-
chloroethane, approximately 78 percent of the dose is excreted in 72 hours;
from 21 to 62 percent of this dose is excreted in the breath and from 18 to
56 percent as metabolites in the urine (Yllner, 1971). Other studies also
indicate that 1,1,1,2-tetrachloroethane is excreted in the urine as
metabolites and in the expired breath as the parent compound (see above).
IV. EFFECTS
A. Carcinogenicity
1,1,1,2-Tetrachloroethane is currently being tested by NCI for
possible carcinogenicity; results are not available (NTCTP, I960).- Other
information relative to the potential carcinogenicity of
1,1,1,2-tetrachloroethane was not located in the available literature.
B. Mutagenicity
Simmon, et al. (1977) tested 71 chemicals identified in the W.S.
drinking water for mutagenesis with an Ames Salmonella/microsome assay.
1,1,1,2-Tetrachloroethane was found not to be mutagenic in this study.
-------
C. Teratogenicity and Other Reproductive Effects
The isomer of 1,1,1,2-tetrachloroethane, syn-tetrachloroethane, is
a weak teratogeh in two strains of mice (Schmidt and Reiner, 1976). Both
tetrachloroethanes are embryotoxic (Schmidt and Reiner, 1976; Truhaut, et
al., 1974). Other pertinent data have not been found.
0. Chronic Toxicity
Adverse occupational exposure to 1,1,1,2-tetrachloroethane has not
been reported by NIOSH. (U.S. EPA, 1979a). Animal experiments measuring
acute, and subacute effects indicate that chronic "inhalation exposure may
produce liver damage (see below).
E. Acute and Subacute Toxicities
At 24 hours after, the oral administration of Q',5 g 1,1,1,2-tetra-
chloroethane/kg to rabbits, the blood cholesterol and total lipid levels
were increased and the glutamic-pyruvic transaminase, glutamic-oxalacetic
transaminase, creatine phosphokinase, lactate dehydrogenase, and a-hydroxy-
butyrate dehydrogenase activities were enhanced. Except for creatine phos-
phokinase, these enzyme levels remain elevated at 72 hours after poisoning
(Truhaut, et al. 1973). Subsequent studies by this research group found
that in rabbits, 1,1,1,2-tetrachloroethane was only slightly irritating to
the skin and ocular mucous membrane, and its cutaneous LD was 30 g/kg.
Its acute toxicity by inhalation, for an exposure of 4 hours, was similar in
rats and rabbits, with the LC5Q being 2500 mg/m3. The oral LD5Q
values in rats and mice were 800 and 1500 mg/kg, respectively. Histological
examination revealed hepatotoxic activity, including formation of micro-
vacuolizations and centrolobular necrosis. 1,1,1,2-Tetrachloroethane .was
from two to three times less toxic than 1,1,2,2-tetrachloroethane (Truhaut,
et al. 1974).
-------
Recent studies exploring subacute effects indicate that in female
Wistar rats, 1,1,1,2-tetrachloroethane (0.30 g/kg, 5 days/week, for 2 weeks,.
orally) induced hepatic steatosis by accumulation of txiglycerides, accom-
panied by a decrease in liver lactate dehydrogenase, malate dehydrogenase,
and glutamic pyruvic transaminase activities. The tetrachloroethane caused
no changes in the liver of male rats (Truhaut, et al. 1975). However,
another team of investigators found that 1,1,1,2-tetrachloroethane (from 100
to 800 pmoles/kg/day for 7 days, i.p.) to male rats increased liver
succinate dehydrogenase,. acid phosphatase and glucose 6-phosphatase
activities and decreased liver DMA content. In addition, the white cell
count was increased and the red cell count and. blood cholesterol content
were decreased (Chieruttini, et al. 1976).
V. AQUATIC TOXICITY
Pertinent data could not be located in the available literature re-
garding either the acute and chronic toxicity to aquatic animals, or the
aquatic residues of 1,1,1,2-tetrachloroethane.
VI. EXISTING GUIDELINES AND STANDARDS
Guidelines for occupational exposure to 1,1,1,2-tetrachloroethane do
not exist (International Labor Office, No. 77, 1977; NIOSH, 1978); however,
1,1,2,2-tetrachloroethane exposure is limited in the workplace to 5 ppm (35
mg/cu m) as an 8-hour time-weighted average (TWA) concentration.
-------
1,1,1,2-TETRACHLOROETHANE
REFERENCES
Chieruttini, M.E., et al. 1976. The toxicology of the tetrachloroethanes.
Br.. Jour. Pharmacol. 57: 421.
Ikeda, M. and H. Ohtsuji. 1972. Comparative study of the excretion of
Fujiwara reaction-positive substances in urine of humans and rodents given
trichloro- or tetrachloro-derivatives of • ethane and ethylene. Br. Jour.
Ind. Med. 29: 99.
International Labor Office. 1977. Occupational exposure limits for airborn
toxic substances — A tabular compulation of values for selected countries.
Occupational Safety and Health Series, NO. 37. Geneva .
Kirk, R. and 0. Othmer. 1963. Encyclopedia of chemical technology. 2nd
ed. John Wiley and Sons, Inc., New York.
Lange, N. (ed.) 1956. Handbook of chemistry. 9th ed. Handbook Pub-
lishers, Inc., Sandusky, Ohio.
National Toxicology Carcinogenesis Testing Program. 1980. Chemicals on.
Standard Protocol.
National Institute for Occupational. Safety and Health. 197&. Current in-
telligence bulletin, No. 27, OHEW Pub. No. 78-181, p. 4..
Nguyen, P., et al. 1971. 1,1,1,2-Tetrachloroethane metabolism. C.R. Acad.
Sci., Ser. 0. 272: 1173.
Pearson, C.R., and G.. McConnell. 1975. Chlorinated hydrocarbons in the
marine environment. Proc. R. Soc. London. Ser. 8. 189: 305.
Schmidt and Reiner. 1976. The embryotoxic and teratogenic effect of tetra-
chloroethane - experimental studies. Biol. Rundsch. 14: 220.
Simmon, V., et al. 1977. Mutagenic activity of chemicals identified in
drinking water. Dev. Toxicol. Environ. Sci. 2: 249.
Truhaut, R. and P. Nguyen. 1973. Metabolic transformations of
1,1,1,2-tetrachloroethane in the rat, guinea pig, and rabbit. Jour. Eur.
Toxicol. 6: 211.
Truhaut, R., et al. 1973. Serum enzyme activities and biochemical blood
components in subacute 1,1,1,2-tetrachloroethane poisoning in the rabbit.
Jour. Eur. Toxicol. 6: 81.
Truhaut, R., et al. 1974. Toxicological study of 1,1,1,2-tetrachloro-
ethane. Arch. Mai. Prof. Med. Trav. Secur. Soc. 35: 593.
-------
Truhaut, R., et al. 1975. Preliminary biochemical study of the hepato-
toxicity of 1,1,1,2-tetrachloroethane in the Wistar rat. Effect of sex.
Eur. Jour. Toxicol. Environ. Hyg. 3: 175.
U.S. EPA. 1974. "Draft analytical report - New Orleans area water supply
study," EPA 906/10-74-002. Lower Mississippi River Facility, Slidell, La.,
Surveill. Anal. Oiv. Region VI, Dallas, Tex.
U.S. EPA; 1975. Identification of organic compounds in effluents from in-
dustrial sources. EPA. 560/3-75-002.
U.S. EPA. 1979a. Chlorinated Ethanes: Ambient. Water Quality Criteria.
(Draft)
U.S. EPA. 1979b.. Hazard Profile: Chlroinated Ethanes (Draft).
Yllner, S. 1971. Metabolism of 1,1,1,2-tetrachloroethane in the mouse.
Acta Pharmacol. Toxicol. 29(5-6): 471-480, 1971.
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No. 157
1,1,2,2-Tetrachloroethane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
1*7-1
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL. NOTATION
U.S.. EPA's Carcinogen Assessment Group (GAG) has evaluated
1,1,2,2,-tetrachloroethane and has found sufficient evi-
dence to indicate that this compound is carcinogenic.
-------
1,1,2,2-TETRACHLOROETHAN E
SUMMARY
An increased incidence of hepatocellular carcinomas has
been shown in mice following oral administration of 1,1,2,2-
tetrachloroethane.' Mutagenic effects have been reported in
the Ames Salmonella assay and in E~ coli.. There is no avail-
able evidence to indicate that. 1,1,2,2-tetrachloroethane"pro-
duces teratogenic effects. Occupational exposure to 1,1,2,2-
tetrachloroethane has produced several toxic effects includ-
ing neurological symptomsr liver and kidney damage, pulmonary
edema, and fatty degeneration of heart muscle.
The toxicity of 1,1,2,2-tetrachloroethane has been exam-
ined in one species each of freshwater and marine fish, in-
vertebrates, and plants.. Freshwater invertebrates appear to
be the most sensitive species examined, with acute toxic- con-
centrations of 9,320 ug/1 being reported.
-------
1,1,2,2-TETRACHLOROETHANE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Cri-
teria Document for Chlorinated Ethanes (U.S. EPA, 1979a).
The chloroethanes are hydrocarbons in which one or more
of the hydrogen atoms of ethane are replaced by chlorine
atoms- In general, water solubility and vapor pressure
decrease with increasing chlorination, while density and
melting point increase. 1,1,2,2-Tetrachloroethane (molecular
weight 167-9) is a liquid at room temperature with a boiling
point of 146.3°C, a melting point of -36°C, a specific
gravity of 1.596, and a solubility in water of 2.9 gm/1 (U.S.
EPA, 1979a) .
The chloroethanes are used as solvents, cleaning and de-
greasing agents, and in the chemical synthesis of a number of
compounds-
The chlorinated ethanes form azeotropes with water (Kirk
and Othmer, 1963). All are very soluble in organic solvents
(Lange, 1956).. Microbial degradation of the chlorinated
ethanes has not been demonstrated (U.S. EPA, 1979a). For
additional information regarding the chlorinated ethanes in
general, the reader is referred to the Hazard Profile on
Chlorinated Ethanes (U.S- EPA, 1979b).
II. EXPOSURE
The chloroethanes present in raw and finished waters are
due primarily to industrial discharges. Small amounts of
chloroethanes may be formed by chlorination of drinking water
or treatment of sewage. Atmospheric chloroethanes result
.. -/fo
-------
from evaporation of volatile chloroethanes during use as
degreasing agents or in dry cleaning operations (U.S. EPA,
1979a). ' '
Routes of human exposure to chloroethanes include water,
air, contaminated foods and. fish, and dermal absorption-
Fish and shellfish have shown level's of chloroethanes in the
nanogram range (Dickson and Riley, 1976).. Information on the
levels of 1,1,2,2-tetrachloroethane in foods is not avail-
able.
The EPA (1979a) has estimated a weighted average biocon-
centration factor for 1,1,2,2-tetrachloroethane to be 18 for
the edible portions of fish and shellfish consumed by Ameri-
i
cans.. This estimate was based on steady-state bioconcentra—
tion studies in the bluegill.
III.. PHARMACOKINETICS
A- Absorption
The chloroethanes are absorbed rapidly following
ingestion or inhalation (U.S. EPA, 1979a). Morgan, et al.
(1972) have determined that 1,1,2,2-tetrachloroethane has a
high octanol/water partition coefficient, high rate of pul-
monary absorption, and low rate of elimination by exhalation.
B.. Distribution
Pertinent data could not be located in the avail-
able literature on 1,1,2,2-tetrachloroethane. The reader is
referred to a more general treatment of chlorinated ethanes*
(U.S. EPA, 1979b), which indicates widespread distribution of
these compounds throughout the body..
-------
C. Metabolism
The metabolism of chloroethanes involves both enzy-
matic dechlorination and hydroxylation and non-enzymatic oxi-
dation (U.S. EPA, 1979a). Oxidation reactions may produce
unsaturated metabolites which are then transformed to the
•alcohol and ester (Yllner, 1971). Trichloroethanol and tri-
chloro acetic acid have been identified in the urine of rats
k
following inhalation of 1,1,2,2-tetrachloroethane vapor
(Ikeda and Ohtsuji, 1972). Metabolism of ..this compound ap-
pears to involve the activity of the mixed-function oxidase
system (Van Dyke and Wineman, 1971).
D. Excretion
\
The chloroethanes are excreted primarily in the
urine and expired air. Murine studies indicate that, after
intraperitoneal (i.p.) injection of 1,1,2,2-tetrachloro-
ethane, approximately 80 percent of the dose is excreted in
72 hours. Half of this dose is excreted as carbon dioxide in
the breath and one-fourth as metabolites in the urine (Yllner,
1971). Human studies (Morgan, et al. 1972) indicate that
after inhalation exposure of 1,1,2,2-tetrachloroethane the
amount expired in the breath is less than that observed in
animal studies, although a different radioactive tracer was
used.
IV. EFFECTS
A. Carcinogenicity
Results of a National Cancer Institute (NCI) car-
cinogenesis bioassay for 1,1,2,2-tetrachlocoethane show that
oral administration produced an increased incidence of hepato-
-------
cellular carcinomas in exposed mice (NCI, 1978). No sta-
tistically significant tumor increase was seen in cats.
B. .Mutagenicity
The mutagenic activity of 1,1,2,2-tetrachloroethane
has been shown in the Ames Salmonella assay and in a ENA
polymerase-deficient strain of JJ. coli (Brem-, et al», 1974).
C. Teratogenictty and Other Reproductive Effects
Embryo toxicity and weak teratogenicity have been
reported in two strains of mice exposed with 1,1,2,2-tetra-
chloroethane (Schmidt and Reiner, 1976) . Other pertinent in-
formation could not be located in the available literature.
D.. Chronic Toxicity
Occupational exposure to 1,1,2,2-tetrachloroethane
has produced toxic effects including neurological symptoms,
liver and kidney damage, pulmonary edema, and fatty degenera-
tion of heart muscle (U.S. EPA, 1979a) .
Animal experiments have indicated that chronic in-
halation exposure may produce liver and kidney degeneration
(U.S.. EPA, 1979a) .
V. AQUATIC TOXICITY
A. Acute Toxicity
Toxicity studies on one species from each category
of freshwater and marine fish and invertebrates have been re-
ported (U.S. EPA, 1978).. In freshwater fish, the study
yielded a 96-hour static LCsg. value of 21,300 ug/1 for
the blueg.ill (Lepomis macrochirus) . For freshwater inverte-
brates, the study yielded a 48-hour static LCgQ value of
-------
9,320 ug/1 for the caldoceran Daphnia- magna. In marine fish
and invertebrates, the studies yielded a 96-hour static LC50
value of 12,300 ug/1 for the sheepshead minnow (Cyprinodon
variegatus), and of 9,020 ug/1 for the mysid shrimp (Mysi-
dopsis bahia).
->•• B. Chronic Toxicity
Pertinent information could not be located in the
•
available literature.
C. Plant Effects
When the freshwater algae Selenastrum capricornutum
was tested for adverse effects of 1,1,2,2-tetrachloroethane
on chlorophyll and cell numbers EC50 values of 136,000
and 146,000 ug/1 were obtained. When the marine algae SSkele-
tonema costatum was tested for these adverse effects, 96-hour
ECgg values were 6,440 and 6,230 ug/1, respectively.
D. Residues
A bioconcentration value of 8 was reported for the
bluegill (U.S.. EPA, 1979a).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived by
U.S. EPA (1979a), which are summarized below, have gone
through the process of public review; therefore, there is a
possibility that these criteria will be changed.
A. .Human
Based on the NCI carcinogenic data, and using a
linear, nonthreshold model, the U.S. EPA (1979a) has esti-
mated the level of 1,1,2,2-tetrachloroethane in ambient water
/S7-?
-------
that will result in an additional cancer risk of 10~5 to
be 1.8 ug/1.
The exposure standard determined by OSHA for 1/1,-
2,2-tetrachloroethane. is 5 ppm as an eight-hour time-weighted
average concentration..
B^ Aquatic
The draft, criterion for protection of freshwater
aquatic life is 170 ug/1 as a 24-hour average, not to exceed
380 ug/1- The draft criterion to protect, marine life from
1,1,2,2-tetrachloroethane is 70 ug/1 as-a 24-hour average,
not to exceed 160 ug/1 (U»S. EPA, 1979a) .
-------
1,1,2,2-TETRACHLOROETHANE
REFERENCES
Brem, H., et al. 1974. The mutagenicity and ONA-modifying effect of halo-
alkanes. Cancer Res. 34: 2576.
Oickson, A.G. and J.P. Riley. 1976. The distribution of short-chain halo-
genated aliphatic hydrocarbons in some marine organisms. Mar. Pollut. Bull.
79: 167."
Ikeda, M. and H. Ohtsuji. 1972. Comparative study of the excretion of
Fujiwara reaction-positive substances in urine of humans and rodents given
trichloro- or tetrachloro-derivatives of ethane and ethylene. Br. Jour.
Ind. Med. 29: 99.
«.
Kirk, R. and D. Othmer. 1963.. Encyclopedia of chemical technology. 2nd
ed. John Wiley and Sons, Inc., New York.
Lange, N. (ed.) 1956. Handbook of chemistry. 9th ed. Handbook Publish-
ers, Inc., Sandusky, Ohio.
Morgan, A., et al. 1972. Absorption of halogenated hydrocarbons and their
excretion in breath using chlorine-38 tracer techniques. Ann. Occup. Hyg.
15: 273.
National Cancer Institute. 1978. Bioassay of 1,1,2,2-tetrachloroethane for
possible carcinogenicity. Natl. Inst. Health, Natl. Cancer Inst. OHEW Pub I.
NO. (NIH) 78-827. Pub. Health Serv., U.S. Oept. Health Edu. Welfare.
Schmidt and Reiner. 1976. The embrvotoxic and teratogenic effect "of
tetrachloroethane - experimental studies. Biol. Rudsch 14: 220.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. Contract NO. 68-01-4646, U.S. Environ. Prot.
Agency.
U.S. EPA. 1979a. Chlorinated Ethanes: Ambient Water Quality Criteria.
(Draft)
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Chlori-
nated Ethanes: Hazard Profile. (Draft)
Van Dyke, R.A. and C.G. Wineman. 1971. Enzymatic dechlorination: Oechlor-
ination of chloroethanes and propanes in vitro. Biochem. Pharmacol.
20: 463. ~~
Yllner, S. 1971. Metabolism of l,l,2,2-tetrachloroethane-14C in the
mouse. Acta. Pharmacol. Toxicol. 29: 499.
-------
No. 158
Tetrachloroethylene
Health and Environmental Effects
- ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C.. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal* The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect'all available information including all the
adverse health and environmental impacts presented by the.
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
.1 fr 7 V
TV fl'7
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (GAG) has evaluated
tetrachloroethylene and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
TETRACHLOROETHYLEN E
SUMMARY
Tetrachloroethylene is widespread in the environment,
and is found in trace amounts in water, aquatic organisms,
air, foodstuffs, and human tissue. Tetrachloroethylene
causes mild intoxication and liver dysfunction following
chronic exposure to high levels associated with certain in-
dustries » Tetrachloroethylene has not been shown to be tera-
togenic, but it has been shown to be mutagenic in bacterial
assays and carcinogenic in mice.
The bluegill (Lepomis macrochirus) is the most sensitive
freshwater species to acute tetrachloroethylene toxicity
with a reported 96-hour LC50 of 12,900 ug/1. In the only
acute toxicity study for saltwater species the mysid shrimp
.(Mysidopsis bahla) has an observed 96-hour LCgg value of
10,200 ug/1- The chronic value for this shrimp is 448 ug/1.
A freshwater algae has a reported no-effect concentration of
tetrachloroethylene at 816,000 ug/1. A marine alga, however,
was adversely affected at the considerably lower level of
10,000 ug/1. Tetrachloroethylene is only slightly bioconcen-
trated by the bluegill (49 times) after 21 days of exposure,
and has an elimination half-life of less than one day.
-------
I. INTRODUCTION
This profile is based on the Ambient Water Quality Cri-
teria Document for Tetrachloroethylene (U.S. EPA, 1579)..
Tetr'achloroethylene (02^4, 1,1,2,2-tetrachloroethy—
lene, perchloroethylene, PCE? molecular weight 165.85) is a
colorless, nonflammable liquid.. It has the following physi-
cal/chemical properties (Patty, 1963)t
Melting-Point: -23.25°C
Density: 1.623 g/ml
Vapor Pressure: 19 mm Hg
Water Solubility: 150 ug/ml
Octanol/Water
Partition Coefficient: 339
Tetrachloroethylene is primarily used as a solvent in
the dry cleaning industry and,, to a lesser extent, as a de-
greasing solvent in metal industries (Windholz, 1976).
II... EXPOSURE
The National Organics Monitoring Survey (U.S. EPA, 1978)
detected tetrachloroethylene in 9 out of 105 drinking water
samples between November 1976 and January 1977 (range, <0.2
to 3.1 ug/1; median <0,2 ug/1). No data exist for ingestion
of tetrachloroethylene from food for the United States. How-
ever, in England, tetrachloroethylene concentrations in foods
ranged from nondetectable amounts in orange juice to 13 ugA<3
in butter (McConnel, et al,, 1975). The U.S. EPA (1979) has
estimated the weighted bioconcentration factor of tetrachlo-
roethylene to be 110 for the edible portion of consumed fish
and shellfish. This estimate is based on measured steady—
»
state bioconcentration studies in bluegills. Generally,
IS?-5
-------
environmental tetrachloroethylene concentrations in air tend
to be low. A survey of eight locations in the U.S. indicated
concentrations up to 6.7 ug/m^ in urban areas and less than
0.013 ug/m-3 in rural areas (Lillian, et al., 1975). By far
the most significant exposure to tetrachloroethylene is in
the industrial environment (Fishbein, 1976)» Significant der-
mal exposure would be confined to occupational settings.
III. PHARMACOKINETTCS
A. Absorption
Using inhalation exposure, Stewart, et al. (1961)
found that tetrachloroethylene reached near steady-state
levels in the blood of human volunteers with two hours of
continuous exposure. However, steady-state conditions in
this study were probably obtained by a redistribution phenom-
enon, since the biological half-life of tetrachloroethylene
metabolites in humans has been measured to be 144 hours
(Ikeda and Imamura, 1973).
B. Distribution
In humans (McConnell, et al., 1975) and rats (Savo—
lainen, et al., 1977), tetrachloroethylene tends to accumu-
late in the body fat, and to a lesser extent in the brain and
liver.. Measurements in the rat suggests that the level of
PCS in the liver and blood remains constant after three hours
of exposure.
C. Metabolism
In a qualitative sense, metabolic products appear
to be similar in humans (ikeda, et al., 1972; Ikeda, 1977)
and experimental animals (Yllner, 1961; Daniel, 1963; Ikeda
-------
and Ohtsuji, 1972). The metabolism of tetrachloroethylene
leads to the production of trichloroacetic acid, and is ap-
parently saturable (Ikeda, 1977).. The- enzyme systems respon-
sible for this metabolism are indueible with phenobarbital
(Ikeda and Imamura, 1973) and polychlorinated biphenyls
(Moslen, et al., 1977).
D~ Excretion.
In humans tetrachloroethylene is primarily elimi-
nated from the body via the lungs with a half-life of elimi-
nation estimated to be 65 hours (Stewart, et al., 1961, 1970r
Ikeda and Imamura, 1973)- Its metabolite, trichloroacetic
acidr is eliminated in the urine of humans with a half-life
estimated to be- 144 hours (Ikeda and Imamura, 1973).
IV.. EFFECTS
A. Carcinogenicity
Tetrachloroethylene caused hepatocellular carcino-
mas- in B6C3-F1 mice of both sexes (NCI, 1977).. An experiment
in Osborne-Mendel rats produced negative results, although
early mortality precluded the use of this data in evaluating
the carcinogenicity of PCE: (NCI, 1977) ..
Greim, et. al- (1975) could not demonstrate an in-
crease in the mutation rate 'of _§. coli K12 with tetra-
chloroethylene.. Howeverr Cerna and Kypenova (1977) tested
PCE and found elevated rautagenic activity in Salmonella
strains sensitive to both base pair substitution and frame-
shift mutations.
C. Teratogenicity
Only one report has appeared concerning possible
-------
tetrachloroethylene—induced teratogenesis (Schwetz, et al.
1975). Female rats and mice were exposed to 2000 mg/rn^ 7
hours daily on days 6 to 15 of gestation. Significant de-
creases in fetal body weight and resorption, subcutaneous
edema and delayed ossification of skull bones and sternabone
in the pups were noted* These effects were mild, however,
and led the authors to conclude that PCE was not teratogenic.
Additional work is necessary to determine whether PCE is ter-
atogenic (U.S. EPA, 1979).
D. Other Reproductive Effects
No information available.
E. Chronic Toxicity
Repeated exposure to tetrachloroethylene has re— .
suited in damge to liver and kidney in dogs (Klaassen and
Plaa, 1967). Toxic nephropathy has also been observed in
mice and rats (NCI, 1977)» In humans, chronic exposure to
. 1,890 to 2,600 mg PCE/m-^ caused three of seven men to have
impaired liver function (Coler and Rossmiller, 1953). Occa-
sional reports have even associated tetrachloroethylene expo-
sure with the symptomatology of more serious chronic diseases
such as Raynaud's disease (Lob, 1957; Sparrow, 1977).. Spar-
row (1977) .reported a case which involved depressed immune
function, mildly depressed liver function, polymyopathy and
severe acrocyanosis* In a group of workers occupationally
exposed to lower concentrations of tetrachloroethylene at ap-
proximately 400 mg/m3 (one for 15 years), subjective com- ,
plaints, such as headache, fatigue, somnolence, dizziness,
-------
and a sensation of intoxication were noted (MedeJc and
Kovarik, 1973).
F.. Other Relevant'Information
, Intolerance, of alcohol has been reported with tet-
rachloroethylene exposure (Gold, 1969).,
V.. AQUATIC TOXICITY
A.. Acute Tox:icity """'"'
Ninety—six hour LCgg values foe flow—through
and static tests are 18,400 and 21,400 ug/lr respectively,
with the fathead minnow, Pimephales promelas (Alexander, et
al.. 1978)... With the bluegill, Lepomis macrochirus, the 96-
hour LC5Q value is 12,900 ug/1 (U.S.. EPA, 1978). For
Daphnia maqna, an observed 48-hour LCSO value of 17,700
ug/1 has been recorded (U.S. EPA, 1978).
No acute data are available for saltwater fish.
The mysid shrimp (Mysidopsis bahia) has an observed 96-hour
LC50 of 10,200 ug/1 (U..S. EPA, 1978) »
B. Chronic Toxicity
Chronic test data are not available for freshwater
species.. A chronic value for the. saltwater mysid shrimp in a
life cycle test is 448 ug/1 (U.S, EPA, 1978).
C. Plant Effects
No adverse effects on chlorophyll ^ concentration
or cell numbers with the alga, Selenastrum capricornutum,
were observed at exposure concentrations as high as 816,000
ug/1 (U.S. EPA, 1978)- Two 96-hour EC50 values were re- .
ported for the marine micro alga, Skeletonema costaturo:
504,000 ug/1 based on cell numbers and 509,000 ug/1 based on
-------
chlorophyll £ concentration (U.S. EPA, 1978). The raacroalga,
Phaeodectylum tricornuturn, was considerably more sensitive to
tetrachloroethylene toxicity with a reported EC50 of
10,500 ug/1 (Pearson and McConnell, 1975).
0. Residues
_ The bioconcentration factor for bluegills, Lepomis
macrochirusr has been reported to be 49 (U.S. EPA, 1978).
Equilibrium was reached within 21 days and the depuration
rate was rapid with a half-life of less than one day.
VI.G EXISTING GDIDLINES AND STANDARDS
A. Human
Based on the NCI mice data, and using the "one-hit"
model, the U.S. EPA (1979) has estimated levels of tetrachlo-
roethylene in ambient water which will result in specified
risk levels of human cancer:
Risk Levels and
Exposure Assumptions Corresponding Draft Criteria
(per day) . 0 10 710~610"5
2 liters of drinking
water and consumption
of 18.7 grams fish and
shellfish. 0 0.020 ug/1 0.20 ug/1 2.0 ug/1
Consumption of fish and.
shellfish only. 0 0.040 ug/1 0.40 ug/1 4.0 ug/1
The present American Governmental Conference on Industrial
Hygiene (AGCIH, 1977) threshold limit value (TLV) is 670
i^fTj^
*} 0 I IA£
-------
B. Aquatic
For tetrachloroethylene, the draft criterion to
protect saltwater aquatic life is 79 ug/1 as a 24-hour aver-
age; the' concentration should never exceed 180 ug/1 at any
time (U.S. EPA, 1979).
For freshwater aquatic life, the draft criterion is.
310 ug/1 as a 24-hour average; the concentration should never
exceed 700 ug/L at any time (U.S. EPA, 1979).
This: draft criteria to protect aquatic life is
presently being" reviewed before final recommendation.
-------
TETRACHLOROETHYLENE
REFERENCES
Alexander, H., et al. 1978. Toxicity of perchloroethylene,
trichloroethylene, 1,1,1-trichloroethane, and methylene chlo-
ride to fathead minnows. Bull.. Environ. Contam. Toxicol.
20: 344.
American Conference of Governmental Industrial Hygienists.
1977. Documentation of the threshold limit value. 3rd ed.
Cerna, M., and H. Kypenova. 1977. Mutagenic activity of
chloroethylenes analyzed by screening system tests. Mutat.
Res. 46: 214.
Coler, H.R., and H.R. Rossmiller. 1953. Tetrachloroethylene
exposure in a small industry. Arch. Ind. Hyg. Occup. Med,
8: 227.
Daniel, J.W. 1963. The metabolism of 36cl-labelled tri-
chloroethylene and tetrachloroethylene in the rat. Biochem.
Pharmacol. 12: 795.
Fishbein, L.. 1976. Industrial mutagens and potential rauta—
gens I. Halogenated aliphatic hydrocarbons. Mutat. Res.
32: 267.
Gold, J.H. 1969.. Chronic perchloroethylene poisoning. Can.
Psychiat. Assoc.. Jour. 14: 627,
I
Greim, H., et al.. 1975.. Mutagenicity in vitro and potential
carcinogenicity of chlorinated ethylenes as a function of
metabolic oxirane formation. Biochem. Pharmacol. 24: 2013.
Ikeda, M. 1977. Metabolism of trichloroethylene and tetra-
chloroethylene in human subjects. Environ. Health Perspect.
21: 239.
Ikeda, M., and T. Imamura. 1973. Biological half-life of
trichloroethylene and tetrachloroethylene in human subjects.
Int. Arch. Arbeitsmed. 31: 209.
Ikeda, M., and H. Ohtsuji. 1972. A comparative study of the
excretion of Fujiwara - reaction-positive substances in urine
of humans and rodents given trichloro- or tetrachloro- deriv-
atives of ethane and ethylene. Br. Jour. Ind. Med. 29: 99.
Ikeda, M., et al. 1972. Urinary excretion of total tri-
chloro-compounds, trichloroethanol and trichloracetic acid as
a measure of exposure to trichloroethylene and tetrachloro—
ethylene. Br. Jour.. Ind. Med. 29: 328.
-------
Klaassen, C.D.., and G.L.. Plaa. 1967. Relative effects of
chlorinated hydrocarbons on liver and kidney function in
dogs. Toxicol. Appl.. Pharmacol. 10: 119.
Lillian, D., et al.. 19.75. Atmospheric fates of halogenated
compounds. Environ. Sci. Technol. 9: 1042.
Lob, M. 1957. The dangers of perchloroethylene. Int.. Arch.
Gewerbe—patholog... und Gewerfahyg. 16: 45..
McConnell, G-., et al. 1975. Chlorinated hydrocarbons and
the environment. Endeavour 34: 13.
Medek, V.r and J".. Kovarik. 1973. The effects of perchloro- .
ethylene on the health of workers. Pracovni Lekarstvi 25:
339.
Moslen,. M.T., .et al. 1977. Enhancement of the metabolism
and hepatoxicity of trichloroethylerie and perchloroethylene.
Biochem.. Pharmacol. 26: 369.
National Cancer Institute. 1977. Bioassay of tetrachloro-
ethylene for possible carcinogenicity. CAS No. 127-18-4- NCI —
CG-TR-13 DREW Publication No. (NIH) 77-813.
Pa.tty, F. 1963. Aliphatic halogenated hydrocarbons.. Ind.
Hyg.. Toxicol. 2r 1314..
4
Pearson, C.R., and G. McConnell. 1975. Chlorinated Ci and
C2 hydrocarbopns in the marine- environment. Proc. R. Soc.
London B. 189: 305-
Savolainen, H.., et al. • 1977. Biochemical and behavioral
effects of inhalation exposure to. tetrachloroethylene and
dichloromethane. Jour. Neuropathol. Exp. Neurol. 36:. 941.
Schwetzv B.A., et al. 1975. The effect of maternally in-
haled trichloroethylene, perchloroethylene, methyl chloro-
form, and methylene chloride on embryonal and fetal develop-
ment in mice and rats. Tox.icol. Appl. Pharmacol. 32: 84.
Sparrow, G.P. 1977. A connective tissue disorder similar to
vinyl chloride disease in a patient exposed to perchloroethy-
lene. Clin. Exp. Dermatol. 2r 17.
Stewart,. R.D, et al.. 1970. Experimental human exposure to
tetrachloroethylene. Arch. Environ- Health 20: 225.
i t TT~l7 f-
I U I ->
-------
Stewart, R.D., et al.. 1961.. Human exposure to tetrachloro-
ethylene vapor. Arch..,Environ. Health 2: 516.
U.S, EPA. 1978. In-depth studies on health and environmen-
tal impacts of selected water pollutants. Contract No. 68-
01-4646. U.S- Environ. Prot. Agency.
U.S. EPA. 1979. Tetrachloroethylenet Ambient Water Quality
Criteria (Draft).
Windholz, M., ed. 1976. The Merck Index. 9th ed. Merck
and Co., Rahway, tf.J^
Yllner, S.. 1961^ Urinary metabolites of 14c-tetrachloro-
ethylene. in rnice^ Nature (Lond.) 191: 820.
KT
-------
No. 159
Thallium
Health and Environmental Effects
U.S.. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse- health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
THALLIUM
Summary
Thallium is a highly toxic element to many organisms,
including humans. Symptoms of acute exposure to thallium
include alopeciar_ataxiar and tremors, occasionally leading
to irreversible- coma- and death.. There- is. no information
available on the mutagenic and carcinogenic properties of
thallium* Although thallium has been reported to be terato—
genier the evidence is not convincing.. The acceptable daily
intake (ADI) of thallium has beea determined to be*IS.4 mg
per day. Thallium can be chronically toxic to fish at con-
centrations as low as 20 ug/1. -Algae are also sensitive,
with effects produced at concentrations as low as 100 ug/1..'
-------
THALLIUM
I. INTRODUCTION
This profile is based on the Ambient Water Quality Docu-
ment for Thallium (U.S. EPA, 1979).
Thallium (Tl;- atomic weight 204.37) is a soft, malle-
able, heavy metal with a silver-white luster (Lee, 1971).
Thallium exists in either the monovalent (thallous) or tri-
valent (thallic) form, the former being the more common and
stable and therefore forming more numerous and stable salts
(Harapel, 1968). Thallium reacts chemically with moisture in
air to form oxides. Thallous oxide is easily oxidized to
thallic oxide, a very hygroscopic compound, or reduced to
thallium. While thallium itself is relatively insoluble in
water (Windholz, 1976), thallium compounds exhibit a wide
range of solubilities.
Current production and use of thallium and iti compounds
approximated 680 kg in 1976 (U.S. Dept. Interior, 1977). In-
dustrial uses of thallium include the manufacture of alloys,
electronic devices, and special glass. Many thallium-con-
taining catalysts have been patented for industrial organic
reactions (Zitko, 1975).
II * EXPOSURE
There is little information on the extent of thallium
contamination of water. In a single study ..by Greathouse
(1978) evaluating drinking water from 3,834 households ran-
domly selected from 35 geographic areas, thallium was dete'ct-
' able in only 0.68 percent of the samples (detection limit was
0.3 ppb), with the average concentration at detection of 0.89
-------
ppb. Assuming a water consumption of 2 Liters per day for
the average adult, over 99 percent of adults would consume <
1 ug per day. The only study pertaining to natural water
measured the thallium content of run-offs from mining and
smelting operations involving copper,, gold, zinc, and cadmium
with which, thallium is associated in trace quantities (U.S.
EPA, 1978) .. The highest, concentrations reported were- 30 ppb
in slag- run-off near Kellog-, Idaho and. 21 ppb in the Colorado
River below drainage from a copper mine.
Ingestion of thallium from food is mainly due to the
consumption of vegetables.. Little data is available, al-
though Geilmann, et al. (1960) found an average of 68.2 ppb
dry weight thallium in four vegetables, analyzed* This may be
high due to the small sample size., Breads contain 0.75 ppb
dry weight thallium, and the thallium content of meats has
not been adequately determined. The EPA (1979) estimated
the weighted average bioconcentration factor for thallium to
be 61 for the edible portions of fish and shellfish consumed
by Americans.. This estimate is. based on measured steady-state
bioconcentration studies in bluegill. A daily intake from
food has been calculated at 3.8 ug/day. However, due to the
sparse data,, this is probably not an accurate estimate-
The contribution of thallium in air to exposure is, in
most instances, small.. However, thallium is a contaminant in
flyash, and in a worst case situation in the vicinity of a
»-
coal-fired plant, daily absorption could be. as high as 4.9
ug (Carson and Smith, 1977). Due to possible high concentra-
tions in vegetable matter, cigarette smoke may be a signifi-
-------
cant source of thallium, with urinary excretion of thallium
in smokers being twice that in non-smokers (Weinig and Zink,
1967).
III. PHARMACOKINETICS
A. Absorption
Gastrointestinal absorption of trace quantities of
thallium appears to be almost complete in both man (Barclay,
et al. 1953) and rats (Lie, et al. 1960). No information was
found in the available literature concerning the deposition
and clearance of inhaled thallium aerosols. The skin would
not be expected to be a significant route of absorption of
thallium; however, systemic pois_oning has resulted from oint-
ments containing- 3-8 percent thallium acetate applied to the
skin (Munch, 1934) .
B. Distribution
Thallium is widely distributed in the body in the
intracellular space. Active transport of thallium, mediated
by Na/K ATPase into erythrocytes has been demonstrated
(Gehring and Hammond, 1964; Cavieres and Ellroy, 1974).
Other factors besides active transport into cells must be
operating, since in both conditions of normal thallium expo-
sure and fatal exposure in man,, there is a tendency for thal-
lium to concentrate in the kidneys, colon and hair (Weinig
and Zink, 1967; Cavanagh, et al. 1974).,
Thallium crosses the placenta freely from the ma—
»
ternal circulation to the fetus. In studies using rats and
mice, steady state maternal/fetal ratios of 0.84 and 0.46,
-------
respectively, were obtained (Gibson, et al.. 1967); and under
non-steady state conditions, wide variations in dosage (0.2-
6.4 mgAg/roin) did not alter, the. distribution from mother to
fetus (Gibson and Becker, 1970).. Richeson (1958) cites one
report in which thallium was found in the tissue of a baby
whose mother had taken 1.2 g thallium at term..
CV Metabolism
Pertinent information could, not be located in the
available literature.
D~ Excretion
Human excretion of thallium has been estimated from
two studies, one involving a tracer dose of 204 Tl given to a
middle—age woman with osteogenic carcinoma raetastatic to the
lungs (Barclay, et al. 1953) and the other involving a woman
suffering from thallium poisoning- (Innis and. Moses, 1978).
From these two less than ideal studies, total excretion of
thallium per day in. adults not exposed to unusual sources of
thallium is probably as follows:
Excretory route ug Tl/day
Qrine 1.20
Feces 0.06
Hair 0..32
Skin and Sweat 0.06
Total 1/64
-------
IV. EFFECTS'
A.. Carcinogenicity and Mutagenicity
Information regarding the carcinogenic and muta-
genie potential of thallium could not be located in the
available literature.
B.. Teratogenicity
There are- two reports of the teratogenicity of
thallium, one involving- chicken embryos (Karnofsky, et al.
„ r
1950) and the other rats (Gibson and Beckerr 1970). In both
cases, overt fetal toxicity due to thallium was noted, making
it impossible to. distinguish teratogenicity from a more
general toxic effect.
C. Other Reproductive Effects
The only known reproductive effect is fetal toxic-
ity in cases of acute poisoning of the mother.
D. Chronic Toxicity
There are few reports of chronic thallium poisoning
in man- In one brief report concerning 13 men exposed 3 to 4,
months, the signs and symptoms were pains in the legs, weari-
ness, loss of hair, disturbance of sensation, psychic trouble
albuminuria and nephritis (Meyer, 1928) ..
Rats fed thallous acetate in their diet for 105 days ex-
perienced no reduction in weight gain at concentrations of 5
and 15 ppm; 30 ppm, however, proved fatal to approximately
half the animals (Downs, et al. 1960).
E. Other Relevant Information
Potassium has been shown to markedly enhance the
%
rate of thallium excretion (primarily urinary) in both rats
A
-------
and dogs (Gehring and Hammond, 1967) .. Potassium also in-
creased somewhat the acute LO^Q of thallium- In humans.,
potassium also increases urinary excretion with accompanying
temporary- accentuation of the neurological signs and symptoms
(Innis and Moses, 1978; Pappr et al. 1969)»
V. AQUATIC TOXICITY
A. Acute Toxicity
The bluegill appears to be- extremely resistant to y
thallium under renewal and static test conditions with 96-
hour LC5Q values of 132rOOO and 121,000 ug/1, respectivel
(U.S.. EPA,'1979). The fathead minnow was tested under flow- ).
through conditions with measured^ concentrations, and the 96- 0
hour LC50 value was found to be 860 ug/1 (U.S. EPA, 1978 .'
Atlantic salmon, when exposed to thallium for as long as 2,60
hours, experienced 40 and 70 percent mortality at. approxi— zO
mately 20 and 45 ug/1, respectively, with mortality occuring
throughout the test (Zitko, et al» 1975)- The 48-hour LC5
for Daphnia magna is 2,180 ug/1 (U.S.. EPA, 1978).
B_ Chronic Tox icity
An embryo—larval test with the fathead minnow indi-1—
cated adverse effects at the lowest thallium concentration
tested of 40 ug/1 (U.S. EPA, 1978). No chronic data are avai
able for freshwater invertebrate speciesr and no chronic ef-
fects of thallium on saltwater organisms have been reported
(U.S.. EPA, 1979) .
-------
C. Plant Effects;
There is a 40 percent inhibition of oxygen evolu-
tion by the alga, Chlamydomonas reinhardi, exposed to a con-
centration of 40,800 ug/1 (Overnell, 1975). The 96-hour
EC5Q values for chlorophyll £ inhibition and cell number
are 110 and 100 ug/lf respectively.
0.-... Residues
The bluegill bioconcentrated thallium 34 times
(whole body),, and the'Atlantic salmon bioconcentrated this
heavy metal '130 times above that of the ambient water (ZltJco,
et al. 1975; U.S. EPA, 1978).,
VI. EXISTING GUIDELINES
A. Human
The American Conference of Governmental Industrial
Hygienists (ACGIH, 1971) and the Occupational Safety and
Health Administration (OSHA) adopted a threshold limit value
of 0.1 mg/m3 for thallium. The acceptable daily intake-
(ADI) of thallium has been calculated to be 15.4 rag per day.
The U.S. EPA (1979) draft water criterion document for
thallium recommends a criterion of 4 ug/1 for the protection
of human health.
B. Aquatic
A criterion for the protection of aquatic species
from excess thallium exposure has not been .derived.
-------
THALLIUM
REFERENCES
American Conference of Governmental Industrial Hygienists.
1971. Documentation of threshold limit values for substances
in workroom air.. 3rd ed.
Barclay, R.K., et al. 1953. Distribution and excretion of
radioactive thalli'um in the chick, embryo, rat and man. Jour.
Pharmacol. Ex. Therap.. 107: 178.
Carson, B.L.., and r..C. Smith. 1977.. Thallium. An- appraisal
of environmental, exposure. Tech. Rep. No. 5, Contract No.
N01-ES-2-2090. Natl. Inst^ Environ. Health Sci.
Cavanagh, J.B., et al.» 1974. The effects of thallium salts
with particular reference to the nervous system changes.
Jour. Med. 43: 293.
Cavieres, J.D.., and J.C. Ellroy. 1974. Thallium and the
sodium pump in human red cells. Jour. Physiol. (London)
243: 243.-
Downs, W.L., et al~ 1960. Acute and subacute toxicity
studies of thallium compounds. Am. Ind. Hyg- Assoc. Jour.
21: 399.
Geilmann,. W., et al. 1960. Thallium ein regelmassig vor-
handenes spurenelement ,im tierschen und pflanzlichen or—
ganismus. Biochem.. Zeit. 333: 62..
Gehring, P.J., and P.B.. Hammond. 1964. The uptake of thal-
lium bv rabbit erythrocvtes.. Jour. Pharmacol. Exp. Therap.
145: 215.
Gehring, P.J., and P.B. Hammond. 1967. The interrelation-
ship between- thallium and potassium in animals. Jour.
Pharmacol. Exp. Therap. 155: 137.
Gibson, J.E., et al. 1967. Placental transport and distri-
bution of. thallium-204 sulfate in newborn rats and mice.
Toxicol. Appl. Pharmacol. 10: 408 (Abstract).
Gibsonr J.E., and B.A. Becker. 1970. Placental. transfer,
embryo toxicity and teratogenicity of thallium sulfate- in
normal and postassium-deficient rats. Toxicol. Appl..
Pharmacol.. 16: 120.
Greathouse, D.G. 1978. Personal communication.
9
Hampel, C.A., ed. 1968. The encyclopedia of chemical ele-
ments. Reinhold Pub., New York.
Itf-ll
-------
Innis, R., and H. Moses. 1978. Thallium poisoning. Johns
Hopkins Med- Jour. 142: 27.
Karnofsky, D.A.., et al. 1950. Production of achondroplasia
in the chick embryo with thallium. Proc. Soc. Exp. Biol.
Med.. 73:. 255.
Lee, A.G. 1971. The chemistry of thallium. Elsevier Pub-
lishing Co., Amsterdam.
Lie, R., et al. I960* The distribution and excretion of
thallium-204 in the rat, with suggested MPC's and a bio-assay
procedure.. Health Physv ..2: 334.
Meyer, S. 1928. Changes in the blood as reflecting
industrial damage. Jour. Ind. Hyg. ^10; 29.
Munch, J.C. 1934. Human thallotoxicosis. Jour. Am. Med.
Assoc» 102t 1929.
Overnell, J. 1975. Effect of some heavy metal ions on
photosynthesis in a freshwater alga. Pest. Biochem. Physiol.
51 19.
Papp, J.P., et al. 1969. Potassium chloride treatment in
thallotoxicosis. Ann. Intern. Med. 71: 119.
Richeson, E.M. 1958. Industrial thallium intoxication.
Ind. Med. Surg. 2: 607..
U.S. Department of the Interior.. 1977. Commodity data sum-
maries. Bur. Mines.
U.S. EPA. 1978. In-depth studies on health and environmen-
tal impacts of selected water pollutants. Contract No. 68—
01-4646. U.S. Environ. Prot. Agency.
U.S. EPA. 1979. Thallium: Ambient Water Quality Criteria.
(Draft) EPA PB-292444. National Technical Information Ser-
vice, Springfield, Va.
Weinig, E., and P. Zink. 1967. Uber die quantitative mas-
senspektroraetrische bestimmung des normalen thallium-gehalts
im menschlichen organismus. Arch. f. Topxikol. 22: 255.
Windholr, M., ed. 1976. The Merck Index.' 9th ed. Merck
and Co., Inc., Rahway, N.J..
Zitko, V. 1975. Toxicity and pollution potential of thallium
Sci. Total Environ. 4: 185.
Zitko, V., et al. 1975. Thallium: Occurrence in the
environment and toxicity to fish. Bull. Environ. Contam.
Toxicol. 13: 23.
-------
LB43-01
No. 160
Toluene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCT
WASHINGTON, D.C. 20460
OCTOBER 30, 1980
160-1
-------
DISCLAIMER
This report represents a survey of the potential health and
environmental hazards from exposure to the subject chemical, The
information contained in the report is drawn chiefly from secondary
sources and available reference documents. Because of the limita-
tions of such sources, this short profile may not reflect all
available information including all the adverse health and environ-
mental impacts presented by the subject chemical* This document
has undergone scrutiny to ensure its technical accuracy.
160-2
-------
TOLUENE
Summary
The available studies that describe the carcinogenic or
mutagenic potential of toluene are inadequate for drawing any con-
clusions about its carcinogenicity. There is suggestive evidence,
based on skin painting experiments in mice, that toluene has a
weak promoting effect on DMBA-initiated skin carcinogenesis. Three
studies in rats indicate that toluene damages chromosomes in bone
marrow cells. Toluene-exposed workers showed an increase (not
statistically significant) of chromosome breaks in peripheral
lymphocytes. Some neuromuscular deficiencies have been reported in
women exposed chronically to toluene in the workplace. Subacute
and chronic studies on experimental animals have failed to show
evidence of severe cumulative toxicity. Acute exposure to high
levels of toluene causes CNS depression. The U.S. EPA (1979) has
calculated an ADI of 29.5 mg for toluene.
Toluene is acutely toxic to freshwater fish at concentrations
of 6,940 to 32,400 ug/1 and to marine fish at concentrations from
4,470 to 12,000 ug/1. A single chronic value of 2,166 ug/1 has
been reported for marine fish. Aquatic plants appear to be resist-
ant to the action ot toluene with effective concentrations ranging
from 8,000 to 433,000 ug/1.
160-3
-------
I. INTRODUCTION
This profile is based primarily on. the Ambient Water Quality
Criteria Document for Toluene (U.S. EPA, 1979) and to a lesser
extent on Criteria for a Recommended Standard: Occupational Exposure
to Toluene (NIOSH, 1973) and its update (NIOSH, 1977).
Toluene. (CgHsCHs;' molecular weight 92.13) is a clear, colorless,
noncorrosive liquid with a sweet pungent odor. It has the following
physical and chemical properties (Kirk and Othmer, 1963; Sutton'and
Calder, 1975; Shell and Ettre, 1971; Weast, et al. 1971):
Boiling Point 110.6°C
Freezing Point -94.9°C
Flash Point 6-108C
Vapor Pressure 28 mm Hg at 25°C
Solubility Water: 534.8 + 4.9 mg/1 in
fresh water and" 379.3 + 2.8 mg/1
in seawater. Miscible with
alcohol, chloroform, ether,
acetone, glacial acetic acid,
carbon disulfate and other
organic solvents.
Production 7.3 x 103 tons/year (USITC, 197.7)
Approximately 85 percent of the toluene produced is converted
into benzene and other chemicals. The remainder is used as a
solvent and as a gasoline additive (NIOSH, 1973).
Little is known about the transport and persistence of toluene
in the environment. Toluene is volatile and can evaporate into the
atmosphere from bodies of water (MacKay and-Wolkoff, 1973), In the
atmosphere, toluene is photochemically degraded to benzaldehyde and
traces of perbxybenzoyl nitrate. Toluene can re-enter the hydrosphere
in rain (Walker, 1976).
160-4
-------
II. EXPOSUR.E
A. Water
' No estimates of average daily uptake of toluene from
water, food, and air are available. In nationwide surveys of
organic chemicals in the drinking water of representative U.S.
communities, toluene was found to contaminate 1 raw and 11 finished
water supplies out of the 133 water supplies surveyed (U.S. EPA,
I975a; 1975b; 1977). Quantitative analyses of five of the above
finished waters revealed levels of toluene ranging' from 0.1 ug/1 to
19 ug/1. Benzaldehyde and benzole acid, metabolites of toluene,
were also detected. Benzaldehyde was found in the water of five
cities, and in two of the cities was measured at levels of 0.1 and
0.5 ug/1. Benzoic acid at 15 ug/1 was found in the water of another
city.
B. Food
Little data on levels of toluene in food are available.
Toluene was detected in sea water and fish obtained near petroleum
and petrochemical plants in Japan (Ogata and Miyake, 1973). The
muscle of one representative fish contained five ug toluene/g of
tissue. Benzaldehyde, a metabolite of toluene, occurs naturally in
some foods and is intentionally added to others as a flavoring agent.
Benzoic acid, another metabolite of toluene, is added to some foods
as a preservative.
The U.S. EPA (1979) has estimated the weighted average
bioconcentration factor for toluene to be 20 for the edible portions
of fish and shellfish consumed by Americans. This estimate is based
160-5
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on the octanol/water partition coefficient of toluene and on
estimates of fish and shellfish consumption.
C.' Inhalation
Toluene has been detected in urban air at concentrations
many times lower than vapor levels considered to be potentially
harmful in occupational settings. An average level of 37 ppb and a
maximum level of 129 ppb were measured in the air of Los Angeles
(Lonneman, et al. 1968). Comparable levels were found in the air
of Toronto, Canada (Filar and Graydon, 1973), and the air of Zurich,
Switzerland (Grob and Grob, 1971). In these latter studies,
atmospheric toluene in urban areas appeared to arise primarily from
motor vehicle emissions.
III. PHARMACOKINETICS
A. Absorption
No reports are available on oral administration of toluene'
to humans (U.S. EPA, 1979). Toluene concentrations in arterial
blood of persons continuously inhaling toluene vapors appeared to
approach equilibrium after 20 to 30 minutes, at which time blood
lev'els were about 1 ug/ml in persons inhaling 100 ppm, and 2 ug/ml
in persons inhaling 200 ppm toluene (Astrand, et al. 1972). Systemic
uptake of toluene was doubled by exercise, due primarily to increased
ventilation rate (Astrand, et al. 1972). This increased uptake of
toluene upon exercise was also noted by Carlsson and Lindqvist (1977),
who in addition noted that obese persons retain more toluene than
thin ones. In their study, the average uptake of toluene vapor
during exercise was approximately 49 percent for obese subjects
160-6
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versus 37 percent for thin subjects. The rate of percutaneous
toluene absorption in humans was reported to be 14 to 23 mg/cm^/hour
(Dutkiewicz and Tyras, 1968).
Rats absorbed toluene much more rapidly and developed
substantially higher peak blood and tissue toluene concentrations
when toluene wa's administered to the lungs, rather than to the gas-
trointestinal tract (Pyykko, et al. 1977). Toluene absorption
through the skin of experimental animals occurred to a considerably
lesser degree than through the lungs or gut (Wahlberg, 1976).
B. Distribution
Toluene is rapidly taken up from the blood into body
tissues according to their lipid content and blood perfusion
(U.S. EPA, 1979). Partition coefficients (tissue:blood) for toluene
in homogenates of rabbit tissues have been determined.- The parti-
tion coefficient for adipose tissue was 50 times greater, the
coefficient for bone marrow was approximately 15 times greater,
and those for brain and liver were roughly 2 times greater than
the partition coefficients for lung, kidney, heart, and muscle
(Sato, et al. 1974). Saturation of liver and brain tissue of mice
was not reached even after 3 hours of inhalation of concentrations
as high as 4000 ppm toluene (Bruckner and Peterson, 1976).
C. Metabolism
In humans and experimental animals, toluene is thought to
be enzymatically converted by the mixed function oxidase (MFO)
system to benzyl alcohol, which is subsequently oxidized to benzal-
dehyde and benzoic acid. Benzoic acid is then conjugated with
160-7
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glycine to form hippuric acid (U.S. EPA, 1979). There has also
been a report, however, of glucuronide conjugation of benzoic acid
in rabbits given large doses (Bray, et al. 1951). Toluene toxicity
is diminished in rats by MFO inducers (Ikeda and Ohtsuji, 1971) and
enhanced by MFO inhibitors (Koga and Ohmiya, 1978), suggesting that
metabolism of toluene 'results in detoxication.
. •
D. Excretion
Toluene is rapidly excreted from the body following
inhalation exposure. Most of the estimated absorbed dose of toluene
can be accounted for within the first.12 hours as the parent compound
in expired air and as hippuric acid in the urine (U.S. EPA, 1979).
Elimination rates are slower for women than for men, perhaps because
of the larger proportion of fatty tissue in women (U.S. EPA, 1979).
Excretion of toluene in experimental animals is similar
to that found in man. In the rat, for example, elimination of
toluene occurs more slowly from adipose tissue than from any other
(Pyykko, et al. 1977; Carlsson and Lindqvist, 1977), including bone
marrow, from which elimination is also relatively slow (U.S. EPA,
1979). Toluene is rapidly lost from the brain, as reflected in
rapid recovery from toluene-induced CNS depression (Peterson and
Bruckner, 1976; Savolainen, 1978).
•7
IV. EFFECTS
A. Carcinogenicity
The data base on the carcinogenic!ty of toluene is
extremely limited. No inhalation studies have been done. No
accounts have been found in the literature in which cancer in
160-8
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humans has been attributed specifically to toluene. . It is difficult
to link cancer -induction with any single solvent, as persons having
occupational exposure to solvents are characterized by considerable
job mobility and exposure to a variety of chemicals (D.S. EPA, 1979).
Toluene was .not demonstrated to be carcinogenic when applied to the
skin of mice for one year (Doak, el al. 1976) or throughout a life-
time (Poel, 1963) (since toluene evaporates rapidly, this method
is not appropriate). Toluene has not shown carcinogenicity when
administered to rats by inhalation at concentrations of up to
300 ppm, 6 hours/day, 5 days/week for as long as 18 months (Gibson,
1979). Frei and Kingsley (1968) reported that toluene has a weak
promoting effect on DMBA-initiated skin carcinogenesis in Swiss
mice. The major metabolite of toluene, benzole acid, is not
carcinogenic, however', .about 1 percent of toluene can be metabolized
to o- and p-cresol, which are cancer promoters (Boutwell and Bosch,
1959).
B. Mutagenicity
There is no conclusive evidence that toluene is mutagenic,
although it has been reported to cause chromosome damage. For
example, the incidence of chromosomal abnormalities in peripheral
blood lymphocytes of humans who had been exposed to an average of
200 ppm toluene for as long as 15 years was no greater than in
controls (Forni, et al. 1971). However, there have been two reports
that toluene induced chromosomal aberrations in the bone marrow
cells of rats (Lyapkalo, 1973; Dobrokhotov and Enikeev, 1977), and
typographers exposed to toluene have a slightly increased frequency
160-9
-------
of chromosome breaks as compared to controls (Funes-Cravloto et al.
1977). Toluene has not been tested in bacterial screening systems
(Dean, 1978).
C. Teratogenicity
Although toluene should readily pass the placenta, no
reports of teratogenic effects in humans are linked to toluene
exposure (U.S. EPA, 1979). Toluene is teratogenic and embryotoxic.
in mice (Nawrot and Staples, 1979). It was shown to be teratogenic
at 1..0 mg/kg, embryolethal at 0.3 ml/kg, and decreased fetal weight
occurred at 0.5 ml/kg. There was no maternal toxicity at any dose
level on days 6-15, but maternal weight gain was noted for doses
given on days 12-15.
D. Other Reproductive Effects
Women occupationally exposed to multiple solvents including
toluene through the use of varnishes had a relatively high incidence^
of menstrual disorders. Their offspring were said to experience
more frequent fetal asphyxia, to be more underweight, and not to
nurse as well as "normal" infants (Syrovadko, 1977). Dysmenorrhea
was a frequent subjective complaint of female shoemakers Chronically
exposed to 60-100 ppm toluene (Matsushita, et al, 1975). In a
single study, some retardation of body weight and skeletal growth
were seen in fetuses of rats exposed continuously to 399 ppm toluene
on days 1 to 8 of gestation; inhalation of lower levels of toluene
had no effect (Hudak and Ungvary, 1978).
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E. Chronic Toxicity
The toxicity of toluene was recently reviewed (Lohr and
Stokholm, 1979). Its major toxic effects are on the central nervous
system, causing depression, headaches, confusion, dizziness, insomnia
and (at high exposure levels) death.
A st'udy of 38 female shoemakers exposed chronically to
solvents including toluene at 60 to 100 ppm for about three years
revealed abnormal tendon reflexes, reduced grasping power, and
decreased finger agility when compared to controls (Matsushita,
et al., 1975). Reports reviewed by the National Institute for
Occupational Safety and Health (1973) have failed to demonstrate
adverse effects on the hematopoietic, hepatic, renal, or other
physiologic systems of workers routinely inhaling approximately 100
ppm toluene. Chronic exposure may also lead to disturbances in the
immune system, dermatitis, and permanent damage to the central
nervous system (Cohr and Stockholm., 1979; U.S. EPA, 1979).
F. Other Relevant Information
The primary hazard associated with acute exposure to high
levels of toluene is excessive CNS depression (U.S. EPA, 1979).
Toluene is capable of altering the metabolism and bioactlvity of
other chemicals which are metabolized by the mixed function oxidase
system. For example, simultaneous administration of toluene and
trichloroethylene or toluene and benzene to experimental animals
resulted in suppression of metabolism of both compounds (Ikeda,
1974; Ikeda, et al., 1972). Another showed marked reduction in the
concentration of benzene metabolites in various tissues, including
160-11
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bone marrow, after simultaneous administration of toluene, and
data that suggested that toluene might protect against benzene
myelotoxicity (Andrews, et al. , 1977).
V. AQUATIC TOXICITY
A. Acute Toxicity
For freshwater fish, 96-hour static LCso values ranged
from 12,700 ug/1 for the bluegill (Lepomis 'macrochirus) to 59,300
ug/1 for the guppy (Poecilia reticulatus) (U.S. EPA, 1978; Pickering
and Henderson, 1966). Only a single 48-hour LC5Q value for Daphnia
magna of 313,000 ug/1 has been obtained for toluene. In marine
fish, two 96-hour static LCso values of 6,300 and 10,000-50,000
ug/1 were obtained for striped bass (Morone saxatilis) and coho
salmon Oncorhynchus kisutch (Benville, et al., 1977). Among four
species of marine invertebrates, the bay shrimp (Crago franciseorum)
was most sensitive, with a 96-hour static LC5Q value of 3,700 ug/1
(Benville, et al., 1977), while the mysid shrimp Mysidopsis bahia
was most resistant, with a 96-hour static LC5Q value of 56,300 ug/1
(U.S. EPA, 1978).
B. Chronic Toxicity
No. freshwater chronic data could be found in the available
literature. The only marine chronic value reported was 2,166 ug/1
•i
for the sheepshead minnow (Cyprinodan variegatus) (U.S. EPA, 1978).
C. Plant Effects
The freshwater algae Chlorella vulgaris and Selenastrum
capricornutum were fairly insensitive to the action of toluene: EC5Q
values for cell numbers range from 245,000 ug/1 for Chlorella
160-12
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(Kauss and Hutchinson, 1975) to 433,000 ug/1 for Selenastrum
(U.S. EPA, 1978). Among five marine algal species tested, Skeletonema
/
costatum was the most sensitive with an adverse effect on growth at
8,000 ug/1 (Donstan, et al., 1975).
D. Residues
No bioconcentration factors are available for toluene in
freshwater or marine organisms.
VI. EXISTING GUIDELINES AND STANDARDS
Both the human health and aquatic criteria derived by U.S. EPA
(1979), which are summarized below, have not yet gone through the
process of public review; therefore, there is a possibility that
these criteria may be changed.
A. Human
The NIOSH (1973) recommended standard for exposure to
toluene is 100 ppm, determined as a time-weighted average for an
8-hour workday, with a ceiling of 200 ppm.
The U.S. EPA (1979) draft criterion for toluene in ambient
water is 12.4 mg/1, corresponding to a calculated acceptable daily
intake of 29.5 mg. This criterion is based on chronic toxicological
test data for rats (maximum no-effect level of 590 mg/kg, 5 days/wk)
and the application of an uncertainty factor of 1000.
B. Aquatic
The draft criterion for the protection of freshwater
organisms is 2,300 ug/1, as a 24-hour average, not to exceed 5,200
ug/1; and for marine life the draft criterion Is 100 ug/1, as a
24-hour average, not to exceed 230 ug/1.
160-13
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TOLUENE
REFERENCES
*
Andrews, L.S,, et al. 1977. Effects of toluene on the metabolism,
disposition and hemopoletic toxicity of (^H) benzene. Biochera.
Pharmacol. 26: 293.
Astrand, I., et al. 1972. Toluene exposure. I. Concentration
in alveolar air and bl'ood at rest and during exercise. Work Environ,
Health 9:- 119.
Benville, P.E., Jr., et al. 1977. The acute toxicity of six
monocyclic aromatic crude oil components to striped bass (Morone
saxatilis) and bay shrimp (Crago franeiscorum). Calif. Fish
Game. 63: 204. •
Boutwell, R.K., and D.K. Bosch. 1959. The tumor-promoting action
of phenols and related compounds for mouse skin. Cancer Res.
19: 413-424.
Bray, H.G., et al. 1951. Kinetic studies of the metabolism of
foreign organic compounds. I. The formation of benzole acid from
benzamide, toluene, benzyl alcohol and benzaldehyde and its conju-
gation with glycine and glucuronic acid in the rabbit. Biochem.
Jour. 48: 88.
Bruckner, J.V.t and R.G. Peterson. 1976. Evaluation of toluene
toxicity utilizing mouse as an animal model of solvent abuse.
Pharmacologist 18: 244.
Carlsson, A., and T. Lindqvist. 1977. Exposure of animals and
man to toluene. Scand. Jour. Work Environ. Health 3: 135.
Cohr, K.H., and J. Stockholm, 1979. Toluene, a toxicologic review.
Scand. J. Environ, and Health. 5: 71-90.
Dean, B.J. 1978. Genetic toxicology of benzene, toluene, xylene,
and phenols. Mutat. Res. 47: 75.
Doak, S.M.A., et al. 1976. The carcinogenic response in-mice to
the topical application of propane sultone to the skin.
Toxicology 6: 139.
Dobrokhotdv, V.B., and M.I. Enikeev. 1977. Mutagenic effect of
benzene, toluene, and a mixture of these hydrocarbons in a chronic
experiment. Gig. Sanit. 1: 32.
160-14
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TOLUENE
REFERENCES (Continued)
Dunstan-, W.M. , et al. 1975. Stimulation and inhibition of phyto-
plankton growth by low molecular weight hydrocarbons. Mar. Biol.
31: 305.
Dutkiewicz, T., and H. Tyras. 1963. The quantitative estimation
of toluene skin absorption in man. Int. Arch. Gewerbepath.
Gewerbehyg. 24': 253
Forni, A., et al. 1971. Chromosome studies in workers exposed to
benzene or toluene or both. Arch. Environ. Health 22: 373.
Frei, J. , and W.F. Kingsley. 1968. 'Observations on the chemically
induced regressing tumors of mouse epidermis. J. Natl. Cancer
Inst. 41: 1307-1313.
Funes-Cavioto, F., et al. 1977. Chromosomal aberrations and
sister-chromatid exchange in workers in chemical laboratories
and a rotoprinting factory and in children of women laboratory
workers. Lancet 2: 322-325.
Gibson, J.E. 1979. Chemical Industry Institute of Toxicology -
Two year vapor inhalation toxicity study with toluene in
Fischer-344 albino rats: 18-month status summary. (Personal
communication).
Grob, K. , and G. Grob. 1971. Gas-liquid chromatographic/mass
spectrometric investigation of Cg-C20 organic compounds in an
urban atmosphere. Jour. Chromatogr. 62: 1.
Hudak, A., and G. Ungvary. 1978. Embryotoxic effects of benzene
and its methyl derivatives: toluene and xylene. Toxicology
11: 55.
Ikeda, M. 1974. Reciprocal and metabolic inhibition of toluene
and trichloroethylene in vivo and in vitro. Int. Arch. Arbeitsmed.
33: 125.
Ikeda, M., and H. Ohtsuji. 1971. Phenobarbitol-induced protection
against toxicity of toluene and benzene in the rat. Toxicol. Appl.
Pharmacol. 20: 30.
Ikeda, M. , et al. 1972. In vivo suppression of benzene and styrene
oxidation by co-administered toluene in rats and effects of pheno-
barbitol. Xenobiotica 2: 101.
160-15
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TOLUENE
«
REFERENCES (Continued)
Kauss, P.B., and T.C. Hutchinson. 1975. The effects of water-
soluble petroleum components on the grown of Chlorella vulgaris
Beijernck. Environ. Pollut. 9: 157.
Kirk, R.E.', and D. Othmer. 1963. Kirk-Othmer Encyclopedia of
Chemical Technology. 2nd ed. John Wiley and Sons, Inc.,
New York.
Koga, K., and Y. Ohmiya. 1978. Potentiation of toluene toxicity
by hepatic enzyme inhibition in mice. Jour. Toxicol. Sci. 3: 25.
Lonneman, W.A., et al. 1968. Aromatic hydrocarbons in the atmos-
phere of the Los Angeles Basin. Environ. Sci. Technol. 2: 1017.
Lyapkalo, A.A. 1973. Genetic activity of benzene and toluene.
Gig. Tr. Prof. Zabol. 17: 24.
Mackay, D., and A.W. Wolkoff. 1973. Rate of evaporation of low-
solubility contaminants from water bodies to atmosphere. Environ.
Sci. Technol. 7: 611.
Matsushita, T., et al• 1975. Hematological and neuro-muscular
response of workers exposed to low concentration of toluene vapor.
Ind. Health 13: 115.
Nawrot, P.S., and R.E. Staples. 1979. Embryofetal toxicity and
teratogenicity of benzene and toluene in the mouse Teratology.
19: 419 (abstract).
National Institute for Occupational Safety and Health. 1973.
Criteria for a recommended standard...occupational exposure to
toluene. HEW Publ. No. HSM 73-11023. U.S. Government Printing
Office. Washington, D.C.
National Institute for Occupational Safety and Health. 1977.
Review, summarization and evaluation of literature to support the
update and revision of criteria documents. V. Toluene.
Ogata, M. , and Y. Miyake. 1973. Identification of substances in.
petroleum causing objectionable odor in fish. Water Res.
7: 1493.
Peterson, R.G., and J.V. Bruckner. 1976. Measurement of toluene
levels in animal tissues. Proc. Int. Symp. Deliberate Inhalation
of Industrial Solvents, Mexico City.
160-16
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TOLUENE
REFERENCES (Continued)
Pickering, Q.H., and C. Henderson. 1966. Acute toxicity of some
important petrochemicals to fish. Jour. Water Follut. Control
Fed. 38: 1419.
Filar, S., and W.F. "Graydon. 1973. Benzene and toluene distribu-
tion in Toronto atmosphere. Environ. Sci. Technol. 7: 628.
Poel, W.E. 1963. Skin as a test site for the bioassay of carcinogens
and carcinogen precursors. Natl. Cancer Inst. Monogr. 10: 611.
*
Pyykko, K. , e t. al. 1977. Toluene concentrations in various tissues
of rats after inhalation and oral administration. Arch. Toxlcol.
38: 169.
Sato, A., et al. 1974. Pharmacokinetics of benzene and toluene.
Int. Arch. Arbeitsmed. 33: 169.
Savolainen, H. 1978. Distribution and nervous system binding of
intraperitoneally injected toluene. Acta Pharmacol. Toxicol.
43: 78.
Shell, F.D., and L.S. Ettre. eds. 1971. Encyclopedia of Industrial
Chemical Analysis; Interscience Publishers, John Wiley and Sons,
Inc., New York.
Sutton, C., and J.A. Calder . 1975. Solubility of alkylbenzenes
in distilled water and seawater at 25 C. Jour. Chem. Eng. Data.
20: 320
Syrovadko, O.N. 1977. Working conditions and health status of
women handling organosiliceous varnishes containing toluene.
Gig. Tr . Prof. Zabol. 12:15.
U.S. EPA. 1975a. New Orleans area water supply study. Analysis
of carbon and resin extracts. Prepared and submitted to the lower
Mississippi River Branch, Surveillance and Analysis Division,
Region VI, by the Analytical Branch, Southeast Environ. Res. Lab.,
Athens, Ga.
U.S. EPA. 1975b. Preliminary assessment of suspected carcinogens
in drinking water. Report to Congress, Washington, D.C.
U.S. EPA. 1977. National Organic Monitoring Survey, general review
of results and methodology: Phases I-III.
160-17
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TOLUENE
REFERENCES (Continued)
U.S. EPA. 1978. In-depth studies on health and environmental
impacts of 'selected water pollutants. Contract No. 68-01-4646.
U.S. EPA. 1979. Toluene: ambient water quality criteria.
(Draft) • '
U.S. ITC, Annual. 1977. Synthetic Organic Chemicals, U.S.
Production and Sales. U.S. International Trade Commission,
Washington, D.C.
Wahlberg, J.E. 1976. Percutaneous toxicity of solvents. A
comparative Investigation in the guinea pig with benzene, toluene
and 1,1,2-trichloroethane. Ann. Occup. Hyg. 19: 115.
Walker, P. 1976. Air pollution assessment of toluene. MTR-7215,
Mitre Corp., McLean, Va.
Weast, R.C., et al. 1971. Handbook of chemistry and physics.
52nd ed. CRC Press, Cleveland, Ohio.
160-18
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No. 161
2* 4-Toluenedlamine
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-fttt-
lt>H
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal* The information contained in the report is drawn chiefly
from secondary sources and available reference documents..
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.. . !
-------
2,4-TOLUENEDIAMlNE
Summary
2,4-Toluenediamine produced carcinogenic effects in rats and mice in a
long-term National Cancer Institute (NCI) feeding study (50 pom; 100 ppm).
2,4-Toluenediamine was found to be mutagenic, using mutants, of Salmonella
typhimurium. hamster embryo cell systems, and Orosophila melanoqaster.
2,4-Toluenediamine was also found to be hepatotoxic to rats and mice in
the NCI study on carcinogenicity. The compound valso hastened the develo-
pment of chronic renal disease and accelerated animal morbidity. Data con-
cerning the teratogenicity of 2,4-toluenediamine was not found in the avail-
able literature. However, a closely related compound, the 2,5-diamino
analog, is teratogenic in mice.
111-3
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I.. INTRODUCTION
2,4-Toluenediamine (molecular weight 122.17) is white solid that
melts at 99,°C, has a boiling point of 292°C, a. density of 1.047 g/cm at
100°C, heat of vaporization of 27.975 kj/mol, heat of fusion of 19.874,
and a specific heat of 2*572 J/g at 150°C (Milligan and Gilbert, 1978).
This compound is very soluble in hot benzene, in hot water,'and in "both
alcohol and ether (Weast, 1971). The major use for 2,4-toluenediamine is in
the manufacture of 2,4-toluenediisocyanate (TOI), the major raw material for
the producton of flexible polyurethane foams and elastomers (Milligan and
Gilbert, 1978). The production of 2,4-toluenediamine has increased more
than 100 percent since 1966 and was reported in 1976 at 2.05 X 10 tons,
with a predicted growth rate of 8-12 percent per year (Milligan and Gilbert,
1973). 2,4-Toluenediamine can also be used in the manufacture, of dyes and
was an important ingredient in human hair dyes of the permanent,, oxidative
type until 1971, when its use was restricted after being implicated in the
induction of liver carcinomas in rats (Ito, et al. 1969). Using mutants of
Salmonella typhimurium, Ames, et al. (1975) found 2,4-toluenediamine to be
mutagenic.
II. EXPOSURE
Two potential sources of exposure to 2,4-toluenediamine are in its
manufacture and its use as an intermediate in the production of 2,4-toluene-
diisocyanate. 2,4-Toluenediamine is manufactured by seven U.S. companies at
nine U.S. locations (Muller, 1979; Gunn and Cooke,\1976), and most of the
corresponding diisocyanate is produced by the same companies at the same
locations. Capacity for the latter compound is 3.75 X 10 tons yearly
(Muller, 1979). Some additional amounts are consumed in the production of
dyes or are exported to manufacturers of 2,4-toluenediisocyanate outside the
United States. The amount consumed as a dye intermediate is believed to be
-------
quite small, and the magnitude of the exports of 2,4-toluenediamine is un-
known (Gunn and Cooke, 1976). Monitoring data are not available concerning
exposure to, 2,4-toluenediamine dermally or by water, food, inhalation.
Dermal carcinogenicity in mice is discussed below under "Effects" ("Chronic
Toxicity").
III. PHARMACOKINETICS
Information on the absorption, distribution, metabolism, and ex-
cretion of 2,4-toluenediamine was not found in the available literature..
IV. EFFECTS
A. Carcinogenicity
Carcinoma of the liver with invasion and metastases was observed
in rats fed diets containing 0.1 or 0.06 percent 2,4-toluenediamine (Ito, et
al. 1969).. When the compound was fed at levels of 50 and 100 ppm to inbred
barrier-raised F344 rats for 2 years, a statistically significant increase
was observed in the incidence of hepatic neoplasia in males, and it induced
a significant dose-related positive trend in the incidence of liver neo-
plasms in both sexes. Hepatocellular changes considered to be associated
with neoplasia were increased at a high level of statistical significance in
both sexes. The compound also caused statistically significant increases in
the incidence of mammary tumors in females, and an increase of mammary
tumors in males, although not significant statistically, was believed
related to the chemical (Cardy, 1979; Ulland, 1979). 2,4-Toluenediamine was
also carcinogenic for female B6C3F1 mice,. ' inducing hepatocellular
carcinomas. The incidence of lymphomas in the female mice suggested that
these tumors may have been related to administration of the test chemical as
well (Ulland, 1979).
-------
8. Mutagenicity
Fahmy and Fahmy (1977) conducted a comparative assay in Drosophila
melanqaster for the assessment of the mutagenic efficiency of the hair dye
components 2,4-toluenediamine and 4-nitro-o-phenylenediamine relative to
benzidine, a human carcinogen which, like 2,4-toluenediamine, is also an
aromatic amine.. All compounds showed mutagenicity activity.. Although-act-
ivities of the chemicals on the different genetic sites varied between com-
pounds and as a function of cell stage, mutagenic activity did not vary in
response to changes in dose. The mutagenicitiesf and selectivities of the
test compounds for ribosomal ONA gradually decreased in the order benzidine
greater than 2,4-toluenediamine greater than 4-nitro-o-phenylenediamine.
For 2,4-toluenediamine a good correlation was found between mutagenicity in
the Salmonella/microsome test and morphological transformation in a hamster
embryo cell system (Shah, et al. 1977). For mutagenesis, the compound re-
quired metabolic activation by a rat liver microsomal enzyme (S9) pre-
paration. In contrast, transformation of hamster cells was induced without
activation by external enzymes.. In the Ames assay there was no mutagenic
activity in the strain TA1QOV indicating that the product is not a base pair
mutagen. The dose response curves obtained with tester strain TA1538 and
TA98 show that 2,4-toluenediamine is metabolized by the S9 to a frameshift
mutagen (Shah, et al. 1977). In a study of the mutagenic effect of 2,4-
toluenediamine in mice, Scares and Lock (1978) found no significant increase
in dominant lethal mutations (seven weeks post-treatment) on males.
C. Teratogenicity
Data concerning the teratogenic effects of 2,4-toluenediamine. were
not found in the available literature. However, 2,5-toluenediamine, a
closely related compound which is a hair dye constituent, was found terato-
genic in mice (Inouye and Murakami, 1977).
-------
D» Other Reproductive Effects
Information on other reproductive effects- was not found in the
available literature.
E.. Chronic. Toxicity
Two reports primarily dealing with carcinogenicity provide infor-
mation on chronic toxicity. Cardy (1979) found that 2, 4-toluenediamine was
hepatotoxic when fed at levels of 50 and 100 ppm to inbred, barrier-raised
F344 rats for 2 years. The compound also accelerated the development of
chronic renal disease in the strain, an effect that contributed to a marked
decrease in the survival rate. Giles and Chung (1976), in a chronic
toxicity study of 2,.4-toluenediamine alone or in combination with selected.
hair dye. complexes, found the compound, to be nontoxic and noncarcinogenic to
the skin of mice.
F. Acute Toxicity '
Lewis and Tatken (1979) summarize the available information:
Oral-human LOQ: 50 mg/kg Subcutaneous-rat LDLQ: 50 mg/kg
Oral-rat LD : 500 mg/kg Subcutaneous-dog TD^: 200 mg/kg
Oral-rat TD: 11 g/kg Subcutaneous-dog LD: AGO mg/kg
where LDQ— lethal dose to all animals; TDLQ—lowest toxic dose (other
than inhalation); LD^-- the lowest published lethal dose (other than
LD50) introduced by any other route than inhalation.
G.. Other Relevant Information
Except as reported above, no additional information was found on
the effects of 2, 4-toluenediamine.
-------
V. AQUATIC. TOXICITY
A. Acute Toxicity, Chronic Toxicity, Plant Effects, and Other
Relevant Information.
NO information was found in the available literature on acute
toxicity, chronic toxicity, plant effects, and other relevant information.
B. Residues
Veith,. et al.. (1979), in a method of estimating the bioconcen-
tration factor of organic chemicals in fathead minnows (Pimephales
promelas), report a log bibcentration factor of 1.96 and log n-octanol/water
partition coefficient of 3.16* for the fathead minnow in 32 days' exposure.
A structure-activity correlation between the bioconcentration factor (BCF)
and the n-octanol/water partition coefficient (P) is expressed by the
equation—log BCF = 0.85 log P-70.. According to the authors,, this permits
the estimation of the bioconcentration factor of chemicals to within 60 per-
cent before laboratory testing..
VI.. EXISTING GUIDELINES AND STANDARDS
NO existing guidelines or standards were found in the available
literature..
*Under the same conditions the log n-octanol/water partition coefficient for
heptachlor was 5.&A; for hexachlorobenzene, 5.23; for mirex, 6.89; and for
dipheylamine, 3.42.
-------
REFERENCES
Ames, B.N., et al. 1975. Hair dyes are mutagenic: Identification of a
variety of mutagenic ingredients. Proc. Nat. Acad. Sci. U.S.A. 72: 2423.
Cardy, R.H. 1979. Carcinogenicity and chronic toxicity of 2,4-toluene-
diamine in F344 rats. Jour. Natl. Cancer Inst. 62: 1107.
Fahmy , M.J. and O.G. Fahmy. 1977. Mutagenicity of hair dye components
relative to the carcinogen benzidine- in Drosphila melanoqaster. Mutat.
Res. 56: 31.
Giles, A.L. and C.W. Chung. 1976. Dermal carcinogenicity study by mouse-
skin painting with 2,4-toluenediamine alone or in representative hair dye
formulations. Jour. Toxicol. Environ. Health. 1: 433.
\
Gunn, T.C. and s. Cooke. 1976.. Toluene In: Chemical Economics Handbook.
Stan- ford Research Institute, p. 696.5033.
Inouye, M. and U. Murakami. 1977. Teratogenicity of 2,5-diaminotoluene, a
hair-dye constituent in mice. Fd. Cosmet. Toxicol. 15: 447.
Ito, N., et al. 1969. The development of carcinoma in liver of rats
treated with m-toluylenediamine and the synergistic effects with other chem-
icals. Cancer Res. 29: 1137.
Lewis, R.J. and R.L. Tatken. 1979. Registry of Toxic Effects of Chemical
Substances. National Institute for Occupational Safety and Health,
Cincinnati, Ohio.
.Milligan, 8. and K.E. Gilbert. 1978. Amines, aromatic (diaminotoluenes).
Vol. 2., p. 321. In: M. Grayson (ed.), Encyclopedia of Chemical Tech-
nology. 3rd ed. John Wiley 4 Sons, New York.
Muller, R.G. 1979. Directory of Chemical Producers. Stanford Research In-
stitute.
Shah, M.J., et al. 1977. Comparative studies of bacterial mutation and
hamster cell transformation induced by 2,4-toluenediamine. Am. Assoc.
Cancer Res. Proc. 18: 23.
Scares, E.R. and L.F. Lock. 1978. The mutagenic effect of 2,4-dinitro-
toluene and 2,4-diaminotoluene in mice. Pharmacologist. 20: 155.
Ulland, B. 1979. Bioassay of 2,4-diaminotoluene, for possible carcino-
genicity. NCI-CG-TR-162. U. S. Department of Health, Education and Wel-
fare. National Institute of Health. U.S. OHEW Pub. No. (NIH) 79-1718. -
Veith, G.D., et al. 1979. Measuring and estimating bioconcentration factor
of chemicals in fish. Jour. Fish. Res. Board Canada. 36: 1040.
Weast, R.C. 1971. Handbook of Chemistry and Physics. 51st ed. Chemical
Rubber Co., Cleveland, Ohio.
fl77 (\ —
"fr~)j -
161-1
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PS:33-01
No. 162
Toluene Diisocyanate
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OCTOBER 30, 1980
162-1
-------
DISCLAIMER
This report, represents a survey of the potential health
and environmental hazards from exposure to the subject
chemical. The information contained in the report is drawn
chiefly from secondary sources and available reference
documents. Because of the limitations of such sources/ this
short profile may not reflect all available information
including all the adverse health and environmental impacts
presented by the subject chemical. This document has undergone
scrutiny to ensure its technical accuracy.
162-^
-------
PS:33-01
TOLUENE DIISOCYANATE
Summary
Toluene diisocyanate (TDI) is used in the manufacture of
polyurethane foam. TDI is formed through the reaction of 2,4-
toluenediamine with phosgene. The TDI is then reacted with
di- and poly-functional hydroxy compounds to form polyurethane
foam.
TDI is readily reactive in water, forming carbon dioxide
and polyurea derivatives. Environmental occurence of TDI is
unlikely due to its high reactivity with hydroxy compounds
and peroxy radicals.
Information on the teratogenicity of toluene diisocyanate
was not found in the available literature. TDI after being
tested by the National Cancer Institute for carcinogenicity
using a standard bioassay protocol, was found not be
carcinogenic. Additionally, toluene diisocyanate did not
show mutagenic activity on testing of Salmonell typhimurium
* ~
strains with and without a mammalian liver microsome activating
system.
Extensive toxicologic data exists for TDI, primarily
from occupational exposure studies. TDI produces respiratory
effects, including mucous membrane irritation, bronchoconstriction,
coughing, and wheezing. Exposure to high concentrations can
result in pulmonary edema or death.
162-3
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The effects of chronic, low-level exposure to TDI vary.
Decreased lung function has been reported from inhalation
of 0.003 ppm TDI, but. other investigators have not seen these
respiratory effects from inhalation of 0.02 ppm TDI.
Hypersensitivity'to TDI has also been observed from occupational
respiratory exposure* Immunologic and pharmacologic reactions
have been proposed as the mechanism of action of TDI.
Other reported effects include memory loss, psychological
disturbances, and skin irritation. Uncertainty exists regard-
ing the frequency of these effects in those occupationally
exposed. Maintaining exposure below 0.005 ppm has proven
effective in protecting health of unsensitized workers.
Where an individual has previously been sensitized, a no-
threshold effect is indicated upon subsequent exposure to
TDI.
162-4
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TOLUENE DIISOCYANTE
• Environmental Fat®
Toluene diisocyanate (TDI) readily reacts with hydroxy
compounds. Its atmospheric half-life is approximately three
days (Brown-, et al. 1975). TDI readily hydrolyzes in neutral
aqueous media, or more rapidly under acidic or basic conditions,
to give unstable carbamic acids (Tennant, 1979). These acids
tend to lose carbon dioxide, giving the corresponding amine
which, in turn, reacts with the starting isocyanate to produce
a urea derivative. This reaction produces a concurrent
decrease in pH (Curtis, et al. 1979). TDI readily hydrolyzes
in water, and has a half-life of 0.5 seconds to 3 days, depending
on pH (Brown, et al., 1975). As temperature increases the
reaction becomes more vigorous (Tennant, 1979).
Brown, et al. (1975) concluded that because of the
short lifetime of toluene diisocyanate in water, its occurrence
in this medium is unlikely.
' Toluene diisocyanate is persistent in the atmosphere.
Under atmospheric conditions reaction with ozone leads to an
atmospheric half-life of 3,981 days. The reaction of TDI
with peroxyradical groups has an environmental half-life of
approximately 7.94 x 105 days in the water phase.
162-5
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I. INTRODUCTION
This profile is based upon relevant literature identified
through bibliographic searches in TOXLINE and Chemical
Abstracts, and through manual searches. The National Insti-
tute for Occupational Sefety and Health (NIOSH) has published
a criteria document for diisocyanates (NIOSH-, 1978). This
report represents a comprehensive review of the available
toxicologic literature on toluene diisocyanate (TDI) and was
the source for much of the data described below.
Toluene diisocyanate is also reported as 2,4-diisocyanate-
1-methylbenzene, tolylene diisocyanate, raethylphenylene
isocyanate, diisocyanotoluene, and stilbene diisocyanate.
The compound is a colorless-to-pale yellow liquid. The
chemical formula is CgHgN202. Physical properties of TDI are
as follows: molecular weight, 174.16; melting point, 20 to
22°C; boiling point, 251eC; vapor pressure, 0.05 ram Hg at
25'C; and specific gravity, 1.22 at 25°C (NIOSH, 1978). TDI
is soluble aromatic hydrocarbons, nitrobenzene, acetone,
ethers, and esters.
The most common method of synthesizing toluene diisocyanate
is through the primary reaction of diaminotoluene with
phosgene. Toluene diisocyanate is then reacted with di- and
poly-functional hydroxy compounds to form poly-urethane foams»
coatings, elastomers, and spandex fibers (NIOSH, 1978).
162-6
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Toluene diisocyanate production in the U.S. was 605
million pounds (Predicasts, Inc., 1980) in 1978, with an
estimated 6.4 percent annual growth in production. Production
capacity amounted to 775 million pounds per year in 1978.
II. EXPOSURE '
Respiratory and dermal exposure to toluene diisocyanate
has been well documented in occupation environments (NIOSH,
1978). Sources of occupational exposures include production
processes of basic TDI manufacture, production of polyurethane
foam, and accidental releases or spills in product synthesis,
transportation, use, or disposal.
Non-occupational exposure to TDI through ingestion of
contaminated food or water is unlikely since TDI released to
the environment would readily react with other compounds,
forming stable polyurea end products. For example, Curtis,
et al. (1979) conducted acute aquatic toxicity studies of TDI
and reported the immediate reaction of TDI with water resulting
in the production of carbon dioxide and a polyurethane foam-
like solid. Human exposures would most likely occur to these
polyurea compounds and not TDI. Accidental releases and
spills may result in respiratory TDI exposure vof persons in
the immediate vicinity. Dermal exposure may also occur in
persons coming in direct contact with the compound.
162-7
-------
III. PHARMACOKINETICS
Information on the abosrption, distribution/ metabolism,
and excretion of TDI was not identified in the available
literature. NIOSH (1978), in describing the sensitization
phenomenon of TDI exposure, hypothesized that this response
may be the result of TDI reaction with in vivo hydroxyl,
amino, sulfhydryl, or similar compounds which form a hapten
complex with TDI. This complex is believed to be responsible
for the sensitization of individuals to TDI.
162-8
-------
IV. EFFECTS
A. •Carcinogenicity
TDI did not show carcinogenic activity after being
tested by NCI using a standard bioassay protocol.
B. Mutagenicity
Toluene diisocyanate did not show mutagenic activity
on testing Salmonella typhimurium strains with or without a
mammalian liver microsome activating system -(NIOSH, 1978).
C. Teratogenicity and Other Reproductive Effects
Information on teratogenic or other reproductive
effects of toluene diisocyanate was not found in the available
literature.
D. Chronic Effects
Inhalation of toluene diisocyanate represents the
primary route of exposure and produces chronic effects; the
mechanism of the chronic respiratory changes is uncertain.
Toluene diisocyanate induces a hypersensitive reaction
in specific individuals. Predisposing factors may include
*
both environmental and endogenous host factors (AdTcinson,
1977). Intensity and duration of exposure are important in
eliciting a hypersensitive reaction. Genetic factors
controlling immune responsiveness, metabolic aberration were
suggested as factors influencing the allergic reaction
(Adkinson, 1977). However, Butcher, et al. (1976) found no
pattern of prior hay fever or asthama, or of skin sensitization
in clinically sensitized individuals.
162-9
-------
Exposure to high concentrations has caused respiratory
sensitization in workers (Walworth and Virchow, 1959; Bruckner,
et al. 1968). These sensitization reactions were described
earlier. The sensitization can progress to a condition
resembling chronic bronchitis and pulmonary edema. Individuals
sensitized to TDI present an asthmatic reaction upon reexposure
to very low concentrations of TDI. Butcher, et al. (1979)
described four specific types of responses in hypersensitive
workers: (1) immediate; (2) late; (3) dual; and (4) dose-
related. The responses were measured as percent change in
one-second Forced Expiratory Volume (PEV]_) over time.
Immediate response occurred within one hour of exposure,
whereas late response exhibited a gradual decline in FEVi
over five hours. The dual response elicited an early response
within one hour and a late response after eight hours. The
dose-related response was exhibited at 0.01 ppm, whereas
exposure to 0.005 ppm did not. show a significant decrease in
FEVi-. T*16 author suggested a pharmacologic basis for the
hypersensitivity, but noted that an allergic mechanism could
not be ruled out.
Porter, et al. (1975) reported sensitization correlated
with the frequency and severity of significant exposures
greater than 0.05 ppm. Once sensitized, an individual exposed
to very low concentrations of TDI will produce asthmatic
reactions upon subsequent TDI exposure.
162-10
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Wegman (1977) reported decrements in FEVi in both
sensitized and unsensitized workers. However, Adams (1975)
and Butcher, et,al. (1977) did not show decreased FEV^ after
occupational exposures of 11 and 2.5 years, respectively.
TDI concentrations were 0.02 ppm and below, with occasional
excursions above this level» Consequently, the National
Institute for Occupational Safety and Health (NIOSH) recommended
an eight hour time-weighted average limit of 5 ppb, noting
that the above studies and others had not reported significant
effects on lung function at concentrations of 14-50 ug/m3
(2.0-7.0 ppb).
Some authors have reported skin sensitization in persons
occupationally exposed to TDI (Nava, et al. 1975; Karol, et al.
1978), but other investigators have not observed such skin
sensitization reactions (Munn, I960.; Bruckner, et al. 1968).
Other chronic effects from TDI exposure include neurologic
effects, eye irritation, and psychological symptoms. Le
Quesne, et al. (1976) reported memory loss lasting 4 years in
«
workers exposed to massive concentrations of TDI while fighting
a fire at a polyurethane foam factory.
F. Acute Effects
Inhalation of TDI is the primary route of exposure
which has demonstrated acute effects. Several authors have
reported daily and cumulative decreases in lung function
following respiratory exposure to TDI. Investigations of
162-11
-------
acute effects from TDI exposure have produced contradictory
results. * Peters, et al. (1968) reported significant decreases
in lung function upon exposure to 0.1-3.0 ppb, whereas Adams
(1975) noted no significant decrease in lung function at 20
ppb.
Occupational exposure to high concentrations of TDI
causes direct irritation of the respiratory tract (Walworth
and Virchow, 1959; Maxon, 1964; Axford, et al. 1976? Gandevia,
1963).
Eye, nose, and throat irritation was observed upon
atmospheric exposures to 500 ppb (Henschler, lf62). Nausea,
vomiting, and abdominal pain may also occur (Key, et al.
1977). Dermal contact with liquid TDI may produce redness,
swelling, and blistering. Contact with eyes may produce
severe irritation and permanent damage. Ingestion of TDI may
cause burns of the mouth and stomach (Key, et al. 1977).
Lewis and Tatken (1979) reported an inhalation LCso for
rats' of 600 ppm following a 6-hour exposure; and an inhalation
f°r mice. of- 10 ppm following a 4-hour exposure.
V. AQUATIC TOXICITY
A. Acute Toxic ity
Curtis, et al. (1979) reported a 96-hour LCso of
164.5 mg/1 in the fathead minnow (Pimephales promelas). No
significant mortality was noted in grass shrimp (Palaemonetes
pugio) exposed to 508.3 mg/1. The authors noted that TDI
162-12
-------
reacted with water of dilution, and concluded that TDI was
toxic to 'the fathead minnow in the unreacted form only, as
evidenced by all mortalities occurring during the first 12
hours of the test. However, the authors did note that a
concurrent decrease in pH was observed as a result of carbon
dioxide formation from TDI reactivity. Lewis and Tatken
(1979) reported an aquatic toxicity rating, TLmgg (equivalent
to a 96-hour LCso)' of 1.0-10.0 ppm. Thus TDI has moderate
acute toxicity to aquatic organisms.
B. Chronic Toxicity, Plant Effects, and Residues
Pertinent data could not be located in the available
literature.
VI. EXISTING GUIDELINES AND STANDARDS
The Occupational Safety and Health Administration (OSHA)
regulates TDI by specifying a PEL for airborne TDI of 0.14
mg/ m3 (40 CPR 1910.1000) as a 15-minute exposure.
The American Conference of Governmental Industrial
Hygienists (1979) has recommended a threshold limit value-time
weighted average for toluene diisocyanate of 5 ppb (0.04
mg/m3). NIOSH (1978) recommended a time-weighted-average
limit-for airborne toluene diisocyanate of 5 ppb, with a
ceiling value of 20 ppb. NIOSH (1978) also reported occupa-
tional exposure limits for TDI in numerous countries. These
limits ranged from 0.07 to 0.5 mg/m3.
162-13
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TOLUENE DIISOCYANATE
References
Adams, W.G.F. 1975. Long-term effects on the health of
men engaged in the manufacture of tolylene di-isocyanate.
Br. Jour. Ind. Med. 32: 72.
. *
Adkinson, N.F. 1977. Environmental influences on the
immune system and allergic responses. Environ. Health
Perspect. 20: 97.
American Conference of Governmental Industrial Hygienists.
1979. Threshold limit values for chemical substances and
physical agents in the workroom environment with intended
changes for 1979. American Conference of Governmental
Industrial Hygienists. Cincinnati, Ohio, p. 94.
Axford, A.T., et al. 1976. Accidental exposure to
isocyanate fumes in a group of firemen. Br. Jour. Ind.
Med. 3: 65.
Brown, S.L., et al. 1975. Research program on hazard
priority ranking of manufactured chemicals. Phase II-
Final Report. NTIS PB-263162.
Bruckner, H.C. , et al. 1968. Clinical and inununologic
appraisal of workers exposed to diisocyanates. Arch.
Environ. Health 16: 619.
Butcher, B.T., et al. 1976. Toluene diisocyante (TDI)
pulmonary disease—immunologic and inhalation challenge
studies. Jour. Allergy. Clin. Immunol. 58: 89.
Butcher, B.T., et al. 1977. Longitudinal study of workers
employed in the manufacture of toluene-diisocyanate. Am.
Rev. Resp. Dis. 116: 411.
Butcher, B.T., et al. 1979. Inhalation challenge and
pharmacologic studies of toluene diisocyanate (TDI)—
sensitive workers. Jour. Allergy. Clin. "Immunol.
64: 146.•
Curtis, M.W., et al. 1979. Acute toxicity of 12 industrial
chemicals to freshwater and saltwater organisms. Water
Res. 13: 137.
162-14
-------
Gandevia, B. 1963. Studies of ventilatory capacity and
histamine response during exposure to isocyante vapour
in polyurethane 'foam manufacture. Br. Jour. Ind. Med.
20: 204.
Henschler, D'., et al. 1962. The toxicology of the
toluene diisocyanates. Arch. Toxicol. 19: 364.
Karol, M.H., et al. "1978. Tolyl-specific IgE antibodies
in workers with hypersensitivity to toluene diisocyanate.
Am. Ind. Hyg. Assoc. Jour. 39: 454.
Key, M.M., et al. 1977. Occupational diseases—a guide
to their recognition. National Institute for Occupational
Safety and Health. Cincinnati, Ohio. p. 233.
LeQuesne, P.M., et al. 1976. Neurological complications
after a single exposure to toluene diisocyanate. Br.
Jour. Ind. Med. 33: 72.
Lewis, R.J. and R.L. Tatken (ed.) 1979. Registry of
toxic effects of chemical substances. National Institute
for Occupational Safety and Health. Cincinnati, Ohio-.
U.S. Government Printing Office, Washington, D.C., p. 180.
Maxon, F.L. 1964. Respiratory irritation from toluene
diisocyanate. Arch. Environ. Health. 8: 755.
Munn, A. 1960. Experience with diisocyanates. Trans.
Assoc. Ind. Med. Off. 9: 134.
National Institute for Occupational Safety adn Health.
1978. Criteria for a recommended standard: Occupational
exposure to diisocyanates. National Institute for
Occupational Safety and Health. Cincinnati, Ohio, p. 138.
Nava, C., et al. 1975. Pathology produced by isocyanates-
raehtods of immunological investigation. Ric. Clin. Lab.
5: 135.
Peters, J.M., et al. 1968. Acute respiratory effects in
workers exposed to low levels of toluene diisocyanted (TDI.
Arch. Environ. Health. 16:642.
Porter, C.V., et al. 1975. A retrospective study of
clinical, physiologic and immunologic changes in workers
exposed to toluene diisocyanate. Am. Ind. Hyg. Assoc.
Jour. 36: 159.
Predicasts, Inc. 1980. Predicast No. 78 (2nd Quarter)
Jan. 18, 1980. Predicasts Inc., Cleveland Ohio.
162-15
-------
Tennant, G. 1979. Imines, nitrones, nitriles and
isocyanates. In; D. Barton, W.d. Ollis (eds.) Compre-
hensive Organic Chemistry, Vol. 2: Nitrogen compounds,
carboxylic acids, phosphorus compounds. Pergamon Press*
New York, p. 521.
Walworth, H.T. and W.E. Virchow. 1959. Industrial
hygiene experience with toluene diisocyanate. Am. Ind.
Hyg. Assoc. Jour. 20: 205.
Wegman, D.H,, et al. 1977. Chronic pulmohary function
loss from exposure to toluene diisocyanate. Br. Jour.
Ind. Med. 34: 196.
162-16
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No. 163
Toxaphene
Health and Environmental Effects
U.S.. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards front exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
O.S. EPA1s Carcinogen Assessment Group (GAG) has evaluated
toxaphene and has found sufficient evidence to indicate
that this compound is carcinogenic..
-------
TOXAPHENE
SUMMARY
Toxaphene is a mixture of polychlorinated camphenes.
It is obtained from camphene by photochemical chlorination,
which produces a heterogeneous mixture of chemicals (177)
containing 67 to 69" percent chlorine. Toxaphene has not
produced tec.at.og.en.ic effects in laboratory animals, but
has been found to be mutagenic in two strains of Salmonella
typhimurium with metabolic activation. A National Cancer
—i»a^—^—«-"^—• \
Institute (NCI) 1979 -study found that toxaphene signifi-
cantly increased the incidences of hepatocellular carcinomas
in mice.
The. insecticide, toxaphene has been demonstrated to
be a potent toxin to a variety of aquatic life. For both
freshwater and marine fish species, acute toxicity values
of 0.8 to 28 ug/1 were reported. Marine invertebrate species
displayed considerable interspecies variation, with LC5Q
values ranging from 0.08 to 2,700 jig/1..
-------
TOXAPHENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria document for Toxaphene (U.S. EPA, 1979).
Toxaphene is a commercially produced, broad spectrum,
chlorinated hydrocarbon consisting primarily of chlorinated
camphene and related compounds and. isomers. It is currently
the most heavily used insecticide in the U.S., with an annual
production rate exceeding 50 x 10 tons (-U.S. EPA, 1979).
On May 25, 1977, because of its carcinogenic effects,
aquatic toxicity, and high bioconcentration factor, the
U.S.. EPA issued a notice of rebuttable presumption against
registration and continued registration of pesticide pro-
ducts containing toxaphene.
Toxaphene is an amber, waxy solid with a mild terpene
odor and an average molecular weight of 414. Its physical
properties include: melting point of 65-90°C; vapor pres-
sure, 0.17-0.40 ram Hg at 25°C; solubility in. water, 0.4-
3.0 mg/1; and is soluble in relatively non-polar solvents,
with an octanol/water partition coefficient of 825 (U.S
EPA, 1979).
The commercial product is relatively stable but may
dehydrochlorinate upon prolonged exposure to sunlight, alkali,
or temperatures above 120°C (Metcalf, 1966';-. Brooks, 1974).
In natural water systems, toxaphene tends to be absorbed
by the particulates present or to be taken up by living
organisms and bioconcentrated. Thus, it is seldom found
as a soluble component in receiving waters but can persist
y
-------
in sediments oc remain absorbed on suspended solids for
prolonged periods (U.S. EPA, 1979).
II. EXPOSURE
A. Water
Toxaphene has been monitored in the U.S. since
1959. Although it has been detected at several locations,
it is not found in all'waters (U.S. EPA, 1979). Seven rou-
tine monitoring studies of U.S., surface water prior to 1975
did not detect toxaphene (U.S. EPA, 1.B19) ."
Nicholson, et al. (1964, 1966) detected toxaphene
in the drink-ing water obtained from Alabama at levels rang-
ing from 0.01-0.1 ug/1. A survey of commercial drinking
water samples by the U.S. EPA (1976a) during 1975 and 1976
found no detectable levels of toxaphene (limit of detection
0.05 ug/1).
Toxaphene has been detected in water around areas
where it is applied to crops as an insecticide. For example,
it has been detected in surface waters in California at
levels ranging from 0.02 to 7.9 jig/1, and in drainage ef-
fluents at levels of 0.130 to 0.950 ;ag/l (Johnston, et al.
1967; Bailey and Hammon, 1967). Several studies of an agri-
cultural watershed in Alabama found that treatment of drink-
ing water, did not reduce toxaphene concentrations (U.S.
EPA, 1979) . ';.
Toxaphene has been detected in the sediment samples
of various waters even when it is not found in samples of *
the surface waters (Mattraw, 1975). Concentrations as high
as 2.46 ug/1 have been found in sediments (U.S. EPA, 1979).
-------
Sediment samples at three locations downstream of a plant
producing toxaphene had a maximum- residue level of 15 ;ig/l
toxaphene before dredging (Reimold and Durant, 1972) .
B. Food
The best available estimate of dietary intake
of toxaphene is 0.021 pg/kg/day, based on the U.S. Food
and Drug Administration basket survey between 1964 and 1970
(Duggan and Corneliussen, 1972) . Based on recent market
basket, surveys indicating a decrease in the incidence of
toxaphene contamination, a stable incidence of toxaphene
in raw meat since 1969, and a two-fold increase in the inci-
dence of toxaphene in unprocessed food samples between 1972
and 1976, the U.S. EPA (1979) estimates the current dietary
intake to be 0.042 jag/kg/day.
The U.S. EPA (1979) has estimated the weighted
average bioconcentration factor for toxaphene to be 18,000
for the edible portions of fish and shellfish consumed by
Americans. This estimate was based on the measured steady-
state bioconcentration studies in five species of fish and
shellfish.
C. Inhalation
The highest toxaphene residues in air have been
found in areas where toxaphene is applied for agricultural
purposes (especially cotton production in the Southern U.S.)
(U.S. EPA, 1979). Studies indicate that airborne residues
are highest during cotton growing season and decrease to
low levels after harvesting, but spring tilling releases
/61-7
-------
soil residues to the air. Concentrations ranging from 0
to 2520 ng/m have been measured in southern agricultural
areas (Arthur, et al. 1976; Stanley, et al.. 1971.) Mean
monthly concentrations have been measured as high as 167
ng/m3 (Arthur, et al. 1976).
Toxaphene* has also been monitored in the atmos-
phere over the east coast near Bermuda and the open ocean
(Bidleman and Olney, 1975). The mean concentrations were
0.79 and 0.53 ng/m , respectively. Using .the maximum mean
monthly concentration of 167 ng/m (Arthur, et al. 1976),
the average daily dose of toxaphene from air is. approximately
0.057 ug/kg (U.S. EPA, 1979)* This amount would reflect
intake at a high toxaphene use area, whereas a more conserva-
tive value using a concentration of 0.53 ng/m monitored
over open ocean (Bidleman and Olney, 1975)' would be an aver-
age da-ily intake of 0.18 ng/kg of toxaphene from air (U.S.
EPA, 1979).
0. Dermal
Toxicity studies with laboratory animals indicate
that toxaphene can be absorbed across the skin in toxic
amounts by humans (U.S. EPA, 1979). Incidence of dermal.
absorption of toxaphene by humans is restricted to occupa-
tional or accidental exposure.
III. PHARMACOKINETICS
A. Absorption
The recently completed U.S. EPA (1978) study sug-
»
gests that inhalation exposures to toxaphene do not result
in sufficient absorption by humans to cause quantifiable
levels in the blood.
-------
Animal studies show absorption of toxaphene across
the alimentary tract, skin, and respiratory tract, as indi-
cated by adverse effects elicited by oral, dermal, and in-
halation exposures (U.S. EPA, 1979). The. vehicle and mode
of administration, as well as individual differences, affect
the rate of absorption of toxaphene. The ratio of oral
LDeg- to. dermal LDgQ (in comparable lipophilic solvents) is
about 0.1 (Lackey, 1949a,b; Conley, 1952; U.S. EPA, 1979).
B. Distribution N
Toxaphene is readily distributed throughout the
body, with highest residues found in fat tissue. Three
hours after single intubations of Cl-36 labelled toxaphene,
rats had .detectable levels of Cl-36 activity in all tissues
examined (kidney, muscle, fat, testes, brain, blood, liver,
intestines, esophagus, spleen, and stomach), with the highest
levels being found in the stomach and blood (Crowder and
Dindal, 1974.) After 9 to 14 days, most of the activity
is found in the fat, blood, kidney, liver, and intestines
(Crowder and Dindal, 1974; Ohsawa, et al. 1975). The pre-
dominance of fat storage had been demonstrated in 12-week
feeding studies with rats, and 2-year feeding studies with
rats and dogs (Clapp, et al. 1971; Lehman, 1952; Hercules,
Inc., undated). In the above studies, toxaphene residues
were highest in fat tissues but always remained below the
levels administered in the diet, thus suggesting that toxa-
phene is not biomagnified in terrestrial organisms (U.S.
EPA, 1979).
-------
C. Metabolism
Toxaphene undergoes reductive dechlorination,
dehydrochlorination, and hydroxylation in mammalian systems
(U.S. EPA,' 1979). Studies by Crowder and Dindal (1974),
Ohsawa, et al. (197.5) and Khalifa, et al. (1976) have ob-
served 50 percent dechlorination of toxaphene after adminis-
tration by intubation to rats, or iri vitro with rat liver
microsomes and NADPH under anaerobic conditions. Toxaphene
has been suggested as a substrate for the hepatic microsomal
mixed-function oxidases because of type I binding spectra
with cytochrome P-450, and NADPH dependence (Kulkarni, et
al- 1975; Chandurkar, 1977).
Several investigators have noted that fat residues
of toxaphene resemble whole toxaphene, while residues in
both the liver and feces are consistently more polar (Pollock,
1978; Saleh, et al. 1977).
D. Excretion
The half-life of C-14 or Cl-36 labelled toxaphene
in rats after single oral doses appears to be from one to
three days, with most of the excretion occurring via the
urine and feces (Crowder and Dindal, 1974; Ohsawa, et al.
1975), Only a small portion of the: urine and fecal metabo-
lites is eliminated as glucuronide or sulfate conjugates
(Chandurkar, 1977).
A study of the blood levels of toxaphene in an
individual consuming contaminated fish (52 pg toxaphene/g
fish) revealed levels of 142 ppb, 47 ppb,<30 ppb on day
1, day 11, and day 14 of measurement (U.S. SPA, 1978).
-------
IV. EFFECTS
A. Carcinogenicity
The National Cancer Institute (1979) has recently
completed a carcinogenicity bioassay of toxaphene. The
80-week feeding study did not follow current NCI standards;
only ten animals were used in each matched control groupr
and: matched-fed control groups were not utilized (NCI, 1977).
The feeding schedule was as follows: for rats - males, time
weighted average (TWA) doses at 556 mg/kg and 1,112 mg/kg,
%
and females, TWA doses at 540 mg/kg and 1,080 mg/kg; and for
mice, males and females, TWA doses at 99 mg/kg and 198 mg/kg.
In male rats in the high dose group, a significant
increase was noted in the incidence of follicular-cell car-
cinomas and adenomas of the thyroid. Of the nine thyroid
tumors which were found in this group, two were carcinomas.
A^ significant increase of follicular-cell. adenomas of the
thyroid was also noted in the high-dose group of female
rats. No carcinomas of the thyroid were found in this group.
In both of these groups, the development of thyroid tumors
was dose-related-
In both male and female mice, significant increases
were noted in the incidence of hepatocellular carcinomas
and in the incidence of hepatocellular carcinomas combined
with neoplastic nodules of the liver.
Based on the results of this study, the National
Cancer Institute has concluded that "Toxaphene was carcino-..
genie in male and female B6C3F1 mice, causing increased
-------
incidences of hepatocellular carcinomas. The test results
also suggest carcinogenicity of tbxaphene for the thyroid
of male and female Osborne-Mendel rats" (NCI, 1979).
Litton Bionetics, Inc. (1978) also reported a
significant excess of hepatocellular tumors (hepatocellular
adenoma plus hepatocellular carcinoma) in male mice fed
dietary levels of 50 ppm toxaphene.
B. Mutagenicity
The mutagenicity of toxaphene has been tested
in bacterial systems using Salmonella typhimurium strains
TA153S, TA1S37, TA1538, TA98, and TA100 (Hill, 1977). Posi-
tive test results were obtained for strains TA98 (frameshift
mutation) and TA100 (base pair substitution) only in tests
without metabolic activation. All other tests were nega-
tive. A "high temperature" toxaphene has elicited positive
dose response increases in strains TA98 and TA100 only with
metabolic activation. In other studies, toxaphene and toxa-
phene subfractions have been found to be mutagenic to strain
TA100 with or without metabolic activation (Hill, 1977).
A study conducted by the U.S. EPA (1973) found
no significant differences in the rates of chromosomal aber-
rations in leukocytes between groups of workers occupation-
ally exposed to toxaphene and those not exposed.
C. Teratogenicity
Toxaphene did not produce teratogenic effects
when administered in the diet of rats, mice, and guinea
pigs (U.S. EPA, 1979). Kennedy, et al. (1973) found no
indication of teratogenic effects in F3 weanlings of rats
-------
fed toxaphene at levels of 25 mg/kg diet and 100 mg/kg diet.
Pregnant rats and mice fed 15 to 35 mg/kg/day of toxaphene
produced young with no teratogenic effects as did pregnant
guinea pigs fed 15 mg/kg body weight (Chernoff and Carver,
1976;. DiPasquale, 1977)..
D. Other Reproductive Effects
Adverse effects on fertility, gestation, viability,
lactation, or survival indices were not observed in male
and female rats fed dietary levels of 25 mg/kg and 100 mg/kg
toxaphene (Kennedy, et al. 1973), or in mice fed dietary
levels of 25 mg/kg toxaphene (Keplinger, et al. 1970).
E. Chronic Toxicity
Long term exposures to low dietary levels of toxa-
phene have been, investigated in several studies involving
rats, dogs, and monkeys (U.S. EPA, 1979). All studies noted
some form of liver pathology in rats at dietary levels of
100 mg/kg or above- At 100 mg/kg, cytoplasmic vacuolization
was noted by Kennedy, et al. (1973). Increased liver weight
with minimal liver cell enlargement was noted in rats at
dietary levels of 25 rag/kg (Fitzhugh and Nelson, 1951).
The lowest dietary level of toxaphene producing unequivocal
liver damage over a two-year feeding period was 20 mg/kg
(U-S. EPA, 1979)- Only at high concentrations, i.e., 1,000
mg/kg diet, does toxaphene elicit central nervous system
effects (Hercules, Inc., undated).
»•
F. Other Relevant Information
Induction of hepatic microsomal mixed-function
oxidase (MFO) appears to account for most of the interactions
-------
of toxaphene with other compounds (U.S. EPA, 1979). Pre-
treatment with known MFO inducers, such as DDT, aldrin,
and dieldrin, increases oral LCgg's two to three-fold (Deich-
man and Ke'plinger, 1970) . Piperonyl butoxide, which inhibits
the metabolism of many toxicants by MFO, has been shown
to potentiate the toxicity of toxaphene in houseflies (Saleh,
et al. 1977).
Keplinger and Deichmann (1967) found that equitoxic
combinations of toxaphene with parathion, diazinon, or tri-
thion were less toxic than expected based on the assumption
of simple similar action.
Acute human intoxication by toxaphene-lindane
mixtures produces signs and symptoms that are not character-
istic of toxaphene or lindane poisoning (Pollock, 1958;
Masumura, 1975). .
V-. AQUATIC TOXICITY
A. Acute
Acute toxicity data of toxaphene to freshwater
fish are derived from 52 96-hour LC^Q values for 18 species
resulting from 48 static and 4 flow-through assays. Observed
LCgg values for these species of fish range from 0.8 pg/1
for the channel catfish (Ictalurus punctatus) to 28 ug/1
for the goldfish, (Carassius auratus) (U.S. EPA, 1979).
No single family or species appeared to be dramatically
more resistant or sensitive to toxaphene. For freshwater
invertebrates, 17 static bioassays on 13 species resulted '
in reported LC^Q values of 1.3 ug/1 for the stonefly (Cla-
asenia sabulosa) to 178 pg/1 for the crayfish (Procambarus
simulans) (U.S. EPA, 1978).
-------
For the marine fish, toxicity data were determined
from five flow-through and two static assay procedures repre-
senting six species. Observed LC50 values ranged from 0.5
ug/1 for the pinfish (Lagodon rhomboides) to 4.7 ^ig/1 for
the threespine stickleback (Gasterosteus aculeatus) (U.S.
EPA, 1979). The toxicity of toxaphene to marine inverte-
brates shows considerable interspecific variation in 31
assays (10 flow-through and 21 static) with reported LC5Q
values ranging from 0.054 pg/1 for larval stages of the
driftline crab (Sesarma cineseum) to 2,700 pg/l-for the
blue crab (Callinecten sapilus).
B. Chronic
Chronic life cycle toxicity tests have produced
chronic values of 0.037 and 0.059 ^ag/1 for the fathead min-
now (Pimephales promelas) and channel catfish (Ictalurus
punctatus) , respectively (Mayer, et al.. 1977) . Growth ef-
fects were noted in brooktrout chronically exposed to concen-
trations of 0.038 ug/1. Life cycle tests on freshwater
invertebrates have been performed on three species with
chronic values of 0.09, 0.18, and 1.8 jig/1 reported for
Daphnia magna; the scud (Gammarus pseudolimnaeus); and midge
larvae (Chironomus plumosus), respectively (Sanders, in
press).- An embryo-larval test on the marine fish sheeps-
head minnow (Cyprinodon variegatus) produced a chronic value
of 0.83 pg/1 (Goodman, et al. 1978). A chronic value of
0.097 pg/1 was obtained for the marine mysid shrimp (Mysi- .
dopsis bahia) (Nimmo, 1977).
-is
-------
C. Plant Effects
No data for the effects of toxaphene were found
for freshwater species. Effective concentrations for five
species of marine plants ranged from 0.15 ug/1 for reduced
growth in the dinoflagellate (Monochrysis lutheri) to ISO
ug/1 for lethality in the dinoflagellate (Danaliella euchlora)
arid no growth of the algae (Protococcus) sp. (U.S.. EPA,
1978).
0. Residues >.
Bioconcentration factors for three species of
fish were reported (Mayer, et al. 1975; Mayer, et al. 1977).
Brooktrout fry (Salvelinus fontinalis) had the highest fac-
tor of 76,000 in 15 days, while yearling brooktrout had
the lowest factor of 16,000 in 161 days. In the marine
longnose killif ish (Fundulas similis) , bioconcentrations
for a number of different life stages were reported as 29,450
for juveniles, 27,900 for fry, 5,400 for adults, and 1,270
to 3,700 for ova of exposed adults (Schimmel, et al. 1977).
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived
by U.S. EPA (1979), which are summarized below, have gone
through the process of public review; therefore, there is
a possibility that, these criteria will be changed.
A. Human
The standards for toxaphene in air , water , and
food which have been established or recommended by various *
groups and agencies were set before the results of the NCI
bioassay for carcinogenicity were available (U.S. EPA, 1979).
~in/Li-
m i t * >
-------
The ACGIH (1977) recommends a time weighted average value
of 500 mg/m for the working environment and a tentative
short-term exposure limit of 1 mg/m . The national interim .
primary drinking water standard for toxaphene is 5 ug/1
(40 PR 11990; U.S. EPA, 1976b, 1976c). The National Academy
of Sciences (1977) .estimated the acceptable daily intake
of toxaphene for man at 1.25 jig/kg and suggested no-adverse-
effect levels from water at 8.75 pg/1 (assigning 20 percent
of the total ADI to water) or 0.44 jag/1 (assigning 1 percent
of the total ADI to water). Effluent standards for toxa-
phene manufacturers have been set at 1-5 pg/1 for existing
facilities and 0.1 p;/l for new facilities (U.S. EPA, 1976a).
Tolerances established by the U.S. Pood and Drug Administra-
tion for toxaphene in various agricultural products range
from 0.1 mg/kg- in sunflower seed's to 7 rag/kg in meat fat
(U.S. EPA, 1979).
The U.S. EPA (1979) draft water quality criterion
—4
for toxaphene is 0.467 ng/1 or 4.7 x 10 pg/1. This cri-
terion is based on the NCI (1979) study that reported hepato-
cellular carcinoma and neoplastic nodules in mice fed toxa-
phene; the criterion was calculated to keep the lifetime
cancer risk below 10 for humans.
B» Aquatic
A drafted criterion for the protection of fresh-
water aquatic organisms is 0.007 ug/1 for a 24-hour average
concentration, not to exceed 0.47 ug/1 at any time. For
marine aquatic life, the drafted criterion is 0..019 pg/1
for a 24-hour average concentration not to exceed 0.12 yag/1
at any time (U.S. EPA, 1979).
162-17
-------
TOXAPHENE
REFERENCES
American Conference of Governmental Industrial Hygienists.
1977. TLV's: Threshold limit values for chemical substances
and physical agents in the workroom environment with intended
changes for 1977. Cincinnati, Ohio.
Arthur, R.D.., et al,, 1976. Atmospheric levels of pesti-
cides in the Mississippi delta. Bull. Environ. Contam.
Toxicol. 15: 129.
Bailey, T.E., and J.R. Hannum. 1967. Distribution of pesti-
cides in California. Jour. San. Eng. Div. Proc. Am. Soc.
Civil Eng. 93: 27.
v
Bidleman, T.F., and C.E.. Olney. 1975. Long range transport
of toxaphene insecticide in the atmosphere of the western
North Atlantic. Nature 257: 475.
Brooks, G.T. 1974. Chlorinated insecticides. CRC Press,
Cleveland, Ohio.
Chandurkar, P.S. 1977. Metabolism of toxaphene components
in rats. Microfilmed by Photogr. Media Center, University
of Wisconsin..
s
Chernoff, N., and B.D. Carver. 1976. Fetal toxicity of
toxaphene in rats and mice. Bull. Environ. Contam. Toxicoi.
15: 660.
Clapp, K.L., et al. 1971.. Effect of toxaphene on the hepatic
cells of rats. In: Proc. Ann. Meet. Western Section, Am.
Soc. Anim. Sci. Tresno State College, Fresno, Calif.
Conley, B.E. 1952. Pharmacological properties of toxaphene,
a chlorinated hydrocarbon insecticide. Jour. Am. Med. Assoc.
149:. 1135.
Crowder, L.A., and E.F. Dindal. ' 1974. Fate of chlorine-
36-labeled toxaphene in rats. Bull. Environ. Contam. Toxicoi.
12: 320.
Deichmann, W.B., and M.L.. Keplinger . 1970. Protection
against the acute effects, of certain pesticides by pretreat-
ment with aldrin, dieldrin, and DDT. Pestic. Symp. Collect.
Pap. Inter-Am. Conf. Toxicoi. Occup. Med., 6.th, 7th, 1968-
1970.
DiPasquale, L.C. 1977. Interaction of toxaphene with ascor-
bic acid in the pregnant guinea pig. Master's Thesis.
Weight State University, 1976. EPA in-house rep. 1977.
Summarized by K. Diane Courtney, Environ. Toxicoi. Div.,
Health Eff. Res. Lab., U.S. Environ. Prot. Agency, in a
Toxaphene ceview dated Nov. 16, 1977.
-------
Duggan, R.E., and P.E. Corneliussen. 1972. Dietary intake
of pesticide chemicals in the United States (III) . June
1968-April 1970 (with summary of 1965-1970). Pestic. Monitor.
Jour. 5: 331.
Fitzhugh, O.G., and A.A. Nelson. 1951. Comparison of chronic
effects produced ia rats by several chlorinated hydrocarbon
insecticides. Fed. Proc. 10: 295.
Goodman, L.R., et al. 1978- Effects of heptachlor and
toxaphene on laboratory-reared embryos and fry of the sheeps-
head minnow.. 30th Ann. Conf. Southeast Assoc. Game Fish
Coitun.
Hercules Inc. Undated. Hercules toxaphene insecticide.
Bull. T-lOSc.
».
Hill, R.N. 1977V Mutagenicity testing of toxaphene. Memo
dated Dec. 15, 1977, to Fred Hageman. Off. Spec. Pestic.
Rev. U.S. Environ. Prot. Agency, Washington, D.C.
Johnston, W.R., et al. 1967. Insecticides in tile drainage
effluent. Water Resour. Res. 3: 525.
Kennedy, G.L., Jr., et al. 1973. Multigeneration reproduc-
tive effects of three pesticides in rats.. Toxicol.. Appl.
Pharmacbl. 25: 589.
Keplinger, M.L., et al. 1970. Effects of. combinations
of pesticides on reproduction in mice. In; Pestic. Symp.
Collect. Pap.. Int. Am. Conf.. Toxicol. Occup. Med.. 6th, .7th.
Khalifa, S., et al. 1976. Toxaphene degradation by iron
(II) protoporphyrin systems. Jour. Agric. Food Chem. 24:
277.
Kulkarni, A.P., et al. 1975.. Cytochrome P-450 optical
difference spectra of insecticides. Comparative study.
Jour. Agric. Food. Chem. 23: 177.
Lackey, R.W. 1949a. Observations on the acute and chronic
toxicity of toxaphene in the dog. Jour. Ind. Hyg. Toxicol.
31: 155. '
Lackey, R.W. 1949b. Observations on the percutaneous absorp-
tion of toxaphene in the rabbit and dog. Jour. Ind. Hyg.
Toxicol. 31: 155.
Lehman, A.J. 1952. Oral toxicity of toxaphene. U.S. Q.
Bull. Assoc. Food Drug Off. 16: 47.
Litton Bionetics, Inc. Carcinogenic evaluation in mice.
Toxaphene.. Final Report. LSI Project No. 20602. Kensington,
MD. Submitted to Hercules, Inc., Wilmington, Del. Nov.
1978.
-------
Matsumura, F. 1975. Toxicology of insecticides. Plenum
Press.
Mattraw, H.C. 1975. Occurrence of chlorinated hydrocarbon
insecticides - southern Florida - 1963-1972. Pestic. Monitor.
Jour. 9: 106.
Mayer, F.L., Jr., et al. 1975. Toxaphene: Effects on
reproduction, growth, and mortality of brook trout. EPA-
600/3-75-013. U.S."Environ. Prot. Agency.
Mayer, F.L., et al. 1977. Toxaphene: Chronic toxicity
to fathead minnows and channel catfish. EPA-600/3-77-069.
U.S. Environ.. Prot. Agency.
Metcalf, R.L. 1966. Kirk-Othmer encyclopedia of chemical
technology. John. Wiley and Sons, Inc., New York.
National Academy of Sciences. 1977. Drinking water and
health. A report of the Safe Drinking Water Committee Ad-
visory Center on Toxicology Assembly of Life Sciences, National
Research Council. Washington, D.C.
National Cancer Institute. 1977. Guidelines for carcino-
genesis bioassays in small rodents. Tec. Rep. No. 1. Publ.
No. 017-042-00118-8. U.S. Government Printing Office,
Washington, D.C.
National Cancer Institute. 1979. Bioassay of toxaphene
for possible carcinogenicity. DHEW Publ. No. (NIH) 73-837.
Nicholson, H.P., et al. 1964. Water pollution by insecti-
cides in an agricultural river basin. I. Occurrence of
insecticides in river and treated water. Limnol. Oceanog.
9: 310.
Nicholson, H.P., et al. 1966. Water pollution by insecti-
cides: A six and one-half year study of a watershed. Proc.
Symp. Agric. Waste Waters Rep. No. 10 of Water Resour.
Center. University of California.
Nirarao, D.W. 1977. Toxaphene: Its effects on mysids.
Memo to Fred Hagman, U.S. Environ.. Prot. Agency, Washington,
D.C. . ^
Ohsawa, T., et al. 1975. Metabolic dechlorination of toxa-
phene in rats. Jour. Agric. Food Chem. 23: 38.
Pollock, G.A. 1978. The toxicity and metabolism of toxa-
phene. University of California, Davis.
Reimold, R.J., and C.J. Durant. 1972. Monitoring toxaphene
contamination in a Georgia estuary. Natl. Tech. Inf. Serv.
COM 73-1072. Springfield, Va.
-------
Saleh, M.A., et al. 1977. Polychlorobornane components
of toxaphene: Structure-toxicity relations and metabolic .
reductive dechlorination.. Science 198: 1256.
Schimmel, S.C., et al. 1977. Uptake and toxicity of toxa-
phene in several estuarine organisms. Arch. Environ. Contam.
Toxicol. 5: 353.
U.S. EPA. 1976a. Laboratory examination of drinking water
pesticide analysis.- Unpublished. Summarized in U.S. EPA
1977.
U.S. EPA. 1976b. National interim primary drinking water
regulations. EPA-570/9-76-003. Off. of Water Supply.
U.S. EPA. 1976c. Quality criteria for water. Report No.
EPA-440/9-76-023. . *
U.S. EPA. 1978. Occupational exposure to toxaphene. Final
Rep. by the Epidemiol. Stud. Progr. Off. Tox. Subst. Wash-
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U.S. EPA. 1979. Toxaphene: Ambient Water Quality Criteria
(Draft).
-------
SJ-46-01
No. 164
1,1,1-Trichloroethane
(Methyl Chloroform (MC))
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
October 30, 1980
164-1
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. - The information contained in this report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
164-2
-------
1,1,1-TRICHLOROETHANE (MC)
SUMMARY
Results of an NCI carcinogenesis bioassay of MC was inconclu-
sive due to experimental problems. NCI and a manufacturer
are currently re-evaluating its carcinogenic potential. In
vitro studies ha-ve indicated that MC is slightly mutagenic
with or without activation, and can cause mammalian cell
transformation. Studies of the teratogenic potential of MC
are suggestive; however, more studies are needed to make a
conclusive statement. Inhalation exposure of healthy adults
to the current PEL for MC (350 ppm) has generally resulted
only in untoward psychophysiologic effects. Animal studies,
as well as accidental human exposure have shown that MC, at
high inhalation concentrations, produces microscopic pathology
of liver and kidneys which is much less severe than that
produced by carbon tetrachloride or tetrachloroethylene. MC
is moderately toxic to aquatic life.
-------
I. INTRODUCTION
%
The chlorinated ethanes are hydrocarbons In which one or
more of the hydrogen atoms of ethane are replaced by chlorine
atoms. Water solubility and vapor pressure decrease with
increasing chlorination, while density and melting point
increase. At room temperature, 1,1,1-trichloroethane (M.W.
133.4) is a liquid with a boiling point 74.1'C, a vapor
pressure (20°C) of 100 torr, a melting point of -33°C, a
specific gravity of 1.3492, and a low solubility in water
(U.S. EPA, 1980a).
The chloroethanes are used as solvents, cleaning and
degreasing agents, and in the chemical synthesis of a number
of compounds.
The 1976 production of 1,1,1-trichloroethane was:
3 X 103 kkg/year (U.S. EPA,1980a).
The chlorinated ethanes form azeotropes with water (Kirk
and Othmer, 1963). All are very soluble in organic solvents
' (Lange, 1956). Microbial. degradation of the chlorinated
ethanes has not been demonstrated (U.S. EPA, 1980a).
The reader is referred to the Chlorinated Ethanes Hazard
Profile for a more general discussion of chl.orinated ethanes
(U.S. EPA, 1980b).
II. EXPOSURE
The chloroethanes present in raw and finished waters are
due primarily to industrial discharges. Small amounts of the
chloroethanes may be formed by chlorination of drinking water
-------
or treatment of sewage. Air levels of chloroethanes are
produced by evaporation of these compounds, widely used as
degreasing agents and in dry cleaning operations (U.S. EPA,
1980a). Occupational air monitoring studies have indicated
1,1,1-trichloroethane levels ranging from 1.5 to 396 ppm
(U.S. EPA, 1980a).
Sources of human exposure to chloroethanes include water,
air, ingestion .of contaminated foods and fish, and dermal
absorption.
Human exposure to MC was estimated from ambient air
monitoring data. At 8 cities values of 0.02 to 1.86 ug/kg/day
were calculated. At one city, however, where an Me manufacturing
facility is located, 12-86 ug/kg/day was calculated (USEPA 1980),
Drinking water showed only traces (0.05-1.0 ppb) of MC,
except near a MC producing facility (USEPA, 1980).
An ana'lysis of several foods indicated 1,1,1-trichloroethane
was present at levels of 1-10 ug/kg (Walter, et al., 1976).
Fish and shellfish have shown levels of 1,1,1-trichloroethane
in the nanogram range (Dickson and Riley, 1976).
The U.S. EPA (1980a) has estimated the weighted average
bioconcentration factor for 1,1,1-trichloroethane to be 21
for the edible portions of fish and shellfish consumed by
Americans. This estimate is based on the measured steadystate
bioconcentration studies in bluegills.
-------
III. ATMOSPHERIC FATE AND TRANSPORT
Because of Its volatility, its transformation into other
*
potentially harmful atmospheric components, its tropospheric
chemical reactivity, and its diffusion into the stratosphere,
MC is thought to pose a hazard to human health.
The. volatilization of MC from water can be reversible
because it is stable in the atmosphere and is transported
back to surface water via rainfall. Tropospheric half-lives
of twenty weeks (Pearson and McConnell, 1975) to 8 years
(McConnell and Schiff, 1978) indicate that MC is highly stable
in the troposphere. Billing et. al., (1976) estimated the de-
composition rate of MC under simulated atmospheric conditions
to be less than 5% in 23.5 hours. It is generally accepted
that the larger the tropospheric residence time of a chemical
species, the greater is the likelihood of its diffusion into
the stratosphere (U.S. EPA, 1980b). In a recent study of
the impact of chloro and chlorofluoro compounds on stratospheric
ozone, based on atmospheric measurement data, the NAS concluded
(1979) that MC contributes one quarter to one half as many
chlorine atoms to the stratosphere as do CFC's 11 and 12; at
the 1976 global emission rate MC is estimated (NAS, 1979) to
destroy 8 to 15 percent as much ozone as do both CFG 11 and
12. Thus, release from improperly disposed solid wastes
containing MC may pose a possible threat to the environment.
-------
IV. PERSISTENCE
.MC is inert to reaction with oxygen under normal
conditions, except at high temperatures. There are two
laboratory studies of the hydrolysis of MC (Billing, 1975;
Pearson and McConnel', 1975). These studies used two different
methods'for calculating the hydrolytic half life (U.S. EPA,
1980c). The hydrolytic half-life is about 5-9 months in
freshwater, and about 39 months in sea water (Pearson and
McConnel, 1975; U.S. EPA, 1980c).
At ambient temperatures MC hydrolyzes to acetic and
hydrochloric acids. Vinylidene chloride (a CAG listed
carcinogen) is a minor product, except at 10°C and at slightly
alkaline pH when it is the major product of hydrolysis (Pearson
and McConnell 1975, U.S. EPA, 1980c).
MC undergoes photochemical oxidation (Dilling et. al.,
1975; Appleby, 1976; U.S. EPA, 1980c), yielding estimates for
global average residence time of 1.4 to 12 years (U.S. EPA,
JL980c) . From these estimated lifetimes it was inferred that
between 10 and 20 percent of the MC molecules produced will
reach the stratosphere.
V. PHARMACOKINETICS
A. Absorption
The chloroethanes are rapidly absorbed following
oral or inhalation routes of exposure (U.S. EPA, 1980a).
Slow dermal absorption of 1,1,1-trichloroethane has been
demonstrated in humans (Stewart and Oodd, 1964).
-------
B. Distribution
Stahl, et al. (1969) have noted the presence of
%
1,1,1-trichloroethane in the liver, brain, kidney, muscle,
lung and blood in post-mortem tissue samples following high
levels of exposures. MC accumulates in the liver, kidney,
and brain of the mouse following inhalation exposure (Holmberg,
et. al., 1977).
C. Metabolism
The metabolism of chloroethanes involves both
enzymatic dechlorination and hydroxylation to corresponding
alcohols (U.S. EPA, 1979a). Oxidation reactions may produce
unsaturated metabolites which are then transformed to the
alcohol and ester (Yllner, 1971a,b,c,d). Trichloroethanol
and trichloroacetic acid have been identified in the urine
of rats following inhalation exposure to 1,1,1-trichloro- .
ethane (Ikeda and Ohtsuji, 1972). Metabolism appears to
involve the mixed-function oxidase system (Van Dyke and
Wineman, 1971).
D. Excretion
The chloroethanes are excreted primarily in the
urine and expired air (U.S. EPA, 1980). Monster and co-
workers (1979) reported that 60-80 percent of 1,1,1-trichloro-
ethane inhaled by volunteers was expired unchanged; two
urinary metabolites represented 3 percent of the uptake.
Excretion of the chloroethanes is generally rapid, the major-
ity of compound being eliminated within 24 hours (U.S. EPA,
1980a).
-------
VI. EFFECTS
A. Carcinogenicity
The NCI (1977) conducted a bioassay of MC using
mice and rats. Although a variety of neoplasms were observed,
no relationship was established bewteen dosage groups, species,
sex type of neoplasm or site of occurence. The shortened
life spans of the test animals due to the toxicity of the
chemical made an assessment of carcinogenicity impossible
(NCI, 1977). The NCI and a manufacturer of MC are currently
retesting the compound for carcinogenicity.
Price et. al., (1978), have demonstrated in vitro trans-
formation of rat embryo cells by MC. Injection of these
cells in vivo produced undifferentiated fibrosarcomas at the
site of inoculation in all tested animals.
B. Mutagenicity
Several groups have investigated the mutagenicity
of MC in the Ames assay. Henschler et. al. (1977) found MC
inactive both with and without addition of microsomes, using
TA-100 strain of S. typhimurium. Simmon et. al. (1977) used
slightly different assay conditions and reported that MC is
slightly mutagenic to this strain. A dose response was
evident, and metabolic activation did not 'alter mutagenicity.
C. Teratogenicity
Schwetz et. al. reported (1974, 1979) on inhalation
studies (at 87.5 ppm) on pregnant mice and rats. A number of
-------
skeletal abnormalities were noted, but these were of marginal
*
statistical significance. Additional studies are needed.
MC, when injected into the air space of fertilized chicken
eggs at 2, 3 and 6 days of incubation is embryotoxic (LD5Q
of 50-100 mM/egg), and induces a variety of birth malfor-
mations (Elovaora et. al.: 1979). Both these studies suggest
that MC has teratogenlc potential, and that further experiments
should be performed to confirm this potential toxicity.
D. Other Reproductive Effects
Pertinent information could not be located in the
available literature on other reproductive effects of 1,1,1-
trichloroethane.
' E. Chronic Toxicity (U.S. EPA, 1980b)
Inhalation exposure of healthy adults to the current
TLV for MC (350 ppm) generally does not result in significant
untoward physiologic effects. Studies of human
exposure to 100-500 ppm have shown only subjective symptoms
of light-headedness, syncope, mild headache and nausea, and
objective symptoms of eye, nose and throat irritation. No
significant clinical chemistry organ function tests (e.g.
liver function) have been noted. However, adverse effects
on the performance of manual tasks have been documented.
At higher exposures (>10,000 ppm) MC produces anesthesia
and cardiovascular effects which can be lethal. Animal
studies, as well as accidental human exposure, have shown that
-------
MC, at these high concentrations, produces a. "chlorinated
hydrocarbon" type of microscopic pathology of liver and
kidneys (fatty infiltration and cellular necrosis) which is
much less severe than that produced by carbon tetrachloride.
VI. AQUATIC.TOXICITY
A. ' Acute Toxicity
For freshwater fish, 96-hour static LCso values of
69,700 ug/1 for the bluegill Lepomis maerochirus and 150,000
ug/1 for the fathead minnow, Pimephales promelas, while a
single 96-hour flow-through LCso value of 52,800 ug/1 was
obtained for the fathead minnow, Pimephales promelas,
(Alexander, at. al. 1978). For marine organisms, 96-hour
static LC5Q values ranged from 31,200 ug/1 for the mysid
shrimp, Mysidopsis bahia, to 70,900 ug/1 for the sheepshead
minnow, Cyprinodon variegatus, (U.S. EPA, 1978).
B. Chronic Toxicity and Plant Effects
Pertinent information could not be located in the
available literature.
C. Residues
A bioconcentration factor of 9 was obtained for the
bluegill (U.S. EPA, 1980a).
VIII. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor aquatic criteria derived
by U.S. EPA.(1980a), which are summarized below, have gone
-------
through the process of public review; therefore, there is a
possibility that these criteria will be changed.
A. Human
Based on mammalian toxicology data, the EPA (1979a)
has prepared a draft ambient water quality criterion to
protect human health at the level of 15.7 mg/1 for 1,1,1-
trichloroethane.
The 8-hour, TWA exposure standard established by OSHA
for 1,1,1-trichloroethane is 350 ppm.
B. Aquatic
The freshwater criterion has been drafted as 5,300
ug/1 as a 24-hour average, not to exceed 12,000 ug/1; while
the criterion to protect marine life has been drafted as a 24-
hour average concentration of 240 ug/1, not to exceed 540
ug/1.
-------
1,1,1-TRICHLOROETHANE
REFERENCES
1. Alexander, H.C., et al. 1978. Toxicity of perchloro-
ethylene, trichloroethylene, 1,1,1-trichloroethane and
methylene chloride to fathead minnow. Bull. Environ.
Contain. -Toxicolr 20:344.
2. Dickson, A. 6. and J. P. Riley. 197.6. The distribution
of short-chain halogenated aliphatic hydrocarbons in some
marine organisms. Mar. Pollut. Bull. 79:167.
3. Dilling, W. L., N. B. Tefertiller and 6. J. Kallos. 1975.
Evaporation rates and reactivities of methylene chloride,
chloroform, 1,1,1-trichloroethane, trichloroethylene,
tetrachloroethylene and other chlorinated compounds in
dilute\\aqueous solutions. Environ. Sci. Technol. 9:833-
838. -\\\V
\
4. Elovaara, E. K., K. Hemminki and H. Vainio. 1978. Effects
of methylene chloride, trichloroethane, trichloroethylene,
tetrachloroethylene and toluene on the development of
chick embryos. Toxicol. 12:111-119.
5. Henschler, D., T. Ednee, T. Mendecker and M. Metzler. 1977,
Carcinogenlclty of trichloroethylene: fact or artfact?
Arch. Toxicol. 37:233.
6. Holmberg, B., et al. 1977. A study of the distribution
of methylchloroform and n-octane in the mouse during and
after Inhalation. Scand. Jour. Work Environ. Health.
3:43.
t
7. Ikeda, M. and H. Ohtsuji. 1972. Comparative study of
the excretion of Fujlwara reaction-positive substances
in urine of humans and rodents given trichloro- or
tetrachloro-derivatives of ethane and ethylene. Br.
Jour. Ind. Med. 29:99.
8. Kirk, R. and D. Othmer. 1963. Encyclopedia of chemical
technology. 2nd ed., John Wiley and .Sons, Inc., New York.
9. Lange, N. (ed.) 1956. Handbook of chemistry. 9th ed.,
Handbook Publishers, Inc., Sandusky, Ohio.
10. McConnell, J. C. and H. I. Schiff. 1978. Methyl chloro-
form: impact on stratospheric ozone. Science 199:174-177.
-------
11. Monster, A. C., et al. 1979. Kinetics of 1,1,1-tri-.
chloroethane in volunteers; influence of exposure con-
.centration'and work load. Int. Arch. Occup. Environ.
Health 42:293.
12. National Academy of Sciences. 1979. Stratospheric
ozone depletion by halocarbons: chemistry and transport.
Panel on Chemistry and Transport. Washington, D.C.
13. National Cancer Institute. 1977. Bioassay of 1,1,1-
trichloroethane for possible carcinogenicity. Carcinog.
Tech. Rep. Ser. NCI-CG-TR-3.
14. Pearson, C. R. and G. McConnell. 1975. Chlorinated C^
and C2 hydrocarbons in the marine environment. Proc.
Roy. Soc. London Ser. B. 189:305-332.
15. Price, P. J., et. al. 1978. Transforming activities of
trichloroethylene and proposed industrial alternatives.
In Vitro 14:290.
16. Schwetz, B. A., et. al. 1974. Embryo- and fetotoxicity
of inhaled carbon tetrachloride, 1,1-dichloroethane, and
methyl ethyl ketone in rats. Toxicol. Appl. Pharmacol.
28:452.
17. Schwetz, B. A. , B. K. J. Leong, and P. J. Gehrig. 1979.
The effect of maternally inhaled trichloroethylene, per-
chloroethylene, methyl chloroform and methylene chloride
on embryonal and fetal developmenting mice and rats.
Toxicol. Appl. Pharmacol. 32:84-96.
18. Simmon, V. F., K. Karhaven, and R. G. Tardiff. 1977.
Mutagenic activity of chemicals identified in drinking
water in: Progress in Genetic Toxicology, I. D. Scott,
B. A. Bridges and F. H. Sobels ed. Elsevier, New York.
, pp. 249-258.
19. Stahl, C. J., et. al. 1969. Tirchloroethane poisoning:
observations on the pathology and toxicology in six fatal
cases. Jour. Forensic. Sci. 14:393.
20. Stewart, R. D. and H. C. Dodd. 1964. Absorption of
carbon tetrachloride, trichloroethylene, tetrachloro-
ethylene, methylene chloride, and 1,1,1-trichloroethane
through the human skin. Am Ind. Hyg. Assoc. Jour. 25:439.
21. U.S. EPA. 1978. In-depth studies on health and environ-
mental impacts of selected water pollutants. Contract No.
68-01-4646, D.S. Environ. Prot. Agency.
-------
22. U.S. EPA 1980a. Chlorinated Ethanes: Ambient Water
Quality Criteria. (Draft)
23. *U.S. EPA 1980. Environmental Criteria and Assessment
Office. Chlorinated Ethanes: Hazard Profile. (Draft)
24. U.S. EPA 1980c. Final Report on Risk Assessment of
1,1,1-tirchloroethane: Contract No. 68-01-0543. Tech-
nical Directive- 2. Batelle Columbus Laboratories,
Columbus, Ohio 43201; August
25. Van Dyke, R. A. and C. 6. Wineman. 1971. Enzymatic
dehlorination: dechlorination of chloroethanes and
propanes in vitro. Biochem. Pharmacol. 20:463.
26. Walter, P., et. al. 1976. Chlorinated hydrocarbon
toxicity (1,1 , 1-trlchloroethane, trichloroethylene, and
tetrachloroethylene) ; a monograph. PB-257 185. Natl.
Tech. Inf. Serv, Springfield, Va.
••^'
27. Yllner, S. 1971a. Metabolism of 1,2 dichloroethane-14C
in the mouse. .Acta. Pharmacol. Toxicol. 30:257.
28. Yllner, S. 1971b. Metabolism of 1, 1 , 2-trichloroethane-
in the mouse. Acta. Pharmacol. Toxicol. 30:248.
29. Yllner, S. 1971c. Metabolism of 1 , 1 , 1, 2-tetrachloro-
ethane in the mouse. Acta. Pharmacol. Toxicol. 29:471.
30. Yllner, S. 1971d. Metabolism of 1 , 1 , 2 , 2-tetrachloro-
ethane in the mouse. Acta. Pharmacol. Toxicol. 29:299.
-------
No. 165
1,1,2,,-Trlchloroethane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained 171 the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of sucik sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy. '
-------
SPECIAL NOTATION
U.S.. EPA's Carcinogen Assessment Group (CA6) has evaluated
1,1,2-trichloroethane and has found sufficient evidence to
indicate that this compound is carcinogenic.
.r»f>f -
-7) u-1
-------
1.1.2-TRICHLOROETHANE
Summary
Results of a National Cancer Institute carcinogenesis bioassay indicate
that oral administration of 1,1,2-trichloroethane produces an increase of
several tumor types in rats and mice.
Information is not available to indicate if 1,1,2-trichloroethane has
any mutagehic effects, teratogenic effects,"or adverse reproductive effects.
Animal studies have indicated that exposure to 1,1,2-trichloroethane
may produce liver and kidney toxicity.
Aquatic toxicity data for 1,1,2-trichloroethane is limited, with only
two acute studies in freshwater fish and invertebrates available. Toxic
doses ranged from 18,000 to 40,200 jjg/1.
' Anl/
7 /IS"
-------
1,1, 2-TRICHLOROETHANE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria. Document
for Chlorinated Ethanes (U.S. EPA, 1979a).
The chloroethanes' are hydrocarbons in which one or more of the hydrogen
atoms of ethane are replaced by .chlorine atoms. Water solubility and vapor
pressure decrease with increasing chlorination, while both density and melt-
ing points increase- 1,1,2-Trichloroethane (molecular weight 133.4) is a
Liquid at room temperature with a boiling point of 113°C, a melting point
of -37.4°C, a specific gravity of 1.4405, and slightly soluble in water
(U.S. EPA, 1979a).
The chloroethanes are used as solvents, cleaning and degreasing agents,
and in the chemical synthesis of a number of compounds. 4
The chlorinated ethanes form azeotropes with water (Kirk and Othmer,
1963) and all are very soluble in organic solvents (Lange, 1956). Microbial
degradation of the chlorinated ethanes has not been demonstrated (U.S. EPA,
1979a) .
The reader is referred to the Chlorinated Ethanes Hazard Profile for a
more general discussion of chlorinated ethanes (U.S. EPA, 1979b).
II. EXPOSURE.
The chloroethanes are present in raw and finished, waters primarily from
industrial discharges- Small amounts of chloroethanes may be formed, by
chlorination of drinking water or treatment of sewage. A metropolitan water
monitoring study has shown finished water levels from 0.1 to 8.5 ^ug/1 for
1,1,2-trichloroethane (U.S. EPA, 1979a). Air levels of chloroethanes are
produced by evaporation of volatile chloroethanes widely used as degreasing
agents and in dry-cleaning operations (U.S. EPA, 1979a).
•_ • 7 r* f_
*1 I * <**
-------
Sources of human exposure to chloroethanes include water, air, contami-
nated foods and fish, and dermal absorption. Fish and shellfish have shown
levels of chloroethanes in the nanogram range (Dickson and Riley, 1976).
Pertinent information was not found in the available literature on
1,1,2-trichloroethane .levels in food.
The U.S. EPA (1979b) has estimated the weighted bioconcentration factor
for 1,1,2-trichloroethane to be 6.3. This estimate was based on the octa-
nol/water partition coefficient for 1,1,2-trichloroethane.'
III. PHARMACOKINETICS
A. Absorption
The chloroethanes are absorbed rapidly following oral or inhalation
routes of exposure (U.S. EPA, 1979a). .Dermal absorption of 1,1,2-trichloro-
ethane may be extensive as indicated by lethal toxicity in animals following
dermal exposure (Smyth, et al. 1969).
B. Distribution
Specific information on the distribution of 1,1,2-trichloroethane
has not been found in the available literature. The reader is referred to a
more general treatment of the chloroethanes (U.S. EPA, 1979b) which indi-
cates widespread distribution of these compounds throughout the body.
C. Metabolism
The metabolism of chloroethanes involves both enzymatic dechlorina-
tion and hydroxylation to corresponding alcohols (U.S. EPA, 1979aK Oxida-
tion reactions may produce unsaturated metabolites which are then transform-
ed to the alcohol and ester (Yllner, 1971). Trichloroethanol and trichloro-
acetic acid have been identified in the urine of rats following inhalation
exposure to 1,1,2-trichloroetnanol (Ikeda and Ohtsuji, 1972). Metabolism
appears to involve the activity of the mixed function oxidase system (Van
Dyke and Wineman, 1971).
-------
0. Excretion
The chloroethanes are excreted primarily in the urine and in ex-
pired air (U.S. EPA, 1979a) with excretion being generally rapid. Experi-
ments conducted by Yllner (1971) indicate that following intraperatoneal in-
jection of 1,1,2-trichloroethane into mice, more than 90 percent of the ad-
ministered dose is excreted in 24 hours, with more than half found in the
urine. Ten to twenty percent of injected compound is found in expired air.
IV. EFFECTS
A. Carcinogenicity
Results of an NCI carcinogenesis bioassay for 1,1,2-trichloroethane
show that oral administration of compound produced an increase of several
tumor types (NCI, 1978). Rats, showed adrenal carcinomas, kidney carcinomas,
and varied hemangiosarcomas, while mice showed an increase in hepatocellular
carcinomas.
B. Mutagenicity, Teratogenicity and Other Reproductive Effects
Available information on this compound is very limited in these
areas. A search of the literature did not reveal any pertinent data.
C. Chronic Toxicity
Animal studies have indicated that exposure to 1,1,2-trichloroeth-
ane may produce liver and kidney toxicity (U.S. EPA, 1979a).
V. AQUATIC TOXICITY
A. Acute Toxicity
The only aquatic toxicity data for 1,1,2-trichloroethane are single
static bioassays on the bluegill. (Lepomis macrochirus) and Daphnia magna.
The acute 96-hour LC5Q value for the bluegill was 40,200 ug/1, while the
48-hour LC-Q value for Daphnia magna was 18,000 ug/1 (U.S. EPA, *1979).
Marine studies are presently not available.
^/<7o*y_
") f U >
If
-------
B. Chronic Toxicity, Plant Effects and Residues
Available information on this compound is very limited in these
areas. A search of the literature did not reveal any pertinent data.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979)., which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed.
A. Human
Based on the NCI carcinogenesis data, and using a linear, non-
threshold model, the U.S. EPA (1979a) has estimated the level of 1,1,2-tri-
chloroethane in ambient water that will result in an additional cancer risk
of ICT5 to be 2.7 jjg/1. i
The 8-hr, TWA exposure standard for 1,1,2-trichloroethane is 10 ppm.
B. Aquatic
The draft criterion for protection of freshwater aquatic life is
310 pg/1 as a 24-hour average; the concentration should not exceed 710 ug/1
at any time (U.S. EPAt 1979a). NO criterion for protection of saltwater
aquatic life has been found.
-------
1,1,2-TRICHLOROETHANE
REFERENCES
Oickson, A..G., and J.P. Riley. 1976. The distribution of short-chain halo-
genated aliphatic hydrocarbons in some marine organisms. Mar. Pollute
Bull. 79: 167.
Ikeda, M., and H. Ohtsuji. 1972., Comparative study of the excretion of
Fujiwara reaction-positive substances in urine of humans and rodents given
trichloro- or tetrachloro-derivatives of ethane and ethylene. Br. Jour.
Ind.. Med. 29: 99.
Kirk, R. and Qthmer. 0. 1963. Encyclopedia of Chemical Technology. 2nd
ed- John Wiley and Sons, Inc. New York.
Lange, N. (ed.) 1956. handbook of Chemistry. 9th ed. Handbook
Publishers, Inc. Sandusky, Ohio.
National Cancer Institute. 1978. Bioassay of 1,1,2-trichloroethane for
possible carcinogenicity. Natl. Inst. Health, Natl. Cancer Inst.. OHEW Publ.
NO. (NIH) 78-1324.^ Pub. Health Serv. U.S. Oep. Health Edu.. Welfare.
Smyth, H.F., Jr., et al. 1969. Range-finding toxicity data: list VII.
Am.. Ind. Hyg. Assoc. Jour. 30: 470.
U.S. EPA. 1979a. Chlorinated Ethanes: Ambient Water Quality Criteria.
(Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment Office.
Chlorinated Ethanes: Hazard Profile (Draft).
Van Dyke, R.A., and C.G. Wineman. 1971. Enzymatic dechlorination:
Oechlorination of chloroethanes and propanes in vitro Biochem. Pharmacol.
20: 463.
Yllner, S. 1971. Metabolism of l,l,2-trichloroethane-l,2-14c in the
mouse. Acta. Pharmacol. Toxicol. 30: 248.
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No. 166
Trichloroethylene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, O.C. 20460
APRIL 30, 1980
-------
SPECIAL NOTATION
U.S. EPA1s Carcinogen Assessment Group (GAG) has evaluated
trichloroethylene and has found sufficient evidence to
indicate that this compound is carcinogenic.
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
TRICHLOROETHYLBC
SUMMARY
Trichloroethylene is a colorless liquid used mainly as a degreasing
solvent. Both acute and chronic exposure to high levels of trichloro-
ethylene produce central nervous system depression and other neurological
effects. Trichloroethylene also causes some kidney and liver damage. Tri-
chloroethylene has not been shown to be a teratogen, and the data suggesting
mutagenicity and carcinogenicity are weak. The studies of mutagenicity and
carcinogenicity have been complicated by the presence of contaminants with
known carcinogenic and. mutagenic activity. However, the cancer assessment
group has determined that Trichloroethylene is carcinogen<|tic.
Only a few studies have been reported on trichloroethylene toxicity'to
i
aquatic species. Fathead minnows, when exposed in flow through and static
tests, had 96 hour LC5Q values of 40,700 and 66,800 ug/1,. respectively.
The 96 hour LC5Q for the bluegill was 44,700 ug/1 in static tests. The 48
hour LC5Q for the freshwater invertebrate, Daohnia maqna, was 35,200
ug/1. In the only reported chronic test, no adverse effects were observed
in Daohnia maqna exposed to 10,000 yg/1. Photosynthesis was reduced by 50
percent in the alga, Phaedactylan tricomutum, at a concentration of 8,000
ug/1. Trichloroethylene was bioconcentrated 17-fold by the bluegill after
14. days exposure. The half life of this compound in tissues was less than 1
day.
-------
TRICHLOROETHYLENE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Trichloroethylene (U.S. EPA, 1979).
Trichloroethylene ((^HCl-, 1,1,2-trichloroethylene, TCE, molecular
weight 131.4) is a clear, colorless liquid. Trichloroethylene has a water
solubility of 1,000 ug/ml; a vapor pressure of 77 mm Hg and a melting point
of 83°C (Patty, 1963). Trichloroethylene is mainly used as a degreasing
solvent, and is used to lesser extents as a household and industrial dry-
cleaning solvent, an extractive solvent in foods, and as an inhalable
anesthetic during certain short-term sorgical procedures (Huff, 1971).
Current Production: Annual production of trichloroethylene in the
United States approximates 234,000 metric tons (U.S. EPA, 1979). The vola-
tilization of trichloroethylene during production and use is the major
source of environmental levels of this compound. Trichloroethylene is not
expected to persist in the environment because of its rapid photooxidation
in air, its low water solubility, and its volatility (Pearson and McConnell,
1975; Oillings, et al. 1976; Patty, 1963).
II. EXPOSURE
A. water
The National Organics Monitoring Survey observed trichloroethylene
in 28 of 113 drinking waters at a mean concentration of 21 ug/1 in May
through July, 1976 (U.S. EPA, 1979). Trichloroethylene may be formed during
the chlorination of water (National Academy of Science, 1977; Bellar,.et al.
1974).
-------
8. food
There is Little information concerning the occurence of trichloro-
ethylene in U.S. foodstuffs. In England, trichloroethylene has been ob-
served at concentrations up to 10 ug/kg in meats, up to 5 ug/kg in fruits,
vegatables, and beverages (McConnell, et al., 1975); packets of tea were
found to contain 60 ugAg (Fishbein, 1976)-. Little trichloroethylene would
be expected in other foodstuffs, except in- the case where it is used as a
solvent for food extractions. The U.S. EPA (1979) has estimated the
weighted bioconcentration factor of trichloroethylene to be 39. This esti-
mate is based on measured steady-state bioconcentration studies in. bluegills
and estimates of fish and shellfish consumption.
C. Inhalation
The only significant exposure to trichloroethylene in air occurs to
a relatively small, industrially exposed population (Fishbein, 1976).
III. PHARMACOKINETICS
»
A. Absorption
Trichloroethylene is readily absorbed by all routes of exposure.
In humans exposed to the compound by inhalation, steady state conditions are
approached within two hours. Absorption of trichloroethylene following in-
gestion has not been studied in humans. In rats, at least 80 percent of an
orally administered dose is systemically absorbed (U.S. EPA, 1979).
-------
8. Distribution
In humans, trichloroethylene is distributed mainly to body fat
(McConnell, et al. 1975). Laham (1970) demonstrated transplacental dif-
fusion of trichloroethylene in humans.
C. Metabolism
Qualitatively the metabolism . of trichloroethylene appears to be
similar across species (Kimmerle and Eben, 1973). The principal products of
trichloroethylene metabolism measured in urine are, trichloroethanol, tri-
chloroacetic acid, and conjugated derivatives (glucuronides) of trichloro-
ethanol. A reactive epoxide, trichloroethylene oxide, has been shown to be
formed during.the metabolism of trichloroethylene; it can alkylate nucleic
acids and proteins (Van Duureen and Banerjee, 1976; Bolt and Filser, 1977).
Patterns of metabolism of trichloroethylene in humans differ between male
and female (Nomiyama and Nomiyama, 1971), and with age (U.S. EPA, 1979).
Increased microsomal enzyme activity enhances the conversion of trichloro-
ethylene to trichloroacetaldehyde (U.S. EPA, 1979). Ethanol interferes with
the metabolism of trichloroethylene, causing ethanol intolerance in exposed
workers (U.S. EPA, 1979).
D. Excretion
Trichloroethylene and its metabolites are excreted in exhaled air,
urine, sweat, feces, and saliva (Kimmerla and Eben 1973; U.S. EPA, 1979).
Trichloroethylene is lost from the body with a half-life of about 1.5 hours
»
(Stewart, et al. 1962); however, its metabolites have longer half-lives
ranging from 12 to 73 hours (Ikeda and Imamura, 1973f Ertle, et al. 1972).
-------
IV. EFFECTS
A. Carcinogenicity
The National Cancer Institute (NCI, 1976) observed. an increased
incidence of hepatocellular carcinoma in mice (strain B6C3-F1) treated with
trichloroethylene. Similar experiments in Osbome-Mendel rats failed to
increase the incidence of tumors in this species. It has been pointed out
that trichloroethylene used in the NCI bioassay (1976) contained traces of
iranofunctional alkylating agents, epichlorohydrin and epoxibutane, as sta-
bilizers, and they might account for the observed carcinogenicity (U.S. EPA,
1979). No systematic study of humans exposed to trichloroethylene have
revealed a correlation with cancer (Axelson, at al. 1978).
B. Mutagenicity
Trichloroethylene has been reported to be mutagenic, in the pee-
sence- of mammalian liver enzymes, to a number of bacterial strains. These
include E.. coli K12, and S.. typhimurium strain TA 100 (U.S. EPA, 1979:
Simmon, et al. 1977), in addition to ,the yeast Saccharomyces cerevisiae
(Shahin and VonBarstel, 1977). However, there is some doubt as to the muta-
genicity of trichloroetnylene due to epichlorohydrin and epoxibutane contam-
ination. Henscher, et al. (1977) observed that these contaminants were
potent mutagens in §_. typhimurium strain TA100. Pure trichloroethylene was
weakly mutagenic.
C. Teratogenicity
Exposure of mice and rats to 1600 .mg/m trichloroethylene for
seven hours a day on days 6 through 15 of gestation did not produce tera-
togenic effects (Schwetz, et al. 1975).
-------
D. Other Reproductive Effects
Pertinent data could not be located in the available literature.
E. Chronic Toxicity
Disturbances of the nervous system, which continue for at least a
year after final exposure, were observed following industrial exposure to
trichloroethylene (Nomiyama and Nomiyama, 1977; Bardodej and. Vyskoch,
1956). Symptoms included headaches, insomnia, tremors, severe neuroasthemic
syndromes coupled with anxiety states, and bradycardia. Prolonged
occupational exposures to trichloroethylene have been also associated with
impairment of the peripheral nervous system. This can include persistent
neuritis (Bardodej and Vyskoch, 1956), temporary loss of tactile sense, and
paralysis of the fingers (McBirney, 1954). Rare cases of hepatic damage
have been observed following repeated abuse of trichloroethylene (Huff,
1971).
F. Other Relevant Information
' Long-term toxicity of trichloroethylene appears to depend largely
' on its metabolic products (U.S. EPA, 1979). Chemicals that enhance or
depress the mixed function oxidase system will have a synergistic or antago-
nistic effect, respectively, on the toxicity of trichloroethylene.
Trichloroethylene has been shown to induce transformation in a
highly sensitive in vitro Fischer rat embryo cell system (F1706) (U.S. EPA,
1979). Following exposure of cells to 1 M trichloroethylenet the cells
formed progressively growing foci made up of cells lacking contact inhibi-
tion, and the cells gained the ability to grow in semi-solid agar.
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
Alexander, et al. (1978) exposed fathead minnows (Pimephales
promelas) 'to trichloroethylene in flow-through and static tests. The
observed 96-hour LCep values were 40,700 and 66,800 ug/1, respectively.
The observed 96-hour LC5Q for the bluegill depends macrochirus) is 44,700
;jg/l in static tests: (U.S. EPA, 1978). The 48 hour LC5Q for Daphnia rcaqna
and is 85,200 ug/1 (U.S. £PA, 1978). No saltwater fish or invertebrate
acute toxicity data were found in the available literature.
8~ Chronic Toxicity
In the only reported chronic test, no adverse effects were observed
with Daphnia magria at the highest test concentration of 10,000 ;jg/l (U.S.
EPA, 1978).
C. Plant Effects
14
There was a 50 percent decrease noted in C uptake by the salt-
water alga, Phaedectylum tricornutum, at a concentration of 8,000 ,ug/l
(Pearson and McConnell, 1975).
0. Residues
Bioconcentration by bluegills was studied (U.S. EPA, 1978) using
radiolabeled trichloroethylene. After 14 days the bioconcentration factor
was 17. The half-life of this compound in tissues was less than one day.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The Food and Drug Administration (1974)v has limited the concen-
tration of trichloroethylene in final food products to 10 mg/kg in instant
-------
coffee, 25 mg/kg in ground coffee and 30 mg/kg in spice extracts. The
American Conference of Governmental Industrial Hygienists (ACGIH) TLV is 535
mg/m .
The Cancer Assessment Group (CAG) has determined that, at the
present time, under existing policy, TCE is a carcinogen. The NCI bioassay
(the results from which CAG has made their determination) is being repeated.
When the data is available, it should be reviewed.
B. Aquatic
For trichloroethylene, the draft criterion to protect freshwater
aquatic life is 1,500 ug/1 as a 24-hour average; the concentration should
not exceed 3,400 jug/1 at any time. Criterion for saltwater species has not
been developed because sufficient data could not be located in the available
literature.
/it-IP
-------
TRICHLOROETHYLEN E
REFERENCES
Alexander, H.C.., et al. 1978. Toxicity of perchloroethy-
lene, trichloroethylene, 1,1,1-trichloroethane, and methylene
chloride ,to fathead minnows. Bull. Environ. Contam. Toxicol.
In press.
Axelson,. 0., et al. 1978.. A cohort study on trichloroethy-
lene exposure and cancer mortality.. Jour. Occup. Med. 20:.
.19.4;. ........
Bardodej, Z., and J. Vyskocil. 1956. The problem of
trichloroethylene in occupational medicine. AMA Arch. Ind.
Health 13: 581.
Bellar, T.A., et al. 1974. The occurrence of organohalides
in chlorinated drinking waters. Jour. Am. Water Works Assoc.
66r 703.
Bolt, H.M-, and J.G. Filser. 1977. Irreversible binding of -
chlorinated ethylenes to macromolecules. Environ. Health
Perspect. 21: 107.
Dill ings, et al. 1976. Simulated atmospheric photodecomposi -,
tion rates of methylene chloride, 1,1,1-trichloroethane, tri-
chloroethylene, and other compounds. Environ. Sci. Technol.
10: 351.
Ertle, T., et al. 1972. Metabolism of trichloroethylene in
man. I. The significance of trichloroethanol in long—term
exposure conditions. Arch. Toxicol. 29: 171.
F.ishbein, L, 1976. Industrial mutagens and potential muta-
gens. I. Halogenated aliphatic derivatives. Mut. Res. 32:
267.
Food and Drug Administration. 1974. Code of Federal Regula-
tions, Title 21, 121.1041. Trichloroethylene.
Henschler, D., et al. 1977. Short communication: Carcino-
genicity of trichloroethylene: fact or artifact? Arch. Toxi-
col. 233.
Huff, J.E. 1971. New evidence on the old problems of
trichloroethylene. Ind. Med. 40: 25.
Kimmerle, G., and A. Eben. 1973. Metabolism, excretion and
toxicology of trichloroethylene after inhalation. 2. Exper-
imental human exposure. Arch. Toxicol. 30: 127.
Laham, S. 1970. Studies on placental transfer trichloro-
ethylene. Ind.. Med. 39: 46.
-------
McBirney, B.S. 1954. Trichloroethylene and dichloroethylene
poisoning. AMA Arch. Ind. Hyg. 10: 130.
McConnellf G., et al. 1975. Chlorinated hydrocarbons and
the environment. Endeavour. 34: 13.
National'Academy of Science. 1977. Drinking water and
health. Safe Drinking Water Comm., Adv. Center on Toxicol.,
Assembly of Life Sci., Natl. Res. Council, Washington, D.C.
National Cancer Institute. 1976. Carcinogenesis bioassay of
trichloroethylene. CAS No. 79-01-6, NCI-CG-TR-2.
Nomiyama, K., and H. Nomiyama. 1971. Metabolism of tri-
chloroethylene in human sex differences in urinary excretion
of trichloroacetic acid and trichloroethanol. Int. Arch.
Arbeitsmed. 28: 37.
Patty, P.A. 1963. Aliphatic halogenated hydrocarbons. Ind.
Hyg. Tox. 2: 1307..
Pearson, C., and G. McConnell. 1975. Chlorinated C^ and
C2 hydrocarbons in the marine environment. Proc. R. Soc.
London B. 189: 302.
Schwetz, B.A.., et al. 1975. The effect of maternally in-
haled trichloroethylene, perchloroethylene, methyl chloroform
and methylene chloride on embryonal and fetal development in
mice and rats. Toxicol. Appl. Pharmacol. 32: 84.
Shahin, M., and R. von Barstal. 1977. Mutagenic and lethal
effects of benzene hexachloride, dibutyl, phatalage and
trichloroethylene in Saccharomvces cervisae. Mut. Res. 48:
173.
Simmon, V.F., et al. 1977. Mutagenic activity of chemicals
identified in drinking water. Paper presented at 2nd Int.
Conf. Environ. Mutagens, Edinburgh, Scotland, July 1977.
Stewart, R.D., et al. 1962. Observations on the concentra-
tions of trichloroethylene in blood and expired air following
exposure to humans. Am. Ind. Hyg. Assoc. Jour. 23: 167.
O.S. EPA. 1978. In-depth studies on health and environmen-r
tal impacts of selected water pollutants.. Contract No. 68-
01-4646. U.S. Environ. Prot. Agency.
U.S. EPA. 1979. Trichloroethylene: Ambient Water Quality
Criteria. U.S. Environ. Prot. Agency.
Van Duuren, B.L., and S. Banerjee. 1976. Covalent interac-
tion of metabolites of the carcinogen trichloroethylene in
rat hepatic microsomes. Cancer Res. 36: 2419.
-------
SJ-46-06
No. 167
Trichlorofluoromethane, Dichlorodifluorome thane
and Trichlorotrifluoroethane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
October 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemical,
The information contained in the report is drawn chiefly from
secondary sources and available reference documetns. Because
of the limitations of such sources, this short profile may not
reflect all available information including all the adverse
health and environmental impacts presented by the subject
chemical. This document has undergone scrutiny to ensure its
technical accuracy.
167-1
-------
TRICHLOROFLUOROMETHANE, DICHLORODIFLUOROMETHANE .
. ' AND TRICHLOROTRIFLUOROETHANE
SUMMARY
Trichlorofluoromethane (F-ll) , dichlorofluoromethane (F-
12) and l;l,2-trichloro-l,2,2-trifluoroethane (F-113) are not
easily degraded in the environment. After release at the
surface of the earth, F-ll and F-12 and F-113 mix with the
atmosphere and rise slowly into the stratosphere where they are
decomposed by ultraviolet radiation to release chlorine atoms.
The chlorine atoms react with ozone, thereby reducing the total
amount of ozone in the stratosphere and permitting an increased
amount of biologically active ultraviolet radation to reach the
earth's surface* The accumulation of F-ll, F-12 and F-113 in
the atmosphere also increases the absorption and emission of
infrared radiation (the "greenhouse" efect).
F-ll, F-12 and F-113 are absorbed via the lungs, gastrointestinal
tract, and skin, however, most of that which is absorbed is
eliminated unchanged in expired air.
F-ll was not found carcinogenic in a long-term mouse study.
The carcinogenic potential of F-113 has not been tested by NCI,
and few specific studies have been documented. F-ll, F-12
and F-113 were negative in the Ames Salmonella test; F-12 was
positive in a Neurospora crassa test system.
167-2
-------
At high concentrations in air, these compounds have
•
been shown to induce cardiovascular and pulmonary effects in
animals.
In March 1979, fully halogenated chlorofluoroalkanes
(including-F-ll, F-12 and F-113) were banned as propellents in
the United States except for essential uses. The action was
taken because the chlorofluoroalkanes may deplete the strato-
spheric ozone, leading to various adverse effects.
1. INTRODUCTION
This paper is based on an EPA report entitled "Environmental
Hazard Assessment Report: Major One- and Two-Carbon Saturated
Fluorocarbons" (U.S. EPA, 1976a).
Trichlorofluoromethane and dichlorofluoromethane are commonly
referred to by their fluorocarbon numbers, which are F-ll and
F-12, respectively. This convention will be followed in this
paper. 1,1,2-Trichlo-1,2,2-trifluoroethane is dubbed F-113.
F-ll, a colorless volatile liquid, F-12, a colorless gas,
and F-113, a non-flammable colorless liquid, have the following
physical/chemical properties (U.S. EPA, 1976a, Downning, 1966).
F-ll F-12 F-113
Molecular Formula CClsF'.. CC12F2 CC12F-CC1F2
Molecular Weight 137 120 187
Boiling Point (°C) 23.8 -29.8 47.6
Freezing Point (°C) -111 -158
Solubility
(gm/lOOgm H20, 0°C, 1 atm.) soluble in water 0.017
and many organic
solvents
167-3
-------
A review of the production range (includes importation)
statistics for trichlorofluoromethane (CAS No. 75-69-4) which
is listed in the initial TSCA Inventory (1979) has shown that
between 100 million and 200 million pounds of this chemical
were produced/imported in 1977.*
A review of the production range (includes importation)
statistics for dichlorodifluoromethane (CAS No. 75-71-8) which
is listed inthe initial TSCA Inventory (1979) has shown that
between 200 million and 300 million pounds of this chemical
were produced/imported in 1977*
The major uses of F-ll and F-12 are as aerosol propellants,
refrigerants, and foaming agents (U.S. EPA, 1976a).
II. EXPOSURE
A* Environmental Fate
Although F-ll and F-12 volatilize quickly from water
and soils, they are considered persistent in the environment
due to their resistance to biodegradation, photodecomposition,
and chemical degradation (U.S. EPA, 1975a). AFter release at
the surface of the earth, F-ll, F-12 and F-113 (as well as
other chlorofluoromethanea) mix with the atmosphere and rise
*This production range Information does not include any
production/importation data claimed as confidential by the
person(s) reporting for the TSCA Inventory, nor does it In-
clude any information which would compromise Confidential
Business Information. The data submitted for the TSCA
Inventory, including production range information, are sub-
ject to the limitations contained in the Inventory Reporting
Regulations (40 CFR 710).
167-4
-------
slowly Into the stratosphere where they are decomposed by
•
ultraviolet radiation to release chlorine atoms. Chlorine
atoms and a subsequent reaction product, chlorine oxide, react
with ozone and oxygen atoms, thereby reducing the total amount
of ozone in the stratosphere and somewhat shifting the distribution
of ozone toward lower altitudes. As a consequence, there is an
increase in the amount of biologically active ultraviolet
radiation (below 295 nm) reaching the earth's surface. In
addition, the temperature distribution in the stratosphere is
somewhat altered*
The accumulation of chlorofluoroalkanes in the atmosphere,
at all levels, also increases the absorption and emission of
infrared radiation (the "greenhouse" effect). This retards
heat loss from the earth and thus affects the earth's temperature
and climate. The amount of change in infrared absorption and
emission is well known, however, the amount and details of the
further effects on the earth's climate are uncertain. This
effect is inevitably combined with the effects due . to increased
carbon dioxide in the atmosphere and works in the same direction
(HAS, 1976, 1979).
' B. Bioconcentration
While chlorofluoroethanes are quite lipophilic and
have the potential to bioaccumulate in organisms, their high
volatility appears to preclude significant bioaccumulation
(U.S. EPA, 1975a).
167-5
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C« Environmental Occurrence
• Trichlorofluoromethane has been detected in finished
drinking water, effluents from raw sewage and sewage treatment
plants, and in rivers and lakes (U.S. EPA, 1976b). F-ll is
formed in small quantities during chlorination and fluoridation
of drinking water (U.S. EPA, 1975b).
The major routes by which the fluorocarbons reach the
environment involve their commercial applications. Because of
their characteristic high vapor pressures and low boiling points,
it is expected that all losses of fluorocarbons would ultimately
the atmosphere (U.S. EPA, 1976a).
III. PHARMACOKINET1CS
The available data on fluorocarbon absorption and elimination
indicate that they are absorbed across the alveolar membrane,
gastrointestinal tract, and. skin. Inhaled fluorocarbons are
taken up readily by the blood. Fluorocarbons absorbed by any
route are eliminated through expired air (U.S. EPA, 1976a).
Data from Allen and Hansbury, Ltd. (1971) show that sub-
sequent to a five-minute exposure in ambient air, F-ll and
F-12 are concentrated to the greatest extent in the adrenals,
fat, and the heart of rats.
Eddy and Griffith (1971) observed metabolism in rats
following oral administrations of 14C-labelled F-12. About 2Z
of the total dose was exhaled as 002 and about 0.52 was excreted
in urine; the balance was exhaled unchanged. Within
thirty hours after administration, the fluorocarbon and its
167-6
-------
metabolites were no longer present in the body. Blake and
Mergner (1974) -have indicated that the apparent resistance of
F-ll and F-12 to biotransformation may be more a function of
their rapid elimination rather than their general stability.
IV. HEALTH EFFECTS'
A.' Carcinogenicity
A bioassay of F-ll for possible carcinogenicity was
conducted using rats and mice. Animals were subjected to F-ll
by gavage for 78 weeks. The results of the bioassay in rats
were not conclusive because an inadequate number of animals
survived to the end of the study. Under the conditions of the
bioassay, F-ll was not carcinogenic in mice (NCI, 1978). The
carcinogenic potential of F-113 has not been dected by NCI, and
few specific studies have been documented. Epstein et. al.
(1967) observed a synergistic effect when piperonyl butoxide
and F-113 were sumultaneously injected in mice, producing an
increase in hepatoms.
B. Mutagenicity
Mutagenicity data on the fluorocarbons are scant.
Neither of the compounds was mutagenic in Salmonella tester
strains TA1535 or TA1538 with activation (Uehleke et al., 1977).
Sherman (1974) found no increase in mutation rates over controls
in a rat feeding study of F-12. Stephens et al., (1970) reported
a significant mutagenic activity of F-12 in a Neurospora crassa
test system. F-113 has not been shown to be positive in the
Ames test, and was reported not to be mutagenic in the dominant
167-7
-------
lethal test in* the mouse.
C. Other Toxicity
Taylor (1974) noted that exposure to 7% oxygen-15Z
tr ichlorof luor ometh-ane (F-ll) caused cardiac arrhythmias in all
rabbits exposed. F-ll was subsequently shown to exert its
toxicity at air concentrations of 0.5-5% in the monkey and dog,
and from 1-10% in the rat and mouse. In all these animals it
induced cardiac arrhythmias, sensitized the heart to epinephrine-
induced arrhythmias, and caused tachycardia (increased heart
rate), myocardial depression, and hypertension. The concentrations
of F-12 that sensitized the dog to epinephrine and that influenced
circulation in the monkey and dog were similar to those reported
for F-ll, however, F-12 differed in its effects on the respiratory
parameters. It caused early respiratory depression and broncho-
constriction which predominated over its cardiovascular effects
(Aviado, 1975a,b).
A possible increased sensitivity to the fluorocarbons in
humans with cardiac or respiratory illness may exist, but this
is difficult to determine definitively on the basis of animal
studies. Azar et al. (1972) noted that human inhalation of 1,000
ppm (4,949 mg/m3) F-12 did not reveal any adverse effect, while
exposure to 10,000 ppm resulted in a 7% reduction in a standardized
psychomotor test score.
V. AQUATIC EFFECTS
No data were found.
167-8
-------
VI. EXISTING GUIDELINES
«
As of March 17, 1979, fully halogenated chlorofluoroalkanes
were banned as propellents in the United States except for
essential uses. Th.fi action was taken because the chlorofluoro-
alkanes. (including F-ll, F-12 and F-113) may deplete the stratos-
pheric ozone, leading to an increase in skin cancer , climatic
changes, and other adverse effects (43 CFR 11301).
167-9
-------
REFERENCES
Allen and Hansburys, LTD. 1971. An Investigation of
possible Cardio-Toxic Effects of the Aerosol Propellanta,
Arctons 11 and 12. Vol. 1, Unpublished Report. (As
cited in U.S. EPA, 1976a.)
Avlado, D. M. 1975a. Toxicity of aerosol propellants
on the respiratory and circulatory systems. IX. Summary
of the most toxic: trichlorofluoromethane (FC-11). Toxic-
cology ^, 311-314. (As cited in the U.S. EPA, 1976a.)
Aviado, D. M. 197Sb. Toxicity of 'aerosol propellants
on the respiratory system and circulatory systems. X.
proposed classification. Toxicology 3, 321-332. (As
cited in U.S. EPA, 1976a.) ~~
Azar, A., C. F. Reinhardt, M. E. Maxfield, P. E. Smith,
and L.S. Mullin. 1972. Experimental human exposure to
fluorocarbon 12 (dichlorofluoromethand). Amer.. Indust.
Hyg. Assoc. J. 33/4), 207-216. (As cited in U.S. EPA,
1976a).
Blake, D. A. and G. W. Mergner. 1974. Inhalation studies
on the biotransformation and elimination of [^*C]-trichloro-
fluoromethane and [14C]-dichlorodifluoromethane in beagles.
Tox. Appl Pharm. 30. 396-407. (As cited in U.S. EPA,
1976a.)
Downing, R. C. Aliphatic Chlorofluorohydrocarbons. In;
Kirk-Othmer's Encyclopedia of Chemical Technology, Volume
9, 2nd Edition, 1966.
Eddy, C. W. and F. D. Griffith. 1961. Metabolism of di-
chlorodif luoromethane-C1* by rats. Presented at Amer. Indust.
Hyg. Assoc. Conf., Toronto, Canada, May 1971. (As cited in
U.S. EPA, 1976a.)
National Academy of Sciences, National Research Council.
1976. Halocarbons: Environmental Effects of Chloromethane
Release.
National Academy of Sciences, National Research Council.
1979. Stratospheric Ozone Depletion by Halocarbons: Chemistry
and Transport.
National Cancer Institute. 1978. Bioassay of trichloro-
fluoromethane for possible carcinogenicity. PB-286-187.
167-10
-------
Sherman, H. 1974. Long-term feeding studies in rats and
dogs with dichlorodif luor omethane (Freon 12 Food Freezant)
unpublished Report, Haskell Laboratory. (As cited in U.S.
EPA, 1976a.)
Stephens, S. et al. 1970. Phenotypic and genetic effects
in Neurospora crassa produced by selected gases and gases
mixed with oxygen. Dev. Ind. Microbiol. 12 , 346.
Taylor, O.C. 1974.. Univ. of California, Riverside, Un-
published Data. (As cited in U.S. EPA, 1976a.)
Uehleke, H. et al . 1977. Metabolic activiation of halo-
alkanes and tests in vitro for mutagenicity . Xenobiotica
U.S. EPA. 1975a. Environmental Hazard Assessment of One-
and Two-Carbon Fluorocarbons. EPA-560/2-75-003.
U.S. EPA. 1975b. Identification of Organic Compounds
in Effluents from Industrial Sources. EPA-560/3-75-002 .
U.S. EPA. 1976a. Environmental Hazard Assessment Report:
Major One- and Two-Carbon Saturated f luorocar bons , Review
of Data. EPA-560/8-76-003.
U.S. EPA. 1976b. Frequency of Organic Compounds Identified
in Water. PB-265-470.
U.S. EPA. 1979. Toxic Substances Control Act Chemical Sub-
stances Inventory, Production Statistics for Chemical on the
Non-Confidential Initial TSCA Inventory.
167-11
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LB:42-2
No. .168
2,4,6-Trichlorophenol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OCTOBER 30, 1980
168-1
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents. Be-
cause of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by th«
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
168-2
-------
2,4,6-TRICHLOROPHENOL
Summary
«
In a 1979 study N.C.I.-concluded that 2,4,6-trichlorophenol
is carcinogenic in rats and mice. EPA's carcinogen Assessment
Group has determined that there is substantial evidence that
2,4,6-trichlorophenol is carcinogenic in man.
2,4,6-Trichlorophenol is a convulsant and an uncoupler of
oxidative phosphorylation.
2,4,6-Trichlorophenol is acutely toxic to freshwater fish
with LCso values ranging from 320 to 9,040 ug/1. No chronic or
marine studies were available. Tainting of rainbow trout flesh
has been noted at concentrations in water greater than 52 ug/1.
168-3
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2,4,6-TRICHLOROPHENOL
I. INTRODUCTION
TJiis profile is based on the Ambient Water Quality Criteria
Document for Chlorinated Phenols (U.S. EPA, 1980).
2,4,6-Trichlorophenol (2,4,6-TCP) is a colorless, crystalline
solid with the empirical formula CgHsClsO and a molecular weight
of 197.5 (Weast, 1978). It has the following physical and chemical
properties (Weast, 1978):
Melting Point: 69.5°C
Boiling Point: 246°C
Vapor Pressure: 1 mm Hg at 76 °C
Solubility: slightly soluble in water; soluble in
alcohol and ether
Trichlorophenols are used as antiseptics and disinfectants,
as well as for intermediates in the synthesis of other chemical
products (U.S. EPA 1980).
It is generally accepted that chlorinated phenols will
undergo photolysis in aqueous solutions as a result of ultraviolet
irradiation and that photodegradation leads to the substitution
of hydroxyl groups in place of the chlorine atoms and subsequent
t
polymerization (U.S. EPA, 1980). For additional information
regarding the chlorinated phenols, the reader is referred to the
Hazrd Profile on Chlorinated Phenols (U.S. EPA, 1980). '
II. EXPOSURE
Unspecified isomers of trichlorophenols have been detected
in surface waters in Holland at concentrations of 0.003 to 0.1
ug/1 (Piet and DeGrunt, 1975). 2,4,6-Trichlorophenol can be
formed from the chlorination of phenol in water (Burttschell, et
al. 1959). Exposure to other chemicals such as 1,3,5-trichlorobenzene,
168-4
-------
lindane, the alpha- and delta-isomers of 1,2,3,4,5,6-hexachloro-
cyclohexane, and hexachlorobenzene could result in exposure to
2,4,6-trichlorophenol via metabolic degradation of the parent
compound.
The U.S. EPA (1980) has estimated the bioconcentration factor
2,4,6-trichlorophenol to be 110 for the edible portion of aquatic
organisms. This estimate is based on the octanol/water partition
coefficient for this chemical.
Trichlorophenols are found in flue gas condensates from
municipal incinerators (Olie, et al. 1977).
A. Absorption, Distribution and Metabolism
Information regarding the absorption, distribution and
metabolism of 2,4,6-trichlorophenol could not be located in the
available literature.
B. Excretion
In rats, 82 percent of an administered dose (1 ppm in
.the diet for 3 days) of 2,4,6-trichlorophenol was eliminated in
the urine and 22 percent in the feces. Radiolabelled trichlorophenol
was not detected in liver, lung, or fat obtained five days after
the last dose (Korte, et al. 1978).
IV. EFFECTS
A. Carcinogenicity
Early studies on the tumor-promoting or-initiating
capacities of 2,4,6-trichlorophenol were negative or inconclusive
(U.S. EPA, 1980). Based on the results of its recent study,
however, the NCI concluded that this compound is carcinogenic in
male F344 rats (inducing lymphomas and leukemias), and in both
168-5
-------
sexes of BgCsFi mice, inducing hepatocellular carcinomas and
adenomas. (National Cancer Institute, 1979).
B. • Mutagenicity
Ames tests using Salmonella, with and without mammalian
microsomal activation, were negative for 2,4,6-trichlorophenol
(Rasanen, et al.'1977). 2,4,6-Trichlorophenol increased the rate
of mutations, but not the rate of intragenic"recombination in a
strain of Saccharomyces cerevisiae (Pahrig, et al. 1978). In
addition, two of the 340 offspring from female mice injected with
50 mg/Xg of 2,4,6-trichlorophenol during gestation were reported
\\..
•to have changes in hair coat color (spots) of genetic significance.
At 100 mg/Xg, 1 out of 175 offspring exhibited this response
(U.S. EPA, 1980).
C. Teratogenicity, Other Reproductive Effects and Chronic Toxicity
Information regarding teratogenicity, other reproductive
effects and chronic toxicity of 2,4,6-trichlorophenol could not
be located in the available literature.
D. Other Relevant Information
2,4,6-Trichlorophenol is a convulsant (Farquharson, et
al. 1958) and an uncoupler of oxidative phosphorylation (Weiribach
and Garbus, 1965; Mitsuda, et al. 1963).
2,4,6-Trichlorophenol affects glucose metabolizing
enzymes at low concentrations (U.S. EPA, 1980). At relatively
high concentrations it'affects the microsoraal oxidizing system
in vitro, which may have implication with respect to the liver's
detoxification or cancer inducing abilities (U.S. EPA, 1980).
168-6
-------
V. AQUATIC TOXICITY (U.S. EPA, 1980)
A. Acute Toxicity
Three assays have been conducted with 2,4-trichlorophenol
to determine its acute toxicity to freshwater fish. A 96-hour
static LCso value of 600 ug/1 has been obtained for the fathead
minnow (Pimephal.es promelas). In a flow-through assay, a 96-hour
LCso value 9,040 ug/1 was obtained for juvenile fathead minnows.
The bluegill (Lepomis macrochirus) has been shown to be the most
sensitive species studied, with a 96-hour static LCso of 320
ug/1. Only one acute study has been performed on a freshwater
invertebrate species. The result of a 48-hour static assay
produced an LCso value of 6,040 ug/1 for Daphnia magna. There
were no acute studies for any species of marine life.
B. Chronic Toxicity
2,4,6-Trichlorophenol is moderabely toxic to the fathead
minnow (720 ug/1) (U.S. EPA, 1980).
C. Plant Effects
Complete destruction of chlorophyll in the algae,
Chlorella pyrenoidosa, has been reported at concentrations of 10
ug/1. A chlorosis LCso value of 5,923 ug/1 was obtained for the
duckweed, Lemna minor. Studies of the effects of 2,4,6-
trichlorophenol on marine plants have not been reported.
D. Residues
No actual bioconcentration factors have been determined,
but, based upon the octanol/water partition coefficient of 4,898,
a bioconcentration factor of 380 has been estimated for those
aquatic organisms having an eight percent lipid content.
168-7
-------
The weighted average bioconcentration factor for the edible
portions of all organisms consumed by Americans is estimated to
*
be 110.
E. Miscellaneous
The tainting of fish flesh by 2,4,6-trichlorophenol has
been observed in the rainbow trout (Salmo gairdneri). The highest
estimated concentration of 2,4,6-trichlorophenol that will not
impair the flavor of trout exposed for 48 hours to the chemical
is 52 ug/1.
vi. EXISTING;GUIDELINES AND STANDARDS
••\W
A. Human
Based on carcinogenicity the U.S. EPA (1980) has
recommended 12 ug/1 as the ambient for the 2,4,6-trichlorophenol
water quality, criterion, for the ingestion of both fish and water
(10~6 excess risk).
No other existing guidelines or standards were found
for human exposure to 2,4,6-trichlorophenol.
B. Aquatic
•
The • criterion to protect freshwater .organisms 970
ug/1, is the chronic exposure value. Data were insufficient to
derive a criterion for marine organisms (U.S. EPA, 1980).
168-8
-------
2,4,6-TRICHLOROPHENOL
REFERENCES
Fahrig, R., et al. 1978. Genetic activity of chlorophenols and
chlorophenol impurities. Pages 325-328. In; Pentachlorophenol:
Chemistry, pharmacology and environmental toxicology. K. Rango
Rao, Plenum Press, New York.
Farquharson, M.E.., et al. 1958. The biological action of
chlorophenols. Br. Jour. Pharmacol. 13:20.
Kohli, J., et al. 1976. The metabolism of higher chlorinated
benzenes. Can. Jour. Biochem. 54:203. .
Korte, P., et al. 1978. Ecotoxicologic profile analysis, a
concept for establishing ecotoxicologic priority list for chemicals
Chemosphere 7:79.
National Cancer Institute 1979. Broassay of 2,4,6-trichlorophenol
for possible carcinogenicity. NCI-CG-TR-155.; PB223-159.
Piet, G.J. and F. DeGrunt. 1975. Organic chloro compounds in
surface and drinking water of the Netherlands. Pages 81.-92 In:
Problems raised by the contamination of man and his environment.
Comm. Eur. Communities, Luxembourg.
Rasanen, L., et al. 1977. The mutagenicity of MCPA and its soil
metabolites, chlorinated phenols, catechols and some widely used
slimicides in Finland. Bull. Environ. Contain. Toxicol. 18:565.
U.S. EPA. 1978. Ambient Water Quality Criteria for Chlorinated
Phenols: EPA 440/5-80-032.
Weast R.C. (ed.) 1978. Handbook of Chemistry and Physics. 59th
ed. CRC Press, Cleveland, Ohio.
168-9
-------
No. 169
1,2,3-Trlchloropropane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
J61-I
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report \is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
1,2,3-TRICHLOROPROPANE
Summary
Pertinent data are not available on the possible carcinogenicity, muta-
genicity, teratogenicity, or chronic toxicity of 1,2,3-trichloropropane.
Acute toxicity studies with animals suggest harmful effects to the liver.
1,2,3-Trichloropropane is reported to be irritating to the eyes and mucous
membranes of humans.
Pertinent data on the toxicity of trichloropropane to aquatic organisms
are not available.
-<
H, 7-3
-------
1,2.3-TRICm.OROPROPANE
I. INTRODUCTION .
1,2,3-Trichloropropane (CAS registry 96-18-4) is a colorless,
clear liquid made from the chlorination of propylene.. It has the following
chemical and physical properties (Windholz, 1976; Hawley, 1971; Verschueren,
1977):
Formula: C^H5C13
Molecular Weight: 147.43
Melting Point: -14.7°c
Boiling Point: 1$6.85°C
Density: 1.388920
Vapor Pressure: 2.0 torr @ 20°C \V.
Solubility: Sparingly soluble in \v
water, soluble in alcohol
and ether.
1,2,3-Trichloropropane is used as a paint and varnish remover, solvent,
and decreasing agent (Hawley, 1971), in addition to its use as a cross-
linking agent in the elastomer Thiokol ST (Johnson, 1971).
II. EXPOSURE
A. Water
1,2,3-Trichloropropane has been detected in drinking water (U.S.
EPA, 1975) and also in 6 of 204 surface water samples taken in various loca-
tions throughout the United States (U.S. EPA, 1977). No information con-
cerning concentration was available.
8. Food
Pertinent data were not found in the available literature.
-------
C. Inhalation
Pertinent data were not found in the available literature; how-
ever, fugitive emissions from manufacturing and production facilities pro-
bably would account for the major portion of 1,2,3-trichloropropane if found
in air.
D. Dermal
Pertinent data were not found in the available literature.
III. PHARMACOKIhETICS
Pertinent data were not found in the available literature.
IV. EFFECTS
A. Carcinogenic!ty, Mutagenicity, Teratogenicity,
Reproductive Effects, Chronic Toxicity.
Pertinent data were not found in the available literature.
B. Acute Toxicity
Exposure to trichloropropane at high concentrations is irritating
to the eyes and mucous membranes and causes narcosis.
McOmle and Barnes (1949) exposed 15 mice to 5000 ppm trichloro-
propane for 20 minutes. Seven of the mice survived exposure; however, four
of these mice died from liver damage 7 to 10 days later. Seven of ten mice
exposed to 2500 ppm trichloropropane for 10 minutes per day for 10 days
died. McOmie and Bames (1949) found that liquid trichloropropane applied
to the skin of rabbits produced irritation and erythema, followed by slough-
ing and cracking. Repeated application of 2 ml of trichloropropane caused a
painful reaction, including subdermal bleeding, and the death of one of
seven rabbits treated.
Silverman, et al. (1946) reported eye and throat irritation and an
objectional odor to human volunteers exposed to 100 ppm trichloropropane for
-------
15 minutes. McOmie and Barnes (1549) found that ingestion of 3g of tri-
chloropropane by humans caused drowsiness, headache, unsteady gait, and lum-
bar pain.
V. AQUATIC TOXICITY
Pertinent data were not found in the available literature~
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The American Conference of Governmental Industrial Hygienists re-
commends a threshold limit value of 50 ppm for occupational exposure to
1,2,3-trichloropropane (ACGIH, 1977).
8. Aquatic
No guidelines on standards to protect aquatic organisms from
1,2,3-trichloropropane toxicity have been established because of the lack of
pertinent data.
161-1
-------
1,2,3-TRICHLOROPROPANE
References
American Conference of Governmental Industrial Hygienists. 1977. Documen-
tation of the Threshold Limit Values for Substances in Workroom Air, 3rd
ed. American Conference of Governmental Industrial Hygienists Cincinnati,
OH.
Hawley, G.G. (ed.) 1971. The Condensed Chemical Dictionary. 8th ed. Van
Nostrand Reinhold Co., New York.
Johnson, R.N. 1971. Polymers containing sulfur. In; Kirk-Othmer Encyclo-
pedia of Chemical Technology. John Wiley and Sons, New York, p. 253.
McOmie, W.A. and T.R. Barnes. 1949. Acute and subacute toxicity of
1,2,3-trichloropropane in mice and rabbits. Fed. Proc. 8: 319.
Silv^rman, L., et al. 1946. Further studies on sensory response to certain
industrial solvent vapors. Jour. Ind. Hyg. Toxicol. 28: 262.
U.S. EPA. 1975. New Orleans area water supply study, draft analytical
report. U.S. Environ. Prot. Agency. April update.
U.S. EPA. 1977. Monitoring to detect previously unrecognized pollutants in
surface waters. U.S. Environ. Prot. Agency. NTIS PB273-349.
Verschueren, K. 1977. Handbook of Environmental Data on Organic Chem-
icals. Van Nostrand Reinhold Co., New York.
Windholz, M. (ed.) 1976. The Merck Index, 9th ed. Merck and Co., Inc.,
Rahway, NJ.
)
-------
No. 170
o,6\o-Trlethyl Phosphorothioate
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
/76-a.
-------
0,0,0-TRIETHYL PHOSPHOROTHIOATE
Summary
There is no information available on the possible carcinogenic, muta-
genic,. teratogenic, or-adverse reproductive effects of 0,0,0-triethyl phos-
phorothioate.. Triethyl phosphate,.-a- possible metabolite of the compound,
has shown weak mutagenic activity in Salmonella, Pseudomonas, and Drosophila.
Like other organophosphates, 0,0,0-triethyl phosphorothioate may be ex-
pected to produce cholinesterase inhibition in humans.
No pertinent data are available on the aquatic effects of the compound.
-------
0,0,0-TRIETHYL PHOSPHOROTHIOATE
I. INTRODUCTION
0,0,0-Triethyl phosphorothioate (CAS registry number 126-68-1), also
known as triethyl thiophosphate, is a colorless liquid with a characteristic
odor. It has the following physical and chemical properties (Hawley, 1971):
Formula: C^oys
Molecular Weight: 198
Boiling Point: 93.5°C-94°C (10 torr)
Density: 1.074
0,0,0-Triethyl phosphorothioate is used as a plasticizer, lubricant ad-
ditive, antifoam agent, hydraulic fluid, and as a chemical intermediate
(Hawley, 1971).
n. EXPOSURE
A. Water and Food
Pertinent data were not found in the available literature.
8.. Inhalation
Pertinent data were- not found in the available literature; how-
ever, fugitive emissions from production and use would probably constitute
the major source of contamination (U.S. EPA, 1977).
D. Dermal
Pertinent data were not found in the available literature.
in. PHARMACQKINETICS
A. Absorption
Pertinent data were not found in the available literature. Acute
toxicity studies with a number of organophosphate insecticides indicate that
these compounds are absorbed following oral or dermal administration
-------
(Gaines, 1960). March, et al. (1955) have reported rapid absorption of the
structurally similar insecticide demeton from the gastrointestinal tract of
mice following oral administration.
8. Distribution
Pertinent data were not found in the available- literature.
C. Metabolism .
Pertinent data, were not found in the available literature. The
thiono isomer of the insecticide demeton may be metabolized via oxidative
desulfuration by the liver at the P=S bond in mammals (March, et al.. 1955)
to form the thiolo derivative. Thus, 0,0,0-triethyl phosphorothioate may be
converted to triethylphosphate in vivo (Matsumura, 1975). >.V\^'
0- Excretion
Pertinent data were not found in the available literature. March,
et al.. (1955) have reported that fallowing oral administration of demeton,
the large majority of compound was eliminated as urinary metabolites, with
.small quantities detected in the feces. Elimination was rapid following
oral administration.
IV.. EFFECTS
A. Carcinogenicity
Pertinent data were not found in the available literature.
B. Mutagenicity
Pertinent data were not found in the available literature. The
insecticide oxydemeton methyl has been shown to produce mutations, in
Drosoohila, £. coli and Saccharomyces (Fahrig, 1974).' Triethyl phosphate, a
possible metabolite of 0,0,0-triethyl phosphorothioate, has produced weak
mutagenic effects in Salmonella and Pseudomonas (Dyer and Hanna, 1973) and
recessive lethals in Drosophila (Hanna and Dyer, 1975).
-------
C. Teratogenicity
Pertinent data were not found in the available literature. A
single intraperitoneal injection of demeton (7 to 10 mg/kg) between days
seven and twelve of gestation has been reported to produce mild teratogenic
effects in mice (Budreau and Singh, 1973).
0. Other Reproductive Effects -
Pertinent data were not found in the available literature. Em-
bryotoxic effects (decreased fetal weights, slightly increased fetal mor-
tality) have been reported following intraperitoneal administration of deme-
ton (7 to 10 mg/kg) to pregnant mice (Budreau and Singh, 1973).
E. Chronic Toxicity
Pertinent data were not found in the available literature.
0,0,0-triethyl phosphorothioate, like other organophosphates, may be ex-
pected to produce symptoms of cholinesterase inhibition in humans (MAS,
1977).
v. AQUATIC TOXICITY
Pertinent data were not found in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
Pertinent data were not found in the available literature.
-------
0,0,0-TRIETtiYL PHOSPHOROTHIOATE
References
Budreau, C. and R. Singh.. 1975. Teratogenicity and embryotoxicity of deme-
ton and fenthion in CT 1 mouse embryos. Toxicol.. Appl. Pharmacol. 24: 324.
Dyer, K. and P. Hanna- 1973.. Comparative mutagenic activity and toxicity
of triethyl phosphate and dichlorvos in bacteria and. Orosophila. Mut. Res*
21: 175. ' -
Fahrig, 0. 1974.- Comparative mutagenicity studies with pesticides. Chem-
ical Carcinogenesis Assays, IARC Scientific Publication. 10:• 161-
Harma, P. and K. Dyer. 1975. Mutagenicity of organophosphorous compounds
in bacteria and Drosophila.. Mut» Res.. 28: 405.
Gaines, T. 1960. The acute toxicity of pesticides to rats. Toxicol. Appl.
Pharmacol.. 2: 88.
Hawley, G.G. (ed.) 1971. The Condensed Chemical. Dictionary. 8th ed. Van
Nostrand Reinhold Co..f New- York.
March, R.,. et al. 1955. Metabolism of syston in white mouse and American
cockroach. Jour- Econ. Entom. 48r 355.
Matsumura, F. 1975. Toxicology of Insecticides. Plenum Press, New York,.
223.
.National Academy of Sciences. 1977. Drinking Water and Health. National
Research Council, Washington, DC, p. 615.
U.S. EPA. 1977. Industrial process profiles for environmental user Plas-
ticizer industry. U.S.. Environ. Prot. Agency, NTIS PB-291-642.
170-J
-------
No. 171
Trinltrobenzene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents..
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical- This document has undergone scrutiny to
ensure its technical accuracy.
-------
TRINITROBENZENE
Summary
Information on the carcinogenicity, mutagenicity, teratogenicity, or
adverse reproductive effects of trinitrobenzene was not found in the avail-
able literature.
Trinitrobenzene has been reported to produce liver damage, central ner-
vous system damage, and methemoglobin formation in animals.
Slight irritant effects have been reported for marine fish exposed to
trinitrobenzene at concentrations of 100 ug/1.
I7/-3
-------
TRINITROBENZENE
t. INTRODUCTION
This profile is based on the Investigation of. Selected Potential
Environmental Contaminants: Nitroaromatics (U.S. EPA, 1976).
Trinitrobenzene (1-,3,5-trinitrobenzene, molecular weight, 213.1) is a
crystalline solid with the following physical properties: melting point,
122.5°C; specific gravity, 1.76. The compound is explosive upon rapid
heating. Trinitrobenzene is insoluble in water, but soluble in alcohol or
«u
ether (Windholz, 1976).
Trinitrobenzene is used as an explosive, and as a vulcanizing agent for
natural rubber (U.S. EPA, 1976).
Hydrolysis of trinitrobenzene under neutral pH conditions is not
expected to be rapid; as pH increases, hydrolysis would be favored (Murto,
1966). Photolytic degradation of trinitrobenzene has not been demonstrated
in aqueous solutions (Burlinson, et al. 1973).
A bioconcentration factor is not available for trinitrobenzene; how-
ever, the work of Neely, et al. (1974) on several nitroaromatics would
suggest a low theoretical bioconcentration of the compound.
Biodegradation of trinitrobenzene by acclimated microorganisms has been
reported by Chambers, et al. (1963).
II. EXPOSURE
Pertinent information on levels of exposure to trinitrobenzene from
occupational contact or from non-occupational 'sources of exposure (air,
water, food) was not found in the available literature.
III. PHARMACOKINETICS
»-
Pertinent information on the absorption, distribution, metabolism, or
excretion of trinitrobenzene was not found in the available literature. The
-------
reader is referred to a discussion of the pharmacokinetics of dinitro-
benzenes, which may show pharmacokinetic similarities (U.S. EPA, 1979).
Acute oral toxicity studies conducted with dogs indicate that trinitro-
benzene is effectively absorbed by this route (Fogleman, et al. 1955).
IV. EFFECTS
Pertinent information on the carcinogenic, mutagenic, teratogenic, -or
adverse reproductive effects of trinitrobenzene was not found in the avail-
able literature.
*.
A series of toxicity studies in rats, mice, and guinea pigs have indi-
cated that orally administered trinitrobenzene causes liver damage and
central nervous system damage (Korolev, et al. 1977). The acute toxicity
study of Fogleman, et al. (1955) has shown that trinitrobenzene, like dini-
trobenzenes, induces methemoglobin formation in vivo.
V. AQUATIC TOXICITY
The only study reporting the effects of trinitrobenzene to aquatic life
has been presented by Hiatt, et al. (1957). Slight irritant effects i.e.,
excitability, violent swimming, opercular movement increases suggesting res-
piratory distress upon short term exposure to marine fish Kuhlia
sandvicensis were observed at exposure levels of 100 ug/1, while moderate
and violent reactions to the chemical were produced at exposures of 1,000
and 10,000 pg/1. No effects were noted on exposures to concentrations of 50
or 10 ug/1.
VI. EXISTING GUIDELINES
There is no available 8-hour, TWA exposure limit for trinitrobenzene.
The compound has been declared a hazardous chemical by the Department of
•
Transportation (Federal Register. January 24, 1974).
-------
TRINITROBENZENE
References
Burlinson, N.E. et al. 1973. Photochemistry of TNT: Investigation of the
•pink water' problem. U.S. Nat. Tech. Inform. Serv. Ace. No. AD 769-670.
Chambers, C.W., et al. 1963. Degradation of aromatic compounds by phenol-
adapted bacteria. Jour.'Water Pollut. Contr. Fedr. 35: 1517.
Fogleman, R.W., et al. 1955. Toxicity of trinitrobenzene-aniline complex,
a rodent repellent. Agric. Food Chem. 3(11): 936.
Hiatt, R.W., et al. 1957. Relationship of chemical structure to irratient
response in marine fish. Nature. 179: 904.
>.
Korolev, A., et al. 1977. Experimental data for hygienic standardization
of dinitrotoluene and trinitrobenzene in reservoir waters. Gig. Sanit.
10: 17.
Murto, J. 1966. Nucleophilic reactivity. VII. Kinetics of the reactions
of hydroxide ion and water with picrylic compounds. Acta Chem. Scand.
20: 310.
Neely, W.B., et al. 1974.. Partition coefficient to measure bioconcen-
tration potential of organic chemicals in fish. Environ. Sci. Technol.
8: 1113. .
U.S. EPA. 1976. Investigation of selected potential environmental contam-
inants : Nitroaromatics.
U.S. EPA. 1979. Environmental Criteria and Assessment Office. Dinitro-
benzene: Hazard Profile. (Draft).
Windholz, M.. (ed.). 1976. The Merck Index, 9th ed. Merck and'Co., Inc.
Rahway, N.J. p. 9392.
SPO 998-oae
-------
SJ40-6
No. 172
Aniline
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
October 30, 1980
172-1
-------
DISCLAIMER
This report represents a survey of the potential health
and environment hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy*
172-2
-------
ANILINE SUMMARY
Aniline is an aromatic ami tie. Like many members of this
group it is characterized by an outstanding property: the
ability to form methemoglobin in mammalian organisms. Aniline
and some of its analogues have been suspected as carcinogens
since the turn of the century. An increased incidence of
urinary bladder tumors has been noted in workers in the
aniline and aniline dyestuff industries. Oral feeding studies
conducted by the National Cancer Institute have shown aniline
to be carcinogenic in rats. Aniline is reported not to be
mutagenic to six strains of S. typhimurium, however, several
aniline analogues and derivatives are mutagenic.
172-3
-------
ANILINE
I. INTRODUCTION
Aniline (aolnobenzene) is a liquid at room temperature
Its physical properties can be summarized as follows:
(Hawley, 1977; Weast, 1977-78; Strecher, 1968):
Molecular formula
Molecular weight
Melting point
Boiling point
Flash point
Solubility in cold water
Temperature at which
vapor pressure equals 1 mtn/Hg
pKa
C6H5NH2
93.13
-6.2°C
184.4°C
158.0°F (Closed Cup)
35.0 grams/liter
(0.38 M).
34.8eC
4.63
Of particular interest is aniline's water solubility - i.e.,
* •
aniline is soluble even in cold water.
The Stanford Research Institute's Chemical Economics
Handbook cites the nitrobenzene reduction process as the
current method of aniline synthesis (McCaleb, 1976). It is
estimated that 270,000 kkg of aniline was produced in 1978
(Slimak, et. al., 1980). Aniline was reported to be used
for the following uses:
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s.ynthesis of isocyanate (50Z of total consumption) 9 of rubber
«
chemicals (27%), dyes and Intermediates (6%), hydroquirxone
(5Z), drugs (37%), and miscellaneous chemicals including herbicides
(9%).
II. EXPOSURE
A. Water
Aniline levels in surface or drinking water was not
reported in the available literature. However, overall
emission of aniline to receiving waters as a result of the
production of aniline, consumptive use, carry-over as impurities
in manufactured products, and degradation of manufactured
products was estimated in 1978, to be 9970 kkg (Slimak, et.
al., 1980).
B. Food
Pertinent data on aniline concentrations could not
be located in the available literature.
C. Inhalation
Pertinent data on aniline concentrations could not
be located in the.available literature. However, overall
emissions of aniline to air as a result of aniline, isocyanates,
rubber chemicals, dyes and intermediates, hydroqulnone, and
miscellaneous products production is estimated to be 69.4 kkg
in 1978 (Slimak, et. al., 1980). Aniline is also reported
to occur in cigarette smoke (Gosselin, et. al., 1976).
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PHARMACOKINETICS
A. Absorption
Both inhalation and dermal absorption are important
exposure routes in humans (Pietrowski, 1957). At air concen-
trations of up to 20 mg/m3, absorption is about equal by
both routes, that is, 6 mg/hr; at higher concentrations the
respiratory pathway becomes progressively a more important
factor. Dermal contact with liquid aniline also results in
rapid systemic absorption: 0.2-0.7 mg/cm^ of skins/hr has
been shown to occur (Pietrowski, 1957).
B. Distribution
Aniline is rapidly absorbed into the blood stream;
its subsequent systemic distribution has not been reported.
Its metabolic transformations (see below) are mainly dependent
on liver enzymes.
C. Metabolism
Aniline is metabolized in the liver by oxidation
and conjugation. Hepatic microsomal oxidizing enzymes cause
metabolic transformation to N-acetylaminophenol and to o- and
p-aminophenol. Conjugating enzymes then cause metabolic
transformation to the glucuronide and sulfonate (Casarett and
Doull, 1975).
D. Excretion
The administration of aniline leads to urinary excretion
of glucuronic acid and sulfonic acid conjugates and of its
metabolites, o- and p-aminophenol (Williams, 1959; Parke,
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1960). In addition, small amounts of free aniline, phenyl
sulfamic acid, aniline- glucuronide, aminophenyl and
acetylaminophenyl, mercaptonic acids, phenylhydroxylamine,
and acetanilide are excreted in varying amounts by different
species tested (Park'e, 1960). The conjugates of p-amino-
phenol are the most important urinary metabolites of aniline
(Williams, 1959). The urinary excretion of these
metabolites gives an accurate measure of the absorption of
aniline vapor (Pietrowski, 1972). It is probable that the
other aniline metabolites mentioned above also appear in the
urine of people exposed to aniline (IARC, 1974).
IV. EFFECTS
A. Carcinogenicity
The carcinogenic potential of aniline has been of
great interest because, since 1895, an increased incidence of
urinary bladder tumors has been noted in workers in the
aniline dye industry (IARC, 1974). It has subsequently been
shown that other amines which occur in the environment, such
as 2-naphthylamine, 4-aminobiphenyl and benzidine, are probably
more important in the causation of these occupational cancers
(IARC, 1974). Although most animal studies appear to have
exonerated aniline as a human carcinogen (IARC, 1974), an NCI
study showed a dose-related increase in fibrosarcomas or
sarcomas in the spleen and in several organs of the body
cavity. Although the results were not statistically signifi-
cant, the rarity of these tumors and their dose-dependency
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led to the conclusion that aniline is carcinogenic in female
Fisher 334 rats* The male rats showed a statistically
significant increase in the incidence of hemangiosarcomas of
the spleen and a significant increase in the combined incidence
of fibrosarcomas and sarcomas of the spleen and in multiple
body organs (NCI, 1978).
B. Mutagenicity
In the Ames assay aniline is not mutagenic toward
any of the six standard S. typhimurium strains, when tested
in the presence or absence of microsomes (Geomet, 1980).
However, in the presence of nor-harman (a 2-carboline derivative),
significant mutagenicity has been observed (Nagao, et. al.,
1977; Sugimura, 1979).
C. Teratogenicity
Pertinent data could not be located in the available
literature. However, cyanotic effects such as those produced
by aniline can adversely affect the fetus, leading the ITC
to recommend that reproductive effect tests be conducted (44
FR 31871).
D. Other Reproductive Effects
Aniline can cross the placenta to form methemoglobin
in the fetus, affecting its development (Gosselin, 1976).
Courtney, (1979), reported that, after treatment of CD-I
mouse dams with aniline (150 to 200 mg/kg) during gestation
and lactation, CPK and LDH isozyme patterns in serum and
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cardiac tissue in offspring were altered on days 1 and 20
postpartua. The serum CPK pattern was markedly altered on
day 1 postpar.tum and by day 20, an additional enzyme appeared.
E. Acute and Chronic Effects
Aniline is moderately lethal to the rat: the oral
LD50 is 440 mg/kg. The LD50 value via the dermal route is
1400 mg/kg in the rat. For human beings the oral LDLO is
reported as 50 mg/kg (NIOSH, 1979). The no-effect level for
humans has been estimated as 0.25 mg/kg (NIOSH, ref. 169).
Aniline absorption causes anoxia due to the formation of
methemoglobin. Most of the signs and symptoms of overexposure
to aniline can be attributed to methemoglobin formation.
Such symptoms include fatigue, headache, irritability and
dizziness (Proctor and Hughes, 1979). In addition there may
be direct effects of aniline on the central nervous system
(e.g., insomnia, paresthesias) and cardiotoxic effects
(Patty, 1979; Sax, 1979).
Chronic exposure induces amenia (Patty, 1979; Sax, 1979;
Proctor and Hughes, 1979). Other chronic effects of aniline
exposure are hepatic injury, (perhaps caused by an aniline
metabolite) (Jenkins, 1972; Geomet, 1980) and splenic hemosi-
derosis (NCI, 1978).
V. AQUATIC TOXICITY
The lethal concentration and threshold concentration for
aniline with respect to Chironomus doraalis Meig. larvae are
6 and 3 mg/1, respectively (Puzikova and Markin, 1975).
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Aniline also produces toxic effects in Daphnia, at 0.4 mg/1
(Verschueren, 1977).
B. Chronic Toxicity
Lakhnova 1975, reported that aniline at a.
concentration of 0.2 mg/1 is lethal to Daphnia magna Straus
within nine days. Therefore, Lakhnova recommended a maximum
permissible limit of 0.02 mg/1.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The maximum allowable concentration in class I
waters for the production of drinking water in the U.S. is 5
o
mg/1. Several European countries have set lower limits: 0.1
t
mg/1 (USSR), 5 ppm (Federal German Republic), 2.6 ppm
(Deutsche Demokratische Republik), and 1.3 ppm (CSSR)
(Verschueren, 1977).
B. Aquatic
Data were insufficient to draft a criterion for
protection of freshwater or marine life. Lakhnova (1975)
recommended a maximum permissible limit of 0.02 mg/1.
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