HEALTH AND ENVIRONMENTAL
EFFECT PROFILES
APRIL 30, 1980
U.S. 'ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF SOLID WASTE
-------
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
,•
macrochirus s 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-
X
-13.01-
-------
water invertebrate Daphnia magna appears to have a low
sensitivity to fluoranthene with a reported 48-hour EC50
value of 325,000 pg/1. The 96-hour LC5Q value for the salt-
water raysid shrimp, Mysidopsis bahia , is 16 jag/1.
B. Chronic Toxicity
There are no chronic toxicity data presented on
exposure of fluoranthene to freshwater species. A chronic
value for the mysid shrimp is 16 pg/1.
C. Plant Effects
The freshwater alga, Selenastrum capricornutum,
when exposed to fluoranthene resulted in a 96-hour ECcrv
value for cell number of 54,400 pg/1. On the same criterion,
the 96-hour EC50 value for the marine alga, Skeletonema
costatum, is 45,600 pg/1 (U.S. EPA, 1979).
0. 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 PAH 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 ^ug/1
for fluoranthene. However, the lower level derived for
-------
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 p.g/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.
Basu, D.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-l, 2-bis-(3 pyridyl)-l-propanone(metopirone ciba)
and/? -diethylaminoethyldiphenyl-n-propyl acetate (SKR 525-A)
-Br-._J_O-Ur. Cancer 24 : 548 .
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. I_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.
ToJciwa, 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 and 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 Cri*-
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, 3.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
'1*06-
-------
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.
-12.07-
-------
FORMALDEHYDE
SUMMARY
The major 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. EPA's 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
mutagenic 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 1977.1/
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
product ion/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 paraformaldehyde 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
NIOSH (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). Hydrogen peroxide can
also be formed during photodecomposition of formaldehyde (Purcell
and Cohen, 1967; Bufalini e^ al_., 1972). The atmospheric half-
»
life of formaldehyde is less than one hour in sunlight (Bufalini
£t_ ,al_., 1972).
y
-I9JO-
-------
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 208C; 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
-------
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 blood. Ingestion of
.formaldehyde is followed immediately by•inflammation of the
mucosa of the mouth,.throat, and gastrointestinal tract (U.S.
f
EPA, 1976). Absorption appears to occur in the intestines
(Malorny et. al., 1965) .
72/2.-
-------
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 f^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 C02 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
j-
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
-1213-
-------
exposed for an additional 29 weeks at 122 ppm. No tumors or
metaplasias were found, although numerous changes were observed
in respiratory tissues (Horton e_t_ ^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 15 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
x^0 . 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 jt_ _al_. (1977)
and U.S. EPA (1976).
Reports in the recent literature have supported the finding
that formaldehyde is a mutagen: Magana-Schwencke ^t_ jal_. (1978)
in a study with S. cerevisiae; Wilkens and MacLeod (1976) in
E. coli; Martin et al. (1978) in an unscheduled DNA synthesis
test in human HeLa cells; Obe and Seek (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/m of formaldehyde
for 90 days. Hematologic values were normal, however, some
-13JS-
&
-------
interstitial inflamination occurred in the lungs of all species
(Coon ^t_ £l_., 1970).
F. 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 LCgg of 15 to 35 ppm.
The LC-g 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 blandj.ngi)
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/m^).
-------
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. J_(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., ^4_(5), 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., 30(1) , 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, 39_(6) , 1227 (as cited in U.S. EPA, 1976)
Magana-Schwencke, N., B. Ekert, and E. Mpustacchi. 1978. Bio-
chemical analysis of damage induced in yeast by formaldehyde. I.
-------
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 Formaldeshyds 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 Toxic 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, 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.
-------
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.
-------
FORMIC ACID
I. INTRODUCTION
Formic acid (CAS registry number 64-18-6) is a colorless, clear, fuming
liquid with a pungent odor (Hawley, 1971; Windholz, 1976; Walker, 1966). It
is a naturally formed product, produced by bees, wasps, and ants (Casarett
and Doull, 1975). 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 Pure 90% 85%
Formula: CH_Q_ ___ _„..
Molecular Weight: 46.02 — —
Melting Point: 8.4°c -4°C -12°C
Boiling Point: 100.5°C
Density: 1.22020 1.202|| J
Vapor Pressure: 33.1 torr i 20°C
Solubility: Miscible in water,alcohol,
and ether; soluble in
acetone,benzene, and toluene
Demand (1979): 67.5 million Ibs. (CMR, 1979)
-------
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, 1979;
Walker, 1966).
II. EXPOSURE
A. Water
Formic acid has been detected in raw sewage, in effluents from
sewage treatment plants, and in river water (Mueller, et al. 1558). It has
also been identified in effluents from chemical plants and paper mills (U.S.
EPA, 1976).
8. 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, 1971). 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, 1971). 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 raVige from A to 72 ppb
(Graedel, 1978). 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).
D. 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, 1963; NIOSH, 1977)-.
B. Distribution
Pertinent data were not found in the available literature.
C. Metabolism •- j
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 difference?-..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 forn.ace 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 WC02 were detected in these samples (Palese and
Tephly, 1975).
IV. EFFECTS
A. Pertinent data could not be located in the available literature.
-------
B. 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 LC5Q value of
175,000 ,jjg/l for bluegill sunfish (Lepomis macrochirus) exposed to formic
acid. Bringmann and Kuhn (1959) observed a 48-hour LC-- value 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 jjg/1 was lethal to freshwater scuds (Gammarus pulex) and 1,000,000
;ug/l 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 ;ug/l 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 100,000>ug/l was toxic to the freshwater algae, Scenedesmus sp.
•_HB^^_^^^_^W« ^
0. Residue
Pertinent data were not found in the available literature.
-------
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The eight-hour, TWA exposure limit for occupational exposure to
formic acid is 5 ppm (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-g 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 L. 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, 8.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. Bell. " ) (eds.) 1971. Fenaroli's Handbook of Flavor In-
gredients. The Chemical Kubber Company, Cleveland, 0.
Gleason, M. 1969. Clinical Toxicology of Commercial Products, 3rd ed.
Williams and Wilkins, Baltimore, MD.
Graedel, T.E. 1978. Chemical Compounds in the Atmopshere. Academic Press,
New York.
Hahn, R.W. and P.A. Jensfc.-i'. 1977. Water Quality Characteristics of Hazard-
ous Materials^ Texas A 4 M University. Prepared for National Oceanographic
aid Atmospheric Administr~*Ion 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 Chromatographic analysis of liquid
condensates from the pyrolysis of solid municipal waste. Jour. Chromato-
graphic Science. 8: 672.
Palese, M. and T. Tephly. 1975. Metabolism of formate in the rat. Jour.
Toxicol. Environ. Health. 1: 13.
-------
Patty, F. 1963. Industrial Hygiene and Toxicology, Vol. II. 2nd ed.
Interscience, New York.
Portmann, J.E. and K.W. Wilson. 1971. The toxicity of 140 substances to
the brown shrimp and 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 Technology, 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.
-------
No. 106
Fumaronitrile
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-uracy.
-------
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.
-------
FUMARONITRILE
I. INTRODUCTION
This profile is based upon relevant literature identified through
mechanized bibliographic searches such as TOXLINE, 8IOSIS, 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. Fumaronitrile 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.
Bioaccumulation. 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
LD^-j values for injected mice and orally dosed rats were 38 and
v
50 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.
-------
REFERENCES
Campagna, F., et al. 1977. A convenient synthesis of nitriles from
primary amides under mild conditions. Tetrahendron Letters. 21: 1813.
Law, A. 1968. Fumaronitrile as a bactericide. Chen, Abst. 68: 1135.
Ono, T. 1979. Maleonitrile, a bactericide and fungicide. Chem. Abst.
82: 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.
-------
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.
-------
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 th'"~ jhlor-
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
dichlorodifluoromethane (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
fjg/l, 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 th£ 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
Oichlorome thane
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/m3 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 0.00085 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 10 mg/m , and concen-
3 7
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 fluorocarbons (Natl. Acad. Sci.,
1978; Davis, et al. 1977; U.S. EPA, 1976; Howard, et'al. 1974).
-------
B. Distribution
Halomethanes are distributed rapidly to various tissues after ab-
sorption into the blood. Preferential distribution usually occurs to
tissues with high 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.
Oichloromethane 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
-1113-
-------
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.
8. Mutagenicity
Simmon, et al. (1977) reported that chloromethane, bromomethane,
and dichloromethane were all mutagenic to Salmonella typnimurium strain
TA100 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. Dichloromethane
was negative in mitotic recombination in S^ cerevisiae 03 (Simmon, et al.
1977) and in mutagenicity tests in Drosophila (Filippova, et al. 1967).
Trichlorofluoromethane and dichlorofluoromethane were negative in the Ames
assay (Uehleke, et 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 feto-
embryotoxicity has been noted in rats and mice exposed to dichloromethane
-------
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
bromodichlorcmethane at 8375 mg/m , 7 hours/day during gestation days 6 to
15 (Schwetz, et al. 1975).
£. 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 jug/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 jug/1. In freshwater invertebrates two acute studies with Daphnia
-------
maqna resulted in LC50 values of 46,500 jjg/1 for bromoform, and 224,000
jjg/1 for methylene chloride. In marine fish, LC values for the sheeps-
head minnow (Cyprinodon variegatus) were 17,900 pg/1 for bromoform and
180,958 pg/1 for methylene chloride. For the tidewater silversides (Menidia
beryllina) LC5Q values of 12,000 pg/1 for methylbromide and 147,610 pg/1
for methylene chloride were obtained. Adjusted LCcQ values for the marine
mysid shrimp (Mysidopsis bahia) were 24,400 pg/1 for bromoform and 256,000
pg/1 for methylene chloride (U.S. EPA, 1979).
B. Chronic Toxicity
The only chronic value for an aquatic species was 9,165 /jg/1 for
the sheepshead minnow.
C. Plant Effects
Effective concentrations for chlorophyll a and cell numbers in
freshwater algae Selenastrum capricornutum ranged from 112,000 to 116,000
pg/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 pg/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
-------
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 ^g/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, NIQSH (1976)
has recommended a 10-hour time-weighted average exposure limit of 261
3 »
mg/m of dichloromethane in the presence of no more carbon monoxide than
9.9 mg/m"5.
-------
Tribromomethane: OSHA (1976a,b) has established an 8-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 pg/1 not to exceed 320 ug/1; bromoform - 840 jug/1 not to
exceed 1,900 ug/1; methylene chloride - 4,000 ug/1 not to exceed 9,000 pg/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 ;jg/l not to exceed 380 pg/1; bromoform - 180 ug/1 not to exceed
420 jjg/1; methylene chloride - 1,900 jug/1 not to exceed 4,400 pg/1; and
methyl chloride - 3,700 jjg/1 not to exceed 8,400 ug/1.
-------
HALOMETHANES
REFERENCES
Ahmed, A.E., et al. 1977. Metabolism of haloforms to carbon
monoxide, I. In 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 '(^4C)-trichloro-
fluoromethane and (l^c)-dichlorodifluoromethane 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,
VJashington, 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.
f
Jongen, W.M.F., et al. 1978. Mutagenic effect of dichloro-
methane on Salmonella typhimurium. Mutat. Res. 56: 246.
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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-
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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) .
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21: 1.
Simmon, V.F., et al. 1977. Mutagenic activity of chemicals
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Progress in genetic toxicology.
Singh, H.B., et al. 1977. Urban-non-urban relationships of
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-/05V-
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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. . .
-1252,-
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SPECIAL NOTATION
U.S. EPA1s Carcinogen Assessment Group (GAG) has evaluated
heptachlor and has found sufficient evidence to indicate
that this compound is carcinogenic.
-------
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 epoxide, 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 LC5Q values for fresh-
. water fish range from 7.0 p.q/1 to 320 jjg/1 and 24 to 96-hour LC5_ 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 ^ig/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 jjg/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.
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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 (chemical name l,4,5,6,7,8,8-heptachloro-3a,4,7,7a-
tetrahydro-4,7-methanoindene; C,gHeCl7; molecular weight. 373.35) is a
white crystalline solid with a camphor-like odor. It has a vapor pressure
of 3 x 10~A 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 (Davidow and
-------
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 jug/1 (U.S. EPA, 1976). Levels of heptachlor ranged from .001
;jg/l to 0.035 ug/1 and heptachlor/heptachlor epoxide 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).
-------
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 pg/1 (fat adjust-
ed) (Savage, 1976). Levels of 5 ;jg/l 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/m"5.
Thus, sprayers, farmers and nearby residents of sprayed fields may receive
significant exposures (Nisbet, 1977).
0. Dermal
Gaines ' (I960)-• found rat dermal LD5Q values of 195 and 250 mg/kg
for males and females, respectively, compared with oral LD 's of 100 and
162 mg/kg, respectively, for technical heptachlor. Thus, dermal exposures
may be important in humans under the right exposure conditions.
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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).
B. 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. EPAr, 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).
-------
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, et 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. Carcinogenic! ty
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 (Cerey, et al. 1973). Bone marrow cells of the
treated animals showed increases in the incidence of abnormal mitoses, chro-
»
matid abnormalities, pulverization, and translocation. Both heptachlor and
heptachlor epoxide induced unscheduled DNA synthesis in SV-AO transformed
•iiso
-------
human cells (VA-4) in culture with metabolic activation (Ahmed, et al.
1977). Neither heptachlor nor heptachlor epoxide was mutagenic for Salmo-
nella tvohimurium 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).
0. 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
i
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). Phenobarbital 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).
13.61
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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, et 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, et al.
1978). . _ . • -j
Fish are less sensitive to heptachlor than are invertebrate spe-
cies. Ninety-six hour LC50 values for fish range from 7.0 ug/1 for the
rainbow trout; Salmo gairdneri, (Macek, et al. 1969) to 320 jug/1 for the
goldfish (Carassius auratus). Ten days after a dose -i.f 0.868 pg/g C-
.)
heptachlor to goldfish, 91.2 percent was unchanged, 5.4 percent was hepta-
chlor epoxide, 1 percent was hydroxychlordene, 1.1 per^_nt 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 ug/1 for the stone-
fly, Pteronarcella badia. (Sanders and Cope, 1968) to 80 pg/1 for the clado-
ceran (Simocephalus 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 52jug/1 to 120 ug/1 as determined in a 26-hour
»
LC5Q Daphnia maqna bioassay (Frear and Boyd, 1967).
-I3L63LT
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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 jug/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 (Easier,
1970; Kutz, 1961). The commercially valuable pink shrimp (Penaeus duorarum)
is especially sensitive, with reported 96-hour values as low as 0.03 ug/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).
8. Chronic Toxicity
In a 40-week life cycle test with fathead minnows (Pimephales prom-
elas), the determined no-adverse-effect concentration was 0.86 ug/1. All
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 jjg/1, 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 0.71jug/l (Hansen and Parrish, 1977).
C. Plant Effects
In the only study available, a concentration of 1,000 ;jg/l 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
-------
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
7,518 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 ID'7 ID'6 10-3
2 liters of drinking water 0 0.0023 ng/1 0.023 ng/1 0.23 ng/1
and consumption of 18.7
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 Standards
Agency Published Standard •• Reference
Occup. Safety 500 ug/m^* on skin from air Natl. Inst. Occup.
Health Admin. Safety Health, 1977
Am. Conf. Gov. 500 ug/m-5 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
-------
U.S. Publ. Health Recommended drinking water Natl. Acad. Sci., 1977
Serv. Adv. Comm. standard (1963) 18 ug/1 of
heptachlor and 18 ug/1 of
heptachlor epoxide
*Time weighted average
8. Aquatic
For heptachlor the draft criterion to protect freshwater aquatic
life is 0.0015 jug/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).
-------
HEPTACHLOR
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14
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.-
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'A 6 7-
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monophosphate- H formation by rat kidney cortex. Jour.
Pharihacol. Exp. Ther. 188: 265.
Khan, M.H., et al. 1969. Insect metabolism of photoaldrin
and photodieldrin. Science 164: 318.
Khan, M.A.Q., et al. 1973. Toxicity-metabolism relation-
ship of the photoisomers of certain chlorinated cyclodien
insecticide chemicals. Arch. Environ. Contain. Toxicol.
1: 159.
Korn, S., and R. Earnest. 1974. Acute toxicity of twenty
insecticides to the striped bass, Morone saxtilis. Calif.
Fish Game 60: 128.
Kutz, F.W., et al. 1977. Survey of pesticide residues
and their metabolites in humans. In: Pesticide management
and insecticide resistance. Academic Press, New York.
Kutz, M. 1961. Acute toxicity of some organic insecticides
to three species of salmonids and to the threespine stickle-
back. Trans. Am. Fish. Soc. 90: 264.
Lichtenstein, E.P. 1960. Insecticidal residues in various
crops grown in soils treated with abnormal rates of aldrin
and heptachlor. Agric. Food Chem. 8: 448.
Lichtenstein, E.P., et al. 1970.. Degradation of aldrin
and heptachlor. in field soils. Agric. Food Chem. 18: 100.
Lichtenstein, E.P., et al. 1971. Effects of a cover crop
versus soil cultivation on the fate of vertical distribution
of insecticide residues in soil 7 to 11 years after soil
treatment. Pestle. Monitor. Jour. 5: 218.
Macek, K.J., et al. 1969. The effects of temperature on
the susceptibility of bluegills and rainbow trout to selected
pesticides. Bull. Environ. Contain. Toxicol. 4:174.
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 potential using Salmonella typhimurium mutants.
Jour. Agric. Food Chem. 241560.
Matsumura, F., and J.O. Nelson. 1971. Identification of •
the major metabolite.product of heptachlor epoxide in rat
feces. Bull. Environ. Contain. Toxicol. 5: 489.
-------
Mestitzova, M. 1967. On reproduction studies on the occur-
rence of cataracts in rats after long-term feeding of the
insecticide heptachlor. Experientia 23: 42.
Miranda, C.L., and R.E. Webb. 1974. Effect of diet and
chemicals on pesticide toxici.ty in rats. Philipp. Jour.
Nutr. 27: 30.
Miranda, C.L., et al. 1973. Effect of dietary protein
quality, phenobarbital, and SKF 525-A on heptachlor metabo-
lism in the rat. Pestic. Biochem. Physiol. 3: 456.
Mizyukova, I.G., and G.V. Kurchatav. 1970. Metabolism
of heptachlor. Russian Pharmacol. Toxicol. 33: 212.
Nash, R.G., and W.G. Harris. 1972. Chlorinated hydrocarbon
insecticide residues in crops and soil. Jour. Environ.
Qual.
National Academy of Sciences. 1977. Drinking water and
health. Washington, D.C.
National Institute for Occupational Safety and Health.
1977. Agricultural chemicals and pesticides: a subfile
of the registry of toxic effects of chemical substances.
Nisbet, I.C.T. 1977. Human exposure to chlordane, hepta-
chlor and their metabolites. Unpubl. rev. prepared for
Cancer Assessment Group, U.S. Environ. Prot. Agency, Wash-
ington, D.C.
Podowski, A.A., et al. 1979. Photolysis of heptachlor
and cis-chlordane and toxicity of their photoisomers to
animals. Arch. Enviorn. Contain. Toxicol. 8: 509.
Radomski, J.L., and B. Davidow. 1953. The metabolite of
heptachlor, its estimation, storage, and toxicity. Jour.
Pharmacol. Exp. Ther. 107: 266.
Ritcey, W.R., et al. 1972. Organochlorine pesticide resi-
dues in human milk, evaporated milk, and some milk substi-
tutes in Canada. Can. Jour. Publ. Health 63: 125.
St. Omer, V. 1971. Investigations into mechanisms respon-
sible for seizures induced by chlorinated hydrocarbon insecti-
cides: The role of brain ammonia and glutamine in convul-
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.
Soyocool, 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 F. 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.
-------
No. 109
Heptachlor Epoxide
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
'12.71-
-------
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 *•>
-------
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.
-------
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. Pood
The FDA 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 epoxide; 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 0.5. EPA (1979a) has estimated the weighted
x
average bioconcentration factor for heptachlor to be -5,200
for the edible portions of fish and shellfish consu^d' 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 ug/m
may be encountered (Nisbet, 1977).
0. Dermal
Gaines (1960) found rat dermal LD5Q values of
195 and 200 mg/kg for males and females, respectively, com-
pared with oral LDeQ' 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. PHARMACOKINETICS
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 butterfat, and in the fat
of poultry eggs and livestock as compared to residue levels
found in their normal food rations. "Heptachlor residues"
-------
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 Matsumura, 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 foe 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.
D. 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.
B. Chronic Toxicity
In the only reported chronic study, the 26-hour
LC5Q 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.
0. 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-
-------
tration factor for heptachlor 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/m 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/man/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 ppra in the diet of C3Heb/Fe/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, I979b).
-------
1-EPTACHLOR 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.
ed.
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, O.E.H. and J.E. Boyd. 1967. Use of Daphnia maqna for the microbio-
assay and pesticides. I. Development of standardized techniques for rearing
Daphnia 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. ^
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.
I vie, G.W., ~et al. 1972. Novel photoproducts of heptachlor epoxide, trans-
chlordane, and trans-nonachlor. Bull. Environ. Contam. 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 gpoxide in rat feces. Bull. Environ. Ccntam. 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, D.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. Prot. Agency, Washington, D.C.
Radmoski, J.L. and 8. Oavidow. 1953. The metabolite of heptachlor, its
estimation, storage, and toxicity. Jour. Pharmacol. 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. Prot. Agency.
Tashiro, S. and F. Matsumura. 1978. Metabolism of trans-nonachlor and re-
lated chlortane components in rat and man. Arch. Environ. Contam. Toxicol.
7: 113
U.S. EPA. 1977. Risk assessment of chlordane and heptachlor. Carcinogen
Assessment Group. U.S. Environ. Prot. 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.
-------
No. 110
Hexachlorobenzene
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 th''-
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'5 Carcinogen Assessment Group (GAG) has evaluated
hexachlorobenzene and has found sufficient evidence to
indicate that this compound is carcinogenic.
-Jits-
-------
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 placental 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,
Lagodon rhoimboideSi bioconcentrated this compound 23,000 times in 42 days
of exposure. The concentration of.HCB 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 (HC3; C^Cl^; 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.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 supplies at
•13*7-
-------
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).
8. 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 hexachlordbenzene. The daily intake of hexachloroben-
zene by infants from human breast milk in part of Australia was 39.5 ^g per
day per 4 kg baby. This exceeded the acceptable daily intake recommended by
the FAQ/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 dctanol/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. PHARMACQKINETICS
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 SO percent of doses of hexa-
chlorobenzene ranging from 12 mg/kg to 180 mg/kg were absorbed. Hexachloro-
benzene in food products will selerVvely 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 '. Jtachlorobenzene 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
burden is not lowered (Villeneuve, 1975).
-------
C. Metabolism .
Hexachlorobenzene is metabolized after i.p. administration in the
rat to pentachlorophenol, tetrachlorohydroquinone and pentachlorothiophenol-
(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).
D. 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 hexachlorobenzene is
presumed to be due to biliary secretion. Five percent of the administered
HC8 was excreted in the urine (Koss and Koransky, 1975).
IV. EFFECTS
A. Carcinogenicity
Carcinogenic activity of hexachlorobenzene was assessed in hamsters
fed 4.8 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,
the 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).
8. Mutagenicity
Hexachlorobenzene was assayed for mutagenic activity in the domi-
nant lethal assay. Rats were administered 60 mg/kg/day hexachlorobehzene
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). CD-I mice receiving 100 mg/kg/day hexachlorobenzene orally
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.
0. 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 g-iven 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. 1978). 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 (HC8) 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
jjg/1; sheepshead minnow, Cyprinodon varieqatus, - 2,254 ug/1. In a 42-day
exposure, the pinfish, Laqodon rhomboides, BCF was 23,000. The concen-
tration of HC8 in pinfish muscle was reduced only 16 percent after 28 days
of depuration; this slow rate is similar to that for DDT 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 10-5
«
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.
8. Aquatic
Pertinent information concerning aquatic criteria could not be
located in the available literature.
-------
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 pa--v ., 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.
Food and Agriculture' ..organization. 1974. 1973 evaluations
of some pesticide residues in food. FAO/AGP/1973/M/9/1; WHO
Pestic. Residue Ser. 1..' 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.
Ross, R., and W. Koransky. 1975. Studies on the toxicology
of hexachlorobenzene. I. Pharmacokinetics. 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.S., 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 hexachlorobenzene in the rat. Toxicol.
Appl. Pharmacol. 31: 313.
-------
No. Ill
Hexachlorobutadiene
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. EFA's Carcinogen Assessment Group (CAG) has evaluated
hexachlorobutadiene and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
HEXACHLOROBUTADI EN 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 LC5Q 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.
-J3W-
-------
HEXACHLOROBUTADIENE
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
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
/SOI
-------
plants discharging HECD. 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 mg/kg. 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 u
-------
although values as high as 460 ug/m have been measured
(Li, et al. 1976).
III. PHARMACOKIN ETICS
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. 1974).
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.
-/3D3-
-------
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 mg/kg or 8 mg/kg 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 glomerulonephritis 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,
-------
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 Toxicity
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 sjiagnalis), and a sowbug,
(Asellus aquaicus) , were both exposed for 96-hours to HCBD
resulting in EC5Q values of 210 and 130 ug/l» respective-
v
ly (Leeuwangh, et al., 1975). No acute studies with marine
species have been conducted.
B. Chronic Toxicity
Pertinent information was not found .in the avail-
able literature.
C. Plant Effects
Pertinent data was not found in the available
literature.
D. Residue's
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.
-/3d 6-
-------
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 10-5, 1CT6, and 10~7 (U.S. EPA, 1979).
The corresponding criteria are 0.77 ug/1, 0.077 ug/1, 0.0077
y.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).
-------
HEXACHLOROBUTADIENE
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, D., 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
(HCBD). 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. Delo. 4: 130. HAPAB:72:820. (Translation)
-/308--
-------
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
y
Heachlorocyclohexane
A
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 (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 configurations! 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.
-J3J3-
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HEXACHLOROCYCLOHEXANE
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 (C-.H-C1,; 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 ug/1 (U.S. EPA, 1975).
8. 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 isomers 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).
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 Res. Center,
-------
1972). At least 75 percent of an intraperi-tonial 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).
-1317-
-------
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.
8. 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 jjg/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, th'e 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).
-------
C. Teratogenicity
Lindane given in the diet during pregnancy at levels of 12 or 25
mg/kg body weight/day did not produce teratcgenic effects in rats
(Mametkuliev, 1978; Khera, et al. 1979).
D. 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
F,, and F females. In addition, some of the F. and F2 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/m3) 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
Hexachlordcyclohexane 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).
f
V. AQUATIC TOXICITY
A. Acute Toxicity • ^
Among 16 species of freshwater fish, LC5_ 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/l 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. Zebrafish
(Brachydanio rerio) showed a lindane LC5Q value of 120 ng/1, but rainbow
»
trout (Salmo gairdneri) evidenced respiratory distress at 40 ng/1 (Slooff,
1979). Technical grade HCH was much less toxic than pure lindane;. LCcn
>u
-/IM-
S'
-------
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
ug/1 for 8CH (15.5 percent gamma iscmer) (Henderson, et al. 1959). Static
tests on freshwater invertebrates revealed a range of IC50 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 LC^Q value for the pond snail (Lymnaea
staqnalis) of l,200jjg/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 jjg/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 LC50 values from 7.3/jg/1 for the striped
bass (Morone saxatilis) (Korn and Earnest, 1974) to 240 pg/l for the long
nose killifish (Fundulus similis) (Butler, 1963). A single species, the
pinfish (Lagodon rhomboides), tested with technical grade hexachlorocyclo-
hexane, produced a 96-hour flow-through LC5Q value of 86.4 ug/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 0.17yug/l for the pink shrimp (Panaeus duorarum)
(Schimmel, et al. 1977) to 10.0 jjg/1 for the grass shrimp (Palaemonetas
vulqaris) (U.S. EPA, 1979). An LC50 value of 0.34 xug/l was obtained for
technical grade hexachlorocyclohexane for the pink snrimp (Schimmel, et al.
1977). The American oyster had an EC5Q of 450 ;jg/l based on shell decom-
position (Butler, 1963).
-------
3. Chronic
A chronic value of 14.6 pg/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 jug/1 were obtained for Chironomus tentans,
Gammarus fasciatus, and Oaphnia 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 pg/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
sp. exposed to lindane at the maximum solubility limit. Irreparable damage
to Chlorella sp. occurred at lindane concentrations of more than 300 ^g/1
(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
-------
(Crassostrea virginica), 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 pg/1 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
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-
time cancer risk for humans of 10~5 is 21 ng/1, based on the data of
Nagasaki, et al. (1972).
1323-
-------
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 10~5 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 pg/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 pg/m (skin) for air (U.S. EPA, 1979).
B. Aquatic
For lindane, freshwater criteria have been drafted as 0.21 ug/1
with 24-hour average concentration not to exceed 2.9 ^ig/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
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•13 27-
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Szpunar, K., et al. 1976. Effect of silymarin on hepatoxic
action on lindane. Herba. Pol. 22: 167.
Thorpe, E., and A.I. Walker. 1973. The toxicology of diel-
drin (HEOD) . II. In mice with dieldrin, DDT, phenobarbi-
tone, beta-BCH, and gamma-BCH. Food Cosmet. Toxicol. 11:
433.
Tsoneva-Maneva, M.T., et al. 1971. Influence of diazinon
and lindane on the mitotic activity and the karyotype of
human lymphocytes cultivated in vitro. Bibl. Haematol.
38: 344.
Tu, C.M. 1975. Interaction between lindane and microbes
in soil. Arch. tMicrobiol. 105: 131.
Tu, C.M. 1976. Utilization and degradation of lindane
by soil microorganisms. Arch. Microbiol. 108: 259.
ulmann, E. 1972. Lindane: Monograph of an insecticide.
Verlag K. Schillinger Publishers, Freiburg, West Germany.
U.S. EPA. 1973. BCH-Lindane. Unpublished report. Cri-
teria and Evaluation division. Office of Pest. Programs.
Washington, D.C.
U.S. EPA. 1975. National interim primary drinking water
regulations. Fed. Reg. Vol. 40, No. 248, p. 59566. U.S.
Environ. Prot. Agency.
U.S. EPA. 1979. Hexachlorocyclohexane: Ambient Water Quality
Criteria. (Draft).
-133.9-
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No. 113
gamma—Hexachlorocyclohexane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-J330'
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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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Disclaimer Notice
Mention-of trade-names or commercial products.does not constitute
endorsement or recommendation for use.
-J-33JL-
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GAWA-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 jug/1 are toxic to marine inver-
tebrate species.
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GAMMA-HEXACHLOROCYCLQHEXANE (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 mg/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 8HC (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 Sana,
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).
-ISM-
-------
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 jjg/1 (U.S. EPA, 1975).
B. Food
The daily intake of lindane has been reported at 1 to 5 jjg/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).
D. • Dermal
Lindane has been used to eradicate human ectoparasites, a few ad-
verse reactions have been reported (U.S. EPA, 1979).
-J33S--
-------
Ill, 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; Xoransky, et al. 1963.; Huntingdon Research Cen-
ter, 1971). At least 75 percent of an intraperitoneal dose of C-labeled
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 1^-3,4,5,6-tetra-
chlorocyclohexene. Some other metabolites reported have been 2,3,4,5,6-pen-
tachloro-2-cyclohexene-l-ol, pentachldrophenol, 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
-------
al. 1977; Copeland and Chadwick, 1979). Both free and conjugated chlorophe-
nols with the possible exception of pentachlorophenol (Engst, at 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 °{ ,/& , ~X~, 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 ppm^f -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 "tT 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 <*< , ^', tT~ 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. The f> -isomer-treated animals had no tumors.
-------
Goto, at 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/^-, IT-, 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 d -HCH to Osborne-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 "2^-HCH in mice is ques-
tionable (Natl. Cancer Inst., 1977).
8. Mutagenicity
Some alterations in mitotic 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). 2" _HCH was mutagenic in assays using Salmonella
typhimurium with metabolic activation, the host-mediated .assay, and the
133?-
-------
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 teratcgenic effects in rats (Mametku-
liey, 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 postimplantation 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
-1331-
-------
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 (Litterst and Miller,. 1975) and by treatment
with silymarin (Szpunar, et al. 1976), and various tranquilizers (Ulmann,
1972).
V. AQUATIC TOXICITY
A. Acute Toxicity
The range of adjusted .LC_Q values for one flow-through and ' 24
static bioassays for lindane in freshwater fish ranged from 1 jug/1 for the
brown trout Salmo trutta (Macek, et al. 1970) to 83 jjg/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 jug/1 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, stoneflies (Pteronarcys californi-
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 ;ug/l. Three species of cladocerans
(Daohnia pulex, O^ maona and Simocephalus serralatus) were most resistant
with LC5Q values of 390 to 745 jug/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 acuts LC5Q of 9 jjg/1 (Eisler, 1970), while the striped mullet (Mugil
cephalus) was reported as having an acute static LC^ of 66.0 jjg/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-- of 7.3 jug/1 (Korn and Earnest, 1974); and the
longnose killifish (Fundulus similis) was most resistant with a reported
LC5n of 240 jug/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 jjg/1 for the grass shrimp (Palaemonetes vulgaris).
B. Chronic
A chronic value of 14.6 jjg/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 jjg/1 were obtained for three freshwater inver-
tebrates, Chironomus tentans, Gammarus fasciatus, and Daphnia manna (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 Jug/1, respectively. Irreparable damage to Chlorella
spec, occurred at concentrations greater than 300 jjg/1 (Hansen, 1979).
0. Residues
. Sioconcentration 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
-------
(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.
8. Aquatic
The criterion has been drafted, to protect freshwater organisms as a
0.21 jug/1 24-hour average concentration not to exceed 2.9 pg/1. Data are
insufficient to. draft criterion for the protection of marine life from gam-
ma-hexachlorccyclohexane (lindane).
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GAMMA-HEXACHLOROCYCLOHEXANE(LINDANE)
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-------
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*
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Petrescu, S., et al. 19~4. Studies on the effects of long-
term administration of chlorinated organic pesticides (lin-
dane, DDT) on laborator" white rats. Rev. Med. - Chir.
78: 831.
Poradovsky, R. , et al. 1977. Transplacental permeation
of pesticides during ncrsial pregnancy. Cesk Gynekol. 42:
405.
-------
Lichtenstein, E.P. 1959. Absorption of some chlorinted
hydrocarbon insecticides from soils into various crops.
Jour. Agric. Food Chera. 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.
Contain. 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.
Mather, S.P., and J.G. Saha. 1975. Microbial degradation
of lindane-C-14 in a flooded sand loam soil. Soil Sci.
120: 301.
Nagasaki, H., et al. 1972. Carcinogenicity of benzene
hexachloride (EEC). 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. 1977. A bioassay for possible
carcinogeniclty of lindane. Fed. Reg. Vol. 42. No. 218.
Nigam, S.K., et al. 1979. Effect of hexachlorocyclohexane
feeding on testicular tissue on pure inbred Swiss mice.
Bull. Environ. Contain. Toxicol. 23: 431.
Nishimura, H., et al. 1977. Levels of polychlorinated
biophenyls and organochlorine insecticides in human embryos
and fetuses. Pediatrician 6: 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-
term administration of chlorinated organic pesticides (lin-
dane, DDT) on laboratory white rats. Rev. Med. - Chir.
78: 831.
Poradovsky, R. , et al. 1977. Transplacental permeation
of pesticides during normal pregnancy. Cesk Gynekol. 42:
405.
73 y 7-
-------
Reuber, M.D. 1979. Carcinogenic!ty of Lindane. Environ.
Res. 19: 460.
Rivett, K.F., et al. 1978. Effects of feeding lindane
to dogs for periods of up to 2 years. Toxicology 9: 237.
Schinunel, S.E., et al. 1977. Toxicity and bioconcentration
of BHC and lindane in selected estuarine animals. Arch.
Environ. Contain. Toxicol. 6: 355.
Sloof, W. 1979. Detection limits of a biological monitor-
ing system based on fish respiration. Bull. Environ. Contain.
Toxicol. 23: 517.
Sugiura, R., et al. 1979. Accumulation of organochlorine
compounds in fishes. Difference of accumulation factors
by fishes. Chemosphere 6: 359.
Szpunar, K., et al. 1976. Effect of silymarin on hepatoxic
action .of lindane. Herba. Pol. 22: 167.
Thorpe, E., and A.I. Walker. 1973. The toxicology of diel-
drin (HEOD) . II. In mice with dieldrin, DDT, phenobarbitone,
beta-BCH, and gamma-BCH. Food Cosmet. Toxicol. 11: 433.
Tsoneva-Maneva, M.T., et al. 1971. Influence of Diazinon
and lindane on the mitotic activity and the karyotype of
human lymphocytes cultivated in vitro. Bibl. Haematol.
38: 344. -
Tu, C.M. 1975. Interaction between lindane and microbes
in soil. Arch. Microbiol. 105: 131.
Tu, C.M. 1976. Utilization and 'degradation of lindane
by soil microorganisms. Arch. Microbiol. 108: 259.
Ulmann, E. 1972. Lindane: Monograph of an insecticide.
Verlag K. Schillinger Publishers, Freiburg, West Germany.
U.S EPA. 1979. Hexachlorocyclohexane: Ambient Water Quality
Critera (Draft).
-------
No. 114
Hexachlorocyclopentadlene
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.
-13 fo
-------
HEXACHLORQCYCLOPENTADIENE
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. Teratogeriic effects were not observed in rats receiving oral doses
of HEX during gestation.
The reported 96-hour LCcn value for the fathead minnow under static
-"-i
and flow-through conditions using larval and adult fish ranges from 7.0 ug/1
to 104 jug/1. The chronic value for fish in an embryo-larval test is 2.6
jug/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.
-------
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 gavage. 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.
8. 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 hexanetisopropanol mixture.
D. 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 8ALB/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.
8. 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).
-/3-5T-
-------
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 mg/kg/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.
D. 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 other abnormalities were
reported. Naishstein and Lisovskaya (1965) applied 0.5 to 0.6 ml of a solu-
tion of 20 ppm 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 pg/1 to 104 ug/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 pg/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.
-/3f7-
-------
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).
B. Aquatic
For HEX, the draft criterion to protect freshwater aquatic life is
0.39 jug/1 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.
-------
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. Kexachlorocyclopentadisne. 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. Oep. 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, 197S, 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 8ALB/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.
-73/7-
-------
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, D.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 l^C-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. Dev. 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, D.C.
U.S. EPA. 1979. Hexachlorocyclopentadiene: Ambient Water Quality Criteria
(Draft).
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No. 115
Hexac "" jroethane
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.
-J313.-
-------
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.
-------
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 (Oickson 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.
B. 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).
-13 (f-
-------
C. Teratogenicity
Teratogenic effects were not observed in pregnant rats exposed to
hexachloroethane by inhalation or intubation (Weeks, at al. 1979).
D. 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 (Leoomis
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
LCeg value of the freshwater Cladoceran (Daphnia magna) was reported as
8,070 jjg/1 (U.S. EPA, 1978). For the marine fish, the sheepshead minnow
(Cyprinodon varieqatus), a 96-hour I~C5Q value of 2,400 ug/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 940 jjg/1 (U.S. EPA, 1978).
8. Chronic Toxicity
Pertinent data could not be located in the available literature*.
-------
C. Plant Effects
For the freshwater algae, Selenastrum caoricornutum, the 96-hour
EC50 effective concentrations based on chlorophyll and cell number were
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 Obtained 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.
B. Aquatic Toxicity
The proposed criterion to protect freshwater aquatic life is 62
ug/1 as a 24-hour average and should not exceed 140 jug/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 ug/1 at any time.
-136 7-
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HEXACHLOROETHANE,
REFERENCES
Dickson, A.G., and J.P. Riley. 1976. The distribution
of short-chain halogenated aliphatic hydrocarbons in some
marine organisms. Mar. Pollut. Bull. 79: 167.
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 Publishers, Inc.. Sandusky, Ohio.
National Cancer Institute. 1978. Bioassay of hexachloro-
ethahe for possible carcinogenicity. Natl. Inst. Health,
Natl. Cancer Inst. DHEW Publ. No. (NIH) 78-1318. Pub.
Health Serv. U.S. Dept. 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.
U.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: 187.
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No. 116
Hexachlorophene
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.
-7370-
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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
V
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.
-1171-
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I. INTRODUCTION
Hexachlorophene (CjjHgO^CLg, 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.
V j
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 hexachlorc, ')ne 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 jug/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 pg/1
(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 bl6od)
(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/jg/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).
D. 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-percent and 50-percent so-
lutions of hexachlorophene to mice failed to produce significant car-
cinogenic effects (Stenback, 1975); the levels of compound used caused bigh
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).
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8. 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).
Oesi, 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).
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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.
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REFERENCES
American Medical Association. 1977. AMA Council on Drugs, Chicago.
Arnold, D., • et al. 1975. Mutagenic evaluation of hexachlorophene.
Toxicol. Appl. Pharmacol. 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.
Desi, 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.O. 1979. Importance of hepatic function on the plasma
disappearance and biliary excretion .of hexachlorophene. Toxicol. Appl.
Pharmacol. 49: 113.
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Msjundar, 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). ' DHBY, Publication No. 78-340,
Washington.
Rudali, G. and R. Assa. 1978. Lifespan carcinogenic!ty 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 D. 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.
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No. 117
Hydrofluoric Acid
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.C. 20460
APRIL 30, 1980
-im-
-------
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.
-137?
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. 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.
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' HYDROFLUORIC ACID
I. INTRODUCTION
Hydrofluoric acid (CAS registry number 7664-39-3) (HF) is a colorless,
clear, fuming corrosive liquid made by treating fluorspar (CaFo wj.th 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: -83.550C —
Boiling Point: 19.51QC —
Density: 0.987 1.15 - 1.18
Vapor Pressure: 1 atm 1 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.
B. 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 CCL^Fj with NO and humid air (Saburo, et al. (1977). It is
present. X5the stratosphere (Zander, et al. 1977; Drayson, 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
-2-
-/3U.
-------
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).
8. 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, 1971).
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, 1971).
IV. EFFECTS
A. Carcinogenicity
Pertinent data were not found in the available literature.
8. Mutagenicity
Mohamed (1968) 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 (1976).
Rats inhaling 0.1 mg HF/m^ 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. 1973).
Weak inutagenic effects in the offspring of Drosophila exposed to
•
air bubbled through 2.5 percent HF have been reported (Mohamed, 1971).
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. 2.9 ppm HF (Gerdes, et al. 1971).
E. Chronic Toxicity
Among the adverse physiologic effects of long-term exposure to HF
are skeletal fluorosis, dental mottling and pulmonary impairment (NAS, 1971;
NIOSH, 1975; NIOSH, 1976). 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/m-5 devel-
oped pulmonary, 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).
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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 ,ug/l. Bonner
and Morgan (1976) observed that 50,000 ^jg/1 HF was lethal to bluegill sun-
fish (Lepomis macrochirus) in one hour.
3. 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/m5 (3 ppm) 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.
13*6-
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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,. Cookeville,
Tennessee. Prepared for the Office 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
bums. 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.8. 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.
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Klauder, J.V., st 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. Cont. Assoc. 18: 395.
Mohamed, A. 1971. Induced recessive lethals in second chromosomes of
Drosophila melanogaster by hydrogen fluoride. In: Englung, H., Berry, W.,.
eds. Proc. 2nd Internet. Clean Air Cong.- New Yori<: 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.
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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 P8281-483.
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.
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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.
-------
Hydrogen Sulfide
Summary
Pertinent information could not be located on the
carcinogenicity, mutagenicity, or teratogenicity of H2S.
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.
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I. INTRODUCTION
Hydrogen sulfide (R2S> CAS No • 7783064) is a colorless
flammable gas with a rocten egg odor. It has the following
physical properties:
Formula I^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 H2$ was recovered from
fossil fuels (Standen, 1969).
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II. EXPOSURE
A. Water
Bacterial reduction of sulfates accounts for the
occurrence of 82$ 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 ingestion 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
sul'fide 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 H2S
in sewers and waste from industrial plants where animals
products are handled. Thus,.there has been accidental poisoning
from H2S 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
the 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).
-13
-------
IV. EFFECTS
A. Carcinogenic!ty
Pertinent information could not 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 H2S combines with alkali present in moist
tissues to form sodium sulfide, a caustic (Sax, 1979). Chronic
-an-
-------
poisoning results in headache, inflammation of the conjunctivae
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, H2 S
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 pt/w 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 certax.i cells of the body resulting
from prolonged oxygen starva f"f.o-n (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
-13 97-
-------
Co H2S 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 I^S in wastewater treatment plants
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The 8-hour, time-weighted average occupational
exposure limit for #2$ ^as 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
H2& 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).
-------
References
Baxter, C. F- and R. Van Reen. 1958a. 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. LOG. 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. E., 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.
I.TII. 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. Inves t. U.S. Bureau
of Mines. Number 2776.
-------
No. 119
Indeno (1,2,3-^1 )pyrene
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'/Oh
-------
SPECIAL NOTATION
U.S. EPA1s Carcinogen Assessment Group (GAG) has evaluated
indeno(1,2,3-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, 19796).
IndenoC1,2,3-cd]pyrene (IP; C22H12^ ^s one °^ tne 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.,
benz[b]fluoranthene), weak carcinogens (benz[a]anthracene), and cocarcinogens
(e.g., fluoranthene), as well as numerous non-carcinogens (U.S. EPA,
19796).
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
3asu 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,
benzotk]fluoranthene, benzotj]fluoranthene, benzo[a]pyrene, benzo[g,h,i]-
perylene, and indeno[1,2,3-cd]pyrene) to be 13.5 ng/1.
-------
3. Food
Levels of I? 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 1.34 ng/m3 (Gordon, 1976; Gordon and Bryan, 1973)- Thus, the human
daily intake of I? by inhalation of ambient air may be in the range of
0.57 to 25.5 ng, assuming that a human breathes 19 m^ 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. SPA,
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. ,
-------
IV. EFFECTS
A. Carcinogenicity
IP is regarded as only a weak carcinogen (U.S. SPA, 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.
3. 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, 1979aX.
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, benz[b]-
fluoranthene, benz[h]fluoranthene, indenoC1,2,3-cd]pyrene, and benzlajpyrene)
*
not exceed 0.2 .ug/1. Occupational exposure criteria have been established
-------
for coke oven emissions, coal tar products, and coal tar pitch volatiles,
all of which contain large amounts of PAH, including IP (U.S. SPA, 1979a).
The U.S. EPA (1979a) draft recommended criteria for PAH in water are
based upon the extrapolation of animal carcinogenicity data for benz[a]-
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
Sasu, D.K., and J. Saxena. 1977. Analysis of raw and drinking water
samples for pclynuclear aromatic hydrocarbons. EPA P.O. No. CA-7-2999-A,
and CA-8-2275-B. Exposure Evaluation Branch, HERL, Cincinnati, Ohio.
3asu, D.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, at 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 ?. 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. 1:
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 cherai-
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.
-------
If?
Isobutyl Alcohol
I. Introduction
Isobutyl alcohol (2-methyl-l-propanol, C.H.-0; molecular weight
74.12) is a flammable, colorless, refractive liquid with an odor like of
amyl alcohol, but weaker. Isobutyl alcohol is used in the 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 the intestinal tract and
the lungs.
3. Distribution
No data were readily available.
G. Metabolism
Isobutyl alcohol is oxidized to isobutyraldehyde and isobutyric
acid in the rabbit, with further metabolism proceeding to acetone and carbon
dioxide. Some conjugation with glucuronic acid occurs in the rabbit and dog.
0. Elimination
Approximately 14% of isobutyl alcohol is excreted as urinary
conjugates in the rabbit.
IV. Effects
A. Carcinogenic!ty
Rats receiving isobutyl alcohol, either orally or subcutaneously,
one to two times a week for 495 to 643 days showed liver carcinomas and
-------
sarcomas, spleen sarcomas and myaloid leukemia (Gibel,. e£ al_., Z. Exp.
Chir. Chir. Forsch. 7_: 235 (1974).
B. Teratogenicity
No data ware 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 che liver.
On ingestion.of two molar solution for two months rats developed Mailory's
alcoholic hyaline bodies in the liver, and were observed to have decreases
in fat, glycogen, and SNA 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 LDt.,, of isobutyl alcohol for rates if 2.46 g/kg
(Smith e_t al. , Arch. Ind. Hyg. Occup. Med. 10: 61, 1954).
V. Aquatic Toxicity
A. Acute Toxicity
The LC-Q of isofautyl 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
-------
VII. Information Sources
1. NCM Toxicology Daca Bank.
2. March. Index, 9th ed.
3. NIOSH Registry of Toxic Effects of Chemical Substances, 1978.
4. NCM Toxline.
5. Sax, I. "Dangerous Properties of Industrial Materials."
6. Proctor, N. and Hughes, J. " Chemical Hazards of she Workplace"
Lippincott Co., 1978.
7. Occupational Diseases. A Guide co Their Recognition, NIOSH
publication No. 77-181, 1977.
8. Hunter, D. "The Diseases of Occupations" 5th ed., Hodder and
Stoughton, 1975.
-------
No. 121
Lead
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-jus-
-------
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
SUMMARY
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-
c-''" ;genic 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
expansively studied, particularly in freshwater species.
As with other heavy metals, the toxicity is strongly depen-
' 1
dent on the water hardness. Unadjusted 96-hour LCqQ values
with the common fathead minnow, Pimephales prpmelas, ranged
from 2,400-7,480 /ag/1 in soft water to 487,000 jag/I in hard
water. Toxicity is also dependent on the life stage of
the organism being tested. Chronic values ranged from 32
ug/1 to 87 jag/1 for six species of freshwater fish. Lead
at 500 jag/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 SOO-lOOO-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 pq/1 at pH 5.5 to 1 /ig/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 +4 valence state (Standen, 1967).
Lead comsumption 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).
-fit-
-------
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 yg/day
for adults (Nordman, 1975; Kehoe, 1961). For children (ages'
3 months to 8.5 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 pg/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/m3 (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
-------
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 species 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-
-------
witz, et ai. 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 lead (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'Riordan and Evans, 1974; 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. EPA, 1979). In experimental animals, on the otner
hana, lead 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^ values, and that LCcn values for
lead are greatly different in hard and soft water. Between
soft and hard water, the LC-Q 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 LC5Q values for freshwater fish are
2,400 to 7,480 pg/1 for fathead minnows in soft water (Tarz-
well and Henderson, I960; Pickering and Henderson, 1966),
482,000 for fathead minnows in hard water (Pickering and
Henderson, 1966), 23,800 jug/1 for bluegills in soft water
(Pickering and Henderson, 1966), and 442,000 jug/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 jjg/1 for sludge
worms (Tubifex sp.) obtained from tests conducted at pH
-------
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 LCcn 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
pg/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 lake 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 (Sphemerella grandis) and the stonefly
(Pterpnarcys 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 1,0"'" -fold (Schulz-
,''
Baldes, 1976) .
VI EXISTING GUIDELINES AND STANDARDS
A. Human
As of February 1979, the U.S. <~x-cupational Safety
...I
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.
-------
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.
-MIX-
-------
LEAD
REFERENCES
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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 3.99 _iri 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 met
to embryos of the American oyster Crassostrea virginica.
Ma r Rinl. 1 8 • 1 fi ? _
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. Contam.
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.
-------
Kahoe, 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.
Kiiiunel, 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. 5: 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-
alg.ae. 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. Contam. 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 1973.
National Institute for Occupational Safety and Health.
DHEW (NIOSH) Publication No. 73-158.
-------
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 (Lorid.) 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:-.'""JL.
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. X
»
Tarzwell, C.M., and C. Henderson. 1960. Toxicity of less
common metals to fishes. Ind. Wastes 5: 12.
-------
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.
-------
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.
-------
151
MALE1C 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 that
-------
between 200 million and 300 million pounds of this chemical were
produced/imported in 1977. *J
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 et 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).
s. 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. PHARMACOKINETICS
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 CC»2 and H-0.
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).
-if39-
-------
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.
Br. 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. _7:645-659
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.
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No. 123
Malononitrile
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
vw-
-------
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.
-ItW •
-------
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
Maiononitrile (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.
Maiononitrile 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, 1963).
Maiononitrile 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; Lanza 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.
B. 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.
-MS-
-------
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. PHARMACOKINETICS
. A. Absorption
Animal studies indicated that malononitrile is absorbed through
the lungs and by the skin (Panov, 1969).
B. 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 (Stern 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
ID. vivo and was ultimately excreted as thiocyanate after oxidation
(Ghiringhelli, 1955).
The C=N'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).
-------
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.
0. 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. Carcinogenicity, Mutagenicity, Teratogenicity and Reproductive
Effects
Pertinent data were not found in the available literature.
8. 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 psycniatric 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/nv3 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.
-/m-
-------
Nuclear changes in neurons and satellite spiral ganglia were seen
in rats administered single doses (6-8 mg/kg) of malononitrile (Van Sreeman
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/nv3) 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.
Lonza, 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, D., 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.
Stern, 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.
-------
No. 124
Mercury
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 acc-uracy.
11 &-
-------
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... 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
. v ^
in -.. .Ik. 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
hig.j'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 ug/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.
11
-------
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, 1963).
Mercury exists in three oxidation states: elemental (0),
mercurous (.+!)> 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
3
-------
percent of inhaled mercury vapor is retained (Hursh, et ai.,
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).
Methylmercury 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 (Ta^k 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).
-It ft-
-------
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 ir\ vivo, probably largely
through the enzymatic activities of red blood cells (Clarkson,
et al., 1978).
Mercury 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 j^n 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 (Clarkson, et al., 1978). Limited experi-
ments with subjects exposed to mercury vapor indicate a two com-
ponent loss of mercury from the bloodstream. Clarkson (1973)
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 biotransformation 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
iri 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 Ferm, 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 sper*ma-
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 '" \sturbed, 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 sympt "'TIS, 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).
-1163-
-------
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 LCcQ 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. LC5Q values . ranged from 0.02 to 2,100
ug/1 (U.S. EPA, 1979). Heit and Fingerman (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
(Sphemerella 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 chlor»ide,
LC5Q values ranged from 3.6 to 32,000 pg/1 for 21 species. Embryo
-------
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 pg/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 pg/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, Mysidopsis bahia. The highest concentration producing
no-observed-effect was 0.82 pg/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
-------
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 ug/T and lethalities from 10 to 50
ug/1. Effective concentrations for the alga Isochrysis galbana
ranged up to 2,000,000 pg/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
Bioconcentration 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
i
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 .
IV 66-
-------
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 Kg/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 /jg/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 ug/1 at any time. For methylmercury, the draft
criterion is 0.016 pg/1 for a 24-hour average, not to exceed
8.8 ug/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 ug/1 at any time. For methylmercury, the tenta-
-------
tive criterion is 0.025 pg/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
REFERENCES
Aberg, B., et al. 1969. Metabolism of methyl mercury (Hg-
203) compounds in man. Arch. Environ. Health 19: 473.
Bakir, F., et al. 1973. Methyl mercury poisoning in Iraq.
Science 181: 234.
Baranski, B., and I. Szymczyk. 1973. Effects of mercury
vapor upon reproductive functions of female white rat.
Medycyna. Pracy. 24: 243.
Beisinger, K.E., and G.M. Christensen. 1972. Effects of
various metals on survival, growth, reproduction, and metabo-
lism of Daphnia magna. Jour. Fish. Rev. Board Can. 29:
1691."
Berland, B.R., et al. 1976. Action toxique de quarte metaux
lourds sur la croissance d'algues unicellulaires marines.
C.R. Acad. Sci. Paris, t. 282, Ser. D: 633.
Berlin, M.H., et al. 1969. On the site and mechanism of
mercury vapor resorption in the lung. Arch. Environ. Health
18: 42.
Blinn, D.W., et al. 1977. Mercury inhibition on primary
productivity using large volume plastic chambers i_n situ.
Jour. Phycol. 13: 58.
Cherian, M.G., et al. 1978. Radioactive mercury distribu-
tion in biological fluids and excretion in human subjects
after inhalation of mercury vapor. Arch. Environ. Health
33: 109.
Clarkson, T.W. 1978. Unpublished data. Environ. Health
Sci. Center. University of Rochester.
Clarkson, T.W., et al. 1972. The transport of elemental
mercury into fetal tissues. Biol. Neonate. (Basel) 21:
239.
Clarkson, T.w., et al. 1978. The metabolism of inhaled
mercury vapor in animals and man. Jour. Am. Chem.. Soc.
(In press.)
Cotton, F.A., and G. Wilkinson. 1966. Advanced inorganic
chemistry—a comprehensive text. Wiley-Interscience, N.Y.
#
Davies, A.G. 1975. .An assessment of the basis of mercury
tolerance in Dunaliella tertiolecta. Jour. Mar. Biol.
Assn. U.K. 56: jy.
-------
Druckrey, H., et al. 1957. Carcinogenic action of metallic
mercury after intraperitoneal administration in rats. Z.
Krebsforsch. 61: 511.
Engleson, G., and T. Herner. 1952. Alkyl mercury poison-
ing. Acta. Pediat. Scan. 41: 289.
Friberg, L., and F. Nordberg. 1973. Inorganic mercury-
A toxicological and epidemiological appraisal. Pages 5-
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16
-------
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»
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-IV 7*
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-14 73-
-------
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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
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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 accuracv.
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Disclaimer Notice
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.
-/ /77-
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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 ^ug/rrP. Methomyl in-
hibits the activity of cholinesterase in the body. Studies have shown that
methomyl is not carcinogenic in rats and dogs or mutagenic in the Ames bio-
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, and tera-
togen.
Methomyl is toxic to many aquatic organisms with 96-hour LC5Q levels
ranging from 0.1 to 3.4 ppm.
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METHOMYL
I. INTRODUCTION
Methomyl is a broad-spectrum insecticide used on many vegetables, field
crops, certain fruit crops, and ornamentals (Serg, 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 (Stanforo
Research Institute 1974) 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 and 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 afl, 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 immeoiate-
y
-1177-
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TABLE 1. PHYSICAL AND CHEMICAL PROPERTIES OF METHOMYL
Synonyms: S-methyl N-(methylcarbamoyl)oxy)thioacetamiaate;
l-(methylthio)ethylideneamino methylcarbamate;
l-(methylthio)acetaldehyde Q-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 Density^ d = 1.2946
Melting and/or Boiling Points: mp 78 to 790C .
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): 5.8 g/100 ml at 250Q
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): «ow =2.0
BCF = 1.0
Source: Martin and Worthing, 1974; Fairchild, 1977;
Windholz, 1976, U.S. EPA, 1980.
-/WO-
-------
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 resiaues
were not detected (less than 0.02 ppm) in seed harvested 22 days after
application. Rape plant leaves collected after the application of methcmyl
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 ousters) (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-aay 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.
8. Metabolism
Harvey, et al. (1973) administered l4C-labeled methomyl to
rats. The radioactive methomyl was eliminated in the form of carbon di-
oxide, acetonitrile, and urinary metabolites. They noted the absence of
methomyl, S-methyl N-hydroxythioacetimidate, methyl S,S-dioxide, and conju-
gates of the former two compounds. Radiolabeled methomyl administered in
the rat by Huhtanen and Dorough (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 nitrosomethomyl from
cured meats containing methomyl. and residual sodium nitrite. The samples
were incubated under simulated stomach conditions '(pH2) for 1 and 3
hours. Nitrosomethyl was not found in the test material; the detection
»
limit was less than 1 ppb.
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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). Lijinsky 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 be a po-
tent mutagen, they considered methomyl to be non-mutagenic.
Guerzoni, et al. (1976) tested methomyl for mutagenic activity on
»
Saccnaromyces 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 rabbits on days 8
to 16 of gestation. Teratogenic effects were not founa 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 r"~-"\], 40, and 80 ppm methomyl.
Blevins, et al. (1977) treated normal human skin cells with six
insecticidal esters of N-methylcarbamic acid or their N-nitroso deriva-
tives. The DNA of the cells was sedimented in alkaline sucrose gradients at
various times after/""?eatment. . The insecticides used were aldicarb, baygon
(propoxur), BUX-TENB) (bufencab), carbofuran, landrin, and methomyl.
Numerous singlestranu-"breaks were apparent in the DNA of all the nitroso
derivative-treated cells but not in the DNA of those treated with the parent
insecticides. The effect of the nitroso derivatives on the DNA could be ob-
served for at least 20 hours after removal of the chemical from the cul-
tures. The duration of effect suggested that the DNA-repairing events nor-
mally occurring in human cells after damage initiated by these chemical
agents were different from repairing events which follow UV-type DNA damage
or ionizing-type DNA damage in human cells. These observations suggest that
the human cellular DNA .in .vivo is irreversibly altered by nitrosated
N-methyl carbamate insecticides, resulting in numerous alkali-sensitive
bonds CBlevins, et al. 1977).
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D. 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 nave been re-
ported in the literature. In the first incident, four crews of fielo
»
workers harvesting vegetables and fruits treateo 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 lOb 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 LD5Q 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 LC5Q values for rats, quails, and ducks are 77, 3680, and 1890
ppm, respectively. The dermal. LD5Q for rabbits is 5000 mg/kg. No adverse
effects were noted when bootail quail and alDino 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 cholinesterase 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 Tl_m (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). Fallowing 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/nv5
(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]).
8. Aquatic -
Guidelines or standards to protect aquatic life could not be lo-
cated in the available literature.
-/w-
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REFERENCES
Saron, 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, D.L. 1977. Anticholinesterase action of pesticide carbamates in
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Kaplan, A.M. and H. Sherman 1977. Toxicity studies with methyl
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No. 126
Methyl Alcohol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, B.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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BIOLOGIC EFFECTS OF EXPOSURE
Extent of Exposure
Methyl alcohol, CH30K, also called methanol, is Che 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 acid,
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 XIII-3. [6]
NIOSH estimates that approximately 175,000 workers in the US ,ar.a
potentially exposed to methyl alcohol:
EFFECTS-ON HUMANS
Burk [26] attributed the toxic effects of methyl alcohol to
formaldehyde and forrxic 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
j .
persons suspected of being poisoned with methyl alcohol.
^fercutaneous 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 respiratory 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
betveen application and onset of symptoms of intoxication was 1-13 hours
(7 1/4. hours average). The early, signs of intoxication were described'by
the authors as central nervous system depression with 13 children having
-------
exhibited severe respiratory depression and II of these having convulsions.
31ood ?H 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
cestad 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
volunteers 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
mg/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 conplsx 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 Co urine methyl alcohol
-------
concentrations remained almost constant for the 3 subjects in which it was '
determined, and ths authors [30] concluded that the change in the
concentration of methyl alcohol in the urine was an accurate -.indicator of
the change in methyl 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
Zatnan [30] also stated that only 0.4-1.2% of the ingested methyl alcohol
\ ' •
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 ing/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 mg 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
t
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 the absence of ethvl alcohol.
-------
&hyl 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. L3
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 j
primarily by the catalase-peroxidase system. j
. 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 nonprimates were
early pupillary changes.and corneal opacities following exposure keratitis.
Sone monkeys, however, and many humans developed partial or complete
-ft?7-
-------
blindness accompanied by eyeground changes such as hyperemia of Che optic
discs and venous engorgement. Finally, humans and monkeys often developed
severe acidosis (C02-combining capacity less than 20 volumes Z) 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 [14];
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 alc'^-pl has been said to cause
dermatitis, [14] erythema, and scaling. [27] The reported variability in
susceptibility [14] is probably largely because of variations in tine of
contact with methyl alcohol; it is evident that sufficient -dermal contact
with any lipid 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.
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TABLES AND FIGURE
TABLE XIII-1
PHYSICAL AND CHEMICAL PROPERTIES OF METHYL ALCOHOL
Molecular formula
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)
Vapor density
(air-1)
Corrosivity
Conversion factors
(760 mmHg and 25 C)
CH30H
32.04
0.7910
64.5 C
96 mmHg
-97.6 C
Miscible
Miscible
16 C
12 C
6.72-36.50
1.11
Noncorrosive at
normal atmospheric
temperatures.
Exceptions: lead and
aluminum
1 ppm=1.310 mg/cu m
1 mg/cu m=.763 ppm
Adapted from ANSI Z37 [2], the Manufacturing Chemists Association [3],
and the Handbook of Chemistry and Physics [4]
-.Moo-
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