FTEALTH AND ENVIRONMENTAL
EFFECT PROFILES
APRIL 30, 1980
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF SOLID WASTE
-------
BIS-(2-ETHYLHEXYL)PHTHALATE
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Phthalate Esters (U.S. EPA, 1979).
Bis-(2-ethylhexyl)phthalate, most commonly referred
to as di-(2-ethylhexyl)phthalate, (DEHP) is a diester of
the ortho form of benzene dicarboxylic acid. The compound
has a molecular weight of 391.0, specific gravity of 0.985,
boiling point of 386.9°C at 5 mm Hg, and is insoluble in
water (U.S. EPA, 1979).
DEHP is widely used as a plasticizer, primarily in
the production of polyvinyl chloride (PVC) resins. As much
as 60 percent by weight of PVC materials may be plasticizer
(U.S. EPA, 1979). Through this usage, DEHP is incorporated
into such products as wire and cable covering, floor tiles,
swimming pool liners, upholstery, and seat covers, footwear,
and food and medical packaging materials (U.S International
Trade Commission, 1978).
In 1977, current production was 1.94 x 10 tons/year
(U.S. EPA, 1979) .
Phthalates have been detected in soil, air, and water
samples; in animal and human tissues; and in certain vegeta-
tion. Evidence from iri vitro studies indicates that certain
bacterial flora may be capable of metabolizing phthalates
to the mb'noester form (Englehardt, et al. 1975). --'—'~
-30)-
-------
II. EXPOSURE
Phthalate esters appear in all areas of the environ-
ment. Environmental release of the phthalates may occur
through leaching of plasticizers from PVC materials, vola-
tilization of phthalates from PVC materials, and the inciner-
ation of PVC items. Sources of human exposure to phthalates
include contaminated foods and fish, and parenteral adminis-
tration by use of PVC blood bags, tubings, and infusion
devices (U.S. EPA, 1979).
Monitoring studies have indicated that phthalate concen-
trations in water are mostly in the ppm range, or 1-2 pg/liter
(U.S. EPA, 1979). Air levels of phthalates in closed rooms
that have PVC tiles have been reported to be 0.15 to 0.26
mg/m (Peakall, 1975). Industrial monitoring has measured
air levels of phthalates from 1.7 to 66 mg/m (Milkov, et
al. 1973). Levels of DEHP have ranged from not detect-
able to 68 ppm in foodstuffs (Tomita, et al. 1977). Cheese,
milk, fish and shellfish present potential sources of high
phthalate intake (U.S. EPA, 1979). Estimates of parenteral
exposure of patients to DEHP during use of PVC medical appli-
ances have indicated approximately 150 mg DEHP exposure
from a single hemodialysis course. An average of 33 mg
DEHP exposure is possible during open heart surgery (U.S.
EPA, 1979).
The U.S. EPA (1979) has estimated the weighted average
»
bioconcentration factor for DEHP to be 95 for the edible
portions of fish and shellfish consumed by Americans. This
-------
estimate is based on the measured steady-state bioconcentra-
tion studies in fathead minnow.
III. PHARMACOKINETICS
A. Absorption
The phthalates are readily absorbed from the intes-
tinal tract, the peritoneal cavity, and the lungs (U.S.
EPA, 1979). Daniel and Bratt (1974) found that seven days
following oral administration of radiolabelled DEHP, 42
percent of the dose was recovered in the urine and 57 per-
cent recovered in the feces of rats. Hilary excretion of
orally administered DEHP has been noted by Wallin, et al.
(1974). Limited human studies indicate that 2 to 4.5 per-
cent of orally administered DEKP was recovered in the urine
of volunteers within 24 hours (Shaffer, et al. 1945). Lake,
et al. (1975) have suggested that orally administered phtha-
lates are absorbed after metabolic conversion to the mono-
ester form in the gut.
Dermal absorption of DEHP in rabbits has been
reported at 16 to 20 percent of the initial dose within
three days following administration (Autian, 1973).
B. Distribution
Studies in rats injected with radiolabelled DEHP
have shown that 60 to 70 percent of the administered dose
was detected in the liver and lungs within 2 hours after
administration (Daniel and Bratt, 1974). Wadell, et al.
»
(1977) have reported rapid accumulation of labelled DEHP
in the kidney and liver of rats after i.v. injection, fol-
lowed by rapid excretion into the urine, bile, and intes-
2T
-303-
-------
tine. Seven days after i.v. administration of labelled
DEEP to mice, levels of compound were found preferentially
in the lungs and to a lesser extent in the brain, fat, heart,
and blood (Autian, 1973).
An examination of tissue samples, from two deceased
patients who had received large volumes of transfused blood,
detected DEHP in the spleen, liver, lungs, and abdominal
fat (Jaeger and Rubin, 1970).
Injection of pregnant rats with labelled DEHP
has shown that the compound may .cross the placental barrier
(Singh, et al. 1975).
C. Metabolism
Various metabolites of DEHP have been identified
following oral feeding to rats (Albro, et al. 1973) . These
results indicate that DEHP is initially converted from the
diester to the monoester, followed by the oxidation of the
monoester side chain forming two different alcohols. The
alcohols are oxidized to the corresponding carboxylic acid
or ketone. Enzymatic cleavage of DEHP to the monoester
may take place in the liver or the gut (Lake, et al. 1977).
This enzymatic conversion has been observed in stored whole
blood, indicating widespread distribution of metabolic activ-
ity (Rock, et al. 1978).
D. Excretion
Excretion of orally administered DEHP is virtually
»
complete in the rat within 4 days (Lake, et al. 1975).
Major excretion is through the urine and feces, with biliary
-------
excretion increasing the content of DEEP (or metabolites)
in the intestine (U.S. EPA, 1979). Schulz and Rubin (1973)
have noted an increase in total water soluble metabolites
of labelled DEHP in the first 24 hours following injection
into rats. Within one hour, eight percent of the DEHP was
found in the liver,, intestines and urine. After 24 hours,
54.6 percent was recovered in the intestinal tract, excreted
feces and urine, and only 20.5 percent was recovered in or-
ganic extractable form. Blood loss of DEHP showed a biphasic
pattern, with half-lives of 9 minutes and 22 minutes, respec-
tively (Schulz and Rubin, 1973).
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not be located in the avail-
able literature.
B. Mutagenicity
Testing of DEHP in the Ames Salmonella assay has
shown no mutagenic effects (Rubin, et al. 1979). Yagi,
et al. (1978) have indicated that DEHP is not mutagenic
in a recombinant strain of Bacillus, but the monoester meta-
bolite of DEHP did show some mutagenic effects. Results
of a dominant lethal assay in mice indicate that DEHP has
a dose and time dependent mutagenic effect (Singh, et al.
1974) .
C. Teratogenicity .
DEHP has been shown to produce teratogenic effects
in rats following i.o. administration (Singh, et al. 1972).
-------
Following oral administration there was a significant reduc-
tion in fetus weight at 0.34 and 1.70 g/kg/day.
D. Other Reproductive Effects
Effects on implantation and parturition have been
observed in pregnant rats injected intraperitoneally with
DEHP (Peters and Cook, 1973). A three-generation repro-
duction study in rats has indicated decreased fertility
in rats following maternal treatment with DEHP (Industrial
Bio-Test, 1978).
Testicular damage has been reported in rats ad-
ministered DEHP i.p. or orally. Seth, et al. (1976) found
degeneration of the seminiferous tubules and changes in
spermatagonia; testicular atrophy and morphological damage
were noted in rats fed DEHP (Gray, et al. 1977; Yamada,
et al, 1975). Otake, et al. (1977) noted decreased sperma-
togenesis in mice administered DEHP by intubation.
E. Chronic Toxicity
Oral feeding of DEHP produced increases in liver
and kidney weight in several animal studies (U.S. EPA, 1979),
Chronic exposure to transfused blood containing DEHP has
produced liver damage in monkeys (Kevy, et al. 1978). Lake,
et al. (1975) have produced liver damage in rats by adminis-
tration of mono-2-ethylhexyl phthalate.
F. Other Relevant Information
Several animal studies have demonstrated that
#
pre-treatment of rats with DEHP produced an increase in
hexobarbital sleeping times (Daniel and .Bratt, 1974; Rubin
and Jaeger, 1973; Swinyard, et al. 1976).
*
-3O4-
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
Only one acute study on the freshwater cladoceran
(Daphnia magna) has produced a 96-hour static LCcQ value
of 11,000 jig /I (U.S. EPA, 1978). Freshwater fish or marine
data have not been found in the literature.
B. Chronic Toxicity
Chronic studies involving the rainbow trout (Salmo
gairdneri) provided a chronic value of 4.2 ug/1 in an embryo-
larval assay (Mehrle and Mayer, 1976). Severe reproductive
impairment was observed at less than 3 pg/1 in a chronic
Daphnia magna assay (Mayer and Sanders, 1973).
C. Plant Effects
Pertinent information could not be located in
the available literature.
D. Residues
Bioconcentration factors have been obtained for
several species of freshwater organisms: 54 to 2,680 for
the scud (Gamarus pseudolimnaeus) ; 14 to 50 for the sowbug
(Ascellus brevicaudus) ; 42 to 113 for the rainbow trout
(Salmo gairdneri) ; and 91 to 886 for the fathead minnow
(Pimephales promelas) (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.
-507-
-------
A. Human
Based on "no effect" levels observed in chronic
feeding studies in rats or dogs, the U.S. EPA has calculated
an acceptable daily intake (ADI) level for DEHP of 42 mg/day.
The recommended water quality criteria level for
protection of human health is 10 mg/1 for DEHP (U.S. EPA,
1979) .
B. Aquatic
Criterion was not drafted for either freshwater
or marine environments due to insufficient data.
-------
BIS-(2-ETHYLHEXYL) PHTHALATE
REFERENCES
Albro, P.W., et al. 1973. Metabolism of diethylhexyl phthal-
ate by rats. Isolation and characterization of the urinary
metabolites. Jour. Chromatogr. 76: 321.
Autian, J. 1973. Toxicity and health threats of phthalate
esters: Review of the literature. Environ. Health Perspect.
June 3.
Daniel, J.W., and H. Bratt. 1974. The absorption, metabo-
lism and tissue distribution of di (2-ethylhexyl) phthalate
in rats. Toxicology 2: 51.
Engelhardt, G., et al. 1975. The microbial metabolism
of di-n-butyl phthalate and related dialkyl phthalates.
Bull. Environ. Contam. Toxicol. 13: 342.
Gray, J., et al. 1977. Short-term toxicity study of di-
2-ethylhexyl phthalate in rats. Food Cosmet. Toxicol. 65:
389.
Industrial Bio-Test. 1978. Three generation reproduction
study with di-2-ethylhexyl phthalate in albino rats. Plastic
Industry News 24: 201.
Jaeger, R.J., and R.J. Rubin. 1970. Plasticizers from
plastic devices: Extraction, metabolism, and accumulation
by biological systems. Science 170: 460.
Kevy, S.V., et al. 1978. Toxicology of plastic devices
having contact with blood. Rep. N01 HB 5-2906, Natl. Heart,
Lung and Blood Inst. Bethesda, Md.
Lake, B.G., et al. 1975. Studies on the hepatic effects
of orally administered di-(2-ethylhexyl) phthalate in the
rat. Toxicol. Appl. Pharmacol. 32: 355.
Lake, B.C., et al. 1977. The in vitro hydrolysis of some
phthalate diesters by hepatic and" intestinal preparations
from various species. • Toxicol. Appl. Pharmacol. 39: 239.
Mayer, F.L., Jr., and H.O. Sanders. 1973. Toxicology of
phthalic acid esters in aquatic organisms. Environ. Health
Perspect..3: 153.
Mehrle, P.M., and F.L. Mayer. 1976. Di-2-ethylhexyl phthal-
ate: Residue dynamics and biological effects in rainbow
trout and fathead minnows. Pages 519-524. in Trace sub-
stances in environmental health. University of Missouri
Press, Columbia.
-------
Milkov, L.E., et al. 1973. Health status of workers ex-
posed to phthalate plasticizers in the manufacture of artifi-
cial leather and films based on PVC resins. Environ. Health
Perspect. Jan. 175.
Otake, T., et al. 1977. The effect of di-2-ethylhexyl
phthalate (DEHP) on male mice. I. Osaka-Fuitsu Koshu Eisei
Kenkyusho Kenkyu Hokoku, Koshu Eisei Hen 15: 129.
Peakall, D.B. 1975. Phthalate esters: Occurrence and
biological effects. Residue Rev. 54: 1.
Peters, J.W., and R.M. Cook. 1973. Effects of phthalate
esters on reproduction of rats. Environ. Health Perspect.
Jan. 91.
Rock, G., et al. 1978. The accumulation of mono-2-ethyl-
hexyl phthalate (MEHP) during storage of whole blood and
plasma. Transfusion 18: 553i
Rubin, R.J., and R.J. Jaeger. 1973. Some pharmacologic
and toxicologic effects of di-2-ethylhexyl phthalate (DEHP)
and other plasticizers. Environ. Health Perspect. Jan.
53.
Rubin, R.J., et al. 1979. Ames mutagenic assay of a series
of phthalic acid esters: Positive response of the dimethyl
and diethyl esters in TA 100. Abstract. Soc. Toxicol. Annu.
•Meet. New Orleans, March 11.
Schulz, C.O., and R.J. Rubin. 1973. Distribution, metabo-
lism and excretion of di-2-ethylhexyl phthalate in the rat.
Environ. Health Perspect. Jan. 123.
Seth, P.K., et al. 1976. Biochemical changes induced by
di-2-ethylhexyl phthalate in rat liver. Page 423 in Enviorn-
mental biology. Interprint Publications, New Dehll, India.
Shaffer, C.B., et al. 1945. Acute and subacute toxicity
of di (2-ethylhexyl) phthalate with note upon its metabolism.
Jour. Ind. Hyg. Toxicol. 27: 130.
Singh, A.R., et al. 1972. Te.ratogenicity of phthalate esters
in rats. Jour. Pharmacol. Sci. 51: 51.
Singh, A.R., et al. 1974. Mutagenic and antifertility
sensitivities of mice to di-2-ethylhexyl phthalate (DEHP)
and dimethoxyethyl phthalate (DMEP). Toxicol. Appl. Pharmacol.
29: 35.
*
Singh A.R., et al. 1975. Maternal-fetal transfer of 14c-
di-2-ethylhexyl phthalate and C-diethyl phthalate in rats.
Jour. Pharm. Sci. 64: 1347.
-VO-
-------
Swinyard, E.A., et al. 1976. Nonspecific effect of bis(2-
ethylhexyl) phthalate on hexobarbital sleep time. Jour.
Pharmacol. Sci. 65: 733.
Tomita, I., et al* 1977. Phthalic acid esters in various
foodstuffs and biological materials. Ecotoxicology and
Environmental Safety 1: 275.
U.S. EPA. 1978. In-depth studies on health and environ-
mental impacts of selected water pollutants. U.S. Environ.
Prot. Agency, Contract No. 68-01-4646.
U.S. EPA. 1979.. Phthalate Esters: Ambient Water Quality
Criteria (Draft).
U.S. International Trade Commission. 1978. Synthetic or-
ganic chemicals, U.S. production and sales. Washington,
D.C.
Waddell, W.M., et al. 1977. The distribution in mice of
intravenously administered C-di-2-ethylhexyl phthalate
determined by whole-body autoradiography. Toxicol. Appl.
Ph--— acol. 39: 339.
. J
Wallin, R.F., et al. 1974. Di(2-ethylhexyl) phthalate
(DEHP) metabolism in animals and post-transfusion tissue
levels in man. Bull. Parenteral Drug. Assoc. 28: 278.
Yagi, Y., et al. 1978. Embryotoxicity of phthalate esters
in mouse. Proceedings of the First International Congress
on toxicology, Plaa, G. and Duncan, W., eds. Academic Press,
N.ljp. 59.
Yamada, A., et al. 1975. Subacute toxicity of di-2-ethyl-
hex^.1 phthalate. Trans. Food Hyg. Soc. Japan, 29th Meeting
p. 36 .
-------
No. 28
Bromofonn
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 ac-cxiracy.
-------
If 9
BROMOFORM
SUMMARY
Bromoforra has been detected in finished drinking water in
the United States and Canada. It is believed to be formed by the
haloform reaction that may occur during water chlorination.
Bromoform can be removed from drinking water via treatment with
activated carbon. Natural sources (especially red algae) produce
significant quantities of bromoform. -There is a potential for
bromoform to accumulate in the aquatic environment because of its
resistance to degradation. Volatilization is likely to be an
important means of environmental transport.
Bromoform gave positive results in mutagenicity tests with
Salmonella typhimurium TA100. In a short-term in vivo.oncogen-
icity assay it caused a significant increase in tumor incidence
at one dose level.
Inhalation of bromoform by humans can cause irritation of
.the respiratory tract and liver damage. Respiratory failure is
the primary cause of death in bromoform-related fatalities.
I. INTRODUCTION
This profile is based primarily on the Ambient Water Quality
Criteria document for halomethanes (U.S. EPA 1979b).
Bromoform (tribromomethane; CHBr,) is a colorless, heavy
»
liquid similar in odor and taste to chloroform. Bromoform has
the following, physical/chemical properties (Weast, 1974'):
-------
Molecular Weight: 252.75
Melting Point: 8.3'C
Boiling Point: 149.5'C (at 760 mm Hg)
Vapor Pressure: 10 ram fig al 34'C
Solubility: slightly soluble in water;
soluble in a variety of
organic solvents.
A review of the production range (includes importation)
statistics for bromoform (CAS No. 75-25-2) which is listed in the
initial TSCA Inventory (1979a) has shown that between 100,000 and
900,000 pounds of this chemical were produced/imported in 1977.—'
Bromoform is used as a chemical intermediate; solvent for
waxes, greases, and oils; ingredient in fire-resistant chemicals
and gauge fluids (U.S. EPA 1978a; Hawley, 1977).
II. EXPOSURE
A. Environmental Fate
Bromoform gradually decomposes on standing; air and light
accelerate decomposition (Windholz, 1976). The vapor pressure of
bromoform, while lower than that for chloroform and other chloro-
alkanes, is, nonetheless, sufficient to ensure that volatiliza-
tion will be an important means of environmental transport. The
This production range information does not include any produc-
tion/importation data claimed as confidential by the person(s,'
reporting for the TSCA Inventory, nor does it include any
information which would compromise Confidential Business
Information. The data submitted for the TSCA Inventory,
including production range information, are subject to the
limitations contained in the Inventory Reporting Regulations
(40 CFR 710).
-------
half-life for hydrolysis of bromoform is estimated at 686 years.
Bromoform should be much more reactive in the atmosphere. Oxi-
dation by HO.radical will result in a half-life of a few months
in the troposphere (U.S. EPA, 1977).
B. Bioconcentration
The bioconcentration factor for bromoform in aquatic organ-
isms that contain about 8% lipid is estimated to be 48. The
weighted average bioconcentration factor for bromoform in the
edible portion of all aquatic organisms consumed by Americans is
estimated to be 14 (U.S. EPA, 1979b).
. C. Environmental Occurence
The National Organics Reconnaissance Survey detected bromo-
form in the finished drinking water of 26 of 80 cities, with a
maximum concentration of 92 ug/1. Over 90% of the samples con-
tained 5 ug/1 or less. No bromoform was found in raw water
samples (Symons _et_ _al_. , 1975). Similarly, the EPA Region V
Organics Survey found bromoform in 14% of the finished drinking
water samples and none in raw water (U.S. EPA, 1975). Using a
variety of sampling and analysis methods, the National Organic
Monitoring Survey found bromoform in 3 of 111, 6 of 118, 38 of
113, 19 of 106, and 30 of 105 samples with mean concentrations
ranging from 12-28 ug/1 (U.S. EPA, 1978b). A Canadian survey of
drinking water found 0-0.2 ug/1 with a median concentration of
0.01 ug/1 (Health and Welfare Can., 1977).
»
The National Academy of Sciences (1978) concluded that water
chlorination, via the haloform reaction, results in the produc-
tion of trihalomethanes (including bromoforn) from the organic
precursors present in raw water.
-------
Significant quantities of bromoforra are also produced from
natural sources, especially red algae. For example, the essen-
tial oil of Asparagopsis taxiformis (a red marine algae eaten by
Hawaiians) contains approximately 80% bromoform (Burreson et al.,
1975).
III. PHARMACOKINETICS
Bromoform is absorbed through the lungs, gastrointestinal
tract, and skin. Some of the absorbed bromoform is metabolized
in the liver to inorganic bromide ion. Bromide is found in
tissues and urine following inhalation or rectal administration
of bromoform (Lucas, 1929). Metabolism of bromoform to carbon
monoxide has also been reported (Ahmed, 1977). Recent studies
show that phenobarbital-induced rats metabolize bromoform to. A
(cocu
carbonyl bromide (COB^), the brominated analog of phosgene P*>otrr
£t..al.. / 1979) .
IV. HEALTH EFFECTS
A. Carcinogenicity
Bromoform caused a significant increase in tumor incidence
at one dose level in a short-term in vivo oncogenicity assay
known as the strain A mouse lung adenoma test. The increase was
observed at a. dose of 48 mg/kg/injection with a total dose of
1100 rag/kg. The tumor incidence was not increased significantly
at doses of 4 rag/kg (total dose of 72 rag/kg) or 100 mg/kg (total
dose of 2400 mg/kg) (Theiss et al., 1977.
-------
B. Mutagenicity
Bromoform was mutagenic in S. typhimurium strain TA 100
(without metabolic activation) (Simmon, 1977).
C. Other Toxicity
Rats inhaling 250 mg/nr bromoform for 4 hr/day for 2 months
developed impaired liver and kidney function (Dykan, 1962).
In humans, inhalation of bromoform causes irritation to the
respiratory tract. Mild cases of bromoform poisoning may cause
only headache, listlessness, and vertigo. Unconsciousness, loss
of reflexes, and convulsions occur in severe cases. The primary
cause of death from a lethal dose of bromoform is respiratory
failure. Pathology indicates that the chemical causes fatty
degenerative and centrolobular necrotic changes in the liver
(U.S. PHS, 1955).
Acute'animal studies indicate impaired function and
pathological changes"in the liver and kidneys of animals exposed
to bromoform (Kutob and Plaa, 1962; Dykan, 1962).
V. AQUATIC EFFECTS
A. Fresh Water Organisms
The 96-hr LC5Q (static) in bluegill sunfish is 29.3 mg/1.
The 48-hr LCgg (static) for Daphnia magna is 46.5 mg/1. The 96-
hr ECcgs f°r chlorophyll A production and cell number in S.
capricornutum are 112 mg/1 and 116 mg/1, respectively (U.S. EPA,
t
1978-a) . (See also Section II.B.)
-------
B. Marine Organisms
The 96-hr LC^g (static) in sheepshead minnow is 17.9 mg/1.
The 96-hr LC5Q (static) in nysid shrimp is 20.7 mg/1. The EC5Qs
for chlorophyll A production and cell number in S. costatum are,
respectively, 12.3 mg/1 and 11.5 mg/1 (U.S. EPA, 1978a).
VI. EXISTING GUIDELINES
A. Human
The OSHA standard for bromoform in air is a time weighted
average (TWA) of 0.5 ppm (39CFR23540).
The Maximum Contaminant Level (MCL) for total trihalometh-
anes (including bromoforra) in drinking water has been set by the
U.S. EPA at 100 ug/1 (44FR68624). The concentration of bromoform
produced by chlorination can be reduced by treatment of'drinking
water with powdered activated carbon (Rook, 1974). This is the
technology that has been proposed by the EPA to meet this
standard.
B. Aquatic
The proposed ambient water criterion for the protection of
fresh water aquatic life from excessive bromoform exposure is 840
ug/1 as a 24-hour average. Bromoform levels are not to exceed
1900 ug/1 at any time. The criterion for the protection of
marine life is 180 ug/1 (24 hr avg), not to exceed 1900 ug/1
(U.S. EPA, 1979b).
-------
REFERENCES
Ahmed, A.E., _et_ _a_l_. 1977. Metabolism of haloforms to carbon
monoxide, I. In vitro studies. Drug Metab. Dispos. , _5_:198. (as
cited in U.S. EPA, 1979b).
Burreson, B.J., R.E. Moore, P.P. Roller 1975. Haloforms in the
essential oil of the alga Asparagopsis taxiformis (Rhodophyta).
Tetrahedron Letters, _7_:473-476. (as cited in MAS, 1978).
Dykan, V.A. 1962. Changes in liver and kidney functions due to
methylene bromide and bromoform. Nauchn. Trucy Ukr Nauchn. -
Issled. Inst. Gigieny Truda i Profyabolevanii _29_:82. (as cited
in U.S. EPA, 1979b).
Hawley, G.G. ed. 1971. Condensed Chemical Dictionary. 8th ed.
Van Hostrand Reinhold Co.
Health and Welfare Canada 1977. Environmental Health Direc-
torate national survey of halomethane in drinking water. (as
cited in. U.S. EPA, 1979b).
Kutob, S.D., G.J. Plaa 1962. A procedure for estimating the
hepatotoxic potential of certain industrial solvents, Tox. Appl.
Pharm., j4_:354. (as cited in U.S. EPA, 1979b) .
Lucas, G.H.W. 1929. A study of the fate and toxicity of bromine
and chlorine containing anesthetics, J. Pharm. Exp. Therap.,
21:223-237. (as cited in WAS, 1978).
National Academy of Sciences 1977. Drinking Water and Health,
Part II, Chapters 6 and 7, Washington, D.C.
National Academy of Sciences 1978. Nonfluorinated Halomethanes
in the Environment, Washington, D.C.
Pohl, L.R. _et_ _al_. 1979. Oxidative bioactivation of haloforms
into hepatotoxins, prepublication.
Rook, J.J. 1974. Formation of haloforms during chlorination of
natural waters. J. Soc. Water Treat. Examin. 23 (Part 2):234-
243.
Simmon, V.F. 1977. Mutagenic activity of chemicals identified
in drinking water. In_ Progress in genetic toxicology, S. Scott
_et_ _al_. eds. (as cited in U.S. EPA, 1979b) .
Symons, J.M j_t_ _al_. 1975. National organics reconnaissance '
survey for halogenated organics (NORS). J. Amer. Water Works
Assoc. _6_7_:634-647. (as cited in MAS, 1978).
Theiss, J.C. _e_t_ _al_. 1977. Test for carcinogenicity of organic
contaminants of United States drinking waters by pulmonary tumor
response in strain A mice, Can. Res., _3_7_:2717. (as cited in U.S.
EPA, 1979b).
7f
-320-
-------
U.S. EPA 1975. Formation of Ralogenated Organics by Chlorina-
tion of Water Supplies. EPA-600/1-75-002, PB 241-511. (as cited
in NAS, 1978).
U.S. EPA 1977. Review of the environmental fate of selected
chemicals, EPA-560/5-77-0033.
U.S. EPA 1978a. Indepth studies on health and environmental
impacts of selected water pollutants, contract no. 68-01-4646,
Washington, D.C. (as cited in U.S. EPA, 1979b).
U.S. EPA 1978b. The National Organic Monitoring Survey, Office
of Water Supply, Washington, D.C.
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. Halomethanes, Ambient Water Quality Criteria.
PB 296 797.
U.S. Public Health Service 1955. The halc»jenated hydrocarbons:
Toxity and potential dangers. No. 414. (as cited in U.S. EPA,
1979b).
Weast/ R.C. ed. 1972. CRC Handbook of Chemistry and Physics.
CRC Press, Inc., Cleveland, Ohio.
Windholz, M. ed. 1976. The Merck Index, 'th ed., Merck and Co.,
Inc., Rahway, N.J.
-------
No. 29
Bromoraethane
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.
-------
BROMOMETHANE
Summary
On acute exposure to bromomethane, neurologic and psychiatric
abnormalities may develop and persist for months or years. There is
no information on the chronic toxicity, carcinogenicity, or terato-
genicity of bromomethane. Bromomethane has been shown to be mutagenic
in the Ames S_;_ typhimurium test system.
Acute LC5Q values have been reported in two tests as 12,000 and
11,000 pg/1 for a marine and freshwater fish, respectively.
-------
BROMOMETHANE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Halomethanes (U.S. SPA, 1979a).
Bromomethane (CHjBr, methyl bromide, monobromomethane, and
embafume; molecular weight 94.91*) is a colorless gas. Bromomethane
has a melting point of -93.6°C, a boiling point of 3-56°C, a specific
gravity of 1.676 g/ml at -20°C, and a water solubility of 17-5 g/1
at 20°C (Natl. Acad. Sci., 1978). Bromomethane has been widely used
as a fumigant, fire extinguisher, refrigerant, and insecticide (Kantarjian
and Shaheen, 1963). Today the major use of bromomethane is as a
fumigating agent. Bromomethane is believed to be formed in nature,
with the oceans as a primary source (Lovelock, 1975). The other
major environmental source of bromomethane is from its agricultural
use as a soil, seed, feed and space fumigant. For additional information
regarding Halomethanes as a class the reader is referred to the
Hazard Profile on Halomethanes (U.S. EPA, 1979b).
II. EXPOSURE
A. Water
The U.S. EPA (1975) has identified bromomethane qualitatively
in finished drinking waters in the U.S. There are, however, no data
on its concentration in drinking water, raw water, or waste water
(U.S. EPA, 1979a).
B. Food
There is no information on the concentration of bromomethane
in food. Bromomethane residues from fumigation decrease rapidly
through loss to the atmosphere and reaction with protein to form
-------
inorganic bromide residues. With proper aeration and product processing,
most residual bromomethane will rapidly disappear due to methylation
reactions and volatilization (Natl. Acad. Sci., 1978; Davis, et al.
1977). There are no bioconcentration data for bromomethane (U.S.
EPA, 1979a).
C. Inhalation
Saltwater atmospheric background concentrations of bromomethane
averaging about 0.00036 mg/m^ have been reported (Grimsrud and Rasmussen,
1975; Singh, et al. 1977). This is higher than reported average
continental background and urban levels and suggests that the oceans
are a major source of global bromomethane (Natl. Acad. Sci., 1978).
Bromomethane concentrations of up to 0.00085 mg/m3 may occur outdoors
locally with light traffic, as a result of exhaust containing bromomethane
as a breakdown product of ethylene dibromide, which is used in leaded
gasoline (Natl. Acad. Sci., 1978). •
III. PHARMACOKINETICS
A. Absorption
Absorption of bromomethane most commonly occurs via the
lungs, although it can also occur through the gastrointestinal tract
and the skin (Davis, et al. 1977; von-Oettingen,-196U).
B. Distribution
Upon absorption, blood levels of residual non-volatile
•bromide increase, indicating-rapid uptake of bromomethane or its
metabolites (Miller and Haggard, 19^3). Bromomethane is rapidly
distributed to various tissues and is broken down to inorganic bromide*.
Storage, only as bromides, occurs mainly in lipid-rich tissues.
-------
C. Metabolism
Evidently the toxicity of bromomethane is mediated by the
bromomethane molecule itself. Its reaction with tissue (methylation
of sulfhydryl groups in critical cellular proteins and enzymes)
results in disturbance of intracellular metabolic functions, with
irritative, irreversible, or paralytic consequences (Natl. Acad.
Sci., 1978; Davis, et al. 1977; Miller and Haggard, 1943).
D. Excretion
Elimination of bromomethane is rapid initially, largely
through the lungs. The kidneys eliminate much of the remainder as
bromide in the urine (Natl. Acad. Sci., 1978).
IV. EFFECTS
Pertinent information relative to the carcinogenicity, teratogenicity
or other reproductive effects, or chronic toxcity of bromomethane
were not found in the available literature.
A. Mutagenicity
Simmon and coworkers (1977) reported that bromomethane was
mutagenic to Salmonella typhimurium strain TA100 when assayed in a
dessicator whose atmosphere contained the test compound. Metabolic
activation was not required, and the number of revertants per plate
was directly dose-related.
B. Other Relevant Information
In several species, acute fatal poisoning has involved
marked central nervous system disturbances with a variety of manifestations:
ataxia, twitching, convulsions, coma, as well as changes in lung, liver,
-------
heart, and kidney tissues (Sayer, et al. 1930; Irish, et al. 19^0;
Gorbachev, et al. 1962; von Oettingen, 1964). Also, residual bromide
in fumigated food has produced some adverse effects in dogs (Rosenblum,
et al. 1960).
V. AQUATIC TOXICITY
Two acute toxicity studies on one freshwater and one marine
fish species were reported with LC5Q values of 11,000 ug/1 for freshwater
bluegill (Lepomis macrochirus) and an LC5Q value of 12,000 jig/1 for
the marine tidewater silversides (Menidia beryllina) (U.S. EPA,
1979a). Pertinent information relative to aquatic chronic toxicity
or plant effects for bromomethane were not found in the available
literature.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by
U.S. EPA (1979a), which are summarized below,-have gone through the
process of public review; therefore, there is a possibility that
these criteria will be changed.
A. Human
" The current OSHA standard for occupational exposure to
bromomethane (1976) is 80 mg/m3; the American Conference of Governmental
Industrial Hygienist1s'(ACGIH, 1971) threshold limit value is 78
mg/m3. The U.S. EPA (1979a) draft water quality criteria for bromomethane
is 2 pg/1. Refer to the Halomethane Hazard Profile for discussion
of criteria derivation (U.S. EPA, 1979b).
-------
B. Aquatic Toxicity
The draft criterion for protecting freshwater life is a
24-hour average concentration of 140 ,ug/l, not to exceed 320 >ag/l.
The marine criterion is 170 >ig/l as a 2U-hour average, not to exceed
380 jjg/1.
-------
BROMOMETHANE
References
American Conference of Governmental and Industrial Hygienists. 1971.
Documentation of the threshold limit values for substances in workroom
air. Cincinnati-, Ohio.
Davis, L.N., et al. 1977. Investigation of selected potential environmental
contaminants: monohalomethanes. EPA 560/2-77-007; TH 77-535- Final
rep. June, 1977, on Contract No. 68-01-4315. Off. Toxic Subst. U.S.
Environ. Prot. Agency, Washington, D.C.
Gorbachev, E.M. , et al. 1962,. Disturbances in neuroendocrine regulation
and oxidation-reduction by certain commercial poisons. Plenuma Patofiziol
Sibiri i Dal'n. Vost. Sb. 88.
Grimsrud, E.P. , and R.A. Rasmussen. 1975. Survey and analysis of halocarbons
in the atmosphere by gas chromatography-mass spectrometry. Atmos. Environ. 9:
1014.
Irish, -D.D., et al. 1940. The response attending exposure of laboratory
animals to vapors of methyl bromide. Jour. Ind. Hyg. Toxicol. 22: 218.
Kantarjian, A.D., and A.S. Shaheen. 1963- Methyl bromide poisoning with nervous
system manifestations resembling polyneuropathy. Neurology 13: 1054.
Lovelock, J.E. 1975. Natural halocarbons in the air and in the sea. Nature
256: 193-
Miller, D.P., and H.W. Haggard. 1943. Intracellular penetration of bromide as
feature in toxicity of alkyl bromides. Jour. Ind. Hyg. Toxicol. 25: 423.
National Academy of Sciences. . 1978.. Nonfluorinated halomethanes in the
enviornment. Washington, D.C.
Occupational Safety and Health Administration. 1976. General industry standards.
OSHA 2206, revised January 1976. U.S. Dep. Labor, Washington, D.C.
Rosenblum, I., et al. 1960. Chronic ingestion by dogs of methyl bromide-
fumigated foods. Arch. Enviorn. Health 1: 3'6.
Sayer, R.R., et al. 1930. Toxicity of dichlorodiflouromethane. U.S Bur. Mines
Rep. R.I. 3013-
Simmon, V.F. et al. 1977. Mutagenic activity of chemicals identified in drinking
water. S. Scott, et al., eds^ In; Progress in genetic toxicology.
»
Singh, H.3., et al. 1977. Urban-non-urban relationships of halocarbons, SF& ,
and other atmospheric constituents. Atmos. Environ. 11: 819.
U.S. EPA. 1975. Preliminary assessment of suspected carcinogens in drinking
water, and appendicie's. A report to Congress, Washington, D. C.
U.-S. EPA. 1979a. Halomethanes: Ambient Water Quality Criteria. (Draft).
U.S. EPA, 1979b. Environmental Criteria and Assessment Office. Halomethanes:
Hazard Profile.
-------
von Oettingen, W.F. 1964. The halogenated hydrocarbons of industrial and
toxicological importance. Elsevier Publ. Co., Amsterdam.
--3.3J-
-------
No. 30
4-Bromophenyl Phenyl Ether
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 aec-uracy.
-------
4-Bromophenyl phenyl ether
SUMMARY
Very little information on 4-bromophenyl phenyl ether exists. 4-Bromophenyl
phenyl ether has been identified in raw water, in drinking water and in river
water. 4-Bromophenyl phenyl ether has been tested in the pulmonary adenoma
assay, a short-term carcinogenicity assay. Although the results were negative,
several known carcinogens also gave negative results. No other health effects
were available. 4-Bromophenyl phenyl ether appears to be relatively toxic
to freshwater aquatic life: a 24-hour average criterion of 6.2 ug/L has been
proposed.
I. INTRODUCTION
4-Bromophenyl phenyl ether (BrCgH OC,H_; molecular weight 249.11) is a
liquid at room temperature; it has '"•he following physical/chemical properties
(Weast 1972):
. Melting point: 18.72°C
Boiling point: 310.14°C (760 mm Hg)
163°C (10 mm Hg)
20
Density: 1.4208
Solubility: Insc'^ble in water; soluble in ether
No information could be found on,the uses of this substance.
- ,.J '
A review of the production range (includes Importation) statistics
for 4-bromophenyl phenyl ether (CAS Nol 101-55-3) which is listed in the initial
TSCA Inventory (1979) has shown that between 0 and 900 pounds of this chemical
were produced/imported in 1977.*
*
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).
-------
II. EXPOSURE
No specific information relevant to the environmental fate of 4-bromophenyl
phenyl ether was found in the literature. A U.S. EPA report (1975a) included this
substance in a category with several other drinking water contaminants consid-
ered to be refractory to biodegradation (i.e., lifetime greater than two years
in unadapted soil; point sources unable to be treated biologically). However,
the authors did not present or reference experimental data to support the inclu-
sion of 4-bromopheny phenyl ether in this category. U.S. EPA (1975a) estimated
that three tons of 4-bromophenyl phenyl ether are discharged annually.
4-Bromophenyl phenyl ether has been identified as a contaminant in finished
drinking water on three occasions, in raw water on one occasion and in river
water on one occasion. No quantitative data were supplied (U.S. EPA, 1976). Fri-
loux (1971) and U.S. EPA (1972) have also reported the presence of 4-bromophenyl
phenyl ether in raw and finished water of the lower Mississippi River (New
Orleans area). Again, no quantitative data were supplied. U.S. EPA (1975) sug-
gest that 4-bromophenyl phenyl ether may be formed during the chlorination of
treated sewage and drinking water.
III. PHARMACOKINETICS
No information was located.
IV. HEALTH EFFECTS
A. Carcinogenicity
Three groups of 20 male mice were administered intraperitoneal doses
(23, 17 or 18 doses, respectively) of 4-bromophenyl phenyl ether in tricaprylin
vehicle three times a week for 8 weeks (Theiss et al. 1977). The total doses
were 920, 1700, or 3600 mg/kg, respectively. Animals were sacrificed at 24
weeks from the start of the experiment. Incidences of lung adenomas were not
significantly increased, as compared with vehicle controls. However, this short-
term assay should not be considered indicative of the nononcogenie ity of 4-
bromophenyl phenyl ether as several known oncogens tested negative in this assay.
-------
V. AQUATIC TOXICITY
A. Acute
An unadjusted 96 hour LC of 4,940 ug/L was determined by exposing
bluegills to 4-bromophenyl phenyl ether (Table 1). Adjusting this value for test
conditions and species sensitivity, a Final Fish Acute Value of 690 ug/L is obtained
(U.S. EPA, undated).
Exposure of Daphnia magna, yielded an unadjusted 48 hour LC,_ of 360 ug/L
(Table 2). The Final Invertebrate Acute Value (and the Final Acute Value) for
4-bromophenyl phenyl ether is 14 ug/L (U.S. EPA, undated).
B. Chronic
In an embryo-larval test using the fathead minnow (in which survival and
growth were observed), a chronic value of 61 ug/L was obtained for 4-bromophenyl
phenyl ether exposure (Table 3). Dividing by the species sensitivity factor
(6.7), a Final Fish Chronic Value of 9.1 ug/L is derived. Since no other
information is available, this value is also the .Final Chronic Value (U.S. EPA,
undated).
VI. EXISTING GUIDELINES
A. Aquatic
A 24 hour average concentration of 6.2 ug/L (6.2 ug/L = 0.44 x 14 ug/L
(Final Acute Value)) is the recommended criterion to protect freshwater aquatic
life. The maximum allowable concentration should not exceed 14 ug/L at any
time (U.S. EPA, undated).
-------
Table 1. Freshwater fish acute values
Organiom
Bluegill,
Lepomis macrocjiirus
Bioassay Test Chemical Time
Method* Cone.** Description (hrs)
S U 4-Bromophenyl- 96
phenyl ether
4,940 2,700
* S = static
** U = unmeasured
Geometric mean of adjusted values: 4-Bromophenylphenyl ether
2.700
2,700 ug/L
3.9
690 ug/L
Table 2. Freshwater invertebrate acute values
Organism
Cladoceran,
Daphnia magna
Bioassay Test
Method* Cone.**
S U
Chemical
Description
4-Bromophenyl-
phenyl ether
Time
(hrs)
48
LC50
(ug/L)
360
Adjusted
LC50
(ug/L)
300
* S = static
** U = unmeasured
Geometric mean of adjusted values: 4-Bromophenyl phenyl ether
300
300 ug/L
21
14 ug/L
Table 3. Freshwater fish chronic values, 4-Bromophenyl phenyl ether
Organism
Fathead minnow,
Pirnephales promelas
Limits
Test* (ug/L)
E-L
89-167
Chronic
Value
(ug/L)
61
* E-L = embryo-larva
Geometric mean of chronic values = 61 ug/L
Lowest chronic value = 61 ug/L
|^7 =9.1 ug/L
-•2,37-
-------
BIBLIOGRAPHY
Friloux J. 1971. Petrochemical wastes as a pollution problem in the lower
Mississippi River. Paper submitted to the Senate Subcommittee on Air and Water
Pollution, April 5 (as cited in U.S. EPA, 1975b).
Theiss JC, Stoner GD, Shimkin MB, Weisburger EK. 1977. Test for careinogenieity
of organic contaminants of United States drinking waters by pulmonary tumor
response in strain A mice. Cancer Research 37:2717-2720.
U.S. EPA. 1972 Industrial pollution of the Lower Mississippi River in
Louisiana Region VI. Surveillance and Analysis Division (as cited in U.S.
EPA, 1975b) .
U.S. EPA. 1975a. Identification of organic compounds in effluents from industrial
sources. EPA-560/3-75-002, PB 241 641.
U.S. EPA. 1975b. Investigation of selected potential environmental contaminants:
Haloethers. EPA-560/2-75-006.
U.S. EPA. 1976. Frequency of organic compounds identified in water. EPA-
600/4-76-062.
U.S. EPA. 1979. Toxic Substances Control Act Chemical Substance Inventory.
Production .Statistics for Chemicals on the Non-Confidential Initial TSCA Inventory.
U.S. EPA. (undated). Ambient Water Quality Criteria Document on Haloethers,
Criteria and Standards Division, Office of Water Planning and. Management. PB
296-796.
Weast, RC (ed.). 1972. Handbook of Chemistry and Physics, 53rd. ed. The
Chemical Rubber Co., Cleveland, OH.
-------
No. 31
Cadmium
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.
-Wo-
-------
SPECIAL NOTATION
U.S. EPA1 s Carcinogen Assessment Group (CAG) has evaluated
cadmium and has found sufficient evidence to indicate that
this compound is carcinogenic.
- V-M -
-------
CADMIUM
Summary
The major non-occupational routes of human cadmium exposure are through
food and tobacco smoke. Drinking water also contributes relatively little
to the average daily intake.
Epidemiological studies indicate that cadmium exposure may increase the
mortality level for cancer of the prostate. Long-term feeding and inhal-
ation studies in animals have not produced tumors, while intravenous admin-
istration of cadmium has produced only injection site tumors. Mutagenic
effects of cadmium exposure have been seen in animal studies, bacterial sys-
tems, i£ vitro tests, and in the chromosomes of occupationally exposed
workers.
Cadmium has produced teratogenic effects in several species of animals,
possibly through interference with zinc metabolism. Testicular necrosis and
neurobehavioral alterations in animals following exposure during pregnancy
have been produced by cadmium in animals.
Chronic exposure to cadmium has produced emphysema and a characteristic
syndrome .(Itai-Itai disease) following renal damage and osteomalacia. A
causal relationship between chronic cadmium exposure and hypertension in
humans has been suggested but not confirmed.
Cadmium is acutely toxic to freshwater fish at levels as low as 0.55
jug/1. Freshwater fish embryo/larval stages tended to be the most sensitive
to cadmium. Marine fish were generally more resistant than freshwater
fish. The long half-life of cadmium in aquatic organisms has been postu-
lated, and severe restrictions to gill-tissue respiration have been obs'erved
at concentrations as low as 0.5jug/l.
-------
CADMIUM
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Cadmium (U.S. EPA, 1979).
Cadmium is a soft, bluish-silver-white metal, harder than tin but
softer than zinc. The metal melts at 321°C and shows a boiling point of
765°C (U.S. EPA, 1978b). Cadmium dissolves readily in mineral acids.
Some of the physical/chemical properties of cadmium and its compounds are
summarized in Table 1 (U.S. EPA, 1978b).
Cadmium is currently used in electroplating, paint and pigment
manufacture, and as a stabilizer for plastics (Fulkerson and Goeller, 1973).
Current production; 6000 metric tons (1968) (U.S. EPA, 1978b)
Projected production: 12,000 metric tons (2000) (U.S. EPA, 1973b)
Since cadmium is an element, it will persist in some form in the
environment. Cadmium is precipitated from solution by carbonate, hydrox-
ide, and sulfide ions (Baes, 1973); this is dependent on pH and on cadmium
concentration. Complexing of cadmium with other anions will produce soluble
forms (Samuelson, 1963). Cadmium is strongly adsorbed to clays, muds, humic
and organic materials and some hydrous oxides (Watson, 1973), all of which
lead to precipitation from aqueous media. Cadmium corrodes slightly in air,
but forms a protective surface film which prevents further corrosion (U.S.
EPA, 1978b).
II. EXPOSURE
Cadmium is universally associated with zinc and appears with it in
natural deposits (Hem, 1972). Major sources of cadmium release into the
»
environment include emissions from metal refining and smelting plants, in-
cineration of polyvinyl chloride plastics, emissions from use of fossil
-------
Table 1. Some I'ropertlea of Cadmium and its Importune Compounds
Primary
u;,i; or
Compound occurrence Formula
C, Minium Cadmium nickel Cd
i,..j|.il l.al Icrles
C,-i. liuluig Smelling plant CdO
oxlilt: or coal COD.IIUS-
1 Ion cmlHs Ion
Cadmium Pigment for CdS
uul 1 Ide pluul Ics mid
enamels; phos~
S^ pi. 01 a
j- Cadmium Fruit tree CdSO
f Kulfale fnmlclde
1
i:.i, Iml inn Turf treat- Cdt'O,
cai'lioual e went
lloleculnr Physical '
uelgbt Oenalty utule,
(g/uiolc) (g/ml) 20°C
112.4 6.6 Silver metal
»
12U.4 7.0 Urown powder \
i
144.5 4.8 Yellow crystal
200.5 4.7 Wblte
crystalline
172.4 4.3 Ulilte powder
or crystalline
Solubility
Melting Dolling In water
point point 20°C
("C) CC) (g/llter)
321 765 Insoluble
Decomposes 0:00015
ut 900
1750 Deconposca 0.0013
1000 755
Decomposes 0.001
below 500
Solubility
In oilier
solveiitti
Soluble lit
acid and
Soluble In
acid and
Nll-j nulls
Soluble In
acid, very
tjliglitly
soluble in
Nil, till
Insoluble
In uctd
and ulacliol
Soluble In
acid and
KCN. Ml,
suits
Acute I.etbal
doue"
9 i»g/m Is tlic
upprox Imate
letlial cuiicen-
tiutlou lit man,
InbalL-d au fume
50 uig/m Is tlie
upprox Imai e
lethal cuncen-
trntlon In mini,
Inlialed; 72
mg/kg^ rat,
l.l>50 (oral)
27 mg/kg dug,
U>50 (uuli-
-------
Table 1. Some rrojiertlca of Cailmluin onil Itu IninorCanC Compounds (Cont'il)
<:..».,..>,m.i
Ciiilnil mil
t:lil oil de
C.lilmlum
piiliissltun
i:yanl,le
Catlnil inn
cyan tile
limili .;:;:
l-'u 1 kui'M>n ill
llaluie an>l Ki
l-i hiiiiry Molecular
use or weight Dciiulty
occurrence . Formula (g/inole) (u/nil)
Turf grass C.ICl. 103.3 4.0
fimlcl.le
tltfciioplutlng K.jCJ(CN)^ 294.7 1.U5
Electroplating Cd(CN>2 164.4
n.l C.icller. 1971
immtle, 1973
I'liyulcol
alute.
20°C
Colurleaa
crybtul
Colo.rleaa,
gluua
cryiital
Colorlesu
cryatal
Melting Dolling
pnl ut point
CO CO
568 960
Decomposes
ut 200
Solubility
III water
20°C
(g/ liter)
1400
311
17, uolublo
la liot water
Solubility
In oilier Acute l.ullial
uolventa iloue a
13.2 B/llter UU ing/kg rut.
In ulcoliol I.I) (unil)
Inaoluble In
alcoliol
Soluble In
ucld and KCH
Oilier il.u.i u..ni|.| I. .1 from UcuaC, 1971
I
U)
-------
fuels, use of certain phosphate fertilizers, and leaching of galvanized iron
pipes (U.S. EPA, 1978b). The major non-occupational routes of human expo-
sure to cadmium are through foods and tobacco smoke (U.S. EPA, 1979).
Based on available monitoring data, the U.S. EPA (1979) has estimated
the uptake of cadmium by adult humans from air, water, and food:
Adult
Source jug/day
Maximum conditions
Air-ambient .008 mg/day
Air-smoking 9.0
Foods 75.0
Drinking water 20.0
Total 304.008
Minimum conditions
Air-ambient 0.00002
Air-smoking 0
Food 12.0
Drinking water 1.0
Total 13.00002
The variation of cadmium levels in air, food, and water is quite exten-
sive as indicated above. Leafy vegetables, contaminated water, and air near
smelting plants all present sources of high potential exposure. The U.S.
EPA (1979) has estimated the weighted average bioconcentration factor of
cadmium to be 17 in the edible portions of fish and shellfish consumed by
Americans.
III. PHARMACOKINETICS
. A. Absorption
The main routes by which cadmium can enter the body are inhalation
and ingestion. Particle size.and solubility greatly influence the biolog-
ical fate of inhaled cadmium. When a large proportion of particles are in
-------
the respirable range, up to 25% of the inhaled amount may be absorbed (EFA,
1979). Cadmium fumes may have an absorption of up to 50%, and it is esti-
mated that up to 50% of cadmium in cigarette smoke may be absorbed (WHO,
1977; Slinder, et al. 1976). Large particles are trapped by the mucous mem-
branes and may eventually be swallowed, resulting in gastrointestinal
absorption (EPA, 1979).
Only a small proportion of ingested cadmium is absorbed. Two human
studies using radiolabelled cadmium have indicated mean cadmium absorption
from the gastrointestinal tract of 6% and 4.6% (Rahola, et al. 1973;
McLellan, et al. 1978). Various dietary factors interact with cadmium ab-
sorption; these include calcium levels (Washko and Cousins, 1976), vitamin 0
levels (Worker and Migicovsky, 1961), zinc, iron, and copper levels (Banis,
'• \
et aS. 1969). and ascorbic acid levels (Fox and Fry, 1970). Low protein
diets enhance the uptake of cadmium from the gastrointestinal tract (Suzuki,
et al. 1969).
Dermal absorption of cadmium appears to occur to a small extent;
Wahj._erg (1965) has determined that up to 1.8 percent of high levels of cad-
mium chloride were absorbed by guinea pig skin.
Cadmium levels have been determined in human embryos (Chaube, et
al. 1973) and in the blood of newborns (Lauwerys, 1978), indicating passage
of cadmium occurs across the placental membranes.
B. Distribution
Cadmium is principally stored in the liver, kidneys, and pancreas
with higher levels initially found in the liver (WHO Task Group, 1977).
continued exposure leads to accumulation in all of these organs; levels as
-------
high as 200-300 mg/kg wet weight may be found in the renal cortex. This
storage appears to be dependent on the association of cadmium with the
cadmium binding protein, metallothionen (Nordberg et al., 1975).
Animal studies indicate that following intraperitoneal or intra-
venous administration of cadmium most of the compound is found in the blood
plasma. After 12-24 hours the plasma is cleared and most of the compound is
associated with red blood cells (U.S. EPA, 1978b).
The cadmium body burden of humans increases with age (Friberg, et
al. 1974) from very minimal levels at birth to an average of up to 30-40 mg
by the age of 50 in non-occupationally exposed individuals. Liver accumu-
lation continues through the last decades of life, while kidney concen-
trations increase until the fourth decade and then decline (Gross, et al.
1976). The pancreas and salivary glands also contain considerable concen-
trations of cadmium (Nordberg, 1975). Smoking effects the body burden of
cadmium; levels in the renal cortex of smokers may be double those found in
non-smokers (Elinder, et al. 1976; Hammer, et al. 1971).
C. Metabolism
Pertinent data were not found in the available literature.
D. Excretion
Since only about 6 percent of ingested cadmium is absorbed, a large
proportion of the compound is eliminated by the feces (U.S. EPA, a or b).
Some biliary excretion of cadmium has been demonstrated in rats (Stowe,
1976);. this represented less than 0.1 percent of a subcutaneously adminis-
tered dose.
Urinary excretion of cadmium is approximately 1-2 mg/day in the
f
general population (Imbus, et al. 1963; Szadkowski, et al. 1969). Occupa-
tionally exposed individuals may show markedly higher urinary excretion
-------
levels (Friberg, et al. 1974). A modest increase in human urinary excretion
of cadmium has been noted with increasing age (Katagiri, et al. 1971).
Additional sources of cadmium loss are through salivary excretion
and shedding of hair (U.S. EPA, 1979).
Biological half-life calculations for exposed workers have given
values of up to 200 days (urine). Direct comparisons of urinary excretion
levels and estimated body burden using Japanese, American, and German data,
suggest a half-time of 13-47 years. Using more complex metabolic models,
Frieberg, et al. 1974 concluded that the biologic half-time is probably
10-30 years. . The most recent estimate of biologic half-time is 15.7 years
by Ellis (1979).
IV. EFFECTS
A. Carcinogenicity
The results of several epidemiology studies of the relationship of
cancer to occupational exposure to cadmium are summarized in Table 3 (U.S.
EPA, 1978a). The only consistent trend seen in these studies is an
increased incidence of prostate cancer in cadmium-exposed workers. A recent
study by Kjellstrom, et al. (1979) of 269 cadmium-nickel battery factory
workers found increased cancer mortality from nasopharyngeal cancer (signif-
icant) and increased mortality trends for prostate, lung, and colon-rectum
cancers (not significant). After reviewing these studies, EPA (1979) has
concluded that cadmium cannot be definitely implicated as a human carcino-
gen with the available data.
Animal experiments with the administration of cadmium by subcu-
taneous or intravenous injection have demonstrated that cadmium produces
-------
injection site sarcomas and testicuiar tumors (Leydigiomas) (see Table 2;
U.S. EPA, 1978a). A large number of metals and irritants produced compar-
able injection sits sarcomas. Long term feeding and inhalation studies with
cadmium have not produced tumors (Schroeder, et al. 1964, Levy, et al. 1973;
Decker, et al. 1958; Anwar, et al. 1961; Paterson, 1947; Malcolm, 1972)
At the present time, the draft ambient water quality criterion for
protection of human health is based on the toxicity of cadmium rather than
on any carcinogenic effects. Though the studies summarized above qualita-
tively indicate a carcinogenic potential for cadmium, quantitatively-, the
issue has not been resolved.
B. Mutagenicity
An increased incidence of chromosomal aberrations has been.noted in
workers occupationally exposed to cadmium and in Japanese patients suffering
cadmium, toxicity (Itai-Itai disease) (Bauchinger, et al. 1976; Bui, et al.
1975; Deknudt and Leonard, 1976; Shiraishi and Yoshida, 1972).
Cadmium has been shown to produce mutagenic effects in vitro and _in
vivo in several systems (see Table 4; U.S. EPA, 1978 a or b). These effects
include induction of point mutations in bacterial systems, chromosome aberr-
ations in cultured cells and cytogenetic damage in vivo, and promotion of
error prone base incorporation in ONA _in vitro. Several investigators have
been unable to show dominant lethal effects of cadmium in mice (Epstein, et
al. 1972; Gillivod and Leonard, 1975; Suter, 1975). Point mutation studies
with cadmium in Drosophila have also produced negative findings (Shabalina,
1963; Friberg et al., 1974; Sorsa and Pfeiffer, 1973).
C. Teratogenicity
»
Damage to the reproductive tract resulting from a single dose of
parenterally administered cadmium chloride (2 mg/kg) have been observed in
-------
TA11LE 2
STUDIES ON CADMIUM CARCINOGENESIS IN EXPERIMENTAL ANIMALS*
Authors
Animals
Compounds and routes
Tumors
Heath £t £l. , 1062; Heath and Daniel, 1964 Rats
KuziiittzJs, 1063; Kazautzis and llanbury, 1966 Rats
lladdow j£t u\_., 1964; Roe et_ al^., 1964 Rats
Outhrie, 1964 Clilckens
ttunn £t aj.. , 1963i 196/i; 1965; 1967 Rats, Mice
Schroedcr <;t .a_l. , 1965; Kanlsaua and Rats, Mice
St:hrouilcr, 1969
Nunurl ut aj.. , 1967; Favion _et al_., 1968 Rats
Knorre, 1970; 1971 ' Rats
Lucia £t ^ij_. , 1972; 1973 Rats
Keil.ly ^t u_j_. , 1973 Rats
Levy ia u\_. , 1973 Rats
Levy
-------
TABLE 3
SUMMARY OF RESULTS OF HUMAN EPIDEMIOLOGY STUDIES OF CANCER EFFECTS
ASSOCIATED WITH OCCUPATIONAL EXPOSURES TO CADMIUM
Population Cadmium Compound . Incidences of Incidences of
Croup Studied Exposed To All Cancers Lung Cancer
Hattery factory Cadmium oxide High Normal
workers
liuttury factory Cadmium oxide Normal Normal
workers
Cadmium smelter Cadmium oxide, High High
workers others
Rubber industry Cadmium oxide High Normal
Incidences of
Prostrate Cancer Reference
High Potts (1965)
t
High Kipling and
Uaterhouse
(1967)
High Lemon et al.
(1976)
High McMichael et al.
workers
(1976)
-------
rats, rabbits, guinea pigs, hamsters, and mice (Parizek and Zahor, 1956;
Parizek, 1957; Meek, 1959). This susceptibility appears to be genetically
regulated since different strains of mice show differential susceptibility
(Wolkowski, 1975).
Teratogenic effects of cadmium compounds administered parenterally
have been reported in mice (Eto, et al. 1975), hamsters (Ferm and Carpenter,
1963; Mulvihill, et al. 1970; Ferm, 1971; Gale and Ferm, 1973) and rats
(Chernoff, 1973; Barr, 1973). Oral administration of cadmium (10 ppm) has
demonstrated teratogenic effects in rats (Schroeder and Mitchener, 1971),
but no teratogenicity has been reported in rats and monkeys (Cuetkova, 1970;
Pond and Walker, 1975; Willis, et al. 1976; Campbell and Mills, 1974).
0. Other Reproductive Effects
Rats in late pregnancy are apparently more sensitive to cadmium
than non-gravid animals or those immediately post-partum. A single dose of
2-3 mg/kg of body weight given during the last 4 days of pregnancy resulted
in high mortality (76 percent).
In addition to the embryotoxic effects of cadmium indicated in
Section C, persisting effects of cadmium exposure during pregnancy on postu-
lated development and growth of offspring have been observed. This includes
neurobehavioral alteration in newborn rats (Chowdbury and Lauria, 1976) and
growth deficiencies in lambs (U.S. EPA, 1978a).
E. Chronic Toxicity
Friberg . (1948, 1950) observed emphysema in workmen exposed to cad-
mium dust in an alkaline battery factory. This finding has subsequently
been well documented (U.S. EPA, 1979).
-------
TABLE 4
SUMMARY OF MUTAGENICITY TEST RESULTS
Test System
Genetic Effect
Reported
Mutagenicity
References
Human cells
Hamster Cells
Systems in vitro
Cltromosomal damage
Point imitation
Point mutation
.PI. s11htj'l_ 1 s recomblnant Gene mutation
assay
Polynueleotides Base mispairlng
+
+
+
+
Shiraishl et_ al.', 1972
Costa _et^ al., 1976
Takahoslii, 1972
Nlshioka, 1975
Sirover and Loeb, 1976
Human leukocytes
Human leukocytes
Human leukocytes
Human leukocytes
KiiL b|)orinatogoni.a »
Motive OOCytUS
Mt)iise I) feed ing
Mouse breeding
Mouse breeding
Mammals
I), me lauoga.-iter
Systems in vivo
Chromosomal damage
Chromosomal damage
Chromosomal damage
Chromosomal damage
Altered spermatogenesis
Cytogenetic damage
Dominant lethal mutations
Dominant lethal mutations
Dominant lethal mutations
Chromosomal abnormalities
Sex-linked recessive lethal
Shirashi and Yoshida, 1972
Bui et^^l., 1975
Deknudt and Leonard, 1975
Bauchinger et al., 1976
Lee and Dixon, 1973
Shlmada ej^ al., 1976
Epstein et_ al., 1972
Gllliavod and Leonard, 1975
Suter, 1975
Shlmada e£ £l., 1976
Sorsa and Pfeifer, 1973
-------
Chronic cadmium exposure produces renal tabular damage that is
characterized by the appearance of a characteristic protein 9B_-micro-
globulin) in the urine. Renal damage has been estimated to occur when
cadmium levels in the renal cortex reach 200 mg/kg (Kjellstron, 1977).
Itai-Itai disease is the result of cadmium induced renal damage plus osteo-
malacia (U.S. EPA, 1978a).
Exposure to high ambient cadmium levels may contribute to the etio-
logy of hypertension (U.S. EPA, 1979). Several studies, however, have been
unable to show a .correlation between renal levels of cadmium and hyper-
tension (Morgan 1972; Lewis, et al. 1972; Beevers, et al. 1976).
Friberg (1950) and Blejer (1971) have noted abnormal liver function
tests in workers exposed to cadmium; however, these workers were occupa-
tionally exposed to a variety of agents.
The immunosuppressive effects of cadmium exposure, including an in-
creased susceptibility to various infections, have been reported in several
animal studies (Cook, et al. 1975; Koller, 1973; Exon, et al. 1975).
V. AQUATIC TOXICITY
A. Acute Toxicity
Acute toxicity in freshwater fish has been studied in a number of
96-hour bioassays consisting of one static renewal, 22 static, and 19 flow-
through tests. L(-5n values ranged from 1 ug/1 for stripped bass, larvae
(Roccus saxatilus) (Hughes, 1973) to 73,500 for the fathead minnow
(Pimephales promelas) (Pickering and Henderson, 1966). Increased resistance
to the toxic action of cadmium in hard waters was observed. The LC_n
values for freshwater invertebrates ranged from 3.5 for Cladoceran
(Simoeohalus serrulatus) to 28,000 pg/1 for the mayfly (Eohemerella orandis
grandis). Acute LC-- values for marine fish ranged from 1,600 yg/1 for
-------
larval Atlantic silversides (Menidia menida) (Middaugh and Dean, 1977) to
114,000 jjg/1 for juvenile mummichog (Fundulus heteroclitus) (Voyer, 1975).
Intraspecific and life stage differences have shown that larval stages of
the Atlantic silversides and mummichog are four times more sensitive than
adults under the same test conditions (Middaugh and Dean, 1977). Marine
invertebrates are more sensitive to cadmium than are marine fishes. LC_Q
values ranged from 15.5 ug/1 for the mysid shrimp (Nimmo, et al. 1977a) to
46,600 for the fiddler crab (Uca puqilator) (O'Hara, 1973).
8. Chronic Toxicity
Chronic values for freshwater fish ranged from 0.9 ug/1 in a brook
trout (Salvelinus fontinalis) embryo larval assay (Sauter, et al. 1976) to
50 pg/1 in a life cycle (or partial life cycle) assay for the bluegill
(Lepomis marcochirus) in hard water (Eaton, 1974). Salmonids were in
general the most sensitive species examined. Data for freshwater inverte-
brates depend on a single jug/1 obtained for Daphnia maqna (Biesinger and
Christensen, 1972). No chronic studies were available for cadmium effects
in marine fishes. The only marine invertebrates data reported was the
chronic value of 5.5 jug/1 for the mysid shrimp, Mysidoosis bahia. In this
animal no measurable effects on brood appearance in the pouch, release,
average number per female, or survival were observed at concentrations of
C. Plant Effects
Effective concentrations for freshwater plants ranged from 2 jug/1,
which causes a 10 fold growth rate decrease in the diatom, Asterionella
formosa (Conway, 1978), to 7,400 pg/1, which causes a 50% root weight, inhi-
bition in Eurasian water-milfoil (Myrioohyllum soicatum) . In marine algae,
-------
96-hour EC.Q growth rate assays yielded values of 160 and 175 pq/l for
Cyclotslla nana and Skeletonema costatum respectively (Gentile and Johnson,
1974).
0. Residues
Bioconcentration factors ranged from 151 for brock trout to 1,988
for the flagfish (Jordanella floridae). One characteristic of cadmium tox-
icity in aquatic organisms was the possible long half-life of the chemical
in certain tissues of exposed brook trout even after being placed in clean
water for several weeks. Testicular damage to adult mallards was observed
when fed 20 mg/kg cadmium in the diet for 90 days. In marine organisms
bioconcentration values ranged from 37 for the shrimp Cranqon crangon to
1,230 for the American oyster, Crassostrea virginica (Schuster and Pringle,
1969). ^
E. Miscellaneous
Several, studies on marine organisms have demonstrated significant
reduction in gill-tissues respiratory rates in the cunner, Tautoqolabrus
adepersus, the winter flounder, Pseudopleuron&Jtes americanus, and the
stripped bass, MOrone saxatilis, at concentration? ^s low as 0.5 pg/1.
VI. EXISTING GUIDELINES
A. Human
It is not recommended that cadmium be considered a suspect- human
carcinogen for purposes of calculating a water quality criterion (U.S. EPA,
1979).
The EPA Primary Drinking Water Standard for protection of human
health is 10 pg/1. This level was also adopted as the draft ambient water
»
quality criterion (U.S. EPA, 1979).
-------
The OSHA time-weighted average exposure criterion for cadmium is
100 jjg/m .
8. Aquatic
The draft criterion proposed for freshwater organisms to- cadmium
has been prepared following the Guidelines, and is listed according to the
following equation:
(0.867 In-(hardness) - 4.38)
e
for a 24-hour average and not to exceed the level described by the following
equation:
(1.30 In-(hardness) - 3.92)
The proposed marine criterion derived following the Guidelines is 1.0 ug as
a 24-hour average not to exceed 16 jug/1 at any time (U.S. EPA, 1979).
-------
CADMIUM
REFERENCES
Anwar, R.A., et al. 1961. Chronic toxicity studies. III. Chronic
toxicity of cadmium and chromium in dogs. Arch. Environ. Health
3: 456.
Baes, C.F., Jr. 1973. The properties of cadmium. Pages 29
to 54 in W. Fulkerson, and H.E. Goeller, eds. Cadmium, the dis-
sipated element. Oak Ridge Natl. Lab., Oak Ridge, Tenn.
Banis, R.J., et al. 1969. Dietary cadmium, iron and zinc inter-
actions in the growing rat. Proc. Soc. Exp. Biol. Med. 130: 802.
Barr, M. 1973. Teratogenicity of cadmium chloride in two stocks
of Wiser rats. Teratology 7: 237.
Bauchinger, M.E., et al. 1976. Chromosome aberrations in lympho-
cytes after occupational lead and cadmium exposure. Mut. Res.
40: 57.
Beevers, D.C., et al. 1976. Blood cadmium in hypertensives
and normotensives. Lancet 2: 1222.
Biesinger, K.E., and G.M. Christensen. 1972. Effects of various
metals on survival, growth, reproduction, and metabolism of Daphnia
magna. Jour. Fish. Res. Board Can. 29: 1691.
Blejer, H.P., et al. 1971. Occupational health aspects of cadmium
inhalation poisoning with special reference to welding and silver
brazing. 2nd ed. State of Calif. Dept. Pub. Health, Bur. Occup.
Health Environ. Epidemiol.
Bui, T-H., et al. 1975. Chromosome analysis of lymphocytes
from cadmium workers and Itai-itai patients. Environ. Res.
9: 187.
Campbell and Mills. 1974. Effects of dietary cadmium and zinc
on rats maintained on diets low in copper. Proc. Nutr. Foe.
33: 15a.
Chaube, S., et al. 1973. Zinc and cadmium in normal human embryo
and placenta. Arch. Environ. Health. 26: 237.
Chen, R.W-. , et al. 1975. Selenium-induced redistribution of
cadmium binding to tissue proteins: A possible mechanism of
protection against cadmium toxicity. Bioinorg. Chem. 4: 125.
»
Chernoff, N. 1973. Teratogenic effects of cadmium in rats.
Teratology. 8: 29.
-------
Chowdbury, P. and D.B. Lauria. 1976. Influence of cadmium and
other trace metals on human a-,-antitrypsin - An _i_n vitro study.
Science 191: 480.
Conway, H.L. 1978. Sorption of Arsenic and cadmium and their
effects on growth, micronutrient utilization, and photosynthetic
pigment composition of Asterionella formosa. Jour. Fish. Res.
Board Can. 35: 286.
Cook, J.A., et al. 1975. Factors modifying susceptibility to
bacteria endotoxins: The effect of lead and cadmium. Crit.
Rev. Tox. 3: 201.
Cuetkova, R. 1970. Materials on the study of the influence
of cadmium compounds on the generative functions. Gig. Tr. Prof.
Zabol. 14: 31.
Decker, L.E., et al. 1958. Chronic toxicity studies. I. Cad-
mium administered in drinking water to rats. AMA Arch. Ind.
Health 18: 228.
Deknudt, Gh. and A. Leonard. 1976. Cytogenic investigations
on leucocytes of workers occupationally exposed to cadmium.
Mut. Res. 38: 112.
Eaton, J.G. 1974. Chronic cadmium toxicity to the bluegill
(Lepomis macrochirus Rafinesque). Trans. Am. Fish. Soc. 4: 729.
Blinder, C.G., et al. 1976. Cadmium in kidney cortex, liver
and pancreas from Swedish autopsies. Arch. Environ. Health 30: 292.
Ellis, K.J., et al. 1979. Cadmium: In vivo measurement in
smokers and nonsmokers. Science 205: 325.
Epstein, S., et al. 1972. Detection of chemical mutagens by
the dominant lethal assay in the mouse. Toxicol. Appl, Pharmacol.
23: 288.
Eto, K., et al. 1976. Developmental effects of teratogens influ-
encing the incidence of cleft lip. Jour. Dent. Res. 55(B): 203.
Exon, et al. 1975. Cited in Health Assessment Document for
Cadmium, U.S. EPA, p. 2-91.
Ferm, V. 19.71. Developmental malformations induced by calcium
— A study at timed injections during embryogenesis. Biol. Nenon.
19: 101.
Ferm, V. and S. Carpenter. 1968. The relationship of cadmium
and zinc in experimental mammalian teratoaenesis. Lab. Invest.
18: 429.
Fox, M.R.S. and B.E. Fry.. 1970. Cadmium toxicity decreased
by dietary ascorbic acid supplements. Science 169: 98~9.
-------
Friberg, L. 1948a. Proteinuria and kidney injury among workers
exposed to cadmium and nickel dust. Jour. Ind. Hyg. 30: 33.
Friberg, L. 1950. Health hazards in the manufacture of alkaline
accumulators with special reference to chronic cadmium poisoning -
a clinical and experimental scudy. Acta. Med. Scand. 138.
Supplement CCXL.
Friberg, L., et al. 1974. Cadmium in the environment. 2nd
ed. CRC Press, Cleveland, Ohio.
Fulkerson, W. and H.E. Goeller, eds. 1973. Cadmium the dissi-
pated element. Oak Ridge Natl. Lab., Oak Ridge, Tenn.
Gale, T. and V. Ferm. 1973. Skeletal malformations resulting
from cadmium treatment in the hamster. Biol. Neou. 23: 149.
Gentile, J. and M. Johnson. 1974. EPA Semi-annual Rep., Narra-
gansett, Rhode Island.
Gilliavod, N. and A. Leonard. 1975. iMutagenicity tests with
cadmium in the mouse. Toxicology 5: 43.
Gross, S.B., et al. 1976. Cadmium in liver, kidney and hair
of humans, fetal through old age. Jour. Toxicol. Environ. Health
2: 153.
Hammer, D.I., et al. 1971. Hair trace metal levels and environ-
mental exposure. Am. Jour. Epidem. 93: 84.
Hem, J. 1972. Chemistry and occurrence of cadmium and zinc
in surface water and groundwater. Water Resour. Res. 8: 661.
Hughes, J.S. 1973. Acute toxicity of thirty chemicals to striped
bass (Morone saxatilis). Pres. Western Assoc. State Game Fish
Comm., Salt Lake City, Utah. July, 1973.
Imbus, H.R., et al. 1963. Boron, cadmium, chromium and nickel
in blood and urine. Arch. Environ. Health. 6: 286.
Katagiri, Y., et al. 1971. Concentration of cadmium in urine
by age. Med. Biol. 82: 239.
Kjellstrom, T. , et al. 1979. Mortality and cancer morbidity
among cadmium-exposed workers. Environ. Health Perspect. 28: 199.
Roller, L.D. 1973. Immunosuppression produced by lead, cadmium,
and mercury. Am. Jour. Vet. Res. 34: 1457.
Lauwerys, R. , et al. 1978. Placental transfer of lead, mercury,
cadmium and carbon monoxide in women. I. Comparison of the fre-
quency distribution of the biological indices in maternal and
umbilical cord blood. Environ. Res. 15: 278.
-------
Levy, L.S., et al. 1973. Absence of prostatic changes in rts
exposed to cadmium. Ann. Occup. Hyg. 16: 111.
Lewis, G.P., et al. 1972. Cadmium accumulation in man: Influence
of smoking occupation, alcoholic habit and disease. Jour. Chronic
Dis. 25: 717.
Malcolm, D. 1972. Potential carcinogenic effect of cadmium
in animals and man. Ann. Occup. Hyg. 15: 33.
McLellan, J.S., et al. 1978. Measurement of dietary cadmium
in humans. Jour. Toxicol. Environ. Health. 4: 131.
Meek, E.S. 1959. Cellular changes induced by cadmium in mouse
testis and liver. Br. Jour. Exp. Pathol. 40: 503.
Middaugh, D.P. and Dean. 1977. Comparative sensitivity of eggs,
larvae and adults of the estuarine telebsts, Fundulus heteroclitus
and menidia menidia to cadmium. Bull. Environ. Contain^Toxicol.
17: 5T5T
Middaugh, D.P., et al. 1975. The response of larval fish Leio-
stomus xanthurus to environmental stress following sublethal
cadmium exposure. Contrib. Mar. Sci. 19.
Morgan, J.M. 1972. "Normal" lead and cadmium content of the
human kidney. . Arch. Environ. Health. 24: 364.
Mulvihill, J.F. , et al. 1970. Facial formation in normal and
cadmium-treated golden hamsters. Jour. Embryol. Exp. Morph.
24: 393.
Nimmo, D.R., et al. 1977a. Mysidopis bahia; An estuarine spe-
cies suitable for life-cycle toxicity tests to determine the
effects of a pollutant. Aquatic Toxicol. Hazard Eval.• ASTM
STP634.
Nordberg, G.F. 1974. Health hazards of. environmental cadmium
pollution. Ambio. 3: 55.
Nordberg, G.F., et al. 1975. Comparative toxicity of cadmium-
metallothionein and cadmium chloride on mouse kidney. Arch.
Path. 99: 192.
O'Hara, J. 1973. The influence of temperature and salinity
on the toxicity of cadmium to the fiddler crab, Uca pugilator.
U.S. Dept. Commer. Fish. Bull. 71: 149.
Parizek, J. 1957. The destructive effect of cadmium ion on
testicular tissue and its prevention by zinc. Jour. Endoctin.
15: 56.
Parizek, J. and A. Zahor. 1956. Effect of cadmium; salts on
testicular tissue. I. Nature. 177: 1036.
-------
Paterson, J.C. 1947. Studies on the toxicity of inhaled cad-
•mium. III. The pathology of cadmium smoke poisoning in man and
..'i'n ..experimental animals. Jour. Ind. Hyg. Toxicol. 29: 294.
•Pickering, Q.H. and C. Henderson. 1966. The acute toxicity
of some heavy metals to different species of warmwater fishes.
'Air Water .Pollut. Int. Jour. 10: 453.
Pond, W. and E. Walker. 1975. Effect of dietary Ca and Cd level
of. pregnant rats on reproduction and on dam progeny tissue mineral
concentrations. Proc..Soc. Exp. Biol. Med. 148: 665.
•Potts', C.L. 1965. Cadmium proteinuria - The health of battery
workers exposed to cadmium oxide dust. Ann. Occup. Hyg. 8: 55.
Rahola,. T.,'et al. 1973. Retention0 and elimination of 115mCd
in man. In health physics problems of internal contamination.
pp. 213-218. Budapest: Akademiai Kiado.
Samuelson, 0. . 1963. Ion exchange separations in analytical
chemistry. John Wiley and Sons, New York.
Sauter, S., et al. 1976. Effects of exposure to heavy metals
on selected freshwater fish — Toxicity of copper, cadmium, chro-
mium and lead to eggs and fry of seven fish species. EPA-600/3-
76-105, Contract No. 68-01-0740. U.S. Environ. Prot. Agency.
Schroeder, H.A. and M. Mitchener. 1971. Toxic effects of trace
elements on the reproduction of mice and rats. Arch. Environ.
'Health. 23: 102. .
Schroeder, H.A., et al. 1964. Chromium, lead, cadmium, nickel
and titanium in mice: effect on mortality, tumors and tissue
levels. Jour. Nutr. 83: 239.
Schuster, C.N. and B.H. Pringle. 1969. Trace metal accumulation
by the American oyster, Crassostrea virginica. 1968 Proc. Natl.
Shellfish Assoc. 59: 91.
Shabalina, F.P. 1968.. Industrial hygiene in the production
and use of cadmium stearate. Hyg. San. 33: 187.
Shiraishi, Y. and T.A. Yoshida. 1972. Chromosomal abnormalities
in cultured leucocyte cells from Itai-Itai diseae patients.
Proc. Jap. Acad. 48: 248.
Shiraishi, Y., et al. 1972. Chromosomal aberrations in cultured
human leucocytes induced by cadmium sulfide. Proc. Jap. Acad.
48: 133.
f
,-Sorsa, M. and S. Pfeifer. 1973. Effect of cadmium on develop-
'rnent time and prepupal putting patterns in D. melanogaster.
Hereditas. 75: 2.73.
-3,63-
-------
Stowe, H.D. 1976. Biliary excretion of cadmium by rats: Effects
of zinc, cadmium and selenium pretreatments. Jour. Toxicol.
and Environ. Health.
Sunderman, F.W., Jr. 1977. Cadmium. Chapter 9 In; Advances
in modern toxicology, Vol. 2, ed. by R.A.-Coyer and M.A. Mehlman.
Hemisphere Pub. Corp., John Wiley and Sons, New York.
Suter, K.E. 1975. Studies on the dominant-lethal and fertility
effects of the heavy metal compounds methymercuric hydroxide,
mercuric chloride and cadmium chloride in male and female mice.
Mut. Res. 30: 365.
Suzuki, S., et al. 1969. Dietary factors influencing upon reten-
tion rate of orally administered mCdC!2 in mice with special
reference to calcium and protein concentrations in diet. Ind.
Health. 7: 155.
Szadkowski, D., et al. 1969. Relation between renal cadmium
excretion, age and arterial blood pressure. Z. Klin. Chem. Bio-
chem. 7: 551.
Tsuchiya, K. 1970. Distribution of cadmium in humans in Kankyo
Hoken. Report No. 3. Japanese Association of Public Health.
U.S. EPA. 1978a. Health Assessment Document for Cadmium. Draft
No. 1, Environmental Protection Agency, Washington, D.C., May,
1978.
U.S. EPA. 1978b. Reviews of the Environmental Effects of Pollut-
ants: IV. Cadmium. EPA 600/1-78-026, 1978.
U.S. EPA. 1979. Cadmium: Ambient Water Quality. Criteria.
Environmental Protection Agency, Washington, D.C.
Voyer, R.A. 1975. Effect of dissolved oxygen concentration
on the acute toxicity of cadmium to te mummichog, Fundulus hetero-
clitus. Trans. Am. Fish. Soc. 104: 129. ~~
Wahlberg, J.E. 1965. Percutaneous toxicity of metal compounds
- A comparative investigation in guinea pigs. Arch. Environ.
Health. 11: 201.
109
Washko, P.W. and R.J. Cousins. 1976. Metabolism of Cd in
rats fed normal and low-calcium diets. Jour. Toxicol. and Environ.
Health. 1: 1055.
Watson, M.R. 1973. Pollution control in metal finishing. Noyes
Data Corp., Park Ridge, N.J.
*
Weast, R.C. . {ed.) 1975. Handbook of chemistry and physics,
56th ed. CRC Press, Cleveland.
-341-/-
-------
WHO Task Group. 1977. Environmental health aspects of cadmium.
World Health Organ., Geneva.
Willis, J., et al. 1976. Chronic and multi-generation toxicity
of cadmium for the rat and the Rhesus monkey. Environ. Qual.
Safety.
Worker, N.A. and B.B. Migicovsky. 1961. Effect of Vitamin D
on the utilization of zinc, cadmium and mercury in the chick.
Jour. Nutr. 75: 222.
-36.5--
-------
No. 32
Carbon Disulfide
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 irccacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
CARBON DISULFIDE
I. PHYSICAL AND CHEMICAL PROPERTIES
It is soluble in water at 0.294% at 20°C. It can chelate trace metals,
especially Cu and Zn. Its formula weight is 76.14 and it is a colorless,
volatile, and extremely flammable liquid at Rt. No odor when pure. At 27°C,
its vapor pressure is 200 mm Hg.
II.PRODUCTION AND USE
It is produced in pretroleum and coal tar refining. Its principal uses
are in the manufacture of rayon, rubber, chemicals, solvents, and pesticides.
2
In 1974, 782 million pounds of CS2 were produced in the United States. In
1971, 53% was used in production of viscose rayon and cellphane and 25% for
manufacture of CC,..
III. EXPOSURE
3 25
It was detected in 5 of 10 water supplies surveyed by the EPA. NIQSH
estimates that 20,000 employees are potentially exposed to CS- fulltime in the
United States.
III. PHARMACOKINETICS
A. Absorption: Absorption differs with species and route of administra-
4
tion.
B. Distribution: Large concentrations of both free and bound CS2 are
found in brain (guinea pig) and peripheral nerves (rats) of exposed animals.
The ratio of bound to free CS2 in brain is 3:1. Blood and fatty tissues
4
contain mainly bound CS« while liver contains mainly free.
C. Metabolism: It is 90% metabolized by the P-450 system to inorganic
sulfate. A portion of the S released by CS2 is thought to react with SH
groups of. cysteine residues in the microsomal protein to form hydro-sulfide.
M. Greenberg
. ECAO/RTP NC
-------
0. Excretion: Small amounts are excreted (0.5%) as thiourea, 5-mercapto-
thioazolidone, and inorganic constituents in urine. Some portion (8-10%) is
also excreted unchanged in the breath. Inhalation studies have shown that 18%
of the.CS2 inhaled is exhaled unchanged. Of the remaining inhaled dose, 70%
is excreted as free or bound CS- and urinary sulfates and 30% is stored in the
body and slowly excreted as CS- and its metabolites.
V. EFFECTS ON MAMMALS
4
A. Carcinoqenicity: No available data.
4
B. Mutagenicity: No available data.
8 3
C. Teratogenicity: Bariliah et al. showed that inhalation of 10 mg/m
was lethal to embryos before and after implantation. C$2 at 2.2 gm/m for 4
hr/day was embryotoxic if given to female rats during gestation and had no
Q
effect on male rats. Inhalation of lower concentrations (0.34 mg/1 for 210
days) caused disturbances of estrus. In a dominant lethal test, inhalation
3 8
of 10 mg/m by male rats before copulation proved lethal to.embryos.
D.
E. Toxicity
1. Humans
The lowest lethal concentration has been reported as 4,000 ppm in 30
minutes. In the same study, a person subjected to a concentration of 50
mg/m for 7 years had CNS.effects. Moderate chronic exposure of humans at
3 12
less than 65 mg/m for' several years has been reported by Cooper to cause
polyneuropathy. In a study by Baranowska et al. humans have been shown to
absorb 8.8-37.2 mg from an aqueous solution containing 0.33-1.67 q/1. This
was over a period of 1 hour of hand-soaking.
The most thoroughly documented studies on health effects of CS^ exposure
2g—29 26 27
have been on cardiovascular system. Heinberg et al. ' reported significantly
-------
elevated rates of coronary heart disease mortality, angina, and high blood
pressure. In a 5-year followup of these vicose rayon workers, he reported
again increased coronary heart disease mortality and higher than expected
incidences of total infarctions, nonfatal infarctions, angina. In an 8-year
followup in 1976, Heinberg found no excess coronary heart disease mortality
during the last 3 years of the followup.
2. Other species.
14
IP injection of 400 mg/hg was the lowest lethal dose in guinea pigs.
An IV LD50 of 694 mg/kg in mice was reported by Hylen and Chin.
With SC injection, LD50 was 300 mg/kg in rabbits. Toxic effects have
been observed at 1.7 mg/kg in rabbits. Rats showed toxic SC effects at 1
17 18 19
mg/kg. Oral doses in rats produce .Joxic effects at 1 mg/kg. ' Vinogradov
showed that 1 ppm in drinking water was nbntoxic to rabbits; 70 ppm was fatal.
21
In a chronic study, Paterni et al. found that 6 mg/kg/day produced
toxic effects in rabbits. The lowest lethal chronic dose for rabbits was
22
shown to be 0.1 ml 3 times a week fo,J7 months.
Applied topically, it produced a higher incidence of anemia in female than
23
in male rats and teratogenic effects were observed. When rats inhaled CS2
at 10 mg/m , abnormalities of genitourinary, and skeletal systems were found.
Disturbances of ossification and blood formation and dystrophic changes in
rt
liver and kidney were noted.
- 370-
-------
VI. EXISTING GUIDELINES AND STANDARDS
4
The NAS did not recommend limits for drinking water because estimates of
effects of chronic oral exposure cannot be made with any confidence.
24 3
The NIOSH recommended standard IS 3 mg/m .
Human studies have shown that exposure effects the cardiovascular system,
24
the nervous system, the eyes, the reproductive organs, and other systems.
25 3
The current federal standard is 20 ppm (62 mg/m ) with a ceiling
concentration of 30 ppm (93 mg/m ) for an 8-hour day, 5 day work week.
-371-
-------
REFERENCES
1. U.S. Environmental Protection Agency. Identification of organic compounds
in effluents from industrial sources, 1975.
2. U.S. International Trade Commission, Syn. Org. Chem., 1974.
3. U.S. Environmental Protection Agency. Preliminary Assessment of suspected
carcinogens in drinking water. Report to Congress. EPA 560-14-75-005 PB
260961, 1975.
4. NAS. Drinking Water and Health, 1977.
5. Oalve et al. Chem. Biol. Inter. 10:347-361, 1975.
6. Catiguani and Neal. BBRC 65(2):629-636, 1975.
.7. Theisinger. Am. Ind. Hyg. Assoc. 35(2):55-61, 1974.
8. Bariliah et al. -Anat. Gistol. Embriol. 68(5):77-81, 1975.
9. Sal'nikova and Chirkova. Gig. Tr. Prof. Zabol 12:34-37, 1974.
10. Rozewiski et al. Med. Pr. 24(2):133-139, 1973.
11. Registry of Toxic Effects of Chemical Substances, 1975.
12. Cooper. Food Cosmet. Toxicol. 14:57-59, 1976.
13. Baranowska et al. Ann. Acad. Med. Lodz 8:169-174, 1966. Chem. Abs.
70-.31443W, February 24, 1969.
14. Davidson and Feinlab. Am. Heart J. 83(1):100-114, 1972.
15. Hylin and Chen. Bull. Environ. Contam. Toxicol. 3(6):322332, 1968.
16. Merch Index, 1968.
17. Okamoto. Tokyo Jikeikai Ika Daigaku Zasshi 74:1184-1191, 1959.
18. Freundt et al. Int. Arch Arbeitsmed. 32:297-303, 1974.
19. Freundt et al. Arch. Toxicol. 32:233-240, 1974.
20. Vinogradov. Gig. Sanit. 31(1):13-18, 1966.
21. Paterm et al. Folia Med. 41:705-722, 1958.
22. Michalova et al. Arch. Gewerbepth Gewerbehgy 16:653-665, 1959.
-372-
-------
23. Gut. Prac. Lek. 21(10):453-458, 1969.
24. NIOSH. Criteria for a Recommended Standard CS-, May, 1977.
25. 29 CFR 1910, 1000.
26. Hernberg. Br. J. Ind. Med. 27:313-325, 1970.
27. Hernberg et al. Work Env. Health 8:11-16, 1971.
28. Hernberg et al. Work Env. Health 10:93-99, 1973.
29. Tolonen et al. Br. J. Ind. Med. 32:1-10, 1975.
30. Heinberg et al. Work Env. Health 2:27-30, 1976.
si
-373-
-------
No. 33
Carbon Tetrachloride (Tetrachlororaethane )
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.
-375-
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
carbon tetrachloride and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
CARBON TETRACHLORIDE
Summary
Carbon tetrachloride (CCl^) is a haloalkane with a wide range of in-
dustrial and chemical applications. Toxicological data for non-human mam-
mals are extensive and show that CC1. causes liver and kidney damage, bio-
chemical changes in liver function, and neurological damage.. CCl^ has
been found to induce liver cancer in rats and mice. Mutagenic effects have
not been observed and teratogenic effects have not been conclusively demon-
strated.
The data base on aquatic toxicity is limited. LCcg (96-hour) values
for bluegill range from 27,300 to 125,000 pg/1 in static tests. For Oaphnia
magna, the reported 48-hour EC5Q is 35,200 jug/1. The 96-hour LC5Q for
the tidewater silverside is 150,000 pg/1. An embryo-larval test with the
fathead minnow showed no adverse effect from carbon tetrachloride concentra-
tions up to 3,400 jug/1. No plant effect data are available. The bluegill
bioconcentrated carbon tetrachloride to a factor of 30 times within 21 days
exposure. The biological half-life in the bluegill was less than 1 day.
-•2,77-
-------
CARBON TETRACHLORIDE
I. INTRODUCTION
Carbon tetrachloride (CCl^) is a haloalkane with a wide range of in-
dustrial and chemical applications. Approximately 932.7 million pounds are
produced at 11 plant sites in the U.S. (U.S. EPA, 1977b; Johns, 1976). The
bulk of CC1. is used in the manufacture of fluorocarboris for aerosol pro-
pellants. Other uses include grain fumigation, a component in fire extin-
guisher solutions, chemical solvent, and a degreaser in the dry cleaning in-
dustry (Johns, 1976).
Carbon tetrachloride is a heavy, colorless liquid at room temperature.
Its physical/chemical properties include: molecular weight, 153.32; melting
point, -22.99°C; solubility in water, 800,000 jug/1 at .25°C; and vapor
pressure, 55.65 mm Hg at 10°C. CCl^ is relatively non-polar and misci^
ble with alcohol, acetone and most organic solvents.
Carbon tetrachloride may be quite stable under certain environmental
conditions. The hydrolytic breakdown of CC1 in water is estimated to re-
quire 70,000 years for 50 percent decomposition (Johns, 1976). This decom-
position is accelerated in the presence of metals such as iron (Pearson and
McConnell, 1975). Hydrolytic decomposition as a means of removal from water
is insignificant when compared with evaporation. In one experiment the
evaporative half-life of CCl^ in water at ambient temperatures was found
to be 29 minutes (Dilling, at al. 1975), but this is highly dependent on ex-
perimental conditions, such as surface area to bulk volume ratios. For ad-
ditional information regarding Halomethanes as a class, the reader is refer-
red to the Hazard Profile on Halomethanes (U.S. EPA, 1979b).
-------
II. EXPOSURE
A. Water
CC1. has been found in many water samples including rain, sur-
face, potable, and sea, in the sub-part per billion range (McConnell, et ai.
1975). The National Organics Monitoring Survey (NOMS) found CC14 in 10
percent of 113 public water systems sampled, with mean values ranging from
2.4-6.4jjg/l (U.S. EPA, 1977a).
Although CCl^ is a chlorinated hydrocarbon, it is 'not produced in
finished drinking water as a result of the chlorination process (Natl. Res.
Coun., 1977,1978).
3. Food
Carbon tetrachloride has been detected in a variety of foodstuffs
other than fish and shellfish in levels ranging from 1 to 20 ;jg/kg (McCon-
nell, et al. 1975).
Results of various studies on CC1, fumigant residues in food in-
dicate that the amount of residue is dependent upon fumigant dosage, storage
conditions, length of aeration and the extent of processing (U.S. EPA,
1979a). Usually, proper storage and aeration reduce CC1. residues to
trace amounts.
The U.S. EPA (1979a) has estimated the weighted average bioconcen-
tration factor for.carbon tetrachloride to be 69 for the edible portions of
fish and shellfish consumed by Americans. This estimate is based on measur-
ed steady-state bioconcentration studies in bluegills.
C. Inhalation
The occurrence of CC1. in the atmosphere is due largely to the
»
volatile nature of the compound. Concentrations of CC1, in continental
ana marine air masses range from .00078 - .00091 ma/m"5. Although some
Z'
-------
higher quantities (.0091 mg/m3) have been measured in urban, areas, concen-
trations of CC1. are universally widespread with little geographic varia-
tion (U.S. EPA, 1979a).
III. PHARMACQKINETICS
A. Absorption
CC1. is readily absorbed through the lungs, and more slowly
through the gastrointestinal tract (Nielsen and.Larsen, 1965). It can also
be absorbed through the skin. The rate and amount of absorption are enhanc-
ed with the ingestion of fat and alcohol (Nielson and Larson, 1965; Moon,
1950). Robbins (1929) found that considerable amounts of CC14 are absorb-
ed from the small intestine, less from the colon, .and little from the stom-
ach. Absorption from the gastorintestinal tract appears to vary by species,
i.e., it occurs more rapidly in rabbits than dogs.
B. Distribution
The organ distribution of GC1. varies with the route of adminis-
tration, its concentration, and the duration of exposure (U.S. EPA, 1979a).
After oral administration to dogs, Robbins (1929) found the highest
concentrations of CC1. in the bone marrow. The liver, pancreas and spleen
had one-fifth the amount found in the bone marrow. The highest concentra-
tions of CCl^ after inhalation, however, were found in the brain (Von Oet-
tingen, et al. 1949,1950). After inhalation of CC14 by monkeys, the high-
est levels were detected in fat, followed by liver and bone marrow (McColli-
ster, et al. 1950). McConnell, et al. (1975) found human tissue levels of
CCl^ to range as follows: kidney, 1-3 mg/1; liver, 1-5 mg/1 and fat, 1-13
mg/1.
On the cellular level, McClean, et al. (1965) found CC14 in all
cell fractions with higher concentrations in ribosomes.
-3SO-
-------
C. Metabolism
When CC1. is administered to mammals, it is metabolized to a
small extent, the majority being excreted through the lungs. The metabo-
lites include chloroform, hexachloroethane, and carbon dioxide. These meta-
.oolites play an important role in the overall toxicity of CCl^ (U.S. EPA,
1979a). Some of the CCl^ metabolic products are also incorporated into
fatty acids by the liver and into liver microsomal proteins and lipids (Gor-
dis, 1969).
The chemical pathology of liver injury induced by CCl^ is a re-
sult of the initial homolytic cleavage of the C-C1 bond which liberates tri-
chloromethyl- and chlorine-free radicals (Fishbein, 1976). The next step
may be one of two conflicting reactions: direct attack via alkylation on
cellular constituents (especially sulfhydryl groups), or peroxidative decom-
position of lipids of the endoplasmic reticulum as a key link between the
initial bond • cleavage and the pathological phenomena characteristic of
CC14 (Butler, 1961; Tracey and Sherlock, 1968).
D. Excretion
The largest portion of absorbed CC14 is rapidly excreted. Ap-
proximately 50-79 percent of absorbed radioactive CC14 is eliminated
through the lungs, and the remainder is excreted in the urine and faces. No
CCl^ was detected in the blood or in the expired air, 48 hours and 6 days,
respectively, after CC14 inhalation (Beamer, et al. 1950). CC1, is ex-
creted as 85 percent parent compound, 10 percent carbon dioxide, and smaller
quantities of other products including chloroform (NRC, 1977).
IV. EFFECTS
»
A. Carcinogenicity
CC14 has been shown to be carcinogenic in rats, mice, and ham-
sters via subcutaneous injection, intubation, and rectal instillation (U.S.
-------
EPA, 1979). Current knowledge lead to the conclusion that carcinogenesis is
a non-threshold, non-reversible process. However, some scientists do argue
that a threshold may occur.
Rueber and Glover (1970) administered injections of 1.3 ml/kg of
body weight of a 50 percent solution of CCl^ in corn oil to rats, two
times per week until death. Carcinoma of the liver were present in 12/15
(80 percent) .Japanese male rats, 4/12 (33 percent) Wistar rats, and 8/13 (62
percent) Osborne-Mendel rats, whereas Black Rats or Sprague-Oawley rats did
not develop carcinomas. The incidence of cirrhosis of the liver also dif-
fered with the strain of the rat. Carcinoma of the liver tended to develop
along with mild or moderate, rather than severe cirrhosis of the liver.
When administered with CC1,, methylcholanthrene (a potent enzyme inducer)
was found to increase the incidence of hyperplastic hepatic nodules and
early carcinomas in rats (Rueber, 1970). Females were found to be more sus-
ceptible to the development of hyperplastic nodules and carcinomas.
The National Cancer Institute (1976) studied the carcinogenic ef-
fect of.CCl^ in male and female mice (1,250 mg/kg or 2,500 mg/kg of body
weight, oral gavage 5 times/week/78 weeks). Hepatocellular carcinomas were
found in almost all of the mice receiving CC1,. Andervant and Dunn (1955)
transplanted 30 CC1.-induced tumors into mice. They observed growth in 28
of the hepatomas, through 4 to 6 transplant generations.
8. Mutagenicity
Conclusive evidence on the mutageniciity of CC14 has not been re-
ported. Kraemer, et al. (1976) found negative results•using the Ames- bac-
terial reversion tests. However, they explain that halogenated hydrocarbons
»
are usually negative in the Ames test.
-3*2-
-------
C. Teratogenicity
Very little data are available concerning the teratogenic effects
of CC1,. Schwetz, et al. (1974) found CC14 to be slightly embryotoxic,
Jf *+
and to a certain degree retarded fetal development, when administered to
rats at 300 or 1,000 mg/1 for 7 hr/day oh days 6 through 15 of gestation.
Bhattacharyya (1965) found that . subcutaneous injection occasionally gave
rise to changes in fetal liver.
0. Other Reproductive Effects
Pertinent data concerning other reproductive effects of CCl^ were
not encountered in the available literature.
E. Chronic Toxicity
Cases of chronic poisoning have been reported by Butsch (1932),
Wirtschafter (1933), Strauss (1954), Von Oettingen (1964), and others. The
clinical picture of chronic CCl^ poisoning is much less characteristic
than that of acute poisoning. Von Oettingen (1964) has done an excellent
..job of reviewing the symptoms. Patients suffering from this condition may
i -
/
complain of fatigue, lassitude, giddiness, anxiety, and headache. They suf-
~.3r from paresthesias and muscular twitchings, and show increased reflex ex-
citability. They may be moderately jaundiced, have a tendency to hypogly-
cemia, and biopsy specimens of the liver may show fatty infiltration. Pa-
tients may complain of a lack of appetite, nausea, and occasionally of diar-
rhea. In some instances, the blood pressure is lowered and is accompanied
by pain in the cardiac region and mild anemia. Other patients have develop-
ed pain in the kidney region, dysuria, and slight nocturia, and have had
urine containing small amounts of albumin and a few red blood cells. Burn-
#
ing of the eyes and, in a few instances, blurred vision are frequent com-
plaints of those exposed. If these symptoms are not pronounced, or of long
-333-
-------
standing, recovery usually takes place upon discontinuation of the exposure
if the proper treatment is received (Von Oettingen, 1964).
Reports on pathological changes in fatalities from CCl^ poison-
ings are generally limited to findings in the liver and kidneys. The brain
and lungs may be edematous. The intestines may be hyperemic and covered
with numerous petechial hemorrhages and the spleen may be enlarged and hy-
peremic. Occasionally the adrenal glands may show degenerative changes of
the cortex and the heart may undergo toxic myocarditis (Von Oettingen, 1964).
F. Other Relevant Information
The toxic effects of CCl^ are potentiated by both the habitual
and occasional ingestion of alcohol (U.S. EPA, 1979a). Pretreatment of lab-
oratory animals with ethanol, methanol_, or isopropanol increases the suscep-
tibility of the liver to CC14 (Wei, et al. 1971; Traiger and Plaa, 1971). -
Hafeman and Hoekstra (1977) reported that protective effects
against CCl.-induced lipid peroxidation are exhibited by vitamin E, sele-
nium, and methionine.
According to Davis (1934), very obese or undernourished persons or
those suffering from pulmonary diseases, gastric ulcers or a tendency to
vomiting, liver or. kidney diseases, diabetes or glandular disturbances, are
especially sensitive to the toxic effect of CCl.'CVon Oettingen, 1964).
V. AQUATIC TOXICITY
A. Acute Toxicity
Two studies have investigated the acute toxicity of carbon tetra-
chloride to bluegills (Leoomis macrochirus) in static tests. The determined
LC5Q varied from 27,300 )jg/l to 125,000 jjg/1 (Dawson, st al. 1977; U.S.
»
EPA, 1978). With Daohnia maana, the reported 48-hr. EC=0 is 35,200 jug/1
(U.S. EPA, 1978). The 96-hr. LCCQ for the tidewater silversides (Menidia
bervllina) is 150,000 ,ug/l (Oawson, et al. 1977).
-------
8. Chronic Toxicity
An embryo-larval test with the fathead minnow (Pimeohales promelas)
showed no adverse effect from carbon tetrachloride concentrations up to
3,400 jjg/1 (U.S. EPA, 1978). Other chronic data are not available.
C. Plant Effects
There are no data in the available literature describing the ef-
fects of carbon tetrachloride on freshwater or saltwater plants.
0. Residues
The bluegill bioconcentrated carbon tetrachloride to a factor of 30
times within 21 days. The biological half-life in these tissues was less
than 1 day.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979a), which are summarized below, have been reviewed; therefore, there is
a possibility that these criteria will be changed.
A. Human
The American Conference of Governmental Industrial Hygienists
' (1971) recommends a threshold limit value (TLV) of 10 mg/m for CC1 ,
with peak values not to exceed 25 mg/m even for short periods of time.
The Occupational Safety and Health Administration adopted the American Na-
tional Standards Institute (ANSI, 1967) standard Z37.17 - 1967 as the Feder-
al standard for CCl^ (29 CFR 1910.1000). This standard is 10 mg/m3 for
an 8-hour TWA, with an acceptable ceiling of 25 mg/m and a maximum peak
for 5 minutes in any 4-hour period of 200 mg/m .
The draft ambient water quality criteria for carbon tetrachloride
has been set to reduce the human carcinogenic risk levels to 10" , 10~°
or 10" (U.S. EPA, 1979a). The corresponding criteria are 2.6 jjg/1, 0.26
-------
ug/1, and 0.026 jjg/1, respectively. Refer to the Halomethane Hazard Profile
for discussion of criteria derivation (U.S. EPA, 1979b).
3. Aquatic
For carbon tetrachloride, the drafted criteria to protect fresh-
water aquatic life is 620 jjg/1 as a 24-hour average and the concentration
should never exceed 1,400 ug/1 at any time. To protect saltwater aquatic
life, the drafted criterion is 2,000 ug/1 as 24-hour average and the concen-
tration should not exceed 4,600 ug/1 at any time (U.S. EPA, 1979a).
-38-6-
-------
No. 34
Chloral
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.
-------
CHLORAL
Summary
Chloral (trichloroacetaldehyde) is used as an intermediate in the manu-
facture of DDT, methoxychlor, DDVP, naled, trichlorfon, and TCA. Chloral is
readily soluble in water, forming chloral hydrate. Chloral hydrate decom-
poses to chloroform with a half-life of two days. Chloral hydrate has been
used as a therapeutic agent due to its hypnotic and sedative properties.
Chloral (as chloral hydrate) has been identified in chlorinated water
samples at concentrations as high as 5.0 pg/l. Chloral hydrate is formed
through the chlorination of natural humic substances in the raw water. At-
mospheric chloral concentrations up to 273.5 mg/m3 have been reported from
spraying and pouring of polyurethanes in Soviet factories. Similar data on
exposure levels in U.S. plants were not found in the available literature.
Specific information on the pharmacokinetic behavior, carcinogenicity,
mutagenicity, teratogenicity, and other reproductive effects of chloral was
not found in the available literature. However, the pharmacokinetic be-
havior of chloral may be similar to chloral hydrate where metabolism to tri-
chloroethanol and trichloroacetic acid and excretion via the urine (and pos-
*
sibly bile) have been observed. Chloral hydrate produced skin tumors in A
of 20 mice dermally exposed. Information on the chronic or acute effects of
chloral in humans was not found in the available literature. Chronic ef-
fects from respiratory exposure to chloral as indicated in laboratory
animals include reduction of kidney function and serum transaminase activ-
ity, change in central nervous system function .(unspecified), decrease in
-------
antitoxic and enzyme-synthesizing function of the liver, and alteration of
morphological characteristics of peripheral blood. Slowed growth rate, leu-
kocytosis and changes in arterial blood pressure were also observed. Acute
oral LD5Q values in rats ranged from 0.05 to 1.34 g/kg.
U.S. standards and guidelines for chloral were not found in the avail-
able literature.
-390-
-------
CHLORAL
ENVIRONMENTAL FATE
Chloral (trichloroacetaldehyde) is freely soluble in water, forming
chloral hydrate (Windholz, et al. 1976). Chloral hydrate was identified in
drinking water from 6 of 10 cities sampled (Keith, 1976). The author postu-
lated that chloral hydrate was formed by the chlorination of other compounds
during the addition of chlorine to the water supplies. Chloral hydrate was
not identified prior to chlorination. Chloral hydrate may be formed by the
chlorination of ethanol or acetaldehyde and may occur as an intermediate in
the reaction involving the conversion of ethanol to chloroform as follows:
Ethanol - Acetaldehyde - Chloral - Chloral hydrate - Chloroform
Chloral hydrate decomposes to chloroform with a half-life of 2 days at pH 8
and 35°C (Luknitskii, 1975). Rook (1974) demonstrated the formation of
haloforms from the chlorination of natural humic substances in raw water.
Chloral polymerizes under the influence of light and in the presence of
sulfuric acid, forming a white solid trimer called metachloral (Windholz,
1976). Oilling, et al. (1976) studied the effects of chloral on the decom-
position rates of trichloroethylene, NO, and N02 in the atmosphere and ob-
served that- chloral increases the photodecomposition rate of trichloro-
ethylene to a greater extent than it does NO or N02.
-------
CHLORAL
I. INTRODUCTION
This profile is based on literature searches in Biological Abstracts,
Chemical Abstracts, MEDLINE, and TOXLINE.
Chloral [CI^CCHO], also referred to as trichloroacetaldehyde, anhy-
drous chloral, and trichloroethanol, is an oily liquid with a pungent, ir-
ritating odor. The physical properties of chloral are: molecular weight,
147.39; melting point, -57.5°C; boiling point, 97.75°C at 760 mm Hg;
density, 1.5121 at 20/4°C (Weast, 1976). The compound is very soluble in
water, forming chloral hydrate, and is soluble in alcohol and ether.
Industrial production of chloral involves direct chlorination of ethyl
alcohol followed by treatment with concentrated sulfuric acid (Stanford
Research Institute, 1976). Production may also occur by direct chlorination
of either acetaldehyde or paraldehyde in the presence of antimony chloride.
Prior to 1972, essentially all chloral produced was used in the manufacture
of DOT. Production of chloral was greatest in 1963 at 79.8 million pounds,
decreasing to 62.4 million pounds in 1969. Production data after 1969 were
not reported. Consumption of chloral for DDT manufacture was estimated at
25 million pounds in 1975, with an additional 500,000 pounds used in the
•»
manufacture of' other .pesticides, including methoxychlor, DDVP, naled, tri-
chlorfon, and TCA (trichloroacetic acid). Mel'nikov, et al. (1975) identi-
fied chloral as an impurity in chlorofos.
Chloral is also used In the production'of chloral hydrate, a thera-
peutic agent with hypnotic' and sedative effects used prior to the intro-
f
duction of barbituates. Production of U.S.P. (pharmaceutical) grade chloral
hydrate was estimated to be 300,000 pounds per year in 1575 (Stanford
Research Institute, 1976).
X
-------
II. EXPOSURE
Scitsov, et al. (1970) noted that chloral is evolved in spraying and
pouring of polyurethane. The authors reported chloral concentrations as
high as 273.5 mg/rrr in Soviet factories. Similar information on atmos-
pheric occupational exposure to chloral in Western countries was not found
in the available literature.
Chloral exposure from water occurs as chloral hydrate. Keith (1976)
reported chloral hydrate concentrations ranging from 0.01 ;ug/l to 5.0 ^ig/1
in chlorinated drinking water supplies of six of ten U.S. cities studied.
The mean concentration of chloral hydrate in drinking water for the six
cities was 1.92 jug/1.
Chloral hydrate has been used as a hypnotic, and sedative agent. Alco-
• .\
hoi synergistically increases the depressant effect of the compound, creat-
ing a potent depressant commonly referred to as "Mickey Finn" or "knockout
drops". Addiction to chloral hydrate through intentional abuse of the com-
pound has been reported (Goodman and Gillian, 1970).
III. PHARMACOKINETICS
A. Absorption ,• •) '
Specific information on the absorption of chloral was not found in
*
the available literature. Goodman and Gilman (1970) reported that chloral
hydrate readily penetrates diffusion barriers in the body.
8. Distribution
Specific information on the distribution of chloral was not found
in the available literature. Goodman and Gilman (1970), reporting on the
distribution of chloral hydrate from oral adminis.tration, noted its presence
in cerebrospinal fluid, milk, amniotic fluid, and fetal blood. The auth'ors
-------
noted that other investigators were unable to detect significant amounts of
chloral hydrate in the blood after oral administration (owing probably to
its rapid reduction).
C. Metabolism
Information on the metabolic reaction of chloral is obtained in-
directly through a metabolic study of trichloroethylene (Henschler, 1977).
The author reported that trichloroethylene oxidizes to a chlorinated epoxide
which undergoes molecular rearrangement to chloral, which is further metabo-
lized to either trichloroethanol or trichloroacetic acid. The 'rearrange-
ment, detected by in vivo studies, is hypothesized to occur by a catalytic
action of the trivalent iron of P-450.
Goodman and Oilman (1970) noted that chloral hydrate is reduced to
trich loroethanol in the liver and other tissues, including whole blood, with
the reaction catalyzed by alcohol dehydrogenase. Additional trichloro-
ethanol is converted to trichloroacetic acid. Chloral hydrate may be di-
rectly oxidized'to trichloroacetic acid in the liver and kidney.
D. Excretion
Both chloral and chloral hydrate are metabolized to trichloro-
ethanol or trichloroacetic acid (Goodman and Gilman, 1970; Henschler,
%
1977). Trichloroethanol is then conjugated and excreted in the urine as a
glucuronide (urochloralic acid) or is converted to trichloroacetic acid and
slowly excreted in the urine. The glucuronide may also be concentrated and
excreted in the bile. The fraction of the total dose excreted as trichloro-
ethanol, glucuronide, and trichloroacetic acid is quite variable, indicating
other possible routes of elimination.
-------
IV. EFFECTS
A. Carcinogenicity
Specific information on the carcinogenicity of chloral was not
found in the available literature. However, Keith (1976) reported skin
tumors in 4 of 20 mice dermally exposed to chloral hydrate (4 to 5 percent
solution in acetone). Further interpretation of the results and discussion
of the study methodology were not given.
3. Mutagenicity, Teratogenicity, and Other Reproductive Effects
Specific information on the mutagenicity,•teratogenicity, and re-
productive effects of chloral was not found in the available literature.
C. Chronic Effects
Rats receiving 0.1 mg/kg chloral exhibited a reduction of kidney
function and serum transaminase after seven months' exposure (Kryatov,
1970). No-physiological effects were observed in rats receiving 0.01 mg/kg
chloral for periods of seven months. The route of exposure was not reported.
Chronic respiratory exposure of rats and rabbits to chloral at 0.1
mg/1 (100 mg/m^) produced changes in central nervous system function, de-
creased antitoxic and enzyme synthesizing function of the liver, and altered
morphological characteristics of peripheral blood (Pavlova, 1975). Boitsov,
et al. (1970) reported slowed growth rate, leukocytosis, decreased albumin-
globulin ratio, and changes in arterial blood pressure and central nervous
system responses (unspecified) following prolonged respiratory exposure of
mice to chloral at 60 mg/m-'.
Goodman and Oilman (1970) reported gastritis, skin eruptions, and
parenchymatous renal injury in patients suffering from chronic chloral hy-
drate intoxication. Habitual use of chloral hydrate may result in the
-39.5-
-------
development of tolerance, physical dependence, and addiction. Death may oc-
cur either as a result of an overdose or a failure of the detoxification
mechanism due to hepatic damage.
F. Acute Toxicity
According to Hann and Jensen (1974), the human acute oral LDgn
of chloral is between 50 and 500 mg/kg.
Kryatov (1970) reported the following LD5Q values for chloral:
mice, 0.850 g/kg; rats, 0.725 g/kg; and guinea pigs, 0.940 g/kg. The routes
of exposure were not stated. Verschueren (1977) reported an oral LD50 for
rats of 0.05 to 0.4 g/kg, while Pavlov (1975) reported an acute oral LD5Q
of 0.94 and 1.34' g/kg for mice and rats, respectively. Pavlov (1975) also
reported inhalation LC5Q. values of 25.5 g/m3 and 44.5 g/m3 for mice
and rats, respectively. Boitsov, et al. (1970) reported an LD5Q Of 0.710
g/kg in mice. The route of exposure was not stated. Hawley (1971) reported
that chloral is a highly toxic, strong irritant and noted ingestion or in-
halation may be fatal. Information on acute toxic effects from occupational
exposure to chloral was not found in the available literature.
G. Other Relevant Information
Verschueren (1977) reported an odor threshold concentration of
chloral in water of 0.047 ppm. The author also reported an inhibition of
cell multiplication in Pseudomonas' sp. at a chloral hydrate concentration of
1.6 mg/1.
V. AQUATIC TOXICITY
A. Acute Toxicity
Verschueren (1977) reported inhibition' of cell multiplication in
Microcystis sp.- at 78 mg/1 chloral hydrate. Hann and Jensen (1974) rartked
the 96-hour Tl_m aquatic toxicity of chloral in the range from 1 to 10 ppm.
-------
8. Chronic Toxicity
Information on the chronic aquatic toxicity of chloral was not
found in the available literature.
C. Plant Effects
Shimizu, et al. (1974) reported chloral inhibited the growth of
rice stems by 63.4 percent relative to controls, but slightly stimulated
root growth. The concentration of chloral in water culture was not reported.
0. Residue
Keith (1976) identified chloral hydrate In chlorinated drinking
water in six of ten cities sampled. The sample locations and concentrations
of chloral hydrate identified were: Philadelphia, PA, 5.0 jug/1; Seattle,
WA, 3.5/jg/1; Cincinnati, OH, 2.0 ug/1; Terrebonne Parish, LA, 1.0 jug/1; New
York City, NY, 0.02 jug/1; Grand Forks, NO, 0.01 jug/1.
E. Other Relevant Information
Hann and Jensen (1974) ranked the aesthetic effect of chloral on
water as very low (zero), noting that the chemical neither pollutes waters
nor causes aesthetic problems.
VI. EXISTING GUIDELINES AND STANDARDS
Eoitsov, et al. (1970) reported a maximum recommended chloral concen-
tration in workroom air of 0.22 mg/1 (220 mg/nv5) (USSR). Kryatov (1970)
reported a maximum recommended permissible concentration in bodies of water
as 0.2 mg/1 (USSR). Verschueren (1977) reported a maximum allowable chloral
concentration of 0.2 mg/1 in Class I waters used for drinking, but the
nation applying this standard was not identified.
-------
References
Boitsov, A.N., et al. 1970. lexicological evaluation of chloral in the
process of its liberation during spraying and pourina of polyurethane
foams. Gig. Tr. Prof. Zabol. 14: 26. (Chemical Abstracts" CA 73:96934P).
Dilling, W.L., et al. 1976. Organic photochemistry-simulated atmopsheric
photodecomposition rates of methylene chloride, 1,1,1-trichloroethane, tri-
chloroethylene, tetrachloroethylene, and other compounds. Environ. Sci.
Techno 1. 10: 351.
Goodman, L.S. and A. Gilman. 1970. The Pharmacological Basis of Therapeu-
tics. The MacMillan Co., New York. p. 123.
Hann, R.W. and P.A. Jensen. 1974. Water Quality Characteristics of Hazard-
ous Materials. Texas A and M Univ., College Station, TX.
Haw ley, G.G. 1971. Condensed Chemical Oistionary, 8th ed. Von Nostrand
Reinhold Co., New York. p. 195.
Henschler, D. 1977. Metabolism and mutagenicity of halogenated olefins - a
comparison of structure and activity. Environ. Health Perspec. 21: 61.
Keith, L.H. (ed.) 1976. Identification and Analysis of Organic Pollutants
in Water. Ann Arbor Science Publishers, Inc., Ann Arbor, Michigan, p. 351.
Kryatov, I.A. 1970. Hygienic assessment of sodium salts of p-chlorobenzene
sulfate and chloral as contaminating factors in bodies of water. Gig.
Sanit. 35: 14. .(Chemical Abstracts CA 73:69048).
tuknitskii, F.I. 1975. The chemistry of chloral. Chem. Rev. 75: 259.
Mel'nikov, N.N., et al. 1975. Identification of impurities in technical
chlorofos. Khim. Sel'sk. Khoz. 13: 142. (Chemical Abstracts CA 82:165838K).
Pavlova, L.P. 1975. Toxicological characteristics of trichloroacetal-
dehyde. Tr. Azerb. Nauchno-Issled. Inst. Gig. Tr. Pro. Zabol. J.O: 99.
(Chemical Abstracts CA 87:19499611).
Rook, J.J. 1974. Formation of haloforms during chlorination of natural
waters. Water Treatment Exam. 23: 234.
Shimizu, K., et al. 1974. Haloacetic acid derivatives for controlling
Gramineae growth. Japan 7432,063 (Cl.A Oln) 27 Aug. 1974, Appl. 70 77, 535,
05 Sep. 1970 (Chemical Abstracts CA 82:81709F).
Stanford Research Institute. 1976. Chemical Economics Handbook. Stanford
Research Institute, Menlo Park, CA. p. 632.2030A.'
Verschueren, K. 1977. Handbook of Environmental Data on Organic Chem-
icals. Von Nostrand Reinhold Co., New York. p. 170.
-------
Weast, R.C. (ed.) 1976. Handbook of Chemistry and Physics. CRC Press,
Cleveland, OH. p. C-76.
Windholz, M., et al. 1576. The Merck Index. Merck and Co., Inc., Rahway,
N.J. p. 1,236.
-------
No. 35
Chlordane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION; AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-HOC-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
chlordane and has found sufficient evidence to indicate
that this compound is carcinogenic.
- s o 2 -
-------
CHLQRDANE '
Summary
Chlordane is an organochlorinated cyclodiene insecticide commonly used
as a formulation consisting of 24% trans-, 19% cis-chlordane, 10% hepta-
chlor, 21.5% chlordenes, 7% nonachlor, and 18.5% of other organochlorinated
material. Since heptachlor is also an insecticide and is more toxic than
chlordane, technical chlordane is generally more toxic than pure chlordane.
Pure chlordane, which is a cis/trans mixture of isomers, induces liver
cancer in mice and is mutagenic in some assays. Chlordane has not been shown
to be teratogenic. Little information is available on chronic mammalian
toxicity. Repeated doses of chlordane produced alterations in brain poten-
tials and changes in some blood parameters. Chlordane is a convulsant.
Chlordane and its toxic metabolite oxychlordane accumulate in adipose tissue.
Ten species of freshwater fish have reported 96-hr LC^g values rang-
ing from 8 to 1160 jjg/1. Freshwater invertebrates appear to be more resis-
tant to chlordane, with observed 96-hr' LC_n values ranging from 4 to 40
pg/1. Five species of saltwater fish have LC^ values of 5.5 to 160 ug/1,
and marine invertebrate LC5Q values range between 0.4 and 480 pg/1.
Chronic studies involving the bluegill Daphnia maona gave an LCCO of 1.6
— —-~— ^u
ug/i.
-------
CHLORDANE
INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Chlordane (U.S. EPA, 1979).
Chlordane is a broad spectrum insecticide of the group of organocnlori-
nated polycyclic hydrocarbons called cyclodiene insecticides. Chlordane has
been used extensively over the past 30 years for- termite control in homes
and gardens, and as a control for soil insects.
Pure Chlordane (1,2,4,5,6,7,8,8-octachloro-2,3,3a,4,7,7a-hexahydro-4,7-
methanoindene) is a pale yellow liquid having the empirical formula C,_-
Hx-Clg and a molecular weight of 409.8. It is composed of a mixture of
stereoisomers, with the cis- and trans- forms predominating, commonly refer-
red to as alpha- and gamma-isomers, respectively.) The solubility of pure
Chlordane in water is approximately 9 jug/1 at 25°C (U.S. EPA, 1979).
Technical grade Chlordane is a mixture of chlorinated hydrocarbons with
a typical composition of approximately 24 percent trans(gamma)-Chlordane, 19
percent cis(alpha)-chlordane, 10 percent heptachlor (another insecticidal
ingredient), 21.5 percent chlordene isomers, 7 percent nonachlor, and 18.5
percent closely related chlorinated hydrocarbon compounds. Technical chlor-
»
dane is a viscous, amber-colored liquid with a cedar-like odor. It has a
vapor pressure of 1 x 10" mm Hg -at 25°C. The solubility of ' technical
Chlordane in water is 150 to 220 pg/1 at 22°C (U.S. EPA, 1979).
Production of Chlordane was 10,000 metric tons in 1974 (41 FR 7559;
February 19, 1976). Both uses and production volume have declined exten-
sively since the issuance of a registration .suspension notice by the U.S.
EPA (40 FR34456; December 24, 1975) for all food, crop, home, and garden
-------
uses of chlordane. However, use of chlordane for termite control and limit-
ed usage (through 1980) as an agricultural insecticide are still permitted
(43 FR 12372; March, 1978).
Chlordane persists for prolonged periods in the environment (U.S. EPA,
1979). Photo-cis-chlordane can be produced in water and on plant surfaces
by the action of sunlight (Benson, et al. 1971) and has been found to be
twice as toxic as chlordane to fish and mammals (Ivie, et al. 1972; Podow-
ski, et al. 1979). Photo-cis-chlordane (5 ng/1) is accumulated more (ca.
20%) by goldfish (Carassius auratus) than chlordane (5 ng/1) itself (Ducat
and Khan, 1979).
Air transport of chlordane has been hypothesized to account for resi-
dues in Sweden (Jansson, et al. 1979). Residues in agricultural soils may
be as high as 195 ng/g-dry weight of soil (Requejo, et al. 1979).
II EXPOSURE
A. Water
Chlordane has been detected in finished waters at a maximum concen-
tration of 8 jjg/1 (Schafer, et al. 1969) and in rainwater (Sevenue, et al.
1972; U.S. EPA, 1976). There have been reports of individual household
wells becoming contaminated after a house is treated with chlordane for ter-
•»
mite control (U.S. EPA, 1979). A recent contamination of a municipal water
system has been discussed by Harrington, et al. (1978). Chlordane has also
been detected in rainwater (U.S. EPA, 1976).
B. Food
Chlordane has been found infrequently in food supplies since 1965,
when the FDA began systematic monitoring for chlordane (Nisbet, 1976). The
only quantifiable sample collected was 0.059 mg chlordane/kg measured! in a
sample of grain in 1972 (Manske and Johnson, 1975). In the most recently
-------
published results (for 1975), chlordane was not detected (Johnson and
Manske, 1977). Fish are thought to represent the most significant dietary
exposure. The average daily uptake -from fish is estimated at 1 jjg (Nisbet,
1976).
The U.S. EPA (1979) has estimated the weighted average bioconcen-
tration factor for chlordane to be 5,500 for the edible portions of fish and
shellfish consumed by Americans. This estimate was based on measured steady-
state bioconcentration studies in.the sheepshead minnow (Cyprinodon varieqa-
tus).
Eighty-seven percent of 200 samples of milk collected in Illinois
from 1971 to .1973 were positive for chlordane. The average, concentration
was 50 ug/1 (Moore, 1975 as. reviewed by Nat. Acad. Sci., 1977). Cyclo-
dienes, such as chlordane, apparently are ingested with forage and tend to
concentrate in lipids. Oxychlordane, a metabolite of chlordane and hepta-
chlor, was found in 46 percent of 57 human milk samples collected during
1973-74 in Arkansas and Mississippi. The mean value was 5 jug/1, and the
maximum was 20 ug/1 (Strassman and. Kutz, 1977).
C. Inhalation
In a survey of the extent of atmospheric contamination by pesti-
cides, air.was sampled .at nine localities representative of both'urban and
agricultural areas. Chlordane was. not detected in any samples (Stanley, et
al. 1971). In a larger survey, 2,479 samples were collected at 45 sites in
16 states. Chlordane was'detected in only two samples, with concentrations
of 84 and 204 ng/m (Nisbet, 1976). The vapor concentrations to which
spray operators are exposed have not been estimated.
-------
0. Dermal Effects ' •
Chlordane can be absorbed through, the skin to produce toxic effects
(Gosselin, et al.. 1976). Spray operators, Chlordane formulators and farmers
may be exposed. Chlordane has been known to persist for as long as two
years on the hands (Kazen, et al. 1974). Dermal LD5Q values in rats range
from 530 to 700 mg/kg (U.S. EPA, 1979).
III. PHARMACOKINETICS
A. Absorption
Gastrointestinal absorption of Chlordane'- in rats ranged from 6 per-
cent with a single dose to 10-15 percent with smaller daily doses (Barnett
and Dorough, 1974).
8. Distribution
In a study of the distribution of Chlordane and its metabolites
.using radioactive carbon, the levels of residues in the tissues were low,
except in the fat (Barnett and Dorough, 1974). Rats were fed 1, 5, and 25
mg chlordane/g in food for 56 days. Concentrations of Chlordane residues in
fat, liver, kidney, brain, and muscle were 300, 12, 10, 4, and 2 percent,
respectively, of the concentration in the diet. All residues declined
steadily for 4 weeks, at which time concentrations were reduced about 60
percent. During the next four weeks, residues declined only slightly.
C. Metabolism
Mammals metabolize Chlordane to oxychlordane, via 1,2-dichloro-"
chlordene which is about twenty times more toxic than the parent, compound
and persists in adipose tissue (Polen, et al. 1971; Tashiro and Matsumura,
1978; Street and 81au, 1972). Oxychlordane can degrade to form l-hydroxy-2-
*
cyclochlordenes, and l-hydroxy-2-chloro-2,3-epoxy-chlordenes (Tashiro and
Matsumura, 1973). In general, the metabolism of Chlordane takes place via a
-V07-
-------
series of oxidative enzyme reactions. None of the metabolic intermediates
(except for oxychlordane) and end products are more toxic than chlordane
(Barnett and Oorough, 1974; Tashiro and Matsumura, 1977; Mastri, et al.
1969). Trans-nonachlor, a major impurity in technical chlordene, is con-
verted to trans-chlordane in rats, but this is not important in humans.
This explains the fact that trans-nonachlor accumulates in humans but not in
rats (Tashiro and Matsumura, 1978). A very small amount of cis- or trans-
chlordane can be converted to heptachlor in rat liver (Tashiro and Matsu-
mura, 1977).
0. Excretion
Chlordane is primarily excreted in the feces of rats, only about
six percent of the total intake being eliminated in the urine. Urinary ex-
cr '"' ;n of chlordane in rabbits is greater than excretion in the feces (Nye
• .'
and Dorough, 1976).
The half-life of chlordane in a young boy was reported to be ap-
proximately 21 days (Curley and Garrettson, 1969), while for rats it was 23
day'VCBarnett and Dorough, 1974). The half-life of chlordane in the serum
of a young girl was 88 days (Aldrich and Holmes, 1969).
IV. - 'EFFECTS
A. Carcinogenicity
Hepatocellular carcinomas were, induced in both sexes of two strains
of mice fed pure (95%) chlordane (56.2 mg/kg) in the diet for 80 weeks (Na-
tional Cancer Institute, 1977; Epstein, 1976). In contrast to findings with
mice, a significantly increased incidence of hepatocellular carcinomas did
not appear in rats administered chlordane. Dosages were near the maximum
permissible (National Cancer Institute, 1977).
-------
8. Mutagenicity
Purs or technical chlordane induced unscheduled ONA synthesis in
the SV-40 transformed human fibroblast cell line VA-4. Metabolic activation
eliminated this effect (Ahmed, et al. 1977). .Chlordane did not induce muta-
tions in the dominant lethal assay in mice (Arnold, et al. 1977).
While neither pure cis-chlordane nor pure trans-chlordane was muta-
genic in the Ames Salmonella microsome assay, technical grade chlordane was
mutagenic. Microsomal activation did not enhance the mutagenic activity
(Simmon, et al. 1977).
C. Teratogenicity
Chlordane was found not to be teratogenic in rats when fed at con-
centrations of 150 to 300 mg/kg during gestation (Ingle, 1952).
D. Other Reproductive Effects
Pertinent data could not be located in the available literature.
E. Chronic Toxicity
There appears to be little information on chronic mammalian toxi-
city. Daily injections of 0.15 to 25 mg chlordane/kg in adult rats resulted
in dose-dependent alterations of brain potentials (Hyde and Falkenberg,
1976). As changes were directly related to length of exposure, it was con-
»
eluded that chlordane may be a cumulative neurotoxin. Length of exposure
was not specified. Repeated doses of chlordane given to gerbils produced
changes in serum proteins, blood glucose, and alkaline and acid phosphatase
activities (Karel and Saxena, 1976). Again, duration of treatment was not
specified.
F. Other Relevant Information
Carbon tetrachloride produced more extensive hepatocellular necro-
sis in chlordane-pretreated rats than in rats which were not pretreated
(Stenger, et al. 1975). Rats suffered greater cirrhosis when chlordane (50
-------
jjg/kg/day) exposure for ten weeks followed prior exposures of ten weeks for
carbon tetrachloride above (110 mg/1) or with chlordane (Mahon and Oloffs,
1979). Quail treated with chlordane followed by endrin had considerably
more chlordane residues in their brains than did quail treated with chlor-
dane alone (Ludke, 1976). Quail pretreated with 10 rug/kg chlordane exhibit-
ed decreased susceptibility to parathion (Ludke, 1977). Chlordane is a con-
vulsant and emetic. It induces twitching, seizures and electroencephalo-
graphic dysrhythmia in humans. Acute symptoms can be alleviated with pheno-
barbital. Acute oral LD5Q values for the rat range from 100 to 112 mg/kg
(U.S. EPA, 1979). The no observable effect level was found to be 2.5 mg/kg/
day over 15 days (Natl. Acad. Sci., 1977).
Chlordane inhibits growth of human viridans streptococci of the
buccal cavity. Complete inhibition of growth occurred at 3 ppm, and about
20 percent inhibition was seen at 1 ppm (Goes, et al. 1978).
V. AQUATIC TOXICITY
A. Acute Toxicity
Ten species of freshwater fish have reported 96-hr LC-n values
ranging from 8 to 1160 jjg/1 resulting from technical and pure chlordane
exposure with a geometric mean of 16 jjg/1. Rainbow trout, Salmo gairdneri
•>
(Mehrle, et al. 1974) was the most sensitive species tested, the channel
catfish (Ictalurus punctatus) the least sensitive. The freshwater inverte-
brates were more sensitive to chlordane, with a reported LC5Q value rang-
ing from 4.0 for freshwater shrimp Palaemonetes kadiakensis (Sanders, 1972)
to 40 /jg/1 (Gammarus fasciatus), with a geometric mean of 0.36.pg/l. In
goldfish (Carassius auratus), only 0.13 percent of cis-chlordane is metabo-
lized in 24 hours. Only 0.61 percent is converted after 25 days. Some
metabolites were chlordene chlorohydrin and monohydroxy derivatives (Feroz
and Khan, 1979).
/
- w/o-
-------
The LC50's for four species of saltwater fish, sheepshead minnows
(Cvprinodon verieqatus), striped bass (Morone saxatilis), pinfish (Lagodon
rhomboides), and white mullet (Mugil cursma), ranged from 5.5 to 24.5 pg/1.
The three-spine stickleback (Gasterosteus aculsatus) yielded 96-hr LC^Q
values which ranged from 90-160 pg/1 (Katz, 1961). Invertebrate LC.-n val-
ues ranged from 0.4 for the pink shrimp, Penaeus duorarum (Parrish, et al.
1976) to 480 pg/1. The geometric mean of the adjusted LC,-n values for in-
vertebrates was O.lSjug/1 (U.S. EPA, 1979).
Q. Chronic Toxicity
In a life cycle bioassay involving freshwater organisms, the chron-
ic values for. the bluegill Lepomis macrochirus (Cardwell, et al. 1977) was
1.6 jug/1. In two tests involving the sheepshead minnow, Cycrinodon variega-
tus, the chronic values were 0.63 ug/1 for the life cycle test (Parrish, et
al. 1978) and 5.49 ug/1 for an embryo-level test (Parrish, et al. 1976).
Many blood parameters (clotting time, mean corpuscular hemoglobin
and cholesterol level) are lowered after the teleost, Sacco-branchus fossil-
us, is exposed to 120 pg/1 of chlordane for 15 to 60 days (Verna, et al.
1979). Similar results were obtained in Labeo rohita at doses — 23 jag/1
after 30 to 60 day exposures (Bansal, et al. 1979).
C. Plant Effects • . *
A natural saltwater phytoplankton community suffered a 94 percent
decrease in productivity during a 4-hour exposure at 1,000 ug/1 (Butler,
1963).
0. Residues
In Oaphnia maana, chlordane was bioconcentrated 6,000-fold after
seven days' exposure and 7,400-fold by scuds (Hyallela azteca) after 55 days
of exposure (Cardwell, et al. 1977). After 33 days' exposure, the fresh-
- HI / -
-------
water alga (Oedeqonium sp.) bioconcentrated chlordane 98,000-fold; Physa
sp., a snail, concentrated it 133,000-fold (Sanborn,_et al. 1976). Equili-
brium bioconcentration factors for the sheepshead minnow ranged from 6,580
to 16,035 (Goodman, et al. 1978; Parrish, et al. 1976).
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The issue of the carcinogenicity of chlordane in humans is being
reconsidered; thus, there is a possibility that the criterion for human
health will be changed. Based on the data for qarcinogenicity in mice (Ep-
stein, 1976), and using the "one-hit" model, the U.S. EPA (1979) has esti-
mated levels of chlordane in ambient water which will result in risk levels
of human cancer as specified in the table below.
Exposure Assumptions Risk Levels and Corresponding Draft'Criteria
(per day)'
0 10-7 10-6 iQ-5
2 liters of drinking water 0 0.012 ng/1 0.12 ng/1 1.2 ng/1
and consumption of 18.7
grams fish and shellfish.
Consumption of fish and 0 0.013 ng/1 0.13 ng/1 1.3 ng/1
shellfish only.
The ACGIH (1977) adopted a time-weighted average value of 0.5
mg/m for chlordane, with a short-term exposure limit (15 minutes) of 2
mg/m .
A limit of 3 ;jg/l for chlordane in drinking water is suggested
under the .proposed Interim Primary Drinking Water Standards (40 FR 11990,
March 14, 1975).
s
Canadian Drinking Water Standards --(Dept. Natl. Health Welfare,
»
1968) limit chlordane to 3 jug/1 in raw water supplies.
-------
8. Aquatic
For chlordane, the proposed criterion to protect freshwater aquatic
life is 0.024 ;jg/l for a 24-hour average, not to exceed 0.36 jug/I at any
time (U.S. EPA, 1979). For saltwater aquatic species, the draft criterion
is 0.0091 jug/1 for a 24-hour average, not to exceed 0.18 ;jg/l at any time
(U.S. EPA, 1979).
-HJ3-
-------
CHLORDANE
REFERENCES
Ahmed, 'F.E., et al. 1977. Pesticide induced DNA damage
and its repair in cultured human cells. Mutat. Res. 42:
161.
Aldrich, F.D., and J.H. Holmes. 1969. Acute chlordane
intoxication in a child. Arch. Environ. Health 19: 129.
ACGIH. 1977. TLVs thresholds limit values for chemical
substances in workroom air adopted by the American Confer-
ence of Governmental Industrial Hygienists for 1977. Cincin-
nati, Ohio.
Arnold, D.W. , et al. 1977. Dominant lethal studies with
technical chlordane, HCS-3260, and heptachlor : heptachlor
epoxide. Jour. Toxicol. Environ. Health 2: 547.
Bansal, S.K., et al. 1979. Physiological dysfunction of
the haemopoletic system in a freshwater teleost, Rabeo ro-
hita, following chronic chlordane exposure. Part 1. Altera-
tions in certain haemotological parameters. Bull. Environ.
Contam. Toxicol. 22: 666.
Barnett, J.R., and H.W. Dorough. 1974. Metabolism of chlor-
dane in rats. Jour. Agric. Food Chem. 22: 612.
Benson, W.R.,
ducts: Their
Food Chem. 19:
et al. 1971. Chlordane photoalteration pro
preparation and identification. Jour. Agric
857.
Bevenue, A., et al. 1972. Organochlor ine pesticides in-
rainwater Oahu, Hawaii, 1971-72. Bull. Environ. Contam.
Toxicol. 8: 238. t
Butler, P. A., et al. 1963. Effects of pesticides on oy-
sters. Proc. Shell Fish. Assoc. 51: 23.
Cardwell, R.D., et al. 1977. Acute and chronic toxicity
of chlordane to fish and invertebrates. EPA Ecol. Res.
Ser., U.S. Environ. Prot. Agency, Duluth, Minn.
Curley, A., and L.K. Garrettson. 1969.
poisoning. Arch. Environ. Health 18: 211.
Acute chlordane
Department of National Health and Welfare. 1963. Canadian
drinking water standards and objectives. Ottawa, Canada.
Ducat, D.A-.and M.A.Q. Khan. 'L9Ti. Absorption and elimina-
tion of C-cis-chlordane and C-photo-cis-chlordane by
goldfish, Carassius auratus. Arch. Enviorn. Contam. 8: 409.
-HIM-
-------
Epstein, S.S. 1976. Carcinogenicity of heptachlor and
chlordane. Sci. Total Environ. 6: 103.
Feroz, M. , and M.A.Q. Khan. 1979. Fate of 14C-cis-chlor-
dane in goldfish, Carassius auratus. Bull. Enviorn. Contain.
Toxicol. 23: 64.
Goes, T.R., et al. 1978. In vitro inhibition of oral Viri-
dous streptococei by chlordane. Arch. Environ. Contam.
Toxicol. 7: 449.
Goodman, L. , et al. 1978. Effects of heptachlor and toxa-
phene on laboratory-reared embryos and fry of the sheepshead
minnow. Proc. 30th Annu. Conf. S.E. Assoc. Game Fish Comm.
Gosselin, R.E., et al. 1976. Clinical toxicology of commer-
cial products. 4th ed. Williams and Wilkdns Co., Baltimore,
Md.
Harrington, J.M., et al. 1978. Chlordane contamination
of a municipal water system. Environ. Res. 15: 155.
Hyde, K.M., . and R.L. Falkenberg. 1976. Neuroelectrical
disturbance as indicator of chronic chlordane toxicity.
Toxicol. Appl. Pharmacol. 37: 499.
Ingle, L. 1952. Chronic -oral toxicity of chlordane to
rats. Arch. Ind. Hyg. Occup. Med. 6: 357.
Ivie, G.W., et al. 1972. Novel photoproducts of heptachlor
epoxide, trans-chlordane and trans-nonachlor. Bull. Environ.
Contam. Toxicol. 7: 376.
Jansson, B., et al. 1979. Chlorinated terpenes and chlor-
dane components found in fish, guilleiuot and seal from
Swedish waters. Chemosphere 8: 181.
Johnson, R.D., and D.D. Manske. 1977. Pesticide and .other
chemical residues in total diet samples (XI). Pestic. Monitor.
Jour. 11: 116.
Karel, A.K. , and S.C.. Saxena. 1976. Chronic chlordane
toxicity: effect on blood biochemistry of Meriones hurrianae
Jerdon, the Indian desert gerbil. Pestic. Biochem. Physiol.
6: 111.
Katz, 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.
Kazen C., et al. 1974. Persistence of pesticides on ttie
hands of some occupationally exposed people. Arch. Environ.
Health 29: 315.
-------
Ludke, J.L. 1976. Organochlorine pesticide residues associ-
ated with mortality: additivity of chlordane and endrin.
Bull. Environ. Contam. Toxicol. 16: 253.
Ludke, J.L. 1977. DDE increases the toxicity of parathion
to coturnix quail. Pestic. Biochem. Physiol. 7: 28.
Mahon, D.C. , and P.C. Oloffs. 1979. Effects of subchronic
low-level dietary intake of chlordane on rats with cirrhosis
of the liver. Jour. Environ. Sci. Health 314: 227.
Manske, D.D., and R.D.. Johnson. 1975. Pesticide residues
in total diet samples (VIII). Pestic. Monitor. Jour. 9: 94.
Mastri, C., et al. 1969. Unpublished data. Iji 1970 evalua-
tion of some pesticide residues in food. Food Agric. Org.
United Nations/World Health Org.
Mehrle, P.M., et al. 1974. Nutritional effects on chlor-
dane toxicity in rainbow trout. Bull. Enviorn. Contam.
Toxicol. 2: 513
Moore, S., III. . 1975. Proc. 27th Illinois Custom Spray
Operators Training School. Urbana.
National Academy Science. 1977. Drinking water and health.
Washington, D.C.
National Cancer Institute. 1977. Bioassay of chlordane
for possible carcinogenicity. NCI-CG-TR-8.
Nisbet, I.C.T. 1976. Human exposure to chlordane, hepta-
chlor, and their metabolites. Contract WA-7-1319-A. U.S.
Environ. Prot. Agency.
Nye, D.E., and H.W. Dorough. 1976. Fate of insecticides
administered endotracheally,to rats. Bull. Environ. Contam.
Toxicol. 15: 291. *
Parrish, P.R., et al. 1976. Chlordane: effects on several
estuarine organisms. Jour. Toxicol. Environ. Health 1:
485.
Parrish, P.R., et al. 1978. Chronic toxicity of chlordane,
trifluralin and pentachlorophenol to sheepshead minnows
(Cyprinodon variegatus). EPA 600/3-78-010: 1. U.S. Environ.
Prot. Agency.
/•
Podowski, A.A., et al. 1979. Photolysis of heptachlor
and cis-chlordane and toxicity of their photoisomers to
animals. Arch. Environ. Contam. Toxicol. 8: 509.
Polen, P.3., et al. 1971. Characterization of oxychlor-
dane, animal metabolites of chlordane. Bull. Enviorn. Contam.
Toxicol. 5: 521.
-------
Requejo, A.G., et al. 1979. Polychlorinated biphenyls
and chlorinated pesticides in soils of the Everglades National
Park and adjacent agricultural areas. Environ. Sci. Technol.
13: 931.
Sanborn,. J.R., et al. 1976. The fate of chlordane and
toxaphene in a terrestrial-aquatic model ecosystem. Environ.
Entomol. 5: 533.
Sanders, H.O. 1972. Toxicity of some insecticides to four
species of malacostracan crustaceans. U.S. Dept. Interior.
Fish Wildlife Tech. p. 66, August.
Schafer, M.L., et al. 1969. Pesticides in drinking water.
Environ. Sci. Technol. 3: 1261.
Simmon, V.F., et al. 1977. Mutagenic activity of chemicals
identified in drinking water. Presented at 2nd Int. Conf.
Environ. Mutagens, Edinburgh, Scotland, July 1977.
Stanley, C.W., et al. 1971. Measurement of atmospheric
levels of pesticides. Environ. Sci. Technol. 5: 430.
Stenger, R.J., et al. 1975. Effects of chlordane pretreat-
ment on the hepatotoxicity of carbon tetrachloride. Exp.
Mol. Pathol. 23: 144.
Strassman, S.C., and F.W. . Kut'z. 1977. Insecticide residues
in human milk from Arkansas and Mississippi, 1973-74. Pestic.
Monitor. Jour. 10: 130.
Street, J.E., and S.E. Blau. 1972. Oxychlordane: accumu-
lation in rat adipose tissue on feeding chlordane isomers
or technical chlordane. Jour. Agric. Food Chem. 20: 395.
Tashiro, S. , and F. Matsumura. 1977. Metabolic routes
of cis- and trans-chlordane in rats. Jour. Agric. Food
Chem. 25: 872. •»
Tashiro, S., and F. Matsumura. 1978. Metabolism of trans-
nonachlor and related chlordane components in rat and man.
Arch. Enviorn. Contam. Toxicol. 7: 413.
U.S. EPA. 1976. Consolidated heptachlor/chlordane hearing.
Fed. Register 41: 7552.
U.S. EPA. 1979. Chlordane: Ambient Water Quality Criteria
(Draft).
Verna, S.R., et al. 1979. Pesticide induced haemotological
alterations in a freshwater fish Saccobranchus fossilis.
Bull. Environ. Contam. Toxicol. 22: 467.
-HI7-
-------
No. 36
Chlorinated Benzenes
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION-AGENCY
WASHINGTON, D.C. 2046O
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.
-------
CHLORINATED BENZENES
Summary
The chlorinated benzenes are a group of compounds with
a wide variety of physical and chemical characteristics
depending on the degree of chlorination. As chlorination
increases, the persistance of the compound in the environ-
ment increases. On chronic exposure liver and kidney changes
are noted, while the degree of toxicity increases with the
degree of chlorination. The chlorinated benzenes have not
been shown to be teratogens or mutagens. Only hexachloro-
benzene has been demonstrated to be carcinogenic in labora-
tory animals.
Aquatic toxicity data indicate a trend to increasing
toxicity with increasing chlorination for all species tested.
The bluegill for example, has the following 96-hour LC5Q
values; chlorobenzene, 15,900 jag/1; 1,2,4-tr ichlorobenzene
3,360 ug; 1,2,3 ,5-tetrachlorobenzene, 6,420 micrograms/Lf
1, 2, 4 , 5-tetrachlorbenzene 1,550 jag/1 and pentachlorobenzene ,
200 pg/1. Other freshwater and saltwater fish, invertebrates
and plants were generally less sensitive to chlorobenzenes
toxicity than the bluegill. The sheepshead minnow yielded
a chronic value of 14.5 ^tg/1 for I, 2 , 4 , 5-tetrachlorobenzene
in an embryo-level test. After 28 days /exposure, the biocon-
centration factor for the bluegill for pentachlorobenzene
and 1, 2 , 4 , 5-tetrachlorobenzene were 3,400 and 1,800, respec-
tively.
-M2.O-
-------
CHLORINATED BENZENES
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Chlorinated Benzenes (U.S. EPA, 1979).
This document will summarize the general properties of the
chlorinated benzenes. For further information on monochloro-
benzene, 1,2,4-trichlorobenzene, or hexachlorobenzene, refer
to the specific EPA/ECAO Hazard Profiles for these compounds.
For detailed information on the other chlorinated benzenes
refer to the Ambient Water Quality Document (U.S. EPA, 1979).
The chlorinated benzenes, excluding dichlorobenzenes,
are monochlorobenzene (CgH3Cl), 1,2,4-tr ichlorobenzene (CgH-jCl3),
1,3,5-trichlorobenzene (CgH^Cl,), 1, 2 ,3 , 4-tetrachlorobenzene
(CgH2Cl4), 1,2,3,5-tetrachlorobenzene (CgH2Cl4), 1,2,4,5-
Tetrachlorobenzene (CgH2Cl4), pentachlorobenzene (CgHClc),
and hexachlorobenzene (CCC1,;) . All chlorinated benzenes
b o
are colorless liquids or solids with a pleasant aroma.
The most important properties imparted by chlorine .to these
compounds are solvent power, viscosity, and moderate chemi-
•»
cal reactivity. Viscosity and nonflammability tend to in-
crease from chlorobenzene to the more highly chlorinated
benzenes. Vapor pressures and water solubility decrease
progressively with the. degree of chlorination (U.S. EPA,
1979) .
The current production, based on annual production
»
in the U.S., was 139,105 kkg of monochlorobenzene in 1975,
* t
12,849 kkg of 1,2,4-trichlorobenzene, 8,182 kkg of 1,2,4,5-
^ *s * ^
-------
tetrachlorobenzene and 318 kkg of hexachlorobenzene in 1973
(West and Ware, 1977; EPA, 1975a). The remaining chlori-
nated benzenes are produced mainly as by-products from the
production processes for the above four chemicals. Chlori-
nated benzenes have many and diverse uses in industry depend-
ing upon the individual properties of the specific compound.
Some uses are as solvents, chemical intermediates, flame
retardants, and plasticizers.
II. EXPOSURE
A. Water
Mono-, tri-, and hexachlorobenzene have been de-
tected in ambient water. Because of its high volatility,
monochlorobenzene has a short half-life of only 5.8 hours
(Mackay and Leinonen, 1975). However, hexachlorobenzene
has an extremely long residue time in water, appearing to
be ubiquitous in the aqueous environment. Monochloroben-
zene has been detected in "uncontaminated" water at levels
of 4.7 p.g/1. Both trichlorobenzene and hexachlorobenzene
have been detected in drinking waters at concentrations
•»
of 1.0 ug/1 and 4 to 6 ng/1 respectively (U.S. EPA, 1979).
There is no information available on the concentration of
the other chlorinated benzenes in water.
B. Food
There is little data on the consumption of chlorin-
f
ated benzenes in food. All the chlorinated benzenes appear
to concentrate in fat, and are capable of being absoroed
-------
by the plants from contaminated soil. Both pentachloroben-
zene and hexachlorobenzene have been detected in meat fat
(e.g. Stijve, 1971; Ushio and Doguchi, 1977). Hexachloro-
benzene, the most extensively studied compound, has been
found in a wide variety of foods from cereals to milk (includ-
ing human breast milk), eggs, and meat. The U.S. EPA (1979)
has estimated the weighted bioconcentration factor of the
following chlorinated benzenes:
Weighted
Chemical bioconcentration factor
monochlorobenzene 13
1,2,4-trichlorobenzene 290
1,2,4,5-tetrachlorobenzene 1,000
pentachlorobenzene 7,800 •
hexachlorobenzene 12,000 .. ;
These estimates were based on the octanol/water parti-
tion coefficient of the chlorinated benzenes.
C. Inhalation .s
>,
There is no available data on the concentration
of chlorinated benzenes in ambient air with the e>. .l-ption
of measurements of aerial fallout of particulate bound 1,2,4-
trichlorobenzene in southern California. Five sampling
sites showed median levels of 1,2,4-trichlorobenzene of
less than 11 ng/m2/day (U.S. EPA, 1979). The primary site
of inhalation exposure to chlorinated benzenes is the work-
place in industries utilizing and/or producing these compounds.
III. PHARMACOKINETICS
A. Absorption
There is little data on the absorption of orally
administered chlorinated benzenes. It is apparent from
2
-H23-
-------
the toxicity of orally administered compounds that absorp-
tion does take place, and tetrachlorobenzene has been shown
to be absorbed relatively efficiently by rabbits (Jondorf,
et al. 1958). Pentachlorobenzene was absorbed poorly after
subcutaneous injection (Parke and Williams, 1960). Hexa-
chlorobenzene was absorbed poorly from an orally administered
aqueous solution (Koss and Kornasky, 1975), but with high
efficiency when administered in oil (Albro and Thomas, 1974).
The more highly chlorinated compounds in food products will
selectively partition into the lipid portion and be absorbed
far better than that in an aqueous medium (U.S. EPA, 1979).
A. Distribution
The chlorinated benzenes are lipophilic, compounds
with greater lipophilic tendencies in the more highly chlor-
inated compounds. The predominant disposition site is either
suspected to be, or shown to be, in the lipid tissues of
the body (Lee and Metcalf, 1975; U.S. EPA, 1979).
C. Metabolism
The chlorinated benzenes are metabolized -in the
liver by the NADPH-cytochrome P-448 dependent microsomal
enzyme system (Ariyoshi, et al. 1975; Koss, et al. 1976).
At least for monochlorobenzene, there is evidence that toxic
intermediates are formed during metabolism (Kohli, et al.
1976). Various conjugates and phenolic derivatives are
the primary excretory end products of chlorinated benzene
metabolism. In the more highly chlorinated compounds, such'
as hexachlorobenzene, conjugates are formed to only a limited
extent, and metabolism is relatively slow.
-------
D. Excretion
The less-chlorinated benzenes are excreted as
polar metabolites or conjugates in the urine. An exception
occurs with monochlorobenzene where 27 percent of an admin-
istered dose appeared as unchanged compounds in the expired
air of a rabbit (Williams, 1959). The two highly chlorinated
compounds, pentachlorobenzene and hexachlorobenzene, are
eliminated predominately by fecal excretion as unchanged
compounds (Koss and Koransky, 1975; Rozman, et al. press) .
The biological half -lives of these two compounds are extremely
long in comparison to that of the less-chlorinated compounds
(U.S. EPA, 1979) .
IV. EFFECTS
A. Carcinogencity
Mono- and tetrachlorobenzene have not been in-
vestigated for carcinogenic potential (U.S. EPA, 1979).
In one study, trichlorobenzene was not shown to produce
any significant increase in liver tumors (Gotto, et al.
1972) . There is one report, which was not critically evalu-
»
ated by U.S. EPA (1979), which alludes to the carcinogencity
of pentachlorobenzene in mice and the absence of this activity
in rats and dogs (Preussman, 1975) . Life-time feeding studies
in hamsters (Cabral, et al. 1977) and mice (Cabral, et al.
1978) have demonstrated the carcinogenic activity of hexa-
chlorobenzene. However, shorter term studies failed to
demonstrate an increasd tumor incidence in strain A mice
or ICR mice (Theiss, et al. 1977; Shirai, et al. 1978).
-H2S-
-------
B. Mutagenicity
There are no available studies conducted to evalu-
ate the mutagenic potential of mono-, tri-, tetra-, and
pentachlorobenzene (U.S. EPA, 1979). Hexachlorobenzene
was assayed for mutagenic activity in the dominant lethal
assay, and shown to be inactive (Khera, 1974) .
C. Teratogenicity
There are no available studies conducted to evalu-
ate the teratogenic potential of mono-, tri-, tetra-, and
pentachlorobenzene (U.S. EPA, 1979). Khera (1974) concluded
hexachlorobenzene was not a teratogen when given to CD-I
mice at 50 mg/kg/day on gestation days from 7 to 11.
D. Other Reproductive Effects
Hexachlorobenzene can pass through the placenta
and cause fetal toxicity in rats (Grant, et al. 1977).
The distribution of .hexachlorobenzene in the fetus appears
to be the same in the adult, with the highest concentration
in fatty tissue.
E. Chronic Toxicity
There is no available data on the chronic effects
of pentachlorobenzene (U.S. EPA, 1979). Mono- and trichloro-
benzene produce histological changes in the liver and kidney
(Irish, 1963; Coate, et al. 1977). There is also some evi-
dence for liver damage occurring with prolonged exposure
of rats and dogs to tetrachlorobenzene (.Fomenko, 1965; Braun,
»
et al. 1978). Hexachlorobenzene has caused histological
changes in the livers of rats (Koss, et al. 1978). In humans
-------
exposed to undefined amounts of hexachlorobenzene for an
undetermined time, porphyrinuria has been shown to occur
(Cam and Nigogosyan, 1963).
F. Other Relevant Information
Chlorinated benzenes appear to increase the activity
of microsomal NADPH-cytochrome P-450 dependent enzyme systems.
Induction of microsomal enzyme activity has been shown to
enhance the metabolism of a wide variety of drugs, pesticides
and other xenobiotics (U.S. EPA, 1979).
V. AQUATIC TOXICITY
A. Acute Toxicity
The dichlorobenzenes are covered in a separate
EPA/ECAO hazard profile and will not be covered in this
discussion on chlorobenzenes.
All data reported for freshwater fish are from
96-hour static toxicity tests. Pickering and Henderson
(1966) reported 96-hour LC5Q values for goldfish, guppys
and bluegills to be 51,620, 45,530, and 24,000 jjg/1, respec-
tively, for chlorobenzene. Two 96 hour LCcQ values for ,
chlorobenzene and fathead minnows are 33,930 pg/1 in salt-
water and 29,120 pg/1 in hard water. Reported 96-hour values
for the bluegill exposed to chlorobenzene, 1,2,4-trichloro-
benzene, 1,2,3,5-tetrachlorobenzene, 1,2,4,5-tetrachloro-
benzene and pentachlorobenzene are 15,900, 3,360, 6,420,
1,550 and 250 ug/1, respectively (U.S. EPA, 1978). These
«
data indicate a trend to increasing toxicity with chlorina-
tion, except for 1,2,3,5-tetrachlorobenzene (U.S. EPA, 1973).
- 427-
-------
EC5Q (48 hour) values reported for Daphnia magna are: chloro-
benzene 86,000 pg/1, 1,2,4-trichlorobenzene 50,200 pg/1,
1,2,3,5-tetrachlorobenzene 9,710 pg/1, and pentachlorobenzene
5,280 pg/1 (U.S. EPA, 1978).-
Toxicity tests with the sheepshead minnow, Cypri-
nodon variegatus, performed with five chlorinated benzenes
under static conditions and yielded the following 96-hour
LC5Q values: chlorobenzene 10,500 pg/1, 1,2,4-tr ichloroben-
zene 21,400 pg/1, 1,2,3,5-tetrachlorobenzene 3,670 ,ug/l,
1,2,4,5 tetrachlorobenzene 840 pg/1, and pentrachlorobenzene
835 pg/1 (U.S. EPA, 1978). As with sheepshead minnows,
sensitivity of the mysid shrimp, Mysidopsis bahia, to chlori-
nated benzenes generally increases with increasing chlorina-
tion. The reported 96-hour LC5Q values are as follows:
chlorobenzene 16,400 pg/1, 1,2,4-tr ichlorobenzene 450 ug/1,
1,2,3,5-tetrachlorobenzene 340 pg/1, 1,2,4,5-tetrachloro-
benzene 1,480 pg/1, and 160 pg/1 for pentachlorobenzene
(U.S. EPA, 1979).
B. Chronic Toxicity
-»
Chronic toxicity data are not available for fresh-
water fish or invertebrate species. Only one saltwater
species, Cyprinodon yeriegatus, has .been chronically exposed
to any of the chlorinated benzenes. In an embryo-level
test, the-limits for 1,2,4,5-tetrachlorobenzene are 92 to
180 pg/1, with a final chronic value of..64.5 pg/1 (U.S.
EPA, 1978).
-------
C. Plant Effects
The green freshwater algae Selenastrum capricornutum
has been exposed to five chlorinated benzenes. Based on
cell number, the 96-hour HC-Q values are as follows: chloro-
benzene 220,000 p.q/1, 1, 2,4-trichlorobenzene 36,700 ^g/1,
1,2,3,5-tetrachlorobenzene 17,700 jig/1, 1, 2,4 , 5-tetrachloro-
benzene 46,800 /jg/1, and pentachlorobenzene 6,780 ;ag/l.
D. Residues
No measured bioconcentration factor (BCF) is avail-
able for chlorobenzenes. However, the average weighted
BCF of 13 was calculated from octanol-water partition coeffi-
cient and other factors. (U.S. EPA, 1979).
VI. EXISTING GUIDLINES 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
Monochlorobenzene: The American Conference of
i
Governmental Industrial Hygienists (ACGIH, 1971) threshold
limit value for monochlorobenzene is 350 mg/m . The U.S.
EPA draft ambient water quality criterion for monochloro-
benzene is 20/pg/l based on the threshold concentration
for odor and taste (U.S. EPA, 1979).
Trichlorobenzene: The American Conference of
Governmental Industrial Hygienists (ACGIH, 1977) threshold '
limit value for 1,2,4-trichlorobenzene is 40 mg/m (5 ppm).
-------
The U.S. EPA (1979) draft ambient water quality criterion
for 1, 2, 4-tr ichlorobenzene is 13 pg/1 based on the threshold
concentration for odor and taste.
Tetrachlorobenzene: The U.S. EPA (1979) draft
ambient water quality criterion for tetrachlorobenzene is
17 jig/1.
Pentachlorobenzene: The U.S. EPA (1979) draft
ambient water quality criterion for pentachlorobenzene is
0.5 ug/1.
Hexachlorobenzene : The value of 0.6 ug/kg/day
hexachlorobenzene was suggested by FAO/WHO as a reasonable
upper limit for residues in food for human consumption (FAO/WHO,
1974). The Louisiana State Department of Agriculture has
set the tolerated level of hexachlorobenzene in meat fat
a 0.3 mg/kg (U.S. EPA, 1976). The FAO/WHO recommendations
for residues in foodstuffs were 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 cancer bioassy 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 Criteria
(per day) ~ _? _6 _s
0 10 ' 10 ° 10 3
2 liters of drinking water 0 O.OL25 ng/1 0.125 ng.l 1.25 ng/1
and consumption of 18.7
grams fish and shellfish.
Consumption of fish and 0 0.126 ng/1 0.126 ng/1 1.26 ng/1
shellfish only.
-M30-
-------
B. Aquatic
The drafted criteria to protect freshwater aquatic
life as is follows: (U.S. EPA, 1979)
Compound
Chlorobenzene
1,2,4-trichlorobenzene
1,2,3,5-tetrachlorobenzene
1,2,4,5-tetrachlorobenzene
Pentachlorbenzene
Concentration not to
be exceeded at anytime
3,500
470
390
220
36
The drafted criteria to protect saltwater aquatic
life are as follows: (U.S. EPA, 1979)
Comoound
Chlorobenzene
1,2,4-Trichlorobenzene
1,2,3,5-Tetrachlorbenzene
1,2,45-Tetrachlorobenzene
Pentachlorobenzene
24-hr.
Average
Jig/1
120
3.4
2.6
9.6
1.3
Concentration not to
be exceeded at anytime
ug/1
280
7.8
5.9
26
2.9
-------
CHLORINATED BENZENES
REFERENCES
Albro, P.W., and R. Thomas. 1974. Intestinal absorption of hexachloroben-
zene and hexachlorocyclohexane isomers in rats. Bull. Environ. Contam.
Toxicol. 12: 289.
American Conference of Governmental Industrial Hygienists. 1971. Documen-
tation of the threshold limit values for substances in workroom air. 3rd ed.
Ariyoshi, T., et al. 1975a. Relation between chemical structure and acti-
vity. I. Effects of the number of chlorine atoms in chlorinated benzenes on
the components of drug metabolizing systems and hepatic constituents. Chem.
Pharm. Bull. 23: 817.
Braun, W.H., et al. 1978. Pharmacokinetics and toxicological evaluation of
dogs fed 1,2,4,5-tetrachlorobenzene in the diet for two years. Jour. Envi-
ron. Pathol. Toxicol. 2: 225.
Cabral, J.R.P., et al. 1977. Carcinogenic activity of hexachlorobenzene in
hamsters. Nature (London) 269: 510.
Cabral, J.R.P., et al. 1978. Carcinogenesis study in mice with hexachloro-
benzene. 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.
Coate, W.B., et al. 1977. Chronic inhalation exposure of rats, rabbits and
monkeys to. 1,2,4-trichlorobenzene. Arch. Environ. Health. 32: 249.
Fomenko, v.N. 1965. Determination of the maximum permissible concentration
of tetrachlorobenzene in water basins. Gig. Sanit. 30: 8.
Food and Agriculture Organization. 1974. 1973 evaluations of some pesti-
cide residues in food. FAO/AGP/1973/M/9/1; WHO Pestic. Residue Ser. 3.
World Health Org., Rome, Italy, p. 291. *
Gotto, M., et al. 1972. Hepatoma formation in mice after administration of
high doses of hexachlorocyclohexane isomers. Chemosphere 1: 279.
Grant, D.L., et al. 1977. Effect of hexachlorobenzene on reproduction in
the rat. Arch. Environ. Contam. Toxicol. 5: 207.
Irish, D.D. 1963. Halogenated hydrocarbons: II. Cyclic. In Industrial Hy-
giene and Toxicology, Vol. II, 2nd ed., F.A. Patty, (ed.) Interscience, New
York. p. 1333.
Jondorf, W.R., et al. 1958. Studies in detoxication. The metabolism of
halogenobenzenes 1,2,3,4-, 1,2,3,5- and 1,2,4,5-tetrachlorobenzenes. Jour.
Biol. Chem. 69: 189.
-------
Khera, K.S. 1974. Teratogenicity and dominant lethal studies on hexa-
chlorobenzene in rats. Food Cosmet. Toxicol. 12: 471.
Kohli, I., et al. 1976. The metabolism of higher chlorinated benzene iso-
mers. Can. Jour. Biochem. 54: 203.
Koss, G., and W. Koransky. 1975. Studies on the toxicology of hexachioro-
benzene. I. Pharmacokinetics. Arch. Toxicol. 34: 203.
Koss, G., et al. 1976. Studies on the toxicology of hexachlorobenzene.
II. Identification and determination of metabolites. Arch. Toxicol.
35: 107.
Koss, G., et al. 1978. Studies on the toxicology of hexachlorobenzene.
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.
Mackay, D., and. P.J. Leinonen. 1975. Rate of evaporation of low-solubility
contaminants from water bodies to atmosphere. Environ. Sci. Technol.
9: 1178.
Parke, O.V., and R.T. Williams. 1960. Studies in detoxification LXXXI.
Metabolism of halobenzenes: (a). Penta- and hexachlorobenzene: (b) Further
ob- servations of 1,3,5-trichlorobenzene. Biochem. Jour. 74: 1.
Parrish, P.R., et al. 1974. Hexachlorobenzene: effects on several estua-
rine animals. Pages 179-187 In: Proc. 28th Annu. Conf. S.E'. Assoc. Game
Fish Comm.
Pickering, Q.H., and C. Henderson. 1966. Acute toxicity of some important
petrochemicals to fish. Jour. Water Pollut. Control Fed. 38: 1419.
Preussmann, R. 1975. Chemical carcinogens in the human environment. Hand.
Allg. Pathol. 6: 421.
Rozman, K., et al. Metabolism and pharmacokinetics of penta- chlorobenzene
in rhesus monkeys. Bull. Environ. Contam. Toxicol. (in press)
Shirai, T., et al. 1978. Hepatocarcinogenicity of polychlorinated ter-
phenyl (PCT) in ICR mice and its enhancement by hexachlorobenzene (HCB).
Cancer Lett. 4: 271.
Stijve, T. .1971. Determination and occurrence of hexachlorobenzene resi-
dues. Mitt. Geb. Lebenmittelunters. Hyg. 62: 406.
Theiss, J..C., et al. 1977. Test for carcinogenicity of organic contami-
nants of United States drinking waters by pulmonary tumor resopnsa in strain
A mice. Cancer Res. 37: 2717.
yi
-------
U.S. EPA. 1975. Survey of Industrial Processing Data: Task I, Hexachloro-
benzene and nexachlorobutadiene pollution from chlorocarbon processes. Mid.
Res. Inst. EPA, Off. Toxic Subs. Contract, Washington, O.C.
U.S. EPA. 1976. Environmental contamination from hexachlorobenzene. EPA-
560/6-76-014. Off. Tox. Subst. 1-27.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. U.S. Environ. Prot. Agency, Contract No. 68-01-
4646.
U.S. EPA. 1979. Chlorinated Benzenes: Ambient Water Quality Criteria
Document. (Draft)
Ushio, F., and M. Doguchi. 1977. Dietary intakes of some chlorinated
hydrocarbons and heavy metals estimated on the experimentally prepared
diets. Bull. Environ. Contam. Toxicol. 17: 707.
West, W.L., and S.A. Ware. 1977. Preliminary Report, Investigation of
Selected Potential Environmental Contaminants: Halogenated Benzenes. Envi-
ron. Prot. Agency, Washington, D.C.
Williams, R.T. 1959. The metabolism of halogenated aromatic hydrocarbons.
Page 237 I.n: Detoxication mechanisms. 2nd ed. John Wiley and Sons, New
York. v )
-H3H-
-------
No. 37
Chlorinated Ethanes
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.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (GAG) has evaluated
chlorinated ethanes and has found sufficient evidence to
indicate that this compound is carcinogenic.
-------
CHLORINATED ETHANES
SUMMARY
Four of the chlorinated ethanes have been shown to
produce tumors in experimental animal studies conducted
by the National Cancer Institute (NCI). These four are
1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetra-
chloroethane, and hexachloroethane. Animal tumors were
also produced by administration of 1,1,1-trichloroethane,
but this bioassay is being repeated due to premature deaths
in one initial study.
Two of the chlorinated ethanes, 1,2-dichloroethane
and 1,1,2,2-tetrachloroethane, have shown mutagenic activity
in the Ames Salmonella assay and in E. coli. 1,2-Dichloroethane
has also shown mutagenic action in pea plants and in Drosophila.
No evidence is available indicating that the chloroethanes
produce teratogenic effects. Some toxic effects on fetal
development have been shown following administration of
1,2-dichloroethane and hexachloroethane.
Symptoms produced by toxic exposure to the chloroethanes
include central nervous system disorders, liver and kidney
damage, and cardiac effects.
Aquatic toxicity data for the effects of chlorinated
ethanes to freshwater and marine life are few. Acute studies
have indicated that hexachloroethane is the most toxic of
the chlorinated ethanes reviewed. Marine organisms tend
to be more sensitive than freshwater organisms with acute
toxicity values as low as 540 ug/1 being reported.
-------
CHLORINATED ETHANES
I. INTRODUCTION
.This profile is based on the draft Ambient Water Quality
Criteria Document for Chlorinated Ethanes (U.S. EPA, 1979).
The chloroethanes (see table 1) are hydrocarbons in
which one or more of the hydrogen atoms have been replaced
by chlorine atoms. Water solubility and vapor pressure
decrease with increasing chlorination, while density and
melting point increase. Monochloroethane is a gas at room
temperature, hexachloroethane is a solid, and the remaining
compounds are liquids. All chloroethanes show some solubility
in water, and all, except monochloroethane, are more dense
than water.
The chloroethanes are used as solvents, cleaning and
degreasing agents, in the manufacture of plastics and textiles,
and in the chemical synthesis of a number of compounds.
Current production:
monochloroethane 335 x 10-, tons/yr in 1976
1,2-dichloroethane 4,000 x 10^ tons/yr in 1976
1,1,1-trichloroethane 215 x 10 tons/yr in 1976
The chlorinated ethanes form azeotropes with t/ater
(Kirk and Othmer, 1963). All are very soluble in organic
solvents (Lange, 1956). Microbial degradation of the chlorin-
ated ethanes has not been demonstrated (U.S. EPA, 1979).
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. Water monitoring studies
-------
have shown the following levels of various chloroethanes:
1,2-dichloroethane, 0.2-8 ug/1; 1,1,2-trichloroethane, 0.1-
8.5 ug/1; 1,1,1,2-tetrachloroethane, 0.11 ^g/1 (U.S. EPA,
197,9) . In general, air levels of chloroethanes are produced
by evaporation of volatile chloroethanes widely used as
degreasing agents and in dry cleaning operations (U.S. EPA,
1979). Industrial monitoring studies have shown air levels
of 1,1,1-trichloroethane ranging from 1.5 to 396 ppm (U.S.
EPA, 1979).
TABLE 1
Chloroethanes and Synonyms
Compound Name Synonyms
Monochloroethane
1,1,-Dichloroethane
1,2-Dichlorpethane
1,1,1-Tr ichloroethane
1,1,2-Trichloroethane
1,1,1,2-Tetrachloroethane
1,1,2,2-Tetrachloroethane
Pen tach loir oe thane
Hexachloroethane
Chloroethane
Ethylidene Dichloride
Ethylene Dichloride
Methyl Chloroform
Ethane Trichloride
Tetrachloroethane
Acetylene Tetrachloride
Pentalin
Perchloroethane
Ethyl chloride
Ethylidene Chloride
Ethylene Chloride
Chlorothene
Vinyl Trichloride
Sym-Tetrachloroethane
Ethane Pentachloride
Sources of human exposure to chloroethanes include
water, air, contaminated foods and. fish, and dermal absorption.
»
The two most widely used solvents, 1,2-dichloroethane and
1,1,1-trichloroethane, are the compounds most often detected
in foods. Analysis of several foods indicated 1,1,1-trichloro-
-------
ethane levels of 1-10 ug/kg (Walter, et al. 1976), while
levels of 1,2-dichloroethan'e found in 11 of 17 species have
been reported to be 2-23 ug/g (Page and Kennedy, 1975) .
Fish and shellfish have shown levels of chloroethanes in
the nanogram range (Dickson and Riley, 1976).
The U.S. EPA (1979) has derived the following weighted
average bioconcentratioa factors for the edible portions
of fish -and shellfish consumed by Americans: 1,2-dichloro-
ethane, 4.6; 1,1,1-trichloroethane, 21; 1,1,2,2-tetrachloro-
».
ethane, 18; pentachloroethane, 150; hexachloroethane, 320.
These estimates were based on the measured steady-state
bioconcentration studies in bluegill. Bioconcentration
factors for 1,1,2-trichloroethane (6.3) and 1,1,1,2-tetrachloro-
ethane (18) were derived by EPA (1979) using octanol-water
partition coefficients.
III. PHARMACOKINETICS
A. Absorption
The chloroethanes are absorbed rapidly following
ingestion or inhalation (U.S. EPA, 1979). Dermal absorption
is thought to be slower in rabbits based on studies by Sryth,
et al. (1969). However, rapid dermal absorption has been
seen in guinea pigs with the same trichloroethane (Jakobson,
et al. 1977).
Human studies on the absorption of inhaled 1,1,2,2-
tetrachloroethane indicate that the compound is completely
absorbed after exposure to trace levels of radiolabeled
vapor (Morgan, et al., 1970, 1972). At higher exposure
levels absorption is rapid in man and animals, but obviously
not complete.
-------
B. Distribution
Studies on the distribution of 1,1,1-trichloroethane
in mice following inhalation exposure have shown levels
in the liver to be twice that found in the kidney and brain
(Holmberg, et al. 1977). Postmortem examination of human
tissues showed 1,1,1-trichloroethane in body fat (highest
concentration) kidneys, liver, and brain (Walter, et al.
1976). Due to the lipid solubility of chloroethanes, body
distribution may be expected to be widespread. Stahl, et
al. (1969) have noted that human tissue samples of liver,
brain, kidney, muscle, lung, and blood contained 1,1,1-tri-
chloroethane following acute exposure, with the liver contain-
ing the highest concentration.
Passage of 1,1,1,2-tetrachloroethane across the
placenta has been reported by Truhaut, et al. (1974) in
rabbits and rats.
C. Metabolism
The metabolism of chloroethanes involves both
enzymatic dechlorination and hydroxylation to corresponding
alcohols (Monster, 1979; Truhaut, 1972). Oxidation reactions
may produce unsaturated metabolites which are then transformed
to the alcohol and ester (Yllner, 1971 a,b,c,d).
Metabolism appears to involve the activity of
the mixed function oxidase enzyme system (Van Dyke and Wineman,
1971). Animal experiments by Yllner (1971 a,b,c,d,e) indicated
that the percentage of administered '-compound metabolized
»
decreased with increasing dose, suggesting saturation of
metabolic pathways.
-------
D. Excretion
The chloroethanes are excreted primarily in the
urine and in expired air (U.S. EPA, 1979). As much as 60
to 80 percent of an inhaled dose of 1,1,1-trichloroethane
(70 or 140 ppm for 4 hours) was expired unchanged by human
volunteers (Monster, et al. 1979). Animal studies conducted
by Yllner (1971 a,b,c,d) indicate that largest amount of
chloroethanes, administered by intraperitoneal (i.p.) injec-
tion is excreted in the urine; this is followed by expira-
tion (in the changed or unchanged form), with very little
excretion in the feces. Excretion appears to be rapid,
since 90 percent of i.p. administered doses of 1,2-dichloro-
ethane or 1,1,2-trichloroethane were eliminated in the first
24 hours (U.S. EPA, 1979). However, the detection of chloro-
ethanes in postmortem tissue samples indicates that some
portion of these compounds persists in the body (Walter,
et al. 1976).
IV. EFFECTS
A. Carcinogenicity
Several chlorinated ethanes have been shown to
produce a variety of tumors in rats and mice in experiments
utilizing oral administration. Tumor types observed after
compound administration include squamous cell carcinoma
of the stomach, hemangiosarcoma, adenocarcinoma of the mam-
mary gland, and hepatocellular carcinoma (NCI, 1978a,b,c,d).
The four chlorinated ethanes which have been classified
as carcinogens based on animal studies are: 1,2-dichloro-
ethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane,
-------
and hexachloroethane. Increased tumor production was also
noted in animals treated with 1,1,1-trichloroethane, but
high mortality during this study (NCI, 1977) caused retest-
ing of the compound to be initiated. In vitro transforma-
tion of rat embryo cells and subsequent fibrosarcoma produc-
tion by these cells when injected _in vivo, indicate that
1,1,1-trichloroethane does have carcinogenic potential (Price,
et al. 1978).
B. Mutagenicity
».
Two of the chlorinated ethanes, 1,2-dichloroethane
and 1,1,2,2-tetrachloroethane, have shown mutagenic activity
in the Ames Salmonella assay and for DNA polymerase deficient
stra-.n of E. coli (Brem, et al. 1974). In these two systems,
) . —
1,1,2,2-tetrachloroethane showed higher mutagenic activity
than 1,2-dichloroethane (Rosenkranz, 1977).
Mutagenic effects have been produced by 1,2-dichloro-
ethane in pea plants (Kirichek, 1974) and in Drosophila
j
(Nylander, et al. 1978). Several metabolites of dichloro-
' /
etha'i...-' (chloroacetaldehyde/ chloroethanol, and S-chloroethyl
cysteine have also been shown to produce mutations in the
Ames assay (U.S. EPA, 1979).
Testing of hexachloroethane in the Ames Salmonella
assay or in a yeast assay system failed to show any mutagenic
activity (Weeks, et al. 1979).
C. Teratogenicity
Inhalation exposure of pregnant rats and mice
to 1,1,1-trichloroethane was shown to produce some soft
-------
tissue and skeletal deformities; this incidence was not
judged statistically significant by the Fisher Exact proba-
bility test (Schwetz, et al. 1975).
Testing of hexachloroethane administered to rats
by intubation or inhalation exposure did not show an increase
in teratogenic effects (Weeks, et al. 1979). Inhalation
exposure of pregnant rats to 1,2-dichloroethane also failed
to demonstrate teratogenic effects (Schwetz, et al. 1974;
Vozovaya, 1974) .
D. Other Reproductive Effects
Decreased .litter size, reduced fetal weights and
a reduction in live births have been reported in rats exposed
to 1,2-dichloroethane (57 mg/m m four hours/day, six days/week)
by inhalation (Vozovaya, 1974). 1,1-Dichloroethane retarded
fetal development at exposures of 6,000 ppm. (Schwetz, et
al. 1974). Higher fetal resorption rates and a decreased
number of live fetuses per litter were observed in rats
following administration of hexachloroethane by intubation
(15, 48 or 260 ppm, 6 hours/day) or inhalation (50, 100
or 500 mg/kg/day) (Weeks, et al. 1979).
.E. Chronic Toxicity
Neurologic changes and liver and kidney damage
have been noted following long term human exposure to 1,2-
dichloroethane (NIOSH, 1978) . Cardiac effects (overstimulation)
have been noted following human exposure' to 1,1-dichloroethane
(U.S. EPA, 1979).
Central nervous system disorders have been reported
in humans exposed to 1,1,1-trichloroethane. Symptoms noted
-------
were altered reaction time, perceptual speed, manual dexterity,
and equilibrium (U.S. EPA, 1979).
Animal studies indicate that the general symptoms
of toxicity resulting from exposure to the chloroethanes
involve effects in the central nervous system, cardiovascular
system, pulmonary system, and the liver and kidney (U.S.
EPA, 1979). Laboratory animals and humans exposed to chloro-
ethanes show similar symptoms of toxicity (U.S. EPA, 1979).
Based on data derived from animal studies, the
U.S. EPA (1979) has concluded that the relative toxicity
of the chloroethanes is as follows: 1,2-dichloroethane>
1,1,2,2-tetrachloroethane p-1,1,2-tr ichloroethane >hexachloro-
ethane 1,1-dichloroethane;>!,!,1-trichloroethane;? monochloro-
ethane.
F. Other Relevant Information
The hepatotoxicity of 1,1,2-trichloroethane was
increased in mice following acetone or isopropyl alcohol
pretreatment (Traiger and Plaa, 1974). Similarly, ethanol
pretreatment of mice increased the hepatic effects of 1,1,1-
trichloroethane (Klassen and Plaa, 1966).
Hexobarbital sleeping times in rats were reported
to be decreased following inhalation exposure to 1,1,1-tri-
chloroethane (3,000 ppm) , indicating an effect of the compound
on stimulation of hepatic microsomal enzymes (Fuller, et
al. 1970).
V. AQUATIC TOXICITY
»
A. Acute Toxicity
Acute toxicity studies were conducted on three
species of freshwater organisms and two marine species.
i
-------
For freshwater fish, 96-hour static LC50 values for the
bluegill sunfish, Lepomis macrochirus, ranged from 980 pg/1
hexachloroethane to 431,000 ug/1 1,2-dichloroethane, while
the range of 48-hour LC50 values for the freshwater inverte-
brate Dap'nnia magna was 8,070 ug/1 to 213,000 ug/1 for hexa-
chloroethane and 1,2-dichloroethane respectively. Among
marine organisms, the sheepshead minnow (Cyprinodon vagie-
gatus) produced LC5Q values ranging from 2,400 pg/1 for
hexachloroethane to 116,000 ug/1 for pentachloroethane.
The marine mysid shrimp (Mysidopsis bahia) produced LC,-Q
values ranging from 940 ug/1 for hexachloroethane to 113,000
pg/1 for 1,2-dichloroethane. The general order of acute
toxicities for the chlorinated ethanes reviewed for fresh-
water fish is: hexachloroethane (highest toxicity), 1,1,2,2-
tetrachloroethane, 1,1,2-trichloroethane, pentachloroethane,
and 1,2-dichloroethane (U.S. EPA, 1979).
B. Chronic Toxicity
The only chronic study available for the chlori-
nated ethanes is for pentachloroethane's chronic effects
on the marine shrimp (Mysidopsis bahia), which produced
a chronic value of 580 ug/1 (U.S EPA, 1978).
C. Plant Effects
Effective EC^Q concentrations, based on chlorophyll
a and cell numbers for the freshwater algae Selenastrum
capriconutum ranges from 87,000 pg/1, for hexachloroethane
to 146,000 ug/1 for 1,1,2,2-tetrachloroethane, with penta-
chloroethane being intermediate in its phytotoxicity. For
the marine algae Skeletonema costaturn, a greater sensi-
*
-447-
-------
tivity was indicated by effective EC<5Q_ concentrations based
on cell numbers and chlorophyll a ranging from 6,230 ug/1
for 1,1,2,2-tetrachloroethane and 7,750 ug/1 for hexachloro-
ethane to 58,200 ug/1 for pentachloroethane.
D. Residues
The bioconcentration value was greatest for hexa-
chloroethane with a value of 139 ug/1 being reported for
bluegill. Bioconcentration values of 2, 8, and 9 were obtained
for 1,2-dichloro, 1,1,2,2-tetrachloro, and 1,1,1-trichloro-
ethane for bluegills. 1,1,2-Trichloroethane and 1,1,1,2-
tetrachloroethane used the octanol/water coefficients to
derive BCF's of 22 and 62, respectively.
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
Based on the NCI carcinogenesis bioassay data,
and using a linear, non-threshold model, the U.S. EPA (1979)
has estimated levels of four chloroethanes in ambient water
that will result in an additional cancer risk of 10~ : 1,2-
dichloroethane, 7.0 ug/1; 1,1,2-trichloroethane, 2.7 ug/1;
1,1,2,2-tetrachloroethane, 1.8 ug/1; hexachloroethane, 5.9
ug/1. A draft ambient water quality•criterion to protect
human health has been derived by EPA for 1,1,1-tr ichloro-
ethane based on mammalian toxicity data at the level of
15.7 mg/1.
-------
Insufficient mammalian toxicological data prevented
derivation of a water criterion for monochloroethane, 1,1-
dichloroethane, 1,1,1,2-tetrachloroethane, or pentachloro-
ethane (U.S. EPA, 1979).
The following compounds have had eight hour, TWA
exposure standards established by OSHA: monochloroethane,
1,000 ppm; 1,1-dichloroethane, 100 ppm; 1,2-dichloroethane,
50 ppm; 1,1,1-trichloroethane, 350 ppm; 1,1,2-trichloroethane,
10 ppm; 1,1,2,2-tetrachloroethane, 5 ppm; hexachloroethane,
1 ppm.
B. Aquatic
Criteria for protecting freshwater organisms have
been dra " 3 for five of the chlorinated hydrocarbons: 62
pg/1 (average concentation) not to exceed 140 ug/1 for hexa-
chloroethane; 170 ug/1 not to exceed 380 pg/1 for 1,1,2,2-
tetrachloroethane; 440 pg/1 not to exceed 1,000 ,ug/l for
pentachlo''"^ethane; 3,900 pg/1 not to exceed 8,800 ug/1 for
1,2-dichloroethane; and 5,300 pg/1 not to exceed 12,000
ug/1 for x','l, 1-tr ichloroethane. For marine organisms, cri-
teria have been drafted as: 7 pg/1 (average concentration)
not to exceed 16 pg/1 for hexachloroethane; 38 pg/1 not
to exceed 87 pg/1 for pentachloroethane; 70 pg/1 not to
exceed 160 pg/1 for 1,1,2,2-tetrachloroethane; 240 pg/1
not to exceed 540 pg/1 for 1,1,1-trichloroethane; and 880
pg/1 not to exceed 2,000 pg/1 for 1,2-dichloroethane.
-------
CHLORINATED ETHANES
REFERENCES
Brem, H., et al. 1974. The mutagenicity and DNA-Modifying
effect of haloalkanes. Cancer Res. 34: 2576.
Dickson,'A.O. , and J.P. Riley. 1976. The distribution of
short-chain halcgenated aliphatic hydrocarbons in some marine
organisms. Mar. Pollut. Bull. 79: 167.
Fuller, G.C., et al. 1970. Induction of hepatic drug metab-
olism in rats bv methylchloroform inhalation. Jour. Pharma-
col. Ther. 175~: 311."
Holmberq, B., et al. 1977. A study of the distribution of
methylchloroform and n-octane in the mouse during and after
inhalation. Scand. Jour. Work Environ. Health 3: 43.
Jakobson, I., et al. 1977. Variations in the blood concen-
tration of 1,1,2-trichloroethane by percutaneous absorption
and other routes of administration in the guinea pig. Acta.
Pharmacol. Toxicol. 41: 497.
Kirk, R., and D. Othmer. 1963. Encyclopedia of chemical
technology. 2nd ed. John Wiley and Sons, Inc., New York.
Kiricheck, Y.F. 1974. Effect of 1,2-dichloroethane on muta-
tions in peas. Usp. Khim. Mutageneza Se. 232.
Klaassen, C.D., and G.L. Plaa. 1966. Relative effects of
various chlorinated hydrocarbons on liver and kidney function
in mice. Toxicol. Appl. Pharmacol. 9: 139.
Lange, N. (ed.) 1956. Handbook of chemistry. 9th ed.
Handbook Publishers, Inc., Sandusky, Ohio.
Monster, A.C. 1979. Difference in uptake, elimination, and
metabolism in exposure to trichloroethylene, 1,1,1-trichjloro-
ethane and tetrachloroethylene. Int. Arch. Occup. Environ.
Health 42: 311.
Monster, A.C., et al. 1979. Kinetics of 1,1-trichloroethane
in volunteers; influence of exposure concentration and work
load. Int. Arch. Occup. Environ. Health 42: 293.
Morgan, A., et al. 1970. The excretion in breath of some
aliphatic halogenated hydrocarbons following administration
by inhalation. Ann. Occup. Hyg. 13: 219.
Morgan, A., et al. 1972. Absorption of halogenated hydro-
carbons and their excretion in breath using chlorine-38
tracer techniques. Ann. Occup. Hyg. 15: 273.
-------
National Cancer Institute. 1977. Bioassay of 1,1-trichloro-
ethane foe possible carcinogenicity.. Carcinog. Tech. Rep.
Ser. NCI-CG-TR-3.
National Cancer Institute. 1978a. Bioassay of 1,2-dichloro-
ethane for possible carcinogenicity. Natl. Inst. Health,
Natl. Cancer Inst. Carcinogenesis Testing Program. DHEW
Publ. Mo. (NIH) 78-1305. Pub. Health Serv. U.S. Dep. Health
Edu. Welfare.
National Cancer Institute. 1978b. Bioassay of 1,1,2-tri-
chloroethane for possible carcinogenicity. Natl. Inst.
Health, Natl. Cancer Inst. DHEW Publ. No. (NIH) 78-1324. Pub.
Health Serv. U.S. Dep. Health Edu. Welfare.
National Cancer Institute. 1978c. Bioassay of 1,1, 2 , 2-tetra-
chloroethane for possible carcinogenicity. Natl. Inst.
Health, Natl. Cancer Inst. DHEW Publ. No.'- (NIH) 78-827. Pub.
Health Serv. U.S. Dep. Health Edu. Welfare.
National Cancer Institute. 1978d. Bioassay of hexachloro-
ethane for possible carcinogenicity. Natl. Inst. Health,
Natl. Cancer Inst. DHEW Publ. No. (NIH) 78-1318. Pub. Health
Serv. U.S. Dep. Health Edu. Welfare.
National Institute for Occupational Safety and Health. 1978.
Ethylene dichloride (1,2-dichloroethane). Current Intelli-
gence Bull. 25. DFEW (NIOSH) Publ. No. 78-149.
Nylander, P.O., et al. 1978. Mutagenic effects of petrol in
Drosoph ilia melanogaster. I. Effects of benzene of and 1,2-
d ichloroethane. Mutat. Res. 57: 163.
Page, B.D., and B.P.C. Kennedy. . 1975. Determination of
mthylene chloride, ethylene dichloride, and trichloroethylene
as solvent residues in spice oleoresins, using vacuum distil-
lation and electron-capture gas chromatography. Jour.
Assoc. Off. Anal. Chen. 58: 1062.
»
Price, P.J., et al. 1978. -Transforming activities of tri-
chloroethylene and proposed industrial alternatives. In
vitro. 14: 290.
Rosenkranz, H.S. 1977. Mutagenicity of halogenated alkanes
.and their derivatives. Environ. Health Perspect. 21: 79.
Schwetz, B.A., et al. 1974. Embryo- and fetotoxicity of in-
haled carbon tetrachloride, 1,1,-dichloroethane, and methyl
ethyl ketone in rats. Toxicol. Appl. Pharraacol. 28: 452.
Schwetz, B.A., et al. 1975. Effect of maternally inhaled.
trichloroethylene, perchloroethylene, methyl chloroform, and
methylene chloride on embryonal and fetal development in mice
and rats. Toxicol. Appl. Pharmacol. 32: 84.
-------
Snyth, K.F., Jr., et al. 1969. Range-finding toxicity data:
list VII. Am. Ind. Hyg. Assoc. Jour. 30: 470.
Stahl, C.J., et al. 1969. Trichlcroethane poisoning: ob-
servations on the pathology and toxicology in six fatal
cases. Jour. Forensic Sci. 14: 393.
Traiger, G.J., and G.L. Plaa. 1974. Chlorinated hydrocarbon
toxicity. Arch. Environ. Health 28: 276.
Truhaut, R. 1972. Metabolic transformations of 1,1,1,2-
tetrachloroethane in aninals (rats, rabbits). Chem. Anal.
(Warsaw) 17: 1075.
Truhaut, R., et al. 1974. Toxicological study of 1,1,1,2-
tetrachloroethane. Arch. Mai. Prof. Med. Trav. Secur. Soc.
35: 593.
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. 1979. Chlorinated Ethanes: Ambient Water Quality
Criteria (Draft).
Van Dyke, R.A., and C.G. Wineman. 1971. Enzymatic dechlori-
nation: Dechlorination of chloroethanes and propanes _i_n
vitro. Biochem. Pharniacol. 20: 463.
Vozovaya, M.A. 1974. Development of progeny of two genera-
tions obtained from female rats subjected to the action of
dichloroethane. Gig. Sanit. 7: 25.
Walter, P., et al. 1976. Chlorinated hydrocarbon toxicity
(1,1,1-trichloroethane, trichloroethylene, and tetrachloro-
ethylene): a monograph. PE Rep. PB-257185. Matl. Tech.
Inf. Serv., Springfield, Va.
-»
Weeks, M.H., et al. 1979. The toxicity of hexachloroethane
in laboratory animals. Am. Ind. Hyg. Assoc. Jour. 40: 187.
Yllner, S. 1971a. Metabolism of 1,2-dichloroethane-14c
in the mouse. Acta. Pharnacol. .Toxicol. 30: 257.
Yllner, S. 1971b. Metabolism of 1,1,2-trichloroethane-l,2-
^4C in the mouse. Acta. Pharmacol. Toxicol. 320: 248.
Yllner, S. 1971c. Metabolism of 1,1,1,2-tetrachloroethane
in the mouse. Acta. Pharmacol. Toxicol.. 29: 471.
Yllner, S. 1971d. Metabolism of 1,1, 2 , 2-tetrachloroethane'-
14C in the mouse. Acta. Pharmacol. Toxicol. 29: 499.
Yllner, S. 1971e. Metabolism of pentachloroethane in the
mouse. Acta. Pharmacol. Toxicol. 2^: 481.
-------
No. 38
Chlorinated Naphthalenes
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.
-------
CHLORINATED NAPTHALENE5
Summary
Chlorinated naphthalenes have been used in a variety of industries,
usually as .mixtures. Chronic toxicity varies with the degree of chlori-
nation, with the more highly chlorinated species being more toxic. The
clinical signs o'f toxicity in humans are damage to liver, heart, pancreas,
gall bladder, lungs, adrenal glands, and kidney. NO animal or human studies
have been presented on the carcinogenicity, mutagenicity, or teratogenicity
of polychlorinated naphthalenes.
Very little data on aquatic toxicity are available for individual
chlorinated naphthalenes. 48-Hour and 96-hour LC~ values of octachloro-
naphthalene over 500,000 pg/1 have been reported for Daphnia maqna and the
bluegill, respectively. A freshwater alga also resulted in a 96-hour LC50
value for octachloronaphtnalene of over 500,000 pg/l.
Toxicity studies with aquatic organisms are confined to tests with 1-
chloronaphthalene on one freshwater fish and two algal species (one fresh
and one saltwater). All tests have reported 96-hour LC5n values of be-
tween 320 and 2,270 /jg/1. Exposure of sheepshead minnow to 1-chloronaphtha-
i
lene in an embryo-larval study resulted in a chronic value of 328 ug/1.
I
-------
CHLORINATED NAPTHALENES
I. INTRODUCTION
This profile is based on the draft Ambient Water Quality Criteria Docu-
ment for Chlorinated Naphthalenes (U.S. EPA, 1979).
Chlorinated naphthalenes consist of two fused six carbon-membered aro-
matic rings where any or all of the eight hydrogen atoms can be replaced
with chlorine. The physical properties of the chlorinated naphthalenes are
generally dependent on the degree of chlorination. Melting points range
from 17°C for 1-chloronaphthalene to 198°D for 1,2,3,4-tetrachloro-
naphthalene. As the degree of chlorination increases, the specific gravity,
boiling point, fire and flash points all increase, while the vapor pressure
and water solubility decrease. Chlorinated naphthalenes have been used as
the paper impregnant in automobile capacitors (mixtures of tri- and tetra-
chloronaphthalenes), and as oil additives for engine cleaning, and in fabric
dyeing (mixtures of mono- and dichloronaphthalenes). In 1956, the total
U.S. production of chlorinated naphthalenes was approximately 3,175 metric
tons (Hardie, 1964).
II. EXPOSURE
A. Water
To date, polychlorinated naphthalenes have not been identified in
drinking waters (U.S. EPA, 1979). However, these compounds have been found
in waters or sediments adjacent to point sources or areas of heavy poly-
chlorinated biphenyl contamination.
8. Food
Polychlorinated naphthalenes appear to be biomagnified in the aqua-
tic ecosystem, with the degree of biomagnification being greater for the
more highly chlorinated polychlorinated compounds (Walsh, et al. 1977).
-------
Erickson, at al. (1978) also noted a higher relative biomagnification of the
lowest chlorinated naphthalenes by the fruit of apple trees grown on contam-
inated soil. The U.S. EPA (1979) has estimated the weighted average bicccn-
centration factor for Halowax 1014 (a mixture of chlorinated.naphthalenes)
to be 4,300 for the edible portions of fish and shellfish consumed by
Americans. This estimate is based on measured non-steady-state bioconcen-
tration studies in brown shrimp.
C. Inhalation
Erickson, et al. (1978) found ambient -air concentrations of poly-
chlorinated naphthalenes ranging from 0.025 to 2.90 /jg/m near a poly-
chlorinated naphthalene plant. Concentrations of trichloronaphthalene were
as high as 0.95 ug/m , while hexachloronaphthalene concentrations never
exceeded 0.007 jug/m .
III. PHARMACOKINETICS
A. Absorption
Pertinent data could not be located in the available literature.
8. Distribution
In the rat fed 1,2-dichloronaphthalene, the chemical and its metab-
olites were found primarily in the intestine, kidney, and adipose tissue
4
(Chu, et al. 1977).
C. Metabolism
There appears to be appreciable metabolism in mammals of poly-
chlorinated naphthalenes containing four chlorine atoms or less (U.S. EPA,
1979). Cornish and Block (1958) investigated the excretion of polychlori-
nated naphthalenes in rabbits and found 79 percent of 1-chloronaphthalene,
93 percent of dichloronaphthalene, and 45 percent of tetrachloronaphthalene
-------
were excreted in the urine as metabolites .of the parent compounds. Metab-
olism may involve hydroxylation alone or hydroxylation in combination with
dechlorination. In some cases, an arene oxide intermediate may be formed
(Ruzo, et al. 1976).
D. Excretion
In rats fed 1,2-dichloronaphthalene, initially more of the chemical
and its metabolites were found in the urine; however, by the end of seven
days a greater proportion had been excreted in the feces (Chu, et al. 1977).
In the first 24 hours, 62 percent of the dose was excreted in the bile, as
compared to 18.9 percent lost in the feces. This suggests that there is an
appreciable reabsorption and enterohepatic recirculation of this .particular
chlorinated naphthalene.
IV. EFFECTS
No animal or human studies have been reported on the carcinogenicity,
mutagenicity, or teratogenicity of chlorinated naphthalenes. No.other re-
productive effects were found in the available literature.
A. Chronic Toxicity
Chronic dermal exposure to penta- and hexachlorinated naphthalenes
causes a form of chloracne which, if persistent, can progress to fprm a cyst
or sterile abcess (Jones,. 1941; Shelley and Kligman, 1957; Kleinfeld, et al.
1972). Workers exposed to these two isomers complained of eye irritation,
headaches, fatigue, vertigo, nausea,, loss of appetite, and weight loss
(Kleinfeld, et al. 1972). More severe exposure to the fumes of polychlori-
nated naphthalenes has produced severe liver damage, together with damage to
the heart, pancreas, gall bladder, lungs, adrenal glands, and. kidney tubules
(Greenburg, et al. 1939). Chronic toxicity in animals appears to.be quali-
tatively the same (U.S. EPA, 1979). Polychlorinatsd naphthalenes containing
-------
three or fewer chlorine atoms were found to be nontoxic, while tetrachloro-
naphthalene resulted in mild liver disease at levels as high as 0.7 mg/kg/-
day; the higher chlorinated naphthalenes produce more severe disease at
lower doses (Bell, 1953). Because of their insolubility, hepta- and octa-
chloronaphthalene were less toxic when given in suspension than when given
in solution.
8. Other Relevant Information
Drinker, et al. (1937) showed enhancement of hepatoxicity of a mix-
ture of ethanol/carbon tetrachloride in rats pretreated with 1.16 mg/m of
a penta-/hexachloronaphthalene mixture in air for six weeks. In a similar
study trichloronaphthalene was inactive.
V. AQUATIC TOXICITY , '• ^
A. Acute Toxicity
The 96-hour L^cn value reported for the bluegill, Lepomis
macrochirus,'exposed to 1-chioronaphthalene is 2,270 jug/1 (U.S. EPA, 1578).
With saltwater species, exposure of the sheepshear"'--,minnow, Cyorinodon
varigatus, and mysid shrimp, Mysidopsis bahia. to 1-chloronaphthalene pro-
vided 96-hour LC5Q values . of 1,290 and 370 jug/1, respectively. Daphnia
maqna and the bluegill, Lepomis macrochirus, have a slight sensitivity to
octachloronaphthalene, ' with respective 48-hour and 96-hour LCcn values
5U
greater than 530,000pg/l (U.S. EPA, 1978).
8. Chronic Toxicity
In the only chronic study reported (embryo-larval), exposure of
1-chloronaphthalene to the sheepshead minnow resulted in a chronic value of
329 ug/1 (U.S. EPA, 1978).
-------
C. Plant Effects
A freshwater alga, Selenastrum caoricornutum, and a saltwater alga,
Skeletonema costatum, when exposed to 1-chloronaphthalene, both produced 96-
hour EC5Q values ranging from 1,000 to 1,300 ug/1 based on cell numbers.
Octachloronaphthalene exposure to Selenastrum capricornutum re-
sulted in a 96-hour EC5Q value of over 500,000 ug/1 based on cell numbers
(U.S. EPA, 1978).
0. Residues
Pertinent data could not be located in the available literature.
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The only standards for polychlorinated naphthalenes are the ACGIH
Threshold Limit Values (TLV) .adopted by the Occupational Safety and Health
Administration and are as follow:
ACGIH (1977)
Threshold Limit Values
Trichloronaphthalene 5 . mg/m^
Tetrachloronaphthalene 2 mg/m^
Pentachloronaphthalene 0.5 mg/m^
Hexachloronaphthalene 0.2 mg/m^
Octachloronaphthalene 0.1 . mg/m^
There are no state or federal water quality or ambient air quality standards
for chlorinated naphthalenes.
The U.S. EPA is presently evaluating the available data and has
recommended that a single acceptable daily intake (ADI) of 70 ;jg/man/day be
used for the tri-, tetra-, penta-, hexa-, and octa-chlorinated naphthalenes.
This ADI will be used to derive the human health criteria for the chlori-
nated naphthalenes.
-------
8. Aquatic
For 1-chloronsphthalene, the draft criterion to protect freshwater
aquatic life is 29 pg/1 as a 24-hour average, not to exceed 67 ^ug/1 at any
time. For saltwater aquatic species, the draft criteron is 2.8 jug/1 as a
24-hour average, not to exceed 6.4 pg/1 at any time (U.S. EPA, 1979).
-------
CHLORINATED NAPHTHALENE
REFERENCES
American Conference of Governmental Industrial Hygienists.
1977. TLVs Threshold Limit Value for chemical substances and
physical agents in the workroom environment with intended
changes. Cincinnati, Ohio.
Bell, W.S. 1953. The relative toxicity of the chlorinated
naphthalenes in experimentally produced bovine hyperkeratosis
(X-disease). Vet. Met. 48: 135.
Chu, I., et al. 1977. Metabolism and tissue distribution of
(1,4,5,-^4C)-l, 2-dichloronaphthaline in rats. Bull.
Environ. Contain. Toxicol. 18: 177.
Cornish, H.H., and W.D. Block. 1958. Metabolism of chlori-
nated naphthalenes. Jour. Biol. Chem. 231: 583.
Drinker, C.K., et al. 1937. The problem of possible sys-
temic effects from certain chlorinated hydrocarbons. Jour.
Ind. Hyg. Toxicol. 19: 283.
Erickson, M.D., et al. 1978. Sampling and analysis for
polychlorinated naphthalenes in the environment. Jour.
Assoc. Off. Anal. Chem. 61: 1335.
Greenburg, L., et al. 1939. The systemic effects resulting
from exposure to certain chlorinated hydrocarbons. Jour.
Ind. Hyg. Toxicol. 21: 29.
Hardie, D.W.F. 1964. Chlorocarbons and chlorohydrocarbons:
Chlorinated Naphthalenes. pp. 297-303 In; Kirk-Othmer, En-
cyclo. of Chemical Technology. 2nd ed. John Wiley and Sons,
Inc., New York.
Jones, A.T. 1941. The etiology of acne with special ^refer-
ence to acne of occupational origin. Jour. Ind. Hyg. Toxi-
col. 23: 290.
Kleinfeld, M. , et al. 1972. Clinical effects of chlorinated
naphthalene exposure. Jour. Occup. Med. 14: 377.
Ruzo, L., et al. 1976. Metabolism of chlorinated naphtha-
lenes. Jour. Agric. Food Chem. 24: 581.
Shelley, W.B., and A.M. Kligman. 1957. The experimental
production of acne by penta- and hexa'chloronaphthalenes.
A.M.A. Arch. Derm. 75: 689.
-------
U.S. EPA. 1978. In-depth studies on health and environmen-
tal impacts of selected water pollutants. Contract No. 68-
01-4646. U.S. Environ. Prot. Agency, Washington, D.C.
U.S. EPA. 1979. Chlorinated Naphthalenes: Ambient Water
Quality Criteria. (Draft).
Walsh, G.E., et al. 1977. Effects and uptake of chlorinated
naphthalenes in marine unicellular algae. Bull. Environ.
Contain. Toxicol. 18: 297.
-------
No. 39
Chlorinated Phenols
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
. The National Cancer Institute (1979) has recently published the results
of a bioassay indicating that 2,4,6-trichlorophenol induced cancer in rats
and mice. This study was not included in the Ambient .Water Quality Criteria
Document (U.S. EPA, 1979) and has not been reviewed for this hazard profile.
-------
CHLORINATED PHENOLS
SUMMARY
Mammalian data supporting chronic effects for most of these compounds
is limited. Insufficient data exist to indicate that any of the chlorinated
phenols are carcinogens. In skin painting studies, 3-chlorophenol and
2,4,5-trichlorophenol promoted papillomas. A lifetime feeding study with
2,4,6-trichlorophenol was inconclusive and only provided weak suspicion of
carcinogenicity. 2,4,6-Trichlorophenol gave some evidence of mutagenicity
in two assays. Tetrachlorophenol was not found to be fetotoxic in animals.
Chronic exposure to 4-chlorophenol produced myoneural disorders in humans
and animals. Adverse health effects in workers exposed to 2,4,5-trichloro-
phenol may have been due to 2,3,7,8-tetrachlorodibenzo-p-dioxin contamina-
tion of the chlorophenol.
Workers chronically exposed to tetrachlorophenol, pentachlorcphenol,
and small amounts of chlorodibenzodioxins developed .severe skin irritations,
respiratory difficulties, and headaches. Chlorophenols are uncouplers of
oxidative phosphorylation. 2,6-Oichlorophenol and trichlorocresol are con-
vulsants. Chlorocresol has caused several cases of local and generalized
4
reactions.
In acute toxicity tests, 4-chloro-3-methylphenol has been proven toxic
at concentrations as low as 30 ug/1 in freshwater fish, whereas other fresh-
water and marine organisms appear to be more resistant. The tainting of
rainbow trout flesh has been demonstrated at exposures of 15 to 84 ug/1 for
several of the chlorinated phenols.
-------
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Chlorinated Phenols (U.S. EPA, 1979).
The chlorinated phenols represent a group of commercially produced sub-
stituted phenols and cresols also referred to as chlorophenols or chlorocre-
sols. The compounds 2-chlorophenol, 2,4-dichlorophenol, 2,4,6-trichlorophe-
nol, and pentachlorophenol are discussed in separate hazard profiles.
Purified chlorinated phenols are colorless, crystalline solids (with
the exception of 2-chlorophenol which is a liquid), while the technical
grades may be light tan or slightly pink due to impurities. Chlorophenols
have pungent odors. In general, the volatility of chlorinated phenols de-
creases and the melting and boiling points increase as the number of substi-
tuted chlorine atoms increases. Although the solubility of chlorinated phe-
nols in aqueous solutions is relatively low, it increases markedly when the
pH of the solution exceeds the specific pKa. The solubilities of chlori-
nated phenols and chlorocresols (with the exception of 2,4,6-trichloro-m-
cresol) range from soluble to very soluble in relatively non-polar solvents
such as benzene and petroleum ether (U.S. EPA, 1979).
The chlorinated phenols that are most important commercially *are 4-
chlorophenol, 2,4-dichlorophenol, 2,4,5-trichlorophenol, 2,3,4,6-tetra-
chlorophenol, pentachlorophenol, and 4-chloro-o-cresol. Many of the chloro-
phenols have no commercial application but are produced to some extent as
byproducts of the commercially important compounds. The highly toxic poly-
chlorinated dibenzo-p-dioxins may be formed during the chemical synthesis of
some chlorophenols. During the chlorination of drinking waters and waste-
water .effluents, chlorophenols may be inadvertently produced (U.S. EPA,
1979).
-------
Chlorinated phenols are used as intermediates in the synthesis of dyes,
pigments, phenolic resins, pesticides, and herbicides. Certain chlorophe-
nols are used directly as flea repellants, fungicides, wood preservatives,
mold inhibitors, antiseptics, disinfectants, and antigumming agents for
gasoline.
It is generally accepted that chlorinated phenols will undergo photoly-
sis in aqueous solutions as a result of ultraviolet irradiation and that
photodegradation leads to the substitution of hydroxyl groups in place of
the chlorine atoms with subsequent polymerization (U.S. EPA, 1979). Micro-
bial degradation of chlorophenols has been reported by numerous investiga-
tors (U.S. EPA, 1979).
3-CHLOROPHENOL and 4-CHLORQPHENuL
II. EXPOSURE
Monochlorophenols have been found in surface waters in the Netherlands
at concentrations of 2 to 20 pg/1 (Piet and DeGrunt, 1975). Ingestion of
chlorobenzene can give rise to internal exposure to 2-, 3-, and 4-chlorophe-
nols, as chlorobenzene is metabolized to monochlorophenols (Lindsay-Smith,
et al. 1972). No data were found demonstrating the presence of monochloro-
phenol in food.
For 4-chlorophenol the U.S. EPA has estimated the weighted average bio-
concentration factor for the edible portions of all aquatic organisms con-
sumed by Americans to be 12. This estimate is based on the octanol/water
partition coefficient.
Data were not found in the available literature regarding inhalation
exposure.
-------
III. PHARMACOKINETICS
Systematic studies of the pharmacokinetics of 3- or 4-chlorophenol are
not available. Dogs excreted 87 percent of administered 4-chlorophenol in
the urine as sulfuric and glucuronic conjugates (Karpow, 1893).
IV. EFFECTS
A. Carcinogenicity
Information is not adequate to determine whether 3- or 4-chlorophe-
nol possess carcinogenic properties. A 20 percent solution of 3-chlorophe-
nol promoted papillomas when repeatedly applied to the backs of mice after
initiation with dimethylbenzanthrene (Boutwell and Bosch, 1959).
B. Mutagenicity, Teratogenicity and Other Reproductive Effects
Pertinent data cannot be located in the available literature re-
garding mutagenicity, teratogenicity and other reproductive effects.
C. Chronic Toxicity
Rats exposed 6 hrs/day for four months to 2 mg 4-chlorophenol/m
showed a temporary weight loss and increased myoneural excitability. Body
temperature and hematological parameters were not altered (Gurova, 1964).
In a survey comparing the health of workers, 4-chlorophenol .exposed workers
had a significantly higher incidence of neurological disorders compared to
unexposed workers in the same plant. Peripheral nerve stimulation studies
showed increased myoneural excitability in exposed workers. The minimum
detection distance in a two-point touch discrimination test was increased
(Gurova, 1964).
0. Other Relevant Information
3- and 4-Chlorophenol are weak uncouplers of oxidative phosphoryla-
tion (Mitsuda, et al. 1963; Weinback and Garbus, 1965).
-I-I7O-
-------
2.5-DICHLOROPHENOL. 2,6-OICHLOROPHENOL.
3.4-OICHLOROPHENOL, and 3.5-OICHLOROPHENQL
II. EXPOSURE
Unspecified dichiorophenol isomers have been detected in concentrations
of 0.01 to 1.5 pg/1 in Dutch surface waters (Piet and OeGrunt, 1975). Oi-
chlorophenols have been found in flue gas condensates from municipal incin-
erators (Olie, et al. 1977). No data on exposure from foods or the dermal
route were found. Exposure to other chemicals can result in exposure to
dichlorophenols (i.e., dichlorobenzenes, lindane, and the alpha and delta
isomers of 1,2,3,4,5,6-hexachlorocyclohexane are metabolized by mammals to
dichlorophenols) (Kohli, et al. 1976; Foster and Saha, 1978).
III. PHARMACOKINETICS
Pharmacokinetic data specific to these dichiorophenol isomers could not
be located in the available literature.
IV. EFFECTS
A. Carcincgenicity
Pertinent data cannot be located in the available literature.
B. Mutagenicity •
2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-Oichlorophenols were found to
be non-mutagenic in the Ames test with or without microsomal activation
(Rasaner and Hattula, 1977).
C. Teratogenicity, Other Reproductive Effects and Chronic Toxicity
Pertinent data cannot be located in the available literature re-
garding teratogenicity, other reproductive effects and chronic toxicity.
D. Other Relevant Information
2,6-Oichlorophenol is a convulsant (Farquharson, et al. 1958). '
i
-H7/-
-------
TRICHLQROPHENOLS
II. EXPOSURE
Trichlorophenols have been detected in surface waters in Holland at
concentrations ranging from 0.003 to 0.1 jjg/1 (Piet and DeGrunt, 1975).
2,4,5-Trichlorophenol can be formed from the chlorination of phenol in water
(Burttschell, et al. 1959).
One possible source of trichlorophenol exposure for humans is through
the food chain, as a result of the ingestion by grazing animals of the
chlorophenoxy acid herbicides 2,4,5-T (2,4,5-trichlorophenbxyacetic acid)
and silvex (2-(2,4,5-trichlorophenoxy)-propionic acid). Residues of the
herbicides on -sprayed forage are estimated to be 100-300 ppm. Studies in
which cattle and sheep were fed these herbicides at 300, 1000 and 2000 ppm
(Clark, et al. 1976) showed the presence of 2,4,5-trichlorophenol in various
tissues. In lactating cows fed 2,4,5-T at 100 ppm, an occasional residue of
0.06. ppm or less of trichlorophenol was detected in milk (Bjerke, et al.
1972).
Exposure to other chemicals such as trichlorobenzenes, lindane, the
alpha and delta isomers of 1,2,3,4,5,6-hexachlorocyclohexane, isomers of
benzene hexachloride, and the insecticide Ronnel can result in exposure to
trichlorophenols via metabolic degradation of the parent compound (tl.S. EPA,
1979).
The U.S. EPA (1979) has estimated the weighted average bioconcentration
factors for the edible portions of all aquatic organisms consumed by Ameri-
cans to be 130 for 2,4,5-trichlorophenol and 110 for 2,4,6-trichlorophenol.
These estimates are based on the octanol/water partition coefficients for
these chemicals.
-473,-
-------
Trichlorophenols are found in flue gas condensates from municipal in-
cinerators (Olie, et al. 1977). 2,4,5-Trichlorophenol was detected in 1.7
percent of urine samples collected from the general population (Kutz, et al.
1978).
III. PHARMACOKINETICS
A. Absorption and Distribution
Information dealing with tissue distribution after administration
of trichlorophenols could not be located in the available literature. Feed-
ing of 2,4,5-T and silvex to sheep and cattle produced high levels of 2,4,5-
trichlorophenol in liver and kidney and low levels in muscle and fat (Clark,
et al. 1976). •
B. Metabolism
Pertinent data could not be located in the available literature.
C. Excretion
In rats, 82 percent of an administered dose (1 ppm in the diet for
3 days) of 2,4,6-t-richlorophenol was eliminated in the urine and 22 percent
in the feces. Radiolabelled trichlorophenol was not detected in liver, lung
or 'fat obtained 5 days after the last dose (Korte, et al.- 1978). The ap-
proximate blood half-life for 2,4,5-trichlorophenol is 20 hours, after dos-
ing of sheep with Erbon (an herbicide which is metabolized to 2*,4,5-tri-
chlorophenol) (Wright, et al. 1970).
IV. EFFECTS
A. Carcinogenicity
A 21 percent solution of 2,4,5-trichlorophenol in acetone promoted
papillomas but not carcinomas in mice after initiation with dimethylbenzan-
-1-173-
-------
threne (Boutwell and Bosch, 1959). 2,4,6-Trichlorophenol showed no promot-
ing activity.
Results from a study of mice receiving 2,4,6-trichlorophenol in the
diet throughout their lifespans (18 months) were inconclusive. The inci-
dence of tumors, while higher than that for compounds classified as noncar-
cinogens, was not significantly increased (Innes, et al. 1969).
8. Mutagenicity
2,4,6-Trichlorophenol (400 mg) increased the mutation rate but not
the rate of intragenic recombination in a strain of Saccharomyces cerevisiae
(Fahrig, et al. 1978). Two of the 340 offspring from mice injected with 50
mg/kg of 2,4,6-trichlorophenol during gestation were reported to have
changes in hair coat color (spots) of genetic significance. At 100 mg/kg, 1
out of 175 offspring had a spot (U.S. EPA, 1979). 2,3,5-, 2,3,6-, 2,4,5-,
and 2,4,6-Trichlorophenol were found to be nonmutagenic in the Ames test
with and without microsomal activation (Rasanen and Hattula, 1977).
C. Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the available literature
regarding teratogenicity .and other reproductive effects.
D. Chronic Toxicity
When rats were fed 2,4,5-trichlorophenol (99 percent pure) for 98
days (McCollister, et al. 1961), levels of 1000 mg trichlorophenol/kg feed
(assumed to be equivalent to 100 mg/kg body weight) or less produced no
adverse effects as'judged by behavior, mortality, food consumption, growth,
terminal hematology, body.and .organ weights, and gross or microscopic-patho-
logy. At 10,000 mg/kg diet (1000 mg/kg body weight), growth was slowed in
females. Histopathologic changes were noted in liver and kidney. There
-------
were no hematologic changes. At 3000 mg/kg feed (300 mg/kg body weight),
milder histopathologic changes in liver and kidney were observed. The his-
topathologic changes were considered to be reversible.
Adverse health effects including chloracne, hyperpigmentation, hir-
sutism and elevated uroporphyrins were described in 29 workers involved in
the manufacture of 2,4-0 and 2,4,5-T (Bleiberg, et al. 1964). It is likely
that some of these symptoms represent 2,3,7,8-tetrachlorodibenzo-p-dioxin
toxicosis (U.S. EPA, 1979).
E. Other Relevant Information
Trichlorophenols are uncouplers of oxidative phosphorylation (Wein-
back and Garbus, 1965; Mitsuda, et al. 1963).
TETRACHLOROPHENOL
II. EXPOSURE
There are three isomers of tetrachlorophenol: -2,3,4,5-, 2,3,5,6-, and,
most importantly, 2,3,4,6-tetrachlorophenol. Commercial pentachlorophenol
contains three to 10 percent tetrachlorophenol (Goldstein, et al. 1977;
Schwetz, et al. 1978). Commercial tetrachlorophenol contains pentachloro-
phenol (27 percent) and toxic nonphenolic impurities such as chlorodibenzo-
4
furans and chlorodioxin isomers (Schwetz, et al. 1974). There are reports
suggesting the presence of lower chlorophenols in drinking water, but the
presence, of tetrachlorophenol has not been documented (U.S. EPA, 1979).
Exposure to other chemicals such as tetrachlorobenzenes can result in expo-
sure to tetrachlorophenols via degradation of the parent compound (Kohli, et
al. 1976).
»
Data could not be located in the available literature on ingestion from
foods. The U.S. EPA (1979) has estimated, a weighted average bioconcentra-
-W7S--
-------
tion factor for 2,3,4,6-tetrachlorophenol of 320 for the edible portion of
aquatic organisms consumed by Americans. This estimate is based on the
octanol/water partition coefficient of 2,3,4,5-tetrachlorophenol.
Tetrachlorophenols- have been found in flue gas condensates from munici-
pal incinerators (Olie, et al. 1977).
II. PHARMACOKINETICS
A. Absorption and Distribution
Pertinent data could not be located in the available literature
regarding absorption and distribution.
B. Metabolism and Excretion
In rats, over 98 percent of an intraperitoneally administered dose
of 2,3,5,6-tetrachlorophenol was recovered in the urine in 24 hours. About
66 percent was excreted as the' unchanged compound and 35 percent as tetra-
chloro-p-hydroquinone. About 94 percent of the .intraperitoneal dose of
2,3,4,6-tetrachlorophenol was recovered in the urine in 24 hours, primarily
as the unchanged compound with trace amounts of trichloro-p-hydroquinone.
Fifty-one percent of the intraperitoneal dose of 2,3,4,5-tetrachlorophenol'
was recovered in the urine in 24 hours, followed by an additional seven per-
cent in the second 24 hours, primarily as the unchanged compound with trace
*
amounts of trichloro-p-hydroquinone. In these experiments, the urine was
boiled to split any conjugates (Alhborg and Larsson, 1978).
IV. EFFECTS
A. Carcinogenicity
Pertinent data could not be located in the available literature.
B. Mutagenicity
2,3,4,6-Tetrachlorophenol was reported to be nonmutagenic in the
Ames test, both with and without microsomal activation (Rasanen, et al.
1977).
-476-
-------
C. Teratogenicity
Tetrachlorophenol did not induce teratogenic effects in rats at
doses of 10 or 30 mg/kg administered on days six through 15 of gestation
(Schwetz, et al. 1974).
0. Other Reproductive Effects
Tetrachlorophenol produced fetotoxic effects (subcutaneous edema
and delayed ossification of skull bones) in rats at doses of 10 and 30 mg/kg
administered on days six through 15 of gestation (Schwetz, et al. 1974).
E. Chronic Toxicity
Workers exposed to wood dust containing 100-800 ppm 2,3,4,6-tetra-
chlorophenol, 30-40 ppm pentachlorophenol, 10-50 ppm chlorophenoxyphenols,
1-10 ppm chlorodibenzofurans and less than 0.5 ppm chlorodibenzo-p-dioxins
developed severe skin irritations, respiratory, difficulties and headaches
(Levin, et al. 1976).
No toxicity studies of 90 days or longer were found in the avail-
able literature.
F. Other Relevant Information
2,3,4,6-Tetrachlorophenol is a strong uncoupler of oxidative phos-
phorylation (Mitsuda, et al. 1963; Weinback and Garbus, 1965).
CHLOROCRESOLS
II. EXPOSURE
There are no published data available for the determination of current
human exposure to chlorocresols (U.S. EPA, 1979). p-Chloro-m-cresol (4-
chloro-3-methylphenol) has been detected in chlorinated sewage treatment
effluent (Jolley, et al. 1975). Another potential source of chlorocresols
is the herbicide MCPA (4-chloro-2-methylphenoxyacetate), which (in its tech-
-------
nical grade) is contaminated with four percent 4-chloro-o-cresol (Rasanen,
et al. 1977) and which can be degraded to 5-chloro-o-cresol (Gaunt and
Evans, 1971).
III. PHARMACOKINETICS
A. Absorption
Chlorocresol (unspecified isomer) permeated human autopsy skin more
readily than either 2- or 4-chlorophenol, but less readily than 2,4,6-tri-
chlorophenol (Roberts, et al. 1977).
B. Distribution and Metabolism
Pertinent data could not be located in the available literature.
C. Excretion
Fifteen to 20 percent of a subcutaneous dose of p-chloro-m-cresol
given to a rabbit was recovered in the urine. The same compound given in-
tramuscularly was not recovered in the urine to any appreciable extent (Zon-
dek and Shapiro, 1943).
IV. EFFECTS
A. Carcinogenicity
Pertinent information could not be located in the available litera-
ture.
B. Mutagenicity *
3-Chloro-o-cresol, 4-chloro-o-cresol and 5-chloro-o-cresol were re-
ported to be nonmutagenic in the Ames test, with and without microsomal.ac-
tivation (Rasanen, et al. 1977).
C. • Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the available literature
regarding tertogenicity and other reproductive effects.
-------
0. Chronic Toxicity
No information on chronic toxicity in humans or toxicity studies of
90 days or longer in experimental animals were presented in the Ambient
Water Quality Criteria Document (U.S. EPA, 1979). p-Chloro-m-cresol given
subcutaneously to young rats for 14 days (80 mg/kg/day) produced mild in-
flammation at the injection site but did not affect growth or produce le-
sions in kidney, liver, or spleen (Wien, 1939). Rabbits (weighing 1.5-2.3
kg) injected subcutaneously with 12.5 mg p-chloro-m-cresol/day suffered no
obvious ill effects (Wien, 1939). Liver and kidney were normal histologic-
ally.
E. Other Relevant Information
Chlorocresol, a preservative in heparin solutions, caused several
cases of generalized and local reactions (Hancock and Naysmith, 1975; Ain-
ley, et al. 1977). Systemic reactions included collapse, pallor, sweating,
hypotension, tachycardia and rashes. Trichlorocresol is also a convulsant
(Eichholz and Wigand, 1931).
. CHLORINATED PHENOLS
I. AQUATIC TOXICITY
A. Acute Toxicity
The acute toxicity of eight chlorophenols was determined in nine
bioassays. Acute 96-hour LC5Q values for freshwater fish ranged from 30
jug/1 for the fathead minnow, Pimephales promelas, for 4-chloro-3-methylphe-
nol (U.S. EPA, 1972) to 9,040 ,ug/l for the fathead minnow for 2,4,6-tri-
chlorophenol (Phipps, et al. manuscript). Among the freshwater inverte-
brates, Daohnia maqna was assayed with seven chlorophenols in eight 48-hour
static bioassays. Acute LC5Q values ranged from 290 ug/1 for 2,3,4,6-
tetrachlorophenol and 4-chloro-2-methylphenol to 6,040 ug/1 for 2,4,6-tri-
-------
chlorophenol (U.S. EPA, 1978). Acute 96-hour static LC50 values in the
sheepshead minnow ranged from 1,660 pg/1 for 2,4,5-trichlorophenol to 5,350
pg/1 for 4-chlorophenol. The only marine invertebrate species acutely
tested has been the mysid shrimp, Mysidopsis bahia , with acute 96-hour
static LC5Q values reported by the U.S. EPA (1978) as: 3,830 ug/1 for
2,4,5-trichlorophenol; 21,900 ug/1 for 2,3,5,6-tetrachlorophenol, and 29,700
pg/1 for 4-chlorophenol.
8. Chronic Toxicity
No data other than that presented in the specific hazard profile
for 2^chlorophenol, 2,4-dichloropnenol, and pentachlorophenol were available
for freshwater, organisms. An embryo-larval study provided a chronic value
of 180 ,ug/r for sheepshead minnows -t Cyprinodon varieqatus j exposed to 2,4-
dichloro-6-methylphenol (U.S. EPA, 1978).
C. Effects on Plants
Effective concentrations for 15 tests on four species of freshwater
plants ranged from chlorosis LC5Q of 603 pg/1 for 2,3,4,6-tetrachlorophe-
nol- to 598,584 /ug/1 for 2-chlofo-6-methylphenol in the duckweed, Lemna minor
(Blackman, et al. 1955). The marine algae, Skeletonema costatum7 has been
used to assess the relative toxicities of three chlorinated phenols. Effec-
tive concentrations, based on chlorophyll a content and cell growth, of 440
and 500 fjg/l were obtained for 2,3,5,6-tetrachlorophenol. 2,4,5-Trichloro-
phenol and 4-chlorophenol were roughly two and seven times as potent, re-
spectively, as 2,3,5,6-tetrachlorophenol.
0. Residues
Steady-state bioconcentration factors have not been calculated for
the chlorinated phenols. However, based upon octanol/water partition coef-.
ficients, the following bioconcentration factors have been estimated for
-------
aquatic organisms with a lipid content of eight percent: 41 for 4-chloro-
phenol; 440 for 2,4,5-trichlorophenol; 380 for 2,4,6-trichlorophenol; 1,100
for 2,3,4,6-tetrachlorophenol; and 470 for 4-chloro-3-methylphenol.
E. Miscellaneous
The tainting of fish flesh by exposure of rainbow trout; .Salmo
qairdneri) to various chlorinated phenols has derived a range of estimated
concentrations not impairing the flavor of cooked fish from 15 yg/1 for
2-chlorophenol to 84 ug/1 for 2,3-dichlorophenol (Schulze, 1961; Shumway and
Palensky, 1973).
II. 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. Draft criteria recommended for chlorinated phenols by the U.S. EPA
(1979) are given in the following table:
Draft Ambient Water Quality Criteria
Compound
Criterion from
Organoleptic
Effects
Criterion from
Toxicological
Data
Monochlorophenols
3-chlorophenol
4-chlorophenol
Dichlorophenols
2,5-dichlorophenol
2,6-diehlorophenol
Trichlorophenols
2,4,5-trichlorophenol
2,4,6-trichlorophenol
Tetrachloroohenol*
2,3,4,6-tetrachlorophenol
50 jug/1
30 ug/1
3.0 ug/1
3.0 ug/1
10 jug/1
100 jjg/1
915 jug/1
none
none
none
none
1600 pg/1
263 jjg/1
-------
Chlorocre_sol
Insufficient data on which
to base a criterion .
*Tne criterion will be based on toxicological effects (U.S. EPA, 1979).
8. Aquatic
The proposed draft criterion for 2,4,6-trichlorophenol is 52 pg/1,
not to exceed 150 /jg/1 in freshwater environments. No additional criterion
for other chlorinated phenols can presently be derived for either freshwater
or marine organisms because of insufficient data (U.S. EPA, 1979).
-------
CHLORINATED PHENOLS
REFERENCES
Ahlborg, U.G. and K. Larsson. 1978. Metabolism of tetrachlorophenols in
the rat. Arch. Toxicol. 40: 63.
Ainley, E.J., et al. 1977. Adverse reaction to chlorocresol-preserved
heparin. Lancet 1803: 705.
Bjerke, E.L., et al. 1972. Residue study of phenoxy herbicides in milk and
cream. Jour. Agric. Food Chem. 20: 963.
Blackman, G.E., et al. 1955. The physiological activity of substituted
phenols. I. Relationships between chemical structure and physiological
activity. Arch. Biochem. Biophys. 54: 45.
Bleiberg, J., -et al. 1964. Industrially acquired porphyria. Arch. Derma-
tol. 89: 793.
Boutwell, R.K. and O.K. Bosch. 1959. The tumor-promoting action of phenol
and related compounds for mouse skin. Cancer REs. 19: 413.
Burttschell, R.H., et al. 1959. Chlorine derivatives of phenol causing
taste and odor. Jour. Am. Water Works Assoc. 51: 205.
Clark, O.E., et al. 1976. Residues of chlorophenoxy acid herbicides and
their phenolic metabolites in tissues of sheep and cattle. Jour. Agric.
Food Chem. 23: 573.
Eichholz, F. and R. Wigand. 1931. Uber die wirkung von darmdesinfektion
smilleln. Eingegangen. 159: 81.
Fahrig, R. et al. 1978. Genetic activity of chlorophenols and chlorophenol
impurities. Pages 325-338 In: Pentachlorophenol: Chemistry, pharmacology
and environmental toxicology. K. Rango Rao, Plenum Press, New York/
Farquharson, M.E., et al. 1958. The biological action of chlorophenols.
8r. Jour. Pharmacol. 13: 20.
Foster, T.S. and J.G. Saha. 1978. The in vitro metabolism .of lindane by an
enzyme preparation from chicken liver. Jour. Environ. Sci. Health 13: 25.
Gaunt, J.K. and W.C. Evans. 1971. Metabolism of 4-chlor-2-methylphenoxy-
acetate by a soil pseudomonad. Biochem. Jour. 122: 519.
Goldstein, J.A., et al. 1977. Effects of pentachlorophenol on hepatic
drug-metabolizing enzymes and porphyria related to contamination with chlor-
inated dibenzo-p-dioxins and dibenzofurans. Biochem. Pharmacol. 26: 1549.
Gurova, A.I. 1964. Hygienic characteristics of p-chlorophenol in the ani-
line dye industry. Hyg. Sanita. 29: 46.
-------
Hancock, 8.W. and A. Naysmith. 1975. Hypersensitivity of chlorocresol
preserved heparin. Br. Med. Jour. 746.
Innes, J.R.M., et al. 1969. Bioassay of pesticides and industrial chemi-
cals for tumorigenicity in mice: A preliminary note. Jour. Natl. Cancer
Inst. 42: 1101.
Jolley, R.L., et al. 1975. Analysis of soluble organic constituents in
natural and process waters by high-pressure liquid chromatography. Trace
Subs. Environ. Hlth. 9: 247.
Karpow, G. 1893. On the antiseptic action of three isomer chlorophenols
and of their salicylate esters and their fate in the metabolism. Arch. Sci.
Bid. St. Petersburg. 2: 304. Cited by W.F. von Oettingen, 1949.
Kohli, J., et al. 1976. The metabolism of higher chlorinated benzene iso-
mers. Can. Jour. Biochem. 54: 203.
Korte, I., et al. 1976. Studies on the influences of some environmental
chemicals and their metabolites on the content of free adenine nucleotides,
intermediates of glycolysis and on the activities of certain enzymes of
bovine lenses in vitro. Chemosphere 5: 131.
Kutz, F.W., et al. 1978. Survey of pesticide residues and their metabo-
lites in urine from the general population. Pages 363-369 In: K. Rango Rao,
ed. Pentachlorophenol: Chemistry, pharmacology and environmental toxico-
logy, Plenum Press, New York.
Levin, J.O., et al. 1976. Use of chlorophenols as fungicides in sawmills.
Scand. Jour. Work Environ. Health 2: 71.
Lindsay-Smith, Jr., et al. 1972. Mechanisms of mammalian hydroxylation:
Some novel metabolites of chlorobenzenes. Xenobiotica 2: 215.
McCollister, D.D., et al. 1961. Toxicologic information on 2,4,5-tri-
chlorophenol. Toxicol. Appl. Pharmacol. 3: 63.
Mitsuda, H., et al. 1963. Effect of chlorophenol analogues on tfte oxida-
tive phosphorylation in rat liver mitochondria. Agric. Biol. Chem. 27: 366.
Olie, K., et al. 1977. . Chlorodibenzo-p-dioxins and chlorodibenzoflurans
are trace components of fly ash and flue gas of some municipal incinerators
in the Netherlands. Chemosphere 8: 445.
Phipps, G.L., et al. The acute toxicity of phenol and substituted phenols
to the fathead minnow.. (Manuscript)
Piet, G.J. and F. OeGrunt. 1975. Organic chloro compounds in surface and
drinking water of the Netherlands. Pages 81-92 In: Problems raised by the
contamination of man and his environment. Comm. Eur. Communities, Luxem-
bourg.
Rasanen, L. and M.L. Hattula. 1977. The mutagenicity of MCPA and its soil
metabolites, chlorinated phenols, catechols and some widely used slimicides
in Finland. Bull. Environ. Contam. Toxicol. 18: 565.
-------
Rasanen, L., et al. 1977. The mutagenicity of MCPA and its soil metabo-
lites, chlorinated phenols, catechols and some widely used slimicides in
Finland. Bull. Environ. Contam. Toxicol. 18: 565.
Roberts, M.S., et al. 1977. Permeability of human epidermis to phenolic
compounds. Jour. Pharm. Pharmac. 29: 677.
Schulze, E. 1961. The effect of phenol-containing waste on the taste of
fish. Int. Revue Ges. Hydrobiol. 46, No. 1, p. 81.
Schwetz, 3.A., et al. 1974. Effect of purified and commercial grade tetra-
chlorophenol on rat embryonal and fetal development. Toxicol. Appl. Pharma-
col. 28: 146.
Shumway, O.L. and J.R. Palensky. 1973. Impairment of the flavor of fish by
water pollutants. EPA-R3-73-010. U.S. Environ. Prot. Agency, U.S. gov-
ernment Printing Office, Washington, D.C.
U.S. EPA. 1972. The effect of chlorination on selected organic chemicals.
Water Pollut. Control Res. Ser. 12020.
U.S. EPA. 1978. In-depth studies on health and environmental impacts on
selected *""•) pollutants. Contract No. 68-01-4646.
U.S. EPA. 1979. Chlorinated Phenols: Ambient Water Quality Criteria.
(Draft)
Weinbach, E.C. and J. Garbus. 1965. The interaction of uncoupling phenols
with mitochondria and with mitochondrial protein. Jour. Biol. Chem.
210: 1811.
•^
Wien, R. 1^39. The toxicity of parachlorometacresol and of phenylmercuric
nitrate. Quarterly Jour, and Yearbook of Pharmacy. 12: 212.
/
Wright, F.C.-,J et al. 1970. Metabolic and residue studies with 2-(2,4,5-
trichlorcphenoxy)-ethyl 2,2-dichloropropionate. Jour. Agric. Food Chem.
18: 845. »
Zondek, 8. and 8. Shapiro. 1943. Fate of halogenated phenols in the or-
ganism. Biochem. Jour. 37: 592.
-------
No. 40
Chloroacetaldehyde
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.
-------
CHLOROACETALDEHYDE
Summary
No carcinogenic effects v/ere observed in female ICR Ha Swiss mice follow-
ing administration of chloroacetaldehyde via dermal application or subcutaneous
injection. Mutagenic effects, varying from weak to strong, have been reported
in the yeasts Schizosaccharomyces pombe and Saccharomyces cerivisiae and in
certain Salmonella bacterial tester strains. There is no evidence in the
available literature to indicate that chloroacetaldehyde produces teratogenic
effects. Occupational exposure studies have shown chloroacetaldehyde to be a
severe irritant of the eyes, mucous membranes and skin.
Data concerning the effects.of chloroacetaldehyde on aquatic organisms
were not found in the available literature.
-------
CHLOROACETALDEHYDE
INTRODUCTION
Chloroacetaldehyde (C^rUClO) is a clear, colorless liquid with a pungent
odor. Its physical properties include: boiling point, 90.0-100.1°C (40 per-
cent sol.); freezing point, -16.3°C (40 percent sol.); and vapor pressure, 100
mm at 45°C (40 percent sol.). Synonyms for Chloroacetaldehyde are:
monochloroacetaldehyde, 2-chloroacetaTdehyde and chloroaldehyde. It is soluable
in water, acetone and methanol. Primary uses of Chloroacetaldehyde include:
use as a fungicide, use in the manufacture of 2-aminothiazole, and use in the
removal of bark from tree trunks.
II. EXPOSURE
No monitoring data are available to indicate ambient air or water levels
of Chloroacetaldehyde, nor is any information available on possible exposure
from food.
Occupational routes of human exposure to Chloroacetaldehyde are primarily
.through inhalation and skin absorption.
Bioaccumulation data on Chloroacetaldehyde were not found in the available
literature. However, 2-chloroacetaldehyde is known to be a chemically reactive
compound and its half-life in aqueous solution has been reported as slightly
greater than 24 hours (Van Duuren et a!., 1972).
III. PHARMACOKINETICS
A. Absorption
Exposure to Chloroacetaldehyde is primarily through inhalation and
skin absorption.
Chloroacetaldehyde proved to be very lethal by inhalation. In an iphalation
study conducted by Lawrence et al. (1972), mice were placed in a chloroacetaldehyde-
free chamber and air containing Chloroacetaldehyde vapor was then passed
-------
through the chamber. The time of exposure required to kill 50% of the animals,
LT5Q) was 2.57 min. (the chamber atmosphere was calculated to have reached 45%
equilibrium within that time.)
In comparison studies conducted on chloroacetaldehyde and 2-chloroethanol ,
chloroacetaldehyde was reported as exhibiting greater irritant activity, but
having lesser penetrant capacity (Lawrence et al., 1972).
B. Distribution
Information on the distribution of chloroacetaldehyde was not found
in the available literature.
C. Metaboli sm
Chloroacetaldehyde appears to be a metabolite of a number of compounds
including 1,2-dichloroethane, chloroethanol and vinyl chloride (McCann et. al.',
1975).
Johnson (1967) conducted i_n vitro studies on rat livers, the results of
which indicated that S-carboxymethylglutathione was probably formed via
chloroacetaldehyde metabolic action. Based upon these studies, Johnson suggested
that the same metabolic mechanism was operative in the i_n vivo conversion of
chloroethanol to S-carboxymethylglutathione.
In recent studies, Watanabe et al. (1976a,b) reported .that chloro-
acetaldehyde would conjugate with glutathione and cysteine leading ultimately
to the types of urinary metabolites found in animals exposed to vinyl chloride.
The authors reported that as nonprotein free sulfhydral concentrations are
depleted, the alkylating metabolites, one of which is chloroacetaldehyde, are
likely to react with protein, DNA and RNA, eliciting proportionally greater
toxicity. This is in agreement with other studies conducted on vinyl ch.loride
metabolism (Hefner et al., 1975; Bolt et al., 1977).
-------
Chloroacetaldehyde was shown to cause the destruction of lung hemoprotein,
cytochrome P450, as well as liver microsomal cytochrome P450, with no requirement
for NADPH (Harper and Patel, 1978). The results suggested that the aldehydes
tested, one of which was chloroacetaldehyde, were the toxic intermediates
which inactivated pulmonary enzymes following exposure to some environmental
agents.
D. Excretion
Information specifically on the rates and routes of chloroacetaldehyde
elimination was not found in the available literature. Studies on vinyl
chloride and ethylene dichloride, however, indicate that chloroacetaldehyde,
as an intermediate metabolite, may ultimately convert to a number of urinary
metabolites — including chloroacetic acid, S-carboxymethylcysteine and thiodiacetic
acid—depending on the particular metabolic pathway involved in the biotransforma-
tion of the parent compound (Johnson, 1967; Yllner, 1971; Watanabe, 1976a,b).
IV. EFFECTS
A. Careinogenicity
In a study on the carcinogenic activity of alkylating agents, Van
Duuren et al. (1974) exposed female ICR Ha Swiss mice to 2-chloroacetaldehyde
(assayed as diethylacetal). The routes of administration were via skin and
subcutaneous injection. The authors reported no significant tumor induction.
Later studies confirmed these findings (Goldschmidt, personal communication,
1977). However, in a report by McCann et al. (1975), the authors stated that
previous reports of changes of respiratory epithelium in lungs of rats exposed
to chloroacetaldehyde were suggestive of premalignant conditions.
B. Mutagenicity
Many studies have been reported which show that chloroacetaldehyde
exhibits varying degrees of mutagenic activity (Huberman et al., 1975; Border
-------
and Webster, 1976; Elmore et al., 1976; Rosenkranz, 1977). Loprieno et al.
(1977) reported that 2-chloroacetaldehyde showed only feeble genetic activity
when tested in the yeasts Schizosaccharomyces pombe and Saccharomyces cerevisiae.
However, McCann et al. (1975) reported that chloroacetaldehyde was quite
effective in reverting Salmonella bacterial tester strain TA 100, but did not
revert TA 1535. In a later study, Rosenkranz (1977) found that
2-chloroacetaldehyde did display some mutagenic activity towards TA 1535.
In a study conducted by Elmore et al. (1976) the authors reported that
the chloroacetaldehyde monomer and monomer hydrate were more mutagenically
active that the dimer hydrate and the trimer.
Rannug et al. (1976) reported that the mutagenic effectiveness of
4
chloroacetaldehyde is about 10 times higher than expected from kinetic data.
C. Teratogenicity and Other Reproductive Effects
Pertinent information could not be found.in the available literature.
0. Chronic Toxicity
No chronic information could be found in the available literature.
However, extensive toxicity studies conducted by Lawrence et al. (1972) revealed
some subacute effects of chloroacetaldehyde on Sprague-Dawley and Black Bethesda
rats. Groups of rats received .001879 and .003758 ml/kg of chloroacetaldehyde
(representing 0.3 .and 0.6 of the acute LD5Q dose, respectively) daily for 30
consecutive days. Hematologic tests at the end of 30 days showed that there
was a significant decrease in hemoglobin, hematocrit, and erthrocytes in the
high dose group; the low dose group showed an increase in monocytes accompanied
by a decrease in lymphocytes. The animals were sacrificed and organ-to-body
weight ratios were calculated. Ratios for both brain and lungs were significantly
«
greater in the low dose group, while the high dose group showed a significant
increase in the brain, gonads, heart, kidneys, liver, lungs and spleen.
-------
Histological examination did not reveal any abnormalities attributable to
chloroacetaldehyde except for the lungs which showed more severe bronchitis,
bronchiolitis and bronchopneumonia than were seen in controls.
In another subacute (subchronic) study, chloroacetaldehyde was administered
to rats in doses of .00032, .00080, .00160 and .00320 ml/kg, three times a
week for 12 weeks. Hematologic determinations showed no significant differences
between controls and the two lower dose groups, while animals administered
.0016 ml/kg showed a decrease in red cell count and lymphocytes and an increase
in segmented neutrophiles; the highest dose group showed a significant decrease
in red blood cells and hemoglobin with an increase in clotting time and segmented
neutrophiles. Organ-to-body weight ratios were determined for several organs
and, although there were some significant differences from controls, there
were no apparent dose-related responses.
D. Acute Toxicity
Lawrence et al. (1972) conducted a series of acute toxicity tests on
ICR mice, Sprague-Dawley and Black Bethesda rats, New Zealand albino rabbits
and Hartlez strain guinea pigs. .The results were reported as follows: the
LDqnS (ml/kg) for chloroacetaldehyde administered intraperitoneally ranged
from .00598 in mice to .00464 in rabbits; the LD50s (ml/kg) for chloroacetaldehyde
administered intragastrically were reported as .06918 in male mice, .07507 in
female rats and .08665 in male rats; the dermal ID™ (ml/kg) in rabbits was
reported as .2243; and the inhalation LTrQ in mice was reported as 2.57 min.
E. Other Relevent Information
Case studies show that contact with a strong solution of chloroacetaldehyde
in the human eye will likely result in permanent impairment of vision and skin
contact with a potent solution will result in burns (Proctor and .Hughes,
1978).
-------
V. AQUATIC TOXICITY
Data concerning the effects of chloroacetaldehyde on aquatic organisms
were not found in the available literature.
VI. EXISTING GUIDELINES
The 8-hour, TWA occupational exposure limit established .for chloroacetaldehyde
is 1 ppm. This TLV of 1 ppm was set to prevent irritation (ACGIH, 1976).
i
-------
CHLOROACETALDEHYDE
References
1. American Industrial Hygiene Association. 1976. Threshold limit values
for substances in workroom air. 3rd ed. p. 48. Cincinnati. Cited in
Proctor and Hughes, 1978.
2. Bolt, H. M. et al. 1977. Pharmacokinetics of vinyl chloride in the rat.
Toxicology. 1_:11^.
3. Border, E. A., and I. Webster. 1977. The effect of vinyl chloride
monomer, chloroethylene oxide and chloroacetaldehyde on DNA synthesis in
regenerating rat liver. Chem. Biol. Interact.•• 17:239.
4. Elmore, J. 0. et al. 1976. Vinyl chloride mutagenicity via the metabolites
chlorooxirane and chloroacetaldehyde monomer hydrate. Biochim. Biophys.
Acta. 442:405.
5. Harper, C., and J. M. Patel. 1978. Inactivation of pulmonary cytochrome
P 450 by aldehydes. Fed. Proc. 37:767. •: ''• j
6. Hefner, R. E. , Jr. et al. 1975. Preliminary studies of the fate of inhaled
vinyl chloride monomer in rats. Ann. N.Y. Acad. Sci. 246:135.
7. Huberman, E. et al. 1975. Mutation induction in Chinese hamster V79
cells by two vinyl chloride metabolites, chloroethylene oxide and
2-chloroacetaldehyde. Int. J. Cancer. 16:639.
•'-.
8. Johnson, M. K. 1967. Metabolism of chloroethanol in the rat. Biochem.
Pharmacol. 16:185.
9. Lawrence W. H. et al. 1972. Toxicity profile of chloroacetaldehyde. J.
Pharm. Sci. 61:19.
10. Loprieno, N. et al. 1977. Induction of gene mutations and gene conversions
by vinyl chloride metabolites in yeast. Cancer Res. 36:253.
11. McCann, J. et al. 1975. Mutagenicity of chloroacetaldehyde, a possible
metabolic product of 1,2-dichloroethane (ethylene dichloride), chloroethanol
(ethylene chlorohydrin), vinyl chloride, and cyclophosphamide. Proc.
Nat. Acad. Sci. 72:3190.
12. Proctor, N. H., and J. P. Hughes. 1978. Chemical hazards of the workplace.
p. 160. Lippincott Co., Philadelphia.
13. Rannug, U. et al. 1976. Mutagenicity of chloroethylene oxide,
chloroacetaldehyde, 2-chloroethanol and chloroacetic acid, conceivable
metabolites of vinyl chloride. Chem. Biol. Interact. 12:251.
14. Rosenkranz, H. S. 1977. Mutagenicity of halogenated alkanes and their
derivatives. Environ. Health Perspect. 21:79.
-------
15. Van Duuren, B. L. et al. 1972. Carcinogenicity of halo-ethers. II.
Structure-activity relationships of analogs of bis- (chloromethyl) ether.
J. Nat. Cancer Inst. 48:1431.
16. Van Duuren, B. L. et al. 1974. Carcinogenic activity of alkylating
agents. J. Nat. Cancer Inst. 53:695
17. Watanabe, P. G. et al. 1976a. Fate of 14C vinyl chloride after single
oral administration in rats. Toxicol. Appl. Pharmacol. 36:339.
18. Watanabe, P. G. et al. 1976b. Fate of C vinyl chloride following
inhalation exposure in rats. Toxicol. App. Pharmacol. 37:49.
14
19. Yllner, S. 1970. Metabolism of chloroacetate -1- C in the mouse. Acta
Pharmacol. Toxicol. 30:69.
Yllner, S. -1971. Metaboli:
Pharmacol. Toxicol. 30:257.
14
20. Yllner, S. -1971. Metabolism of 1,2-dichloroethane- C in the mouse. Acta
-------
No. 41
Chloroalkyl Ethers
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
»
U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
chloroalkyl ethers and has found sufficient evidence to
indicate that this .compound is carcinogenic.
-------
CHLOROALKYL ETHERS
SUMMARY
Bis(chloromethyl)ether (BCME), chloromethyl methyl ether
(CMME), and bis(2-chloroethyl)ether (BCEE) have shown carcin-
ogenic effects in animal studies following administration by
various routes. Epidemiological studies in the United States,
Germany, and Japan have indicated that workers exposed to
BCME and CMME developed an increased incidence of respiratory
tract tumors.
Testing of BCME, CMME, BCEE, and bis(2-chloroisopropyl)-
ether (BCIE) in the Ames Salmonella assay and in _E. coli have
indicated that these compounds have mutagenic activity. Cy-
togenetic studies of lymphocytes from workers exposed to BCME
and CMME have reported an increased frequency of aberrations,
which appear to be reversible.
There is no available evidence to indicate chloroalkyl
ethers produce adverse reproductive or teratogenic effects.
The information base for freshwater organisms and chloro-
alkyl ethers is limited to a few toxicity tests of 2-chloro-
ethyl vinyl ether and bis(2-chloroethyl)ether. The.repbrted
96-hour LCjQ value for bis(2-chloroethyl)ether in the
bluegill is greater than 600,000 ug/l« A "no effect" value
of 19,000 ug/1 was observed using the fathead minnow in an
embryo-larval test. Bis(2-chloroethyl)ether has a reported
bioconcentration factor of 11 in a 14-day exposure to blue-
gills. The half-life is from four to seven days. The re-»
ported 96-hour LC5Q value for the bluegill and 2-chloro-
ethyl vinyl ether is 194,000 ug/1.
-S'OO-
/
-------
CHLOROALKYL ETHERS
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for chloroalkyl ethers (U.S. EPA, 1979).
The chloroalkyl ethers are compounds with a hydrogen
atom in one or both of the aliphatic ether chains substituted
by a chlorine atom. The chemical reactivity of these com-
pounds varies greatly, depending on the nature of the ali-
phatic groups and the placement of the chlorine atoms. The
most reactive compounds are those with short aliphatic groups
and those in which chlorine substitution is closest to the
ether oxygen (alpha-chloro) (U.S. EPA, 1979).
As an indication of their high reactivity, chloromethyl
methyl ether (CMME), bis(chloromethyl)ether (BCME), 1-chloro-
ethyl ethyl ester, and. 1-chloroethyl methyl ether decompose
rapidly in water. The beta-chloroethers, bis(2-chloroethyl)-
ether (BCEE) and bis(2-chloroisopropyl)ether (BCIE) are more
stable in aqueous systems; they are practically insoluble in
water but miscible with most organic solvents (U.S. EPA,
1979).
The chloroalkyl ethers have a wide variety of industrial
and laboratory uses in organic synthesis, textile treatment,
the manufacture of polymers and insecticides, in the prepara-
tion of ion exchange resins, and as degreasing agents (U.S.
EPA, 1979).
While the short chain alpha-chloroalkyl ethers (BCME,.
CMME) are very unstable in aqueous systems, they appear to be
relatively stable in the atmosphere (Tou and Kallos, 1974).
Bis(chloromethyl)ether will form spontaneously in the pres-
-------
ence of both hydrogen chloride and formaldehyde (Frankel, et
al. 1974).
II. EXPOSURE
The beta-chloroalkyl ethers have been monitored in
water. Industrial effluents from chemical plants involved in
the manufacture of glycol products, rubber, and insecticides
may contain high levels of these ethers (U.S. EPA, 1979).
The highest concentrations in drinking water of bis(2-chloro-
ethyl)ether, bis(2-chloroisopropyl)ether, and bis-l,2-(2-
chloroethoxy)ethane (BCEXE) reported by the U.S. EPA (1975)
are 0.5, 1.'58, and 0.03 ug/lr respectively. The average con-
centration of these compounds in drinking water is in the
nanogram range (U.S. EPA, 1979). Chloroalkyl ethers have
been detected in the. atmosphere, and human inhalation expo-
sure appears to be limited to occupational settings.
The chloroalkyi ethers have not been monitored in food
(U.S. EPA, 1979). The betachloroalkyl ethers, because of
their relative stability and low water solubility, may have a
tendency to be bioaccumulated. The U.S. EPA (1979) has esti-
mated the weighted biocohcentration factor to be 25 for' the
edible portions of fish and shellfish consumed by Americans.
This is based on the measured' steady-state bioconcentration
studies in bluegills. Bioconcentration factors for BCME (31)
and BCIE (106) have been derived using a proportionality con-
stant related to octanol/water partition coefficients (U.S.
EPA, 1979). Dermal exposure for the chloroalkyi ethers has
not been determined (U.S. EPA, 1979).
-SOZ-
-------
III. PHARMACOKINETICS
A. Absorption
Experiments with radio-labelled BCIE and BCEE in
female rats and monkeys have indicated that both compounds
are readily absorbed in the blood following oral administra-
tion (Smith, et al., 1977; Lingg, et al., 1978). Pertinent
data could not be located in the available literature re-
trieved on dermal or inhalation absorption of the alkyl
ethers.
B. Distribution
Species differences in the distribution of radio-
labelled BCIE have been reported by Smith, et al. (1977).
Monkeys, as compared to rats, retain higher amounts of radio-
activity in the liver, muscle, and brain. Urine and expired
air from the rat contained higher levels of radioactivity
than those found in the monkey. Blood levels of BCIE in mon-
keys reached a peak within two hours following oral adminis-
tration and then declined in a biphasic manner (^1/2's
= 5 hours and 2 days for the first and second phases, respec-
tively) .
C. Metabolism
The biotransformation of BCEE in rats following
oral administration appears to involve cleavage of the ether
linkage and subsequent conjugation (Lingg, et al., 1978).
Thiodiglycolic acid and chloroethanol-D-glucuronide were
identified as urinary metabolites of BCEE. Metabolites of
BCIS identified in the rat included l-chloro-2-propanol, pro-
pylene oxide, 2-(l-methyl-2-chloroethoxy)-propionic acid, and
carbon dioxide (Smith, et al., 1977).
-------
D. Excretion
BCEE administered orally to rats was excreted
rapidly, with more than 60 percent of the compound excreted
within 24 hours. Virtually all of this elimination was via
the urine (Lingg, et al., 1978).
IV. EFFECTS
A. Carcinogenicity
There are several studies with bis(chloromethyl)-
ether (BCME), chloromethyl methyl ether (CMME), and bis(2-
chloroethyl)ether (BCEE) that show carcinogenic effects.
BCME induced malignant tumors of the male rat respiratory
tract following inhalation exposure (Kuschner, et al.,
1975). Application of BCME and BCEXE to the skin of mice
produced skin tumors (Van Duuren, et al., 1968), while subcu-
taneous injection of BCME to newborn mice induced pulmonary
tumors (Gargus, et al., 1969).
Oral administration of bis(2-chloroethyl)ether (BCEE) to
mice has been shown to increase the incidence of hepatocellu-
lar carcinomas in males (Innes, et al., 1969).
Epidemiological studies of workers in the United States,
Germany, and Japan who were occupationally exposed to BCME
and CMME have indicated these compounds are human respiratory
carcinogens (U.S. EPA, 1979).
Both BCME and CMME have been:shown to accelerate the
rate of lung tumor formation in Strain^A mice following inha-
lation exposure (Leong, et al., 1971). BCME and BCEE have*
shown tumor initiating activity for mouse skin, while CMME
showed only weak initiating activity (U.S. EPA, 1979).
X
-------
Preliminary results of a National Cancer Institute
study indicate that oral administration of BCIE does not pro-
duce an increase in tumor incidence (U.S. EPA, 1979).
B. Mutagenicity
Testing of the chloroalkyl ethers in the Ames Sal-
monella assay on _E. coli have indicated that BCME, CMME,
BCIE, and BCEE all produced mutagenic effects (U.S. EPA,
1979). BCEE has also been reported to induce mutations in
Saccharomyces cerevisiae (U.S. EPA, 1979). Neither BCEE nor
BCIE showed mutagenic effects in the heritable translocation
test in mice (Jorganson, et al. 1977). An increase in cyto-
genetic aberrations in the lymphocytes of workers exposed to
BCME and CMME was reported by Zudova and Landa (1977); the
frequency of aberrations decreased following the removal of
workers from exposure.
C. Teratogenicity and Other Reproductive Effects
Pertinent data could not be located in the avail-
able literature.
D. Chronic Toxicity
Chronic occupational exposure to CMME contaminated
with BCME has produced bronchitis in workers (U.S. EPA,
1979). Cigarette smoking has been found to act synergisti-
cally with CMME exposure to-produce bronchitis (Weiss, 1976,
1977).
Animal studies have indicated that chronic exposure
to BCIE produces liver necrosis in mice. Exposure in rats'
causes major effects on the lungs, including congestion and
pneumonia (U.S. EPA, 1979).
-------
E. Other Relevant Information
The initiating activity of several chloroalkyl
ethers indicates that these compounds may interact with other
agents to produce skin papillomas (Van Duuren, et al., 1969,
1972).
V. AQUATIC TOXICITY
A. Acute Toxicity
The reported static 96^hour LC5Q value for the
bluegill (Lepomis macrochirus) with 2-chloroethyl vinyl ether
(concentration unmeasured) is 194,000 ug/1 (U.S. EPA, 1978).
The 96-hour LCgQ values for the bluegill could not be de-
termined in a static test for bis(2-chloroethyl)ether with
exposure concentrations as high as 600,000 ug/1. The concen-
tration of the ether was not monitored during the bioassay.
Pertinent data could not be located in the available litera-
ture on saltwater species.
B. Chronic Toxicity
An embryo-larval test was conducted with bis(2-
chloroethyl)ether and the fathead minnow, (Pimephales prome-
las). Adverse effects were not observed at test concentra-
tions as high as 19,000 ug/1-
C. Plant Effects
Pertinent data could not be located in the avail-
able literature.
D. Residues
Using bis(2-chloroethyl)ether, a bioconcentratiofi
factor of 11 was determined during a 14-day exposure of blue-
gills (U.S. EPA, 1979). The half-life was observed to be
between four and seven days.
-------
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
Based on animal carcinogenesis bioassays, and using
a linear, nonthreshold model, the U.S. EPA (1979) has esti-
mated the following ambient water levels of chloroalkyl
ethers which will produce an increased cancer risk of
10~5: BCIE,' 11.5ug/l; BCEE, 0.42 ug/1; and BCME 0.02
ng/1.
Eight-hour TWA exposure values (TLV) for the fol-
lowing chloroalkyl ethers have been recommended by the Ameri-
can Conference of Governmental and Industrial Hygienists
(ACGIH, 1978): BCME, 1 ppb; BCEE, 5 ppm.
B. Aquatic
Freshwater and saltwater drafted criteria have not
been derived for any chloroalkyl ethers because of insuffi-
j
cient data (U.S. EPA, 1979).
-5-07-
-------
CHLOROALKYL ETHERS
REFERENCES
American Conference of Governmental Industrial Hygienists.
1978. Threshold limit values for chemical substances and
physical agents in the workroom environment with intended
changes for 1978. Cincinnati, Ohio.
Frankel, L.S., et al. 1974. Formation of bis (chloromethyl)
ether from formaldehyde and hydrogen chloride. Environ. Sci.
Technol. 8: 356.
Gargus, J.L., et al. 1969. Induction of lung adenomas in
newborn mice by bis(chloromethyl) ether. Toxicol. Appl.
Pharmacol. 15: 92.
Irines, J.R.M., et al. 1969. Bioassay of pesticides and in-
dustrial chemicals for tumorigenicity in mice: A preliminary
note. Jour. Natl. Cancer Inst. 42: 1101.
Jorgenson, T.A., et al. 1977. Study of the mutagenic poten-
tial of bis(2-chloroethyl) and bis (2-chloroisopropyl) ethers
in mice by the heritable translocation test. Toxicol. Appl.
Pharmacol. 41: 196.
Kuschner, M., et al. 1975. Inhalation carcinogenicity of
alpha halo esthers. III. Lifetime and limited period inhala-
tion studies with bis(chloromethyl)ether at 0.1 ppm. Arch
Environ. Health 30: 73.
Leong, B.K.J., et al. 1971. Induction of lung adenomas by
chronic inhalation of bis(chloromethyl)ether. Arch. Environ.
Health 22: 663.
Lingg, R.D., et al. 1978. Fate of bis(2-chloroethyl)ether
in rats after acute oral administration. Toxicol. Appl.
Pharmacol. 45: 248.
Smith, C.C., et al. 1977. Comparative metabolism of halo-
ethers. Ann. M.Y. Acad. Sci. 298: 111.
Tou, J.C., and G.J. Kallos. 1974. Kinetic study of the sta-
bilities of chloromethyl methyl ether and bis(chloromethyl)-
ether in humid air. Anal. Chem. 46: 1866.
U.S. EPA. 1975. Preliminary assessment of suspected carcin-
ogens in drinking water. Rep. Cong. U.S. Environ. Prot.
Agency, Washington, D.C.
»
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.
a
-------
U.S. EPA. 1979. Chloroalkyl Ethers: Ambient Water Quality
Criteria. (Draft).
Van Duuren, B.L., et al. 1968. Alpha-haloethers: A new type
of alkylating carcinogen. Arch. Environ. Health 16: 472.
Van Duuren, B.L., et al. 1969. Carcinogenicity of halo-
ethers. Jour. Natl. Cancer Inst. 43: 481.
Van Duuren> B.L. , et al. 1972. Carcinogenicity of halo-
ethers. II. Structure-activity relationships of analogs of
bis(chloromethyl)ether. Jour. Natl. Cancer Inst. 48: 1431.
Weiss, W. 1976. Chloromethyl ethers, cigarettes,, cough and
cancer. Jour. Occup. Med. 18: 194.
Weiss, W. 1977. The forced end-expiratory flow rate in
Chloromethyl ether workers. Jour. Occup. Med. 19: 611.
Zudova, Z., and K. Landa. 1977. Genetic risk of occupation-
al exposures to haloethers. Mutat. Res. 46: 242.
-------
No. 42
Chlorobenzene
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-SVO-
-------
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.
-5JI-
-------
.CHLOROBENZENE
Summary
There is little data on the quantities of chlorobenzene in air, water
and food, although this compound has been identified in these media. Chron-
ic exposure to chlorobenzene appears to cause a variety of pathologies under
different experimental regimens; however, the liver and kidney appear to be
affected in a number of species. There have been no studies conducted to
evaluate the mutagenic, teratogenic, or carcinogenic potential of chloro-
benzene.
Four species of freshwater fish have 96-hour LC50 values ranging from
24,000 to 51,620 ug/1. Hardness does not significantly affect the values.
In saltwater, a fish and shrimp had reported 96-hour l_C50 values of 10,500
ug/1 and 6,400 jug/1, respectively. No chronic data involving chlorobenzene
are available. Algae, both fresh and saltwater, are considerably less sen-
sitive to chlorobenzene toxicity than fish and invertebrates.
-------
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria Document
for Chlorinated Benzenes (U.S. EPA, 1979).
Chlorobenzene, most often referred to as monochlcrobenzene (fC3;
CgHjCl; molecular weight 112.56), is a colorless liquid with .a pleasant
aroma. Monochlorobenzene has a melting point of -45.6°c, a boiling point
of 131-132°C, a water solubility of 488 mg/1 at '25°C, and a density of
1.107 g/ml. Monochlorobenzene has been used as a synthetic intermediate in
the production of phenol, DDT, and aniline. It is also used as a solvent in
the manufacture of adhesives, paints, polishes, waxes, diisocyanates,
Pharmaceuticals and natural rubber (U.S. EPA, 1979).
Data on current production derived from U.S. International Trade Com-
mission reports show that between 1969 and 1975, the U.S. annual production
of monochlorobenzene decreased by 50 percent, from approximately 600 million
pounds to approximately 300 million pounds (U.S. EPA, 1977).
II. EXPOSURE
A. Water
Based on the vapor pressure, water solubility, and molecular weight
of Chlorobenzene, Mackay and Leinonen (1975) estimated the half-life of
evaporation from water to be 5.8 hours. Monochlorobenzene has been detected
in ground water, "uncontaminated" upland water, and in waters contaminated
either by industrial, .municipal or agricultural waste. The concentrations
ranged from 0.1 to 27 pg/1, with raw waters having the lowest concentration
and municipal waste the highest (U.S. EPA, 1975, 1977). These estimates
should be considered as gross estimates of exposure, due to the volatile
nature of monochlorobenzene.
-SV3-
-------
8. Food
The U.S. EPA (1979) has estimated the weighted average bioconcen-
tration factor of monochlorobenzene to be 13 for the edible portions of fish
and shellfish consumed by Americans. This estimate was based on octanol/-
water partition coefficients.
C. Inhalation
Data have not been found in the available literature which deal
with exposure to chlorobenzene outside of the industrial working environment.
III. PHARMACOKINETICS
A. Absorption
There is little question, based on human effects and mammalian
toxicity studies, that chlorobenzene is absorbed through the lungs and from
the gastrointestinal tract (U.S. EPA, 1977).
B. Distribution
Because chlorobenzene is highly lipophilic and hydrophobia, it
would be expected that it would be distributed throughout total body water
space, with body lipid providing a deposition site (U.S. EPA, 1979).
C. Metabolism
Chlorobenzene is metabolised via an NADPH-cytochrome P-448 depen-
dent microsomal enzyme system.. The first product, and rate limiting step,
is a epoxidation; this is followed by formation of diphenolic and monophe-
nolic compounds (U.S. EPA, 1979). Various conjugates of these phenolic
derivatives are the primary excretory products (l_u, et al. 1974). Evidence
indicates that the metabolism of monochlorobenzene results in the formation
of toxic intermediates (Kohli, et al. 1976). Brodie,. et. al. (1971) induced
microsomal enzymes with phenobarbital and showed a potentiationin in 'the
toxicity of monochlorobenzene. However, -the use of 3-methylcho-
-------
lanthrene to induce microsomai enzymes provided protection for rats (Oesch,
et al. 1973). The metabolism of chiorobenzene may also lead to the forma-
tion of carcinogenic active intermediates (Kohli, et al. 1976).
0. Excretion
The predominant route of elimination is through the formation of
conjugates of the metabolites of monochlorobenzene and elimination of these
conjugates by the urine (U.S. EPA, 1979). The types of conjugates formed
vary with species (Williams, et al. 1975). In the rabbit, 27 percent of an
administered dose appeared unchanged in the expired air (Williams, 1959).
IV. EFFECTS
Pertinent data could not be located in the available literature on the
carcinogenicity, mutagenicity, teratogenicity, or other reproductive effects
of chiorobenzene.
A. Chronic Toxicity
Data on the chronic toxicity of chiorobenzene is sparse and some-
what contradictory. "Histopathological changes" have been noted in lungs,
liver and kidneys following inhalation of monochlorobenzene (200, 475, and
1,000 ppm) in rats, rabbits and guinea pigs (Irish, 1963). Oral administra-
tion of doses of 12.5, 50 and 250 mg/kg/day to rats produced little patholo-
gical change, except for growth retardation in males (Knapp, et al. 1971).
B. Other Relevant Information
Chiorobenzene appears to increase the activity of microsomai NADPH-
cytochrome P-450 dependent enzyme systems. Induction of microsomai enzyme
activity has been shown to enhance the metabolism of a wide variety of
drugs, pesticides and other xenobiotics (U.S. EPA, 1979).
- 5J5--
-------
V. AQUATIC TOXICITY
A. Acute Toxicity
Pickering and Henderson (1966) reported observed 96-hour LC5Q
values for goldfish, Carassius auratus, guppy, Poecilia reticulatus, and
bluegill, Lepomis macrochirus, to be 51,620, 45,530, and 24,000 jug/1, re-
spectively, for chlorobenzene. Two 96-hour LC^ values for chlorobenzene
and fathead minnows, .Pimephales promelas, are 33,930 ug/1 in soft water (20
mg/1) and 29,120 Aig/1 in hard water (360 mg/1), indicating that hardness
does not significantly affect the acute toxicity -of chlorobenzene (U.S. EPA,
1978). With Daphnia maqna, an observed 48-hour EC5g value of 86,000 pg/1
was reported. In saltwater studies, sheepshead minnow had a reported un-
adjusted LC5g (96-hour) value of 10,500 jug/1, with a 96-hour EC5Q of
16,400 jug/1 for mysid shrimp (U.S. EPA, 1978).
8. Chronic Toxicity
NO chronic toxicity studies have been reported on the chronic
toxicity of chlorobenzene and any salt or freshwater species.
C. Plant Effects
The freshwater alga Selenastrum capricornutum is considerably less
sensitive than fish and Daphnia magna. Based on cell numbers, the species
has a reported 96-hour EC5Q value of 224,000 /jg/1. The saltwater alga,
Skeletonema costatum, had a 96-hour EC50, based on cell numbers of 341,000
jug/1.
0. Residues
A bioconcentration factor of 44 was obtained assuming an 8 percent
lipid content of fish.
-SV6-
-------
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human health nor the aquatic criteria derived by U.S. EPA
(1979), which are summarized below, have gone through the process of public
review; therefore, there is a possibility that these criteria will be
changed.
A. Human
The American Conference of Governmental Industrial Hygienists
(ACGIH, 1971) threshold limit value for chlorobenzene is 350 mg/m3. The
acceptable daily intake (ADI) was calculated to be-.1.008 mg/day. The U.S.
EPA (1979) draft water criterion for chlorobenzene is 20 pg/1, based on
threshold concentration for odor and taste.
B. Aquatic
For chlorobenzene, the drafted criterion to protect freshwater
aquatic life is 1,500 ;jg/l as a 24-hour average; the concentration should
not exceed 3,500 ;jg/l at any time. To protect saltwater aquatic life, a
draft criterion of 120 jjg/1 as a 24-hour average with a concentration not
exceeding 280 pg/1 at any time has been recommended (U.S. EPA, 1979).
-sn-
-------
CHLOROBENZENE
REFERENCES
American Conference of Governmental Industrial Hygienists.
1971. Documentation of the threshold limit values for sub-
stances in workroom air. 3rd. Ed.
Brodie, B.B., et al. 1971. Possible mechanism of liver ne-
crosis caused by aromatic organic compounds. Proc. Natl.
Acad. Sci. 68: 160.
Irish, D.D. 1963. Halogenated hydrocarbons: II. Cyclic.
TniIndustrial Hygiene and Toxicology, Vol. II, 2nd Ed., ed.
F.A. Patty , Interscience, New York. p. 1333.
Knapp, W.K., Jr., et al. 1971. Subacute oral toxicity of
monochlorobenzene in dogs and rats. Topxicol. Appl. Pharma-
col, 19: 393.
Kohli, I., et al. 1976. The- metabolism of higher chlori-
nated benzene isomers. Can. Jour. Biochem. 54: 203.
.Lu, A.Y.H., et al. 1974. Liver microsomal electron trans-
port systems. III. Involvement of cytochrome b5 in the
NADH-supported cytochrome p^-450 dependent hydroxylation of
chlorobenzene. Biochem. Biphys. Res. Comm. 61: 1348.
Mackay, D., and P.J. Leinonen. 1975. Rate of evaporation of
•low-solubility contaminants from water bodies to atmosphere.
Environ. Sci. Technol. 9: 1178.
Oesch, F., et al. 1973. Induction activation and inhibition
of epoxide hydrase. Anomalous prevention of chlorobenzene-
induced hepatotoxicity by an inhibitor of epoxide hydrase.
Chem. Biol. Interact. 6: 189.
Pickering, Q.H., and C. Henderson. 1966. Acute toxicity of
some important petrochemicals to fish. Jour. Water Pollut.
Control" Fed. 38: 1419.
U.S. EPA. 1975. Preliminary assessment of suspected carcin-
ogens in drinking water. Report to Congress. Environ.
Prot. Agency, Washington, D.C.
U.S. EPA. 1977. Investigation of selected potential envi-
ronmental contaminants: Halogenated benzenes. EPA 560/2-77-
004.
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. Chlorinated Benzenes: Ambient Water Quality
Criteria (Draft).
Williams, R.T. 1959. The metabolism of halogenated aromatic
hydrocarbons. Page 237 in Detoxication mechanisms. 2nd ed.
John Wiley and Sons, New York.
Williams, R.T., et al. 1975. Species variation in the meta-
bolism of some organic halogen compounds. Page 91 Tn'A.D.
Mclntyre and C.F. Mills, eds. Ecological and toxicological
research. Plenum Press, New York.
-------
No. 43
p—Chloro-m-cresol
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-s-ao-
-------
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 ,^flect 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.
-------
p-CHLORO-m-CRESOL
SUMMARY
f
p-Chloro-m—cresol has been found to be susceptible to biodegradation
under aerobic conditions in a synthetic sewage sludge. It has been found
to be formed by the chlorination of waters receiving effluents from electric
power-generating plants and by the chlorination of the effluent from a
domestic sewage treatment facility.
Very little information on the health effects of p-chloro-m-cresol
was located. p-Chloro-m-cresol has been characterized as very toxic
in humans, although support for this statement is 'limited. In rats, a
subcutaneous LI>5Q of 400 mg/kg and an oral LDL of 500 mg/kg have been
reported.
I. INTRODUCTION
p-Chloro-m-cresol (4-chlor/ -7rmethylphenol; C^E^CIO; molecular
weight 142.58) is a solid (dimorphous crystals) at room temperature. The
pure compound is odorless, but it has a phenolic odor in its most common, impure
form. Its melting point is 55.5 C and its boiling point is 235°C.
It is soluble in water and many organic solvents (Windholz 1976).
A review of the production,range (includes importation) statistics
for p-chloro-m-cresol (CAS No. ^j-50-7) as listed in the initial TSCA
Inventory (U.S. EPA 1979) shows that between 10,000 and 90,000 pounds of
"l *
this chemical were produced/imported in 1977.
p-Chloro-m-cresol' is used as an external germicide and as a preserva-
tive for glues, gums, paints, inks, textiles and leather goods (Hawley 1971).
It is also used as a preservative in cosmetics (Wilson 1975, Liem 1977).
EPA (1973) indicates that p-chloro-m-cresol is "cleared for use in adhesives
used in food packaging."
*This production range information does not include any production/importation
data claimed as confidential by the person(s) reporting for the TSCA
Inventory, nor does it include any information which would compromise Con-
fidential Business Information. The data submitted for the TSCA Inventory,
including production range information, are subject to the limitations con-
tained in the Inventory Reporting Regulations (40 CFR 710).
-------
II. EXPOSURE
A. Environmental Face
Voets et al. (1976) reported that p-chloro-m-cresol was quite susceptible
to microbial breakdown under aerobic conditions in an organic medium
(synthetic sewage sludge), while degradation under aerobic conditions in a
mineral solution (simulating oligotrophic aquatic systems) was relatively
difficult. No degradation was observed in either system under anaerobic
conditions.
B. Bioconcentration
No studies on the bioconcentration potential of this compound were
found. Based on its solubility, p-chloro-m-cresol would not be expected
to have a high bioconcentration potential.
C. Exposure
Human exposure to p-chloro-m-cresol occurs through its presence in
certain cosmetics and in a variety of other consumer products in which
it is used as a preservative (Wilson 1975, Liem 1977).
p-Chloro-m-cresol has been found to be formed by the chlorination
of water from a lake and a river receiving cooling waters from electric
power-generating plants, at concentrations of 0.2 ug/1 and 0.7 ug/1, res-
pectively. It has also been found to be formed by the chlorination of the
effluent from a domestic sewage treatment facility at a concentration of
:
1.5 ug/1 (Jolley et al. 1975).
III. PHARMACOKINETICS
No information was found.
IV. HEALTH EFFECTS
Very little toxicological data for p-chloro-m-cresol was available. The
subcutaneous LD-Q for p-chloro-m-cresol in rats is 400 mg/kg (NIOSH 1975).
The oral LD for p-chloro-m-cresol in rats is 500 mg/kg. In mice the
L*O
intraperitoneal LD is 30 mg/kg and the subcutaneous LD is 200 ing/kg
-------
(U.S. DHEW 1978). One author has rated p-chloro-m-cresol as very toxic,
with a probable lethal dose to humans of 50-500 mg/kg. (Von Oettingen
as quoted in Gosselin et al. 1976) . p-Chloro-m—cresol was also reported
as non-irritating to skin in concentrations of 0.5 to' 1.0% in alcohol.
V. AQUATIC TOXICITY
A. Acute
The only information available is that for Daphnia pulex. The
96-hour LC5Q for p-chloro-m-cresol exposure is 3.1 mg/L (Jolley et al. 1977)
VI. GUIDELINES
No guidelines for exposure to p-chloro-m-cresol were located.
-------
References
Gosselin RE et al. 1976. Clinical Toxicology of Commercial Products.
Fourth Edition.
Hawley GG (Ed.) 1971. Condensed Chemical Dictionary, 8th Edition. Van
Nostrand Reinhold Co.
Jolley RL., Jones G, Pitt WW, and Thompson JE. 1975. Chlorination of
Organics in Cooling Waters and Process Effluents. In Proceedings of the
Conference on the Environmental Impact of Water Chlorination, Oak Ridge,
Tennessee, Oct. 22-24, 1975, published July 1976.
Jolley RL, Gorchev H, Hamilton DH. 1978. Water Chlorination Environmental
Impact and Health Effects In Proceedings of the Second Conference on the
Environmental Impact of Water Chlorination, Gatlinburg, Tenn. 1977.
Liem DH. 1977. Analysis of antimicrobial compounds in cosmetics, Cosmetics
and Toiletries, 92: 59-72.
National Institute of Occupational Safety and Health. 1975. Registry of
Toxic Effects of Chemcial Substances. 1978 Edition. DHEW (NIOSH) Publication
79-100, Rockville, MD.
U.S. EPA. 1973. EPA Compendium of Registered Pesticides, Vol. II, Part I,
Page P-01-00.01.
U.S. EPA. 1979. Toxic Substances Control Act Chemical Substance Inventory,
Production Statistics for Chemicals on the Non-Confidential TSCA Inventory.
Voets JP, Pipyn P, Van Lancker P, and Verstraete W. 1976. Degradation of
microbicides under different environmental conditions. J. Appl. Bact.
40:67-72.
Wilson, CH. 1975. Identification of preservatives in cosmetic products by
thin layer chromatography. J. Soc. Cosmet. Chem., 26:75-81.
Windholz M. ed. 1976. The Merck Index, Merck & Co., Inc., Rahway, Mew Jersey.
-------
No. 44
Chloroethane
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.
-------
CHLOROETHANE
SUMMARY
There is no available evidence which indicates that
monochloroethane produces carcinogenic, mutagenic, or terato-
genic effects. Symptoms produced by human poisoning with
monochloroethane include central nervous system depression,
respiratory failure, and cardiac arrhythmias. The results of
animal studies indicate that liver, kidney, and cardiac tox i-
city may be produced by monochloroethane.
Data examining the toxic effects of chloroethane on
aquatic organisms were not available.
-------
CHLOROETHANE
I. INTRODUCTION
This profile is based on the Ambient Water Quality Cri-
teria Document for Chlorinated Ethanes (U.S. EPA, 1979a).
The chloroethanes are hydrocarbons in which one or more
of the hydrogen atoms have been replaced by chlorine atoms.
Water solubility and vapor pressure decrease with increasing
chlorination, while density and melting point increase.
Monochloroethane (chloroethane, M.W. 64.52) is a gas at room
temperature. The compound has a boiling point of 13.1°C, a
melting point of -138.7°C, a specific gravity of 0.9214, and
a solubility of 5.74 g/1 in water (U.S. EPA, 1979a).
The chloroethanes are used as solvents, cleaning and de-
greasing agents, and in the chemical synthesis of a number of
compounds.
The 1976 production of mdnochloroethane was 335 x 10^
tons/year (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 present in raw and finished waters are
due primarily to industrial discharges. Small amounts of the
chloroethanes may be formed by chlorination of drinking water
-------
or treatment of sewage. Air levels of chloroethanes are
produced by evaporation of these volatile compounds widely
used as degreasing agents and in dry cleaning operations
(U.S. EPA, 1979a).
Sources of human exposure to chloroethanes include
water, air/ contaminated foods and fish, and dermal absorp-
tion. Fish and shellfish have shown levels of chloroethanes
in the nanogram range (Dickson and Riley, 1976). Data on the
levels of monochloroethanes in foods is not available.
An average bioconcentration factor for monochloroethane
in fish and shellfish has not been derived by the'EPA.
III. PHARMACOKINETICS
Pertinent data could not be located in the available
literature on monochloroethane 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
following oral or inhalation exposure; widespread distribu-
tion of the chloroethanes throughout the body; enzymatic de-
chlorination and oxidation to the alcohol and ester forms;
and excretion of the chloromethanes primarily in the urine
and expired air. Specifically for monochloroethane, absorp-
tion following dermal application is minor; and excretion
appears to be rapid, with the major portion of the injected
compound excreted in the first 24 hours (U.S. EPA, 1979a).
-------
IV. EFFECTS
Pertinent data could not be located in the available
literature on monochloroethane for carcinogenicity, mutageni-
city, teratogenicity and other reproductive effects.
A. Chronic Toxicity
Hunan symptons of monochloroethane poisoning indi-
cate central nervous system depression, respiratory failure,
and cardiyascular symptoms, including cardiac arrhythmias
(U.S. EPA, 1979a). Animal toxicity has indicated kidney dam-
age and fatty infiltration of the liver, kidney, and heart
(U.S. EPA, 1979a).
V. AQUATIC TOXICITY
Pertinent data could not be located in the available
1iterature.
VI. EXISTING GUIDLINES AMD STANDARDS
A. Human
The eight-hour TWA standard prepared' by OSHA for
monochloroethane is 1,000 ppm. .• -j '
Sufficient data are not available to derive a cri-
terion to protect hunan health from exposure to nonochloro-
ethane in ambient water.
B. Aquatic
There are not sufficient toxicological data to cal-
culate exposure criteria.
-------
CHLOROETHANE
REFERENCES
Dickson, A.G., and J.P. Riley. 1976. The distribution of short-chain halo-
genated aliphatic hydrocarbons in some marine organisms. Mar. Pollut.
Bull. 79: 167.
Kirk, R., and Othmer, 0. 1963. Encyclopedia of Chemical Technology. 2nd
ed. John Wiley and Sons, Inc. New York.
Lange, N.. (ed.) 1956. Handbook of Chemistry. 9th ed. Handbook
Publishers, Inc. Sandusky, Ohio.
U.S. EPA. 1979a. Chlorinated Ethanes: Ambient Water Quality Criteria.
(Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. Chlori-
nated Ethanes:. Hazard Profile. (Draft).
Van Dyke, R.A., and C.G.F. Wineman. 1971. Enzymatic dechlorination:
Dechlorination of chloroethanes and propanes in_ vitro. Biochem.
Pharmacol. 20: 463.
-------
No. 45
Chloroethene
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.
-------
CHLOROETHENE
(VINYL CHLORIDE)
Summary
Vinyl chloride has been used for over 40 years in the produc-
tion of polyvinyl chloride. Animal studies indicate that vinyl
chloride is not teratogenic, but it has been found to be mutagenic
in several biologic test systems. Vinyl chlor.ide has been found to
be carcinogenic in laboratory animals and has jaeen positively asso-
ciated with angiosarcoma of the liver in humans. Recently "vinyl
chloride disease", a multisystem disorder, has been described in
workers exposed to vinyl chloride.
Data are lacking concerning the effects of vinyl chloride
in freshwater and saltwater aquatic life.
X
-------
CHLOROETHENE
(VINYL CHLORIDE)
I. INTRODUCTION
Vinyl chloride (CH2CHC1; molecular weight 62.5) is a highly
flammable chloro-olefinic hydrocarbon which emits a sweet or
pleasant odor, and has a vapor density slightly more than twice
that of air. Its physical properties include: melting point,
-153.8°C; and solubility in water, O.llg/100 g at 28°C. It is
soluble in alcohol and very soluble in ether and carbon tetra-
chloride (Weast, 1972). -Many salts :of metals (including silver,
copper, iron," platinum, iridium) have the ability to complex
with vinyl chloride resulting in its increased solubility in
water. Conversely, alkali metal salts, such as sodium or potas-
sium chloride, may decrease the solubility of vinyl chloride
in aqueous solutions (Fox, 1978).
Vinyl chloride has been used for over 40 years in the produc-
tion of polyvinyl chloride (PVC), which in turn is the most widely
used material in the manufacture of plastics. Production of vinyl
chloride in the U.S. reached slightly over 5 billion pounds in 1977
(U.S. Int. Trade Comm, 1978).
Vinyl chloride and polyvinyl. chloride are used in the manufac-
ture of numerous products in building and construction, the automo-
tive industry, for electrical wire insulation and cables, piping,
industrial and household equipment, packaging for food products,
medical supplies, and are depended upon heavily by the rubber,
paper and glass industries (Maltoni, 1976a).
In the U.S. about 1500 workers were employed in monomer syn-
thesis and an additional 5000 in polymerization operations (Falk,
-------
et al. 1974). As many as 350,000 workers were estimated to be asso-
ciated with fabricating plants (U.S. EPA, 1974). By 1976, it was
estimated that worldwide nearly one million persons were associated
with, manufacturing goods derived from PVC (Maltoni, 1976a).
Potential sources of population exposure to vinyl chloride are
emissions from PVC fabricating plants, release of monomers from
various plastic products, and emissions from the incineration of
PVC products (U.S. EPA, 1975).
II. EXPOSURE
A. Water
Small amounts of vinyl chloride may be present in public
water supplies as a result of industrial waste water discharges.
The levels of vinyl chloride in effluents vary considerably de-
pending on the extent of in-plant treatment of waste water. Vinyl
chloride in samples of waste water from seven areas ranged from
0.05 ppm to 20 ppm, typical levels being 2-3 ppm (U.S. EPA, 1974).
The low solubility and high volatility of vinyl chloride tend to
limit the amounts found in water; however, the presence of certain
salts may increase the solubility and therefore could create situa-
tions of concern (U.S. EPA, 1975).
Polyvinyl chloride pipe.used in water distribution sys-
tems provides another source of low levels of vinyl chloride in
drinking water. In a study by the U.S. EPA of five water distribu-
tion systems which used PVC pipes, water from the newest, longest
pipe system had the highest vinyl chloride concentration (1.4 ug/1)
while the two oldest systems only had traces of vinyl chloride • (0.3
and 0.6 ug/1) (Dressman and McFarren, 1978). The National
-537-
-------
Science Foundation (NSF) has adopted a voluntary standard of 10 ppm
or less of residual monomer in finished pipe and fittings. Three
times a year NSF samples water supplies in several cities. In
1977, more than 95 percent of the samples conformed to the stan-
dard/ however, levels of 5.6 ug/1 and 0.27 pg/1 vinyl chloride have
been detected in at least two cities.
B. Food
Small quantities of vinyl chloride are ingested by humans
when the entrained monomer migrates into foods packaged in PVC
wrappings and containers. The solubility of vinyl chloride in
foods packaged in water is low (0.11 percent); however, the monomer
is soluble in alcohols and mineral oil. In 1973, the U.S. Treasury
Department banned the use of vinyl chloride polymers for packaging
alcoholic beverages (Int. Agency Res. Cancer, 1974).. The FDA anal-
yzed a number of PVC packaged products in 1974. The concentrations
ranged from "not detectable" to 9,000 ppb.
The U.S. EPA (1979) has estimated the weighted average
bioconcentration factor of vinyl chloride to be 1.9 for the edible
portions of fresh and shellfish consumed by Americans. This esti-
mate was based on the octanol/water coefficient of vinyl chloride.
C. Inhalation
Inhalation of vinyl chloride is the principal route of
exposure to people working in or living near vinyl chloride indus-
tries. After 1960, Dow Chemical Co. was successful in reducing ex-
posures to workers to about 25 ppm level, though levels up to 500
' »
ppm still occurred. Inhalation exposures drastically dropped after
appropriate. controls were instituted following case reports of
vinyl chloride induced angiosarcoma of the liver in workers and .ex-
perimental animals .(U.S. EPA, 1979) .
-------
III. PHARMACOKINETICS
A. Absorption
Vinyl chloride is rapidly absorbed through the lungs and
enters the blood stream (Duprat, et al. 1977).
B. Distribution
The liver of rats accumulates the greatest percentage
of vinyl chloride and/or metabolites of vinyl chloride 72 hours
after a single oral dose (Watanabe, et al. 1976). Ten minutes
after a 5-minute inhalation exposure to vinyl chloride at 10,000
ppm, the compound was found in the liver, bile duct, stomach,
and kidney of •• rats (Duprat, et al. 1977). Immediately after
14
exposure by inhalation to C-vinyl chloride at 50 ppm for 5
14
hours, the percent incorporated as C/radioactivity per gram
of tissue was highest for kidney (2.13), liver (1.86), and spleen
(0.73). Forty-eight hours after the beginning of exposure, labeled
material could still.be detected in these tissues.
G. Metabolism
Detoxification of vinyl chloride takes place primarily in
the liver by oxidation to polar compounds which can be conjugated
to glutathione and/or cysteine (Hefner, et al. 1975). These cova-
lently bond metabolites are then excreted in the urine.
Vinyl chloride is metabolized extensively by rats in vivo
and the metabolic pathways appear to be saturable. The postulated
primary metabolic pathway involves alcohol dehydrogenase and, for
rats, appears to be saturated by exposures to concentrations ex-
ceeding 220 to 250 ppm. In rats exposed to higher concentrations,
metabolism of vinyl chloride is postulated to occur via a secondary
-------
pathway involving epoxidation and/or peroxidation. Present data
indicates that vinyl chloride is metabolized to an activated car-
cinogen electrophile and is capable of covalent reaction with
nucleophilic groups or cellular macromolecules (U.S. EPA, 1979).
There is ample evidence that the mixed function oxidase
(MFO) system may be involved in the metabolism of vinyl chloride.
Rat liver microsomes catalyze the covalent binding of vinyl chlor-
ide metabolites to protein and nucleic acids; chloroethylene
oxide is thought to be the primary microsomal metabolite capable
of alkylating these cellular macromolecules (Kappus, et al. 1975;
1976; Laib and Bolt, 1977). Hathway (1977) reports _in vitro
depurination of calf thymus DNA by chloroacetaldehyde identical
to that observed in hepatocyte DNA following the administration
of vinyl chloride to rats i_n vitro.
D. Excretion
Watanabe, et al. (1976) monitored the elimination of
vinyl chloride for 72 hours following a single oral dose adminis-
tered to rats. The total 14c-activity recovered at each dose level
ranged from 82-92 percent. At a dose level of 1 mg/kg, 2 percent
was exhaled as vinyl chloride, 13 percent was exhaled as carbon
dioxide, 59 percent was eliminated in the urine and 2 percent in
the feces. Excretion of vinyl chloride at a dose level of 100 mg/kg
was 66 percent exhaled as vinyl chloride, 2.5 percent as carbon
dioxide, 11 percent in the urine and 0.5 percent in the feces. Ad-
ministration by inhalation produced almost the same results.
•
Green and Hathway (1975) found that more than 96 percent
14
of 250 ug C-vinyl chloride administered via intragastric, intra-
-------
venous or intraperitoneal routes was excreted within 24 hours. The
rats given vinyl chloride by the intragastric -route exhaled 3.7
percent as vinyl chloride, 12.6 percent as C02; 71.5 percent
of the labeled material was in the urine and 2.8 percent in the
feces. Intravenous injections resulted in 9.9 percent exhaled
as vinyl chloride, 10.3 percent as CC^; 41.5 percent in the urine
and 1.6 percent in the feces.
IV. EFFECTS
A. Carcinogenicity
The carcinogenicity of vinyl chloride has been investi-
gated in several animal studies. Viola, et al. (1971) induced skin
epidermoid carcinomas, lung carcinomas or bone steochrondromas in
24/25 male rats exposed to 30,000 ppm vinyl chloride intermittently
for 12 months. Tumors appeared between 10 and 11 months. Caputo,
et al. (1974) observed carcinomas and sarcomas in all groups of
male and female rats inhaling various concentrations of vinyl
chloride except those exposed to 50 ppm.
Maltoni and Lefemine (1974a,b; 1975) reported on a
series of experiments concerning the effects on rats, mice, and
hamsters of inhalation exposure to vinyl chloride at concentra-
tions ranging from 50 to 10,000 ppm for varying periods of time.
The animals were observed for their entire lifetime. Angiosar-
comas of the liver occurred in all three species, as well as
tumors at several other sites. A differential response between
the sexes was not reported.
Maltoni (1976b) observed four subcutaneous angiosar-
comas, four zymbal gland carcinomas, and one nephroblastoma in
t
-SH)-
-------
66 offspring of rats exposed by inhalation 4 hours/day to 10,000
or 6,000 ppm vinyl chloride from the 12th to 18th day of gesta-
tion. Liver angiosarcomas were also observed in rats administered
vinyl chloride via stomach tube for 52 weeks.
Recent experiments by Lee, et al. (1977) with rats
and mice confirm the carcinogenicity of vinyl chloride. Each
species was exposed to 50,250 or 1000 ppm vinyl chloride or 55
ppm vinylene chloride 6 hr/day, 5 days/week for 1-12 months.
After 12 months, bronchioalveolar adenomas, .mammary gland tumors,
and angiosarcomas in the liver and other sites developed in mice
exposed to all•three dose levels of vinyl chloride. Rats exposed
to 250 ppm or 100 ppm vinyl chloride developed angiosarcoma in
the liver, lung and other sites (Lee, et al. 1978).
The primary effect associated with vinyl chloride expo-
sure in man is an increased risk of cancer in several organs in-
cluding angiosarcoma of the liver. Liver angiosarcoma is an ex-
tremely rare liver cancer in humans, with 26 cases reported annual-
ly in the U.S. (Natl. Cancer.Inst., 1975). Human data on the car-
cinogenic effects of vinyl chloride have been obtained primarily
from cases of occupational exposures of workers. The latent period
has been estimated to be .15-20 years; however, recent case reports
indicate a longer average latent period (Spirtas and Kaminski,
1978).
A number of epidemiological studies of vinyl chloride
have been reported (U.S. EPA, 1979). Tabershaw/Cooper Associates
(1974) found no increase in the overall mortality rate for v'inyl
chloride workers nor significant increases in standard mortality
X
-------
rates (SMR's) for malignant neoplasms. Reexamination of this
data by Ott, et al. (1975) including more clearly defined expo-
sure levels confirmed the previous findings: no increase over
that expected for malignant neoplasms in the low exposure group
(TWA 10-100 ppm vinyl chloride) and a non-significant increase
in deaths due to malignant neoplasms in the high exposure group
(TWA, greater than 200 ppm).
However, liver cancer death were twelve-fold, and brain
cancer deaths were five-fold greater than, that expected in a
study by Wagoner (1974). Likewise, Monson, et al. (1974) found
death due to cancer to be 50 percent higher than expected in
vinyl chloride workers who died from 1947-1973, including a 900
percent increase in cancers of the liver and biliary tract.
In the most recent update of the NIOSH register, a total
of 64 cases of hepatic angiosarcoma have been identified, worldwide
among vinyl chloride exposed industrial workers (Spirtas and Kamin-
ski, 1978). Twenty-three of these cases were reported in the
United States. Six cases were documented since 1975.
B. Mutagenicity
Vinyl chloride has been found to be mutagenic in a number
of biological systems including: metabolically activated systems
using Salmonella typhimurium; back mutation systems using
Escherichia coli; forward mutation and gene coversion in yeast; and
germ cells of Drosophila and Chinese hamster V79 cells (U.S. EPA,
1979) .
The dominant lethal assay was used to test the mutag'eni-
city of inhaled vinyl chloride in mice. Levels as high as 30,000
-------
ppm (6 hours/day for 5 days) yielded negative results (Anderson, et
al. 1976).
Several investigators have observed a significantly
higher incidence of chromosomal aberrations in the lymphocytes of
workers chronically exposed to high levels of vinyl chloride
(Ducatman, et al. 1975; Purchase, et al. 1975; Funes-Crav'ioto, et
al. 1975).
C. Teratogenicity
Animal studies using mice, rats and rabbits, indicate
that inhalation of vinyl chloride does not induce gross teratogenic
abnormalities in offspring of mothers exposed 7 hours daily to con-
centrations ranging from 50 to 2,500 ppm (John, et al. 1977); how-
ever, excess occurrences of minor skeletal abnormalities were
noted. Increased fetal death was noted at the higher exposure
levels. These findings were confirmed by Radike, et al. (1977a)
who exposed rats to 600-6,000 ppm vinyl chloride, 4 hours daily on
the 9th to the 21st day of gestation.
Further examination is needed of reported high rates of
congenital defects in three small communities in which vinyl chlor-
ide polymerization plants are located (U.S. EPA, 1979).
D. Other Reproductive Effects
No effect on fertility in mice was noted in a dominant
lethal assay conducted by Anderson, et al. (1976).
E. Chronic Toxicity
There are numerous clinical indications that chronic
exposure to vinyl chloride is toxic to humans (U.S. EPA, 1979) .
Hepatitis-like changes, angioneurosis, Raynaud's syndrome, derma-
-------
titis, acroosteolysis, thyroid insufficiency, and hepatomegaly
have been reported around the world. Other long term effects
include functional disturbances of the central nervous system
with adrenergic sensory polyneuritis (Smirnova and Granik, 1970);
thrombocytopenia, splenomegaly, liver malfunction with fibrosis,
pulmonary changes (Lange, et al. 1974); and alterations in serum
enzyme levels (Makk, et al. 1976).
F. Other Relevant Information
Pretrea.tment of rats with pyrazole'- (an alcohol dehydro-
genose inhibitor) and ethanol inhibits the metabolism of vinyl
chloride (Hefner, et al. 1975). This indicates the involvement
of alcohol dehydrogenose in the metabolism of vinyl chloride.
The chronic • ingestion of alcohol was found to increase
the incidence of liver tumors and tumors in other sites in in-
dividuals exposed to vinyl chloride (Radike, 1977b) .
Jaeger (1975) conducted experiments to determine the
interaction between vinylidene chloride (1,1-DCE) and vinyl chlor ide.
In this experiment, the effects of 4-hour exposures to 200 ppm
of 1,1-DCE and 1,000 ppm vinyl chloride were less than if 1,1-
DCE was given alone.
V. AQUATIC TOXICITY
A. Pertinent information relevant to acute and chronic toxi-
city, plant effects and residues for vinyl chloride were not found
in the available literature.
-------
VI. EXISTING GUIDELINES AND STANDARDS
A. Human
The current federal OSHA standard for vinyl chloride is 1
ppm (TWA) with a maximum of 5 ppm for a period of no longer than 15
minutes in 1 day. (39 FR 35890 (Oct. 4, 1979)).
In 1974, a notice to cancel registrations of pesticide
spray products containing vinyl chloride as a propellant was issued
(39 FR 14753 (April 26, 1974)). Other aerosol productsx such as
hair spray, utilizing vinyl chloride as a propellant were banned
from the market in the U.S. and other countries (Int. Agency Res.
Cancer, 1974). 'The U.S. EPA proposed in 1975 and 1976 an emission
standard of 10 ppm vinyl chloride at the stack for industry.
The draft ambient water quality criterion for vinyl
chloride has been set to reduce the human lifetime cancer risk
level to 10~5, 10"6 and 10~7 (U.S. EPA, 1979). The corresponding
criteria are 517 pg/1, 51.7 ;jg/l and 5.17 pg/1, respectively. The
data base from which this criterion has been derived is currently
being reviewed, therefore, this criteria to protect human health
may change.
B. Aquatic
Fresh or salt water criteria could not be derived because
of insufficient data (U.S. EPA, 1979).
- ff
-------
CHLOROETHENE
(VINYL CHLORIDE)
REFERENCES
Anderson, 0., et al. 1976. Vinyl chloride: dominant lethal studies in male
CD-I mice. Mutat. Red. 40: 359.
Caputo, A., et al. 1974. Oncogenicity of vinyl chloride at low concentra-
tions in rats and rabbits. IRCS 2: 1582.
Dressman, R.C. and E.F. McFarren. 1978. Determination of vinyl chloride
migration from polyvinyl chloride pipe into water. Am. Water Works Assoc.
Jour. 70: 29.
Ducatman, A., et al. 1975. Vinyl chloride exposure and human chromosome
aberrations. Mutat. Rec. 31: 163.
Duprat, P., -et al. 1977. Metabolic .approach to industrial poisoning:
blood kinetics and distribution of J-^C-vinyl chloride monomer (VCM).
Toxicol Pharmacol. Suppl. 142.
Falk, H., et al. 1974. Hepatic disease among workers at a vinyl chloride
polymerication plant. Jour. Am. Med. Assoc. 230: 59.
Fox, C.R. 1978. Plant uses prove phenol recovery with resins. Hydrocarbon
processing. November, 269.
Funes-Cravioto, F., et al. 1975. Chromosome aberrations' in workers exposed
to vinyl chloride. Lancet 1: .459.
Green, T. and D.E. Hathway. 1975. The biological fate in rats of vinyl
chloride in relation to its oncogenicity. Chem. Biol. Interactions.
11: 545.
Hathway, D.E. 1977. Comparative mammalian metabolism of vinyl chloride and
vinylidene chloride in relation to oncogenic potential. Environ. Health
Perspect. 21: 55.
Hefner, R.E., Jr., et al. 1975. Preliminary studies of the fate of inhaled
vinyl chloride monomer in rats. Ann. N.Y. Acad. Sci. 246: 135.
International Agency for Research on Cancer. 1974. Monograph on the evalu-
ation of carcinogenic risk of chemicals to man. Vol. 7. Lyon, France.
Jaeger, R.J. 1975. Vinyl chloride monomer: comments on its hepatotoxicity
and interaction with 1,1-dichloroethylene. Ann. N.Y. Acad. Sci. 246: 150.
John, J.A., et al. 1977. The effects of maternally inhaled vinyl chloride
on embryonal and fetal development in mice, rats and rabbits. Toxicol.
Appl. Pharmacol. 39: 497.
-------
Kappus, H., et al. 1975. Rat liver microsomes catalyse covalent binding of
chloride to macromolecules. Nature 257: 134.
Kappus, H., et al. 1976. Liver microsomal uptake of (^C) vinyl chloride
and transformation to protein alkylating metabolites in_ vitro. Toxicol.
. Appl. Pharmacol. 37: 461.
Laib, R.J. and H.M. Bolt. 1977. Alkylation of RNA by vinyl chloride meta-
bolites in vitro and in vivo: formation of 1-N^-ethenoadenosine. Toxico-
logy 8: 185.
Lange, C.E., et al. 1974. The so-called vinyl chloride sickness-and-occu-
pationally-related systemic sclerosis? Int. Arch. Arbeitsmed. 32: 1.
Lee, C.C., et al. 1977. Inhalation toxicity of vinyl chloride and vinyli-
dene chloride. Environ. Health Perspect. 21: 25.
Lee, C.C., et al. 1978. Carcinogenicity of vinyl chloride and vinylidene
chloride. Jour. Toxicol. Environ. Health 4: 15.
Makk, L., et al. 1976. Clinical and morphologic features of hepatic angio-
sarcoma in vinyl chloride workers. Cancer 37:149.
Maltoni, C. 1976a. Carcinogenicity of vinyl chloride: Current results.
Experimental evidence. Proc. 6th Int. Symp. Biological Characterization of
Human Tomours, Copenhagen May 13-15, 1975. Vol. 3 Biological characteriza-
tion of human tumours, 1976. American Elsevier Publishing Co., Inc., New
York.
Maltoni, C. 1976b. Predictive value of carcinogenesis bioassays. Ann.
N.Y. Acad. Sci. 271: 431.
Maltoni, C. and G. Lefemine. 1974a. Carcinogenicity bioassays of vinyl
chloride. I. Research plan and early results. Environ. Res. 7:387.
Maltoni, C. and G. Lefemine. 1974b. La potentiality dei saggi sperimentali
mella predizion; dei rischi oncogeni ambiental: Un esemplo: 11 chlorure di
vinile. Acad. Natl. Lincei. 56: 1.
Maltoni, C. and G.. Lefemine. 1975. Carcinogenicity assays of vinyl chlor-
ide: Current results. Ann. N.Y. Acad. Sci. 246: 195.
Monson, R.R., et al. 1974. Mortality among vinyl chloride workers. Pre-
sented at Natl. Inst. Environ. Health Sci. Conf., Pinehurst, N.C., July
29-31.
National Cancer Institute Monograph 41. 1975. Third national cancer sur-
vey: incidence data.
Ott, M.G., et al. 1975. Vinyl chloride exposure in a controlled industrial
environment: a long-term mortality experience in 595 employees. Arch. Envi-
ron. Health 30.: 333.
-------
Purchase, I.F.H., et al. 1975. Chromosomal and dominant lethal effects of
vinyl chloride. Lancet 28: 410.
Radike, M., et al. 1977a. Transplacental effects of vinyl chloride in
rats. Annual Report. Center for the Study of the Human Environment. USPHS-
ES-00159. Oept. Environ. Health, Med. College, University of Cincinnati.
Radike, M.J., et al. 1977b. Effect of ethanol and vinyl chloride on the
induction of liver tumors: preliminary report. Environ. Health Perspect.
21: 153.
Smirnova, N.A. and N.P. Granik. 1970. Long-term side effects of acute
occupational poisoning by certain hydrocarbons and their derivatives. Gig.
Tr. Prof. Zabol. 14: 50.
Spirtas, R. and R. Kaminski. 1978. Angiosarcojia of the liver in vinyl
chloride/polyvinyl chloride workers. Update of the NIOSH Register. Jour.
Occup. Med. 20: 427.
Tabershaw/Cooper Assoc., Inc. 1974. Epidemiologic study of vinyl chloride
workers. Final report submitted to Manufacturing Chemists Assoc., Washing-
ton, D.C. Berkeley, Calif.
U.S. EPA. 1974. Preliminary assessment of the environmental problems asso-
ciated with vinyl chloride and polyvinyl chloride. EPA 560/4-74-001. Natl.
Tech. Inf. Serv., Springfield, Va.
U.S. EPA. 1975. A scientific and technical assessment report on vinyl
chloride and polyvinyl chloride. EPA-600/6-75-004. Off. Res. Dev., U.S.
Environ. Prot. Agency, Washington, D.C.
U.S. EPA. 1979. Vinyl Chloride: Ambient Water Quality Criteria. (Draft).
U.S. International Trade Commission. 1978. Synthetic organic chemicals.
U.S. Production and Sales, 1977. Publ. 920. U.S. Government Printing Of-
fice, Washington, O.C.
.Viola, P.L., et al. 1971. Oncogenic response of rat skin, lungs, bones to
vinyl chloride. Cancer Res. 31: 516.
Wagoner, J.E. 1974. NIOSH presented before the environment. Commerce Comm.
U.S. Senate, Washington, D.C.
Watanabe, P.G., et al. 1976. Fate of (14C) vinyl chloride after single
oral administration in rats. Toxicol. Appl. Pharmacol. 36: 339.
Weast, R.C. (ed.) 1972. Handbook of chemistry and physics. CRC Press,
Cleveland, Ohio.
-------
No. 46
2-Chloroethyl Vinyl Ether
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 '-u ~>rt 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.
- S'SJ-
-------
2-CHLOROETHYL VINYL ETHER
SUMMARY
Very little information is available for 2-chloroethyl vinyl ether. It
appears to be relatively stable except, under acidic conditions. There is some
potential for bioconcentration of the compound in exposed organisms. No expo-
sure data were available, although 2-chloroethyl vinyl ether has been identified
in industrial effluent discharges.
The acute toxicity of 2-chloroethyl vinyl ether is relatively low: oral
LD : 250 mg/kg; dermal LD 3.2 mL/kg; LC : 250 ppm (4 hrs). Eye irrita-
tion has been reported following exposure to 2-chloroethyl vinyl ether. No
other data on health effects were available.
I. INTRODUCTION
2-Chloroethyl vinyl ether (CICH^CH OCH=CH • molecular weight 106.55) is a
liquid having the following physical/chemical properties (Windholz, 1976; Weast,
1972; U.S. EPA, 1979c):
Boiling point (760 mm Hg): 109°C
Melting point: -70°C
Density: 1.047520
Solubility: Soluble in water to the extent
of 6g/L; very soluble in
alcohol and ether
The compound finds use in the manufacture of anesthetics, sedatives, and
cellulose ethers (Windholz, 1976).
A review of the production range (includes importation) statistics for 2-
chloroethyl vinyl ether (CAS No. 110-75-8) which is listed in the initial TSCA
inventory (1979a) has shown that none of this chemical was produced or imported
in 1977*.
*This production range information does not include any production/importation
data claimed as confidential by the person(s) reporting for the TSCA Inventory,
nor does it include any information which would compromise confidential business
information. The data submitted for the TSCA Inventory, including production
range information, are subject to the limitations contained in the Inventory
Reporting Regulations (40CFR710).
-------
II. EXPOSURE
A. Environmental Rate
The 0-chloroalkyl ethers have been shown to be quite stable to hydrolysis
and to persist for extended periods without biodegradation (U.S. EPA, 1979b).
2-Chloroethyl ethyl ether (a 8-chloroalkyl other) is stable to sodium hydroxide
solutions but will undergo hydrolysis in the presence of dilute acids to acet-
aldehyde and 2-chloroethanol (Windholz 1976). Conventional treatment systems
may be inadequate to sufficiently remove the g-chloroalkyl ethers once present
in water supplies (U.S. EPA 1979b; U.S. EPA 1975).
B. Bioconcentration
A calculated faioconcentration factor of 34.2 (U.S. EPA, 1979b) points to
some potential for 2-chloroethyl vinyl ether accumulation in exposed organisms.
C. Environmental Occurrence
There is no specific information available on general population exposure
to 2-chloroethyl vinyl ether. The compound has been identified three times in
the water of Louisville, Kentucky (3/74): twice in effluent
facturing plants and once in the effluent from a latex plant (U.S. EPA 1976). No
concentration levels were given.
NIOSH, utilizing data from the National Occupational Hazards Survey
(NOHS 1977) has compiled a listing summarizing occupational exposure to 2-
chloroethyl vinyl ether (Table 1). As shown, NIOSH estimates 23,473 people
are exposed annually to the compound. The number of potentially exposed indi-
viduals is greatest for the following areas: fabricated metal products; whole-
sale trade; leather, rubber and plastic, and chemical products.
III. PHARMACOKINETICS
»
Vinyl ethers readily undergo acid catalysed hydrolysis to give alcohols and
aldehydes, e.g., 2-chloroethyl vinyl ether is hydrolyzed to 2-chloroethanol and
acetaldehyde (Salomaa et al. 1966).
-------
TABLE 1
PROJECTED NUMBERS BY INDUSTRY
SIC
CODE
25
28
30
31
34
35
36
37
38
39
50
73
HAZARD DESCRIPTION
84673 Chloroethyl Vinyl Ether, 2-
DESCRIPTION
Furniture and fixtures
Chemicals and allied products
Rubber and plastic products
Leather and leather products
Fabricated metal products
Machinery, except electrical
Electrical equipment and supplies
Transportation equipment
Instruments and related products
Miscellaneous manufacturing industries
Wholesale trade
Miscellaneous business services
ESTIMATED
PLANTS
ESTIMATED
PEOPLE
ESTIMATED
EXPOSURES
920
683
669
279
149
35
432
553
299
240
6,194
20
i
T
V1
Vi
i
TOTAL
2,059
23,473
23,473
-------
IV. HEALTH EFFECTS
A. Mutagenicity
Although no information on the mutagenicity of 2-chloroethyl vinyl ether was
available, its hydrolysis product, 2-chloroethanol, has been shown to be muta-
genic in Salmonella typhimurium TA 1535 (Rannug et al. 1976), TA100 and TA98
(McCann et al. 1976), as well as Klebsiella pneumonia (Voogd et al. 1972).
B. Other Toxicity
Very little toxicological data for 2-chloroethyl vinyl ether is available.
The oral LD_Q for 2-chloroethyl vinyl ether in rats is 250 rag/kg (U.S. EPA, 1975,
Patty 1963). Dermal exposure to the shaven skin of rabbits for 24 hours resulted
in an LD5_ of 3.2 mL/kg (U.S. EPA, 1976). The acute inhalation toxicity of
2-chloroethyl vinyl ether in rats was determined following single four-hour
exposures. The lowest lethal concentration was 250 ppm (U.S. EPA, 1975). In a
similar inhalation study, 1/6 rats exposed by inhalation to 500 ppm died during
the 14-day observation period (U.S. EPA, 1975).
Primary skin irritation and eye irritation studies have also been conducted
for 2-chloroethyl vinyl ether. Dermal exposure to undiluted 2-chloroethyl vinyl
ether did not cause even slight erythema. Application of 0.5 mL undiluted 2-
chloroethyl vinyl ether to the eyes of rabbits resulted in severe eye injury
(U.S. EPA, 1975).
V. AQUATIC TOXICITY
A. Acute
The adjusted 96-hour LC,.-. for blue gill exposure to 2-chloroethyl vinyl
ether is 194,000 ug/L (U.S. EPA, 1979b). Dividing by the species sensitivity
factor (3.9), a Final Fish Acute Value of 50,000 ug/L is obtained (Table 1).
»
There is no data on invertebrate or plant exposure.
VI. EXISTING GUIDELINES
No guidelines were located.
-------
Table 2 . Freshwater fish acute values (U.S. EPA, 1979b)
Adjusted
Bioassay Test Chemical Time LC5o LC5Q
Organism Method Cone.** Description (hrs) (ug/L) (ug/L)
Bluegill, S U 2-chloroethyl 96 354,000 194,000
Lepomis macrochirus vinyl ether
* S = static
** U = unmeasured
Geometric mean of adjusted values: 2-chloroethyl vinyl ether = 194,000 ug/L
= 50,000 ug/L
-------
References
Lange NA (ed.). 1967. Lange's Handbook, of Chemistry, rev. 10th ed., New York:
McGraw-Hill Book Co.
McCahn J, Simmon V., Streitwieser D, Ames BN. 1975. Mutagenicity of chloro-
acetaldehyde, a possible metabolic product of 1,2-dichloroethane (ethylene
dichloride), chloroethanol (ethylene chlorohydrin), vinyl chloride and cyclo-
phosphamide. Proc. Nat. Acad. Sci. 72:3190-3193.
National Occupational Hazard Survey (NOHS) 1977 Vol. Ill, U.S. DREW, NIOSH,
Cincinnati, Ohio (Special request for computer printout: 2-chloroethyl vinyl
ether Dec. 1979)
Rannug U., Gothe R. Wachtmeister CA. 1976. The mutagenicity of chloroethylene
oxide, chloroacetaldehyde, 2-chloroethanol and chloroacetic acid, conceivable
metabolites of vinyl chloride, Chem-Biol. Interactions 12:251-263.
Salomaa P, Kankaanpera A. Lajunen M. 1966. Protolytic cleavage of vinyl
ethers, general acid catalysis, structural effects and deuterium solvent isotope
effects. Acta Chemica Scand. 20:1790-1801.
U.S. EPA, 1975. Investigation of selected potential environmental
contaminants: Haloethers. EPA 560/2-75-006.
U.S. EPA, 1976. Frequency of organic compounds identified in water. EPA 600/4-
76-062. .
U.S. EPA, 1979a. Toxic Substance Control Act, Chemical Substance Inventory,
Production Statistics for Chemicals on the Non-Confidential Initial TSCA Inventory.
U.S. EPA, 1979b. Ambient Water Quality Criteria Document on Chloroalkyl Ethers.
PB 297-921.
U.S. EPA, 1979c. Ambient Water Quality Criteria Document on Haloethers. PB 296-796.
Voogd CE, Jacobs JJJAA, van der Stel JJ. 1972. On the mutagenic action of
dichlorvos. Mutat. Res. 16:413^16.
Weast RC (ed.). 1972. Handbook of Chemistry and Physics, 53rd ed. The Chemical
Rubber Co., Cleveland, OH.
Windholz M. (ed.). 1976. The Merck Index, 9th ed. Merck & Co. Inc., Rahway, NJ.
-5" 5-7-
-------
No. 47
Chloroform (Carbon Trichlororaethane)
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-55**-
-------
DISCLAIMER
This report represents a survey of the potential health
and environmental hazards from exposure to the subject chemi-
cal. The information contained in the report is drawn chiefly
from secondary sources and available reference documents.
Because of the limitations of such sources, this short profile
may not reflect all available information including all the
adverse health and environmental impacts presented by the
subject chemical. This document has undergone scrutiny to
ensure its technical accuracy.
-------
SPECIAL NOTATION
U.S. EPA's Carcinogen Assessment Group (CAG) has evaluated
chloroform and has found sufficient evidence to indicate
that this compound is carcinogenic.
-560-
-------
CHLOROFORM
SUMMARY
Chloroform has been found to induce hepatocellular
carcinomas in mice and kidney epithelial tumors in rats.
Hepatomas have also been induced in mice, but necrosis may
be a prerequisite to tumor formation. Bacterial assays
involving chloroform have yielded no mutagenic effects.
Chloroform has produced teratogenic effects when administered
to pregnant .rats.
Reported y6-hour LCcQ values for two common freshwater
fish range from 43,800 to 115,000 ug/1 in static tests.
A 48-hour static test with Daphnia magna yielded an LC(-n
of 28,900 jjg/1. The observed 96-hour LC5Q for the saltwater
pink shrimp is 81,500 jjg/1. In a life cycle chronic test,
the chronic value was 2,546 ug/1 for Uaphnia_ magna_. Per-
tinent information on chloroform toxicity to plants could
not be located in the available literature. In the only
residue study reported, the bluegill concentrated chloroform
six times after a 14-day exposure. The tissue half-life
was less than one day suggesting that residues of chloroform
would not be an environmental hazard to aquatic life.
-5-4,1-
-------
CHLOROFORM
I. INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Chloroform (U.S. EPA, 1979a).
Chloroform (CHCl^; molecular weight 119.39} is a clear,
colorless liquid with a pleasant, etheric, non-irritating
odor and taste (Hardie, 1964; Windholz, 1976). It has the
following physical/chemical properties (Hardie, 1964; Irish,
1972; Windholz, 1976}:
Boiling Point: 61-62°C
Melting Point: -63.5°C
Flash Point: none (none-flammable)
Solubility: Water - 7.42 x 10° pg/1 at 25°C
Miscible with alcohol, benzene,
ether, petroleum ether, carbon
tetrachloride, carbon disulfide,
and oils.
Vapor Pressure: 200 mm Hg at 25 C
Current Production: 1.2 x 10 metric tons/year (U.S.
EPA, 1978a).
Chloroform is currently used either as a solvent or
as an intermediate in the production of refrigerants (prin-
cipleus) , plastics, and Pharmaceuticals (U.S. EPA, 1975)<.
Chloroform is relatively stable under normal environ-
mental conditions. When exposed to sunlight, it .decomposes
slowly in air but is relatively stable in water. The mea-
sured half-life for hydrolyis was found to be 15 months
(Natl. Acad. Sci., 1978a). Degradation in water can occur
in the presence of metals and is accelerated by aeration
(Hardie, 1964).
-------
For additional information regarding halomethanes as
a class the reader is referred to the Hazard Profile on
halomethanes (U.S. EPA, 1979b).
II. EXPOSURE
Chloroform appears to be ubiquitous in the environment.
A major source of chloroform contamination is from the chlor-
ination of water and wastewater (U.S. EPA, 1975; Bellar,
et al. , 1974). Industrial spills may occasionally be a
pulse source of transient high level contamination (Nat.
Acad. Sci., 1978a; Neely, et al., 1976; Brass and Thomas,
1978).
Based on available monitoring data including informa-
tion from the National Organics Monitoring Survey (NOMS),
the U.S. EPA (1978b) has estimated the uptake of chloroform
by adult humans from air, water, and food:
Source
Atmosphere
Water
Food Supply
Total
Atmosphere
Water
Food Supply
Total
Atmosphere
Water
Food Supply
Total
Adult
mg/yr
Maximum Conditions
204
343
16
563
Minimum Conditions
0.41
0.73
2.00
3. 14
Mean Conditions
20.0
64.0
9.00
93
Percent
uptake
36
61
3
100. 00
13
23
64
100.. 00
22
69
10
100.00
-------
A similar estimate, not using MOMS data, has been made by
the National Academy of Sciences (Nat. Acad. Sci., 1978a).
The U.S. EPA (1979a) has estimated the bioconcentration
factor for chloroform to be 14 for the edible portions of
fish and shellfish consumed by Americans. This estimate-
is based on measured steady-state bioconcentration studies
in bluegills.
III. PHARMACOKINETICS
A. Absorption
The efficiency of chloroform absorption by the
gastrointestinal tract is virtually 100 percent in humans
(Fry, et al., 1972). The.corresponding value by inhalation
is 49 to 77 percent (Lehmann and Hassegawa, 1910). Quantita-
tive estimates of dermal absorption efficiency were not
encountered. Since chloroform was used as an anesthetic
via dermal administration, some dermal absorption by humans
can be assumed (U.S. EPA, 1979a).
B. Distribution
Chloroform is transported to all mammalian body
organs and is also transported across the placenta. Strain
differences for chloroform distribution in mice have been
documented by Vessell, et al., (1976).
C. Metabolism
Most absorbed chloroform is not metabolized by
mammals. Toxication, rather than detoxication, appears
»
to be the major consequence of metabolism and probably involves
mixed-function oxidase (MFO) enzyme systems. This observa-
-------
tion is based on enhancement of chloroform toxicity by MFO
inducers and the diminution of toxicity by MFO inhibitors
(Ilett, et al., 1973, McLean, 1970). At least in the liver,
covalent binding of a metabolite to tissue is associated
with tissue damage (Lavigne and Marchand, 1974). Limited
human data (two people) suggest that about 50 percent of
absorbed chloroform is metabolized to C02 (Fry, et al.,
1972; Chiou, 1975).
D. Excretion
In humans, the half-life of chloroform in the
blood and expired air is 1.5 hours (Chiou, 1975) . Most
unchanged chloroform and C02 generated from chloroform are
eliminated via the lungs. Chlorine generated from chloroform
metabolism is eliminated via the urine (Taylor, et al.,
1974; Fry, et al., 1972).
IV. EFFECTS
A. Carcinogenicity
Eschenbrenner and Miller (1945) demonstrated that
oral doses of chloroform administered over a 16-month period
induced hepatomas in strain A mice. Based on variations
in dosing schedules, these researchers concluded that necro-
sis was prerequisite to tumor induction.
In the National Cancer Institute bioassay of chloro-
form (NCI, 1976), hepatocellular carcinomas were induced
in mice (Table 1) and kidney epithelial tumors were induced
in male rats (Table 2), following oral doses over extended
periods of time.
-------
Ten epidemiologic studies have been conducted
on the association of human exposure to chloroform and/or
other trihalomethanes with cancer. A review of these studies
by the National Academy of Sciences (NAS, 1978b) indicated
that these studies suggest that higher concentrations of
trihalomethanes in drinking water may be associated with
an increased frequency of cancer of the bladder. One of
these studies (McCabe, 1975) claimed to demonstrate a statis-
tically significant correlation between age, sex, race,
adjusted death rate for total cancer, and chloroform levels.
B. Mutagenicity
Chloroform yielded negative results in the Ames
assay (Simmon, et al. 1977).
C. Teratogenicity
At oral dose levels causing signs of maternal
toxicity, chloroform had fetotoxic effects on rabbits (100
mg/kg/day) and rats (316 mg/kg/day) (Thompson, et al., 1974).
Fetal abnormalities (acaudia, imperforate anus, subcutaneous
edema, missing ribs, and delayed ossification) were induced
when pregnant rats were exposed to airborne chloroform at
489 and 1,466 mg/m , 7 hrs/day, on days 6 to 15 of gestation.
At 147 mg/m , the only effects were significant increases
in delayed skull ossification and wavy ribs (Schwetz, et
al. , 1974) .
-------
Table 1. Hepatocellular Carcinoma Incidence in Mice'
Male
Controls
Colony Matched
57TT~^ 1718
Low
Dose
138 mg/kg 1850
High
Dose
277 mg/kg 4VTB"
Female
(6%)
1/80
(1%)
(6%)
0/20
(0%)
(30%)
238 mg/kg 36/45
(80%)
(98%)
477 mg/kg 39/41
(95%)
Table 2. Statistically Significant Tumor Incidence in Rats'
Controls
Colony Matched
Kidney 0/99 0/19
epithelial
tumors/animals
P value 0.0000 0.0016
Males
Low
Dose
High
Dose
90 mg/kg
(8%)
4/50 180/mg/kg 12/50
(24%)
Source: National Cancer Institute, 1976.
D. Other Reproductive Effects
Pertinent data could not be located in the avail-
able literature.
E. Chronic Toxicity
The NIOSH Criteria Document (1974) tabulates data
on the effect of chronic chloroform exposure in humans.
The primary target organs appear to be the liver and kidneys,
with some signs of neurological disorders. These effects
have been documented only with occupational exposures.
-5-47-
-------
With the exception of the possible relationship to cancer
(Section IV.A), chronic toxic effects in humans, attribut-
able to ambient levels of chloroform, have not been documented,
The chronic effects of chloroform in experimental
mammals is similar to the effects seen in humans: liver
necrosis and kidney degeneration (Torkelson, et al., 1976;
U.S. EPA, 1979a).
F. Other Relevant Information
Ethanol pretreatment of mice reportedly enhances
the toxic effects of chloroform on the liver (Kutob and
Plaa, 1961), as does high fat and low protein diets (Van
Oettingen, 1964; McLean, 1970). These data were generated
using experimental mammals.
V. AQUATIC TOXICITY
A. Acute Toxicity
Bentley, et al. (1975) observed the 96-hour LC5Q
values for rainbow trout, (Salmo gairdner i), of 43,800 and
66,800 Jjg/l and for bluegills (Lepomis macrochirus) , 100,000
to 115,000 jjg/1, all in static tests. A 48-hour static
test with Daphnia magna resulted in an LC5Q of 28,900 pg/1
(U.S. EPA 1979a). The observed 96-hour LC5Q for the pink
shrimp (Panaeus duorarum) is 81,500 jjg/1. (Bentley, et
al. , .1975) .
B. Chronic Toxicity
The chronic effects of chloroform on Daphnia magna
were determined using flow-through methods with measured
concentrations. The chronic effect level was 2,546 pg/1
(U.S. EPA, 1979a). No other chronic data were available.
/
-5-4, s-
-------
C. Plant Effects
Pertinent information could not be located in
the available literature concerning acute chronic toxicity
of chloroform to plants.
D. Residues
In the only residue study reported, the bluegill
(Lepomis macrochirus) bioconcentrated chloroform six times
after a 14-day exposure (U.S. EPA, 1979a). The tissue half-
life was less than one day.
VI. EXISTING GUIDELINES AND STANDARDS
Both the human health and aquatic criteria derived
by U.S. EPA (1979a), which are summarized below, are being
reviewed; therefore, there is a possibility that these crite-
ria may be changed.
A. Human
Based on the NCI mice data, and using the "one-
hit" model, the EPA (1979a) has estimated levels of chloro-
form in ambient water which will result in specified risk
levels of human cancer:
Exposure Assumption Risk Levels and Corresponding Criteria
(per" day) . _?
0 10 ' 10 ° 10 5
2 liters of drinking 0 0.021 ug/1 0.21 ug/1 2.1 ug/1
water and consumption
of 18.7 grams fish and
shellfish.
»
Consumption of fish 0 0.175 fig/1 1.75 ug/1 17.5
shellfish only.
Sf
-sv*-
-------
The above risks assume that drinking water treatment
and distribution will have no impact on the chloroform con-
centration.
"The NIOSH time-weighted average exposure criterion
for chloroform is 2 ppm or 9.8 mg/m .
The FDA prohibits the use of chloroform in drugs, cos-
metics, or food contact material (14 FR 15026, 15029 April
9, 1976).
Refer to the Halomethane Hazard Profile for discussion
of criterion derivation (U.S. EPA, 1979b).
B. Aquatic
For chloroform, the draft cr't-~rion to protect
/
freshwater aquatic life, based on chronic invertebrate toxi-
city, is 500 ^ig/1 as a .24-hour average and the concentration
should not (based on acute effects) exceed 1,200 pg/l at
any time (U.S. EPA, 1979a). To protect saltwater aquatic
.)'
life, the concentration of chloroform should not exceed
620 jjg/1 as a 24-hour average and the concentration should
.not exceed 1,400 ^jg/1 at anytime (U.S. EPA, 1979a) . These
were calculated from an experiment on a marine invertebrate.
Sf
-sio-
-------
CHLOROFORM
REFERENCES
Bellar, T.A., et al. 1974. The occurrence of organohalides in chlorinated
drinking water. Jour. Am. Water Works Assoc. 66: 703.
Bentley, R.E., et al. 1975. Acute toxicity of chloroform to bluegill
(Lepomis macrochirus), rainbow trout, (Salmo qairdneri), and pink shrimp
(Penaeus duorarum)T Contract No. WA-6-99-1414-B. U.S. Environ. Prot.
Agency.
Brass, H.J. and R.F. Thomas. 1978. Correspondence with Region III. Tech.
Support Oiv., U.S. Environ. Prot. Agency, Washington, D.C.
Chiou, W.L. 1975. Quantitation of hepatic and pulmonary first-pass, effect
and its implications in pharmacokinetic study. I. Pharmacokinetics of
chloroform in man. Jour. Pharmacokin. Biopharmaceu. 3: 193.
Eschenbrenner, A.B. and E. Miller. 1945. Induction of hepatomas in mice by
repeated oral administration of chloroform, with observations on sex dif-
ferences. Jour. Natl. Cancer Inst. 5: 251.
Fry, B.J., et al. 1972. Pulmonary elimination of chloroform and its meta-
bolites in man. Arch. Int. Pharmacodyn. 196: 98.
Hardie, DJV.F. 1964. Chlorocarbons and chlorohydrocarbons: chloroform.
_In: Kirk-Othmer encyclopedia of chemical technology. 2nd ed. John Wiley
and Sons, Inc., New York.
Ilett, K.F., et al. 1973. Chloroform toxicity in mice: Correlation of
renal and hepatic necrosis with covalent binding of metabolites to tissue
macromolecules. Exp. Mol. Pathol. 19: 215.
Irish, D.O. 1972. Aliphatic halogenated hydrocarbons. Ln: Industrial
hygiene and toxicology. 2nd ed. John Wiley and Sons, Inc., New York.
Kutob, S.D. and G.L. Plaa. 1961. The effect of acute ethanol intoxication
on chloroform-induced liver damage. Jour. Pharmacol. Exp. Ther. 135: 245.
Lavigne, J.G. and C. Marchand. 1974. The role of metabolism in chloroform
hepatotoxicity. Toxicol. Appl. Pharmacol. 29: 312.
Lehmann, K.B. and Hassegawa. 1910. Studies of the absorption of chlori-
nated hyrocarbons in animals and humans. Archiv. fuer Hygiene. 72: 327.
McCabe, L.J. 1975. Association between trihalomethanes in drinking water
(NORS data) and mortality. Draft report. U.S. Environ. Prot. Agency.
»
McLean, A.E.M. 1970. The effect of protein deficiency and microsomal en-
zyme induction by DDT and phenobarbitone on the acute toxicity of chloroform
and pyrrolizidine alkaloid retrorsine. Brit. Jour. Exp. Pathol. 51: 317.
-------
National Academy of Sciences. 1978a. Nonfluorinated halomethanes in the
environment. Environ. Studies Board, Natl. Res. Council, Washington, O.C.
National Academy of Sciences/National Research Council. 1978b. Epidemiolo-
gical studies of cancer frequency and certain organic constituents of drink-
ing water - A review of recent literature for U.S. Environ. Prot. Agency.
National Cancer Institute. 1976. Report on carcinogenesis bioassay of
chloroform. Natl. Tech. Inf. Serv. P8-264018. Springfield, Va.
National Institute for Occupational Safety and Health. 1974. Criteria for
a recommended standard...Occupational-exposure to chloroform. NIOSH Publ.
No. 75-114. Dept. Health Educ. Welfare, Washington, O.C.
Neely, W.8., et al. 1976. Mathematical models predict concentration-time
profiles resulting from chemical spill in river. Environ. Sci. Technol.
10: 72.
Schwetz, B.A., et al. 1974. Embryo and fetotoxicity of inhaled chloroform
in rats. Toxicol. Appl. Pharmacol. 28: 442.
Simmon, J.M., et al. 1977. Mutagenic activity of chemicals identified in
drinking water. In: 0. Scott, et al., (ed.) Progress in genetic toxico-
logy. Elsevier/North Holland Biomedical Press, New York.
Taylor, D.C., et al. 1974. Metabolism of chloroform. II. A sex difference
in the metabolism of (l^C)-chloroform in mice. Xenobiotica 4: 165.
Thompson, D.J., et al. 1974. Teratology studies on orally .administered
chloroform in the rat and rabbit. Toxicol. Appl. Pharmacol. 29: 348.
Torkelson, T.R., et al. 1976. The toxicity of chloroform as determined by
single and repeated exposure of laboratory animals. Am. Ind. Hyg. Assoc.
Jour. 37: 697.
U.S. EPA. 1975. Development document for interim final effluent limita-
tions guidelines and new source performance standards for the significant
organic products segment of the organic chemical manufacturing point source
category. EPA-440/1-75/045. U.S. Environ. Prot. Agency, Washington, D.C.
U.S. EPA. 1978a. In-depth studies on health and environmental impacts of
selected water pollutants. Contract No. 68-01-4646. U.S. Environ. Prot.
Agency.
U.S. EPA. 1978b. Office of Water Supply. Statement of basis and purpose
for an amendment to the national interim primary drinking water regulations
on trihalomethanes. Washington, D.C.
U.S. EPA. 1979a. Chloroform: Ambient Water Quality Criteria. Document.
(Draft)
»
U.S. EPA. 1979b. Environmental Criteria and Assessment Office. .Chloro-
form: Hazard Profile. (Draft)
-------
Van Oettingen, w.F. 1964. The hydrocarbons of industrial and toxicological
importance. Elsevier Publishing Co., New York.
Vessell, E.S., et al. 1976. Environmental and genetic factors affecting
the response of laboratory animals to drugs. Fed. Am. Soc. Exp. Biol. Proc.
35: 1125.
Windholz, M., ed. 1976. The Merck Index. 9th ed. Merck and Co., Inc.,
Rahway, N.J.
-5-73-
-------
No. 48
Chloromethane
Health and Environmental Effects
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
APRIL 30, 1980
-S7H-
-------
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.
-------
CHLOROMETHANE
SUMMARY
Chloromethane is toxic to humans by its action on the
central nervous system. In acute toxicity, symptoms consist
of blurring vision, headache, vertigo, loss of coordination,
slurring of speech, staggering, mental confusion, nausea,
and vomiting. Information is not available on chronic toxicity,
teratogenicity, or carcinogenicity. Chloromethane is highly
mutagenic to the bacteria, Salmonella typhimurium.
Only three toxicity tests have been conducted on three
species of fish yielding acute values ranging from 147,000
to 300,000 ^ag/1. Tests on aquatic invertebrates or plants
have not been conducted.
-------
CHLOROMETHANE
I . INTRODUCTION
This profile is based on the Ambient Water Quality
Criteria Document for Halomethanes (U.S. EPA, 1979a) .
Chloromethane (CH.,C1; methyl chloride; molecular weight
50.49) is a colorless, flammable, almost odorless gas at
room temperature and pressure (Windholz, 1976). Chloromethane
has a melting point of -97.7°C, a boiling point of -24.2°C,
a specific gravity of 0.973 g/ml at -10°C, and a water solubi-
lity of 5.38 x 10 >ig/l. It is used as a refrigerant,
a methylating agent, a dewaxing agent, and catalytic solvent
in synthetic rubber production (MacDonald, 1964). However,
its primary' use is as a chemical intermediate (Natl. Acad.
Sci., 1978). Chloromethane is released to the environment
by manufacturing and use emissions, by synthesis during
chlorination of drinking water and municipal sewage, and
\-
by natural-'synthesis, with the oceans as the primary site
(Lovelock -1975) . For additional information regarding
the halomethanes as a class, the reader is referred to the
Hazard Profile on Halomethanes (U.S. EPA, 1979b) .
II. EXPOSURE
A. Water
The U.S. EPA (1975) has identified Chloromethane
qualitatively in finished drinking waters in the U.S. How-
ever, there are no data on its concentration in drinking
water, raw water, or waste-water (U.S. EPA, 1979a) , probably'
because it is more reactive than other chlorinated methanes
(Natl. Acad. Sci. , 1978) .
-577-
-------
B . Food
There is no information on the presence of chloro-
methane in food. There is no bioconcentration factor for
chloromethane (U.S. EPA, 1979a) .
C. Inhalation
Saltwater atmospheric background concentrations
of chloromethane averaging about 0.0025 mg/m have been
reported (Grimsrud and Rasmussen, 1975; Singh, et al. 1977).
This is higher than reported average continental background
and urban levels and suggests that the oceans are a major
source of global chloromethane (National Acad. Sci., 1978).
Localized sources, such as burning of tobacco or other com-
bustion processes, may produce high indoor-air concentra-
tions of chloromethane (up to 0.04 mg/m ) (Natl. Acad. Sci.,
1978). Chloromethane is the predominant halomethane in
indoor air, and is generally in concentrations two to ten
times ambient background levels.
III. PHARMACOKINETICS
A. Absorption
Chloromethane is absorbed readily via' the lungs,
and to a less significant extent via the skin. Poisonings
involving gastrointestinal absorption have not been reported
(Natl. Acad. Sci., 1977; Davis, et al. , 1977).
B. Distribution '
Uptake of chloromethane by the blood is rapid
i
but results in only moderate blood levels with continued
exposure. Signs and pathology of intoxications suggest
-S7S-
-------
wide tissue (blood, nervous tissue, liver, and kidney) distri-
bution of absorbed chloromethane (Natl. Acad. Sci., 1978).
C. Metabolism
Decomposition and sequestration of chloromethane
result primarily by reaction with sulfhydryl groups in intra-
cellular enzymes and proteins (Natl. Acad. Sci., 1977).
IV. EFFECTS
A. Carcinogenicity
Pertinent information could not be located in
the available literature.
B. Mutagenicity
Simmon and coworkers (1977) reported that chloro-
methane was mutagenic to Salmonella tryphimurium strain
TA 100 when assayed in a dessicator whose atmosphere contained
the test compound. Metabolic activation was not required,
and the number of revertants per plate was directly dose-
related. Also, Andrews, et al. (1976) have demonstrated
that chloromethane was mutagenic to S_._ typhimur ium strain
TA1535 in the presence and absence of added liver homogenate
preparations .
C. Teratogenicity and Other Reproductive Effects
Information on positive evidence of teratogenisis
or other reproductive effects was not available in the literature,
D. Chronic Toxicity
Under prolonged exposures to chloromethane (dura-
»
tion not specified) increased mucous flow and reduced mucosta-
-579-
-------
tic effect of other agents (e.g., nitrogen oxides) were
noted in cats (Weissbecker, et al. , 1971).
E. Other Relevant Information
In acute human intoxication, chloromethane pro-
duces central nervous system depression, and systemic poison-
ing cases have also involved hepatic and renal injury (Hansen,
er al., 1953; Spevac, et al., 1976).
V. AQUATIC TOXICITY
A. Acute Toxic ity
A single 96-hour static renewal test serves as
the only acute study for freshwater providing an adjusted
LC5Q value of 550,000 ug/1 for the bluegill sunfish (Lepomis
macrochirus) . (Dawson, et al., 1977). Studies on fresh-
water invertebrates were not found. For the marine fish,
the tidewater silversides (Menidia beryllina) , a 96-hour
static renewal assayed provided an LC5Q value of 270,000
ug/1 (Dawson, et al. , 1977). Acute studies on marine inverte-
brates were not found.
B. Chronic Toxicity
In a review of the available literature, chronic
testing with chloromethane has not been reported.
C. Plant Effects
Pertinent information could not be located in the
available literature.
VI. EXISTING GUIDELINES AND STANDARDS
Neither the human nor the aquatic criteria derived
by U.S. EPA, 1979a, which are . summarized below, have gone
-580-
-------
through the process of public review; . therefore, there is
a possibly that these criteria may be changed.
A. Human
OSHA (1976) has established the maximum acceptable
time-weighted average air concentrations for daily eight-
hour occupational exposure at 210 mg/m . The U.S. EPA (1979a)
Draft Water Quality Criteria for Chloromethane is 2 ug/1.
Refer to the Halomethanes Hazard Profile for discussion
of criteria derivation (U.S. EPA, 1979b) . *-
B. Aquatic
Criterion recommended to protect freshwater or-
ganisms have been drafted as 7,000 ug/1, not to exceed 16,000
ug/1 for a 24-hour average concentration. For marine life,
the criterion has been drafted as 3,700 pg/I, not to exceed
8,400 pg/1 as a 24-hour average concentration.
-SSJ-
-------
CHLOROMETHANE
REFERENCES
Andrews, A.W., et al. 1976. A comparison of the mutagenic
properties of vinyl chloride and methyl chloride. Mutat.
Res. 40: 273.
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, of Contract
No. 68-01-4315. Off. Toxic Subst., U.S. Environ. Prot.
Agency, Washington, D.C.
Dawson, G.W. , et al. 1977. The acute tojcicity of 47 indus-
trial chemicals to fresh and saltwater fishes. Jour. Hazard.
Mater. 1: 303.
Grimsrud, E.P., and R.A. Rasmussen. 1975. Survey and an-
alysis of halocarbons in the atmosphere by gas chromatography-
mass spectrometry. Atmos. Environ. 9: 1014.
Hansen, H., et al. 1953. Methyl chloride intoxification:
Report of 15 cases. AMA Arch. Ind. Hyg. Occup. Med. 8:
328.
Lovelock, J.E. 1975. Natural halocarbons in the air and
in the sea. Nature 256: 193.
MacDonald, J.D.C. 1964. Methyl chloride intoxication.
Jour. Occup. Med. 6: 81.
National Academny of Sciences. 1977. Drinking water and
health. Washington, D.C.
Nation-al Academy of Sciences. 1978. Nonfluorinated halo-
methanes in the environment. Washington, D.C.
Occcupational Safety and Health Administration. 1976.
General industry standards. OSHA 2206, revised January,
1976. U.S. Dep. Labor, Washington, D.C.
Simmon, V.F., et al. 1977. Mutagenic activity of chemicals
identified in drinking water. S. Scott, et al., (eds.) In:
Progress in genetic toxicology.
Singh, H.B., et al. 1977. Urban-non-urban relationships
of halocarbons, SFg, N2o and other atmospheric constituents.'
Atmos. Environ. 11: 819.
-------
Spevac, L., et al. 1976. Methyl chloride poisoning in
four members of a family. Br. Jour. Ind. Med. 33: 272.
U.S. EPA. 1975. Preliminary assessment of suspected carcino-
gens in drinking water, and appendices. A report to Congress,
Washington, D.C.
U.S. EPA. 1979a. Halomethanes: Ambient Water Quality Cri-
teria (Draft).
U.S. EPA. 1979b. Environmental Criteria and Assessment
Office. Halomethanes: Hazard Profile (Draft).
Weissbecker, L., et al. 1971. Cigarette smoke and tracheal
mucus transport rate: Isolation of effect of components
of smoke. Am. Rev. Resp. Dis. 104: 182.
Windholz, M., (ed.) 1976. The Merck Index. Merck and Co.,
Rahway, N.J.
-533-
-------
No. 49
2-Chlo ronaphthalene
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.
-SSS*-
-------
2-CHLORONAPHTHALENE
SUMMARY
Monochlorinated naphthalenes are relatively insoluble in
water. They can be slowly degraded by bacteria and are subject
to photochemical decomposition. Monochlorinated naphthalenes
appear to bioconcentrate in plants and animals exposed to the
substances. 2-Chloronaphthalene has been identified as a pol-
lutant in a variety of industries.
No information was located on the carcinogenicity, mutagen-
icity, or teratogenicity of 2-chloronaphthalene or other mono-
chlorinated naphthalenes. The metabolism of some chlorinated
naphthalenes, however, proceeds through an epoxide mechanism. If
an epoxide is formed as an intermediate in the metabolism of 2-
chloronaphthalene, it could react with cellular macromolecules
possibly resulting in cytotoxicity, mutagenicity, oncogenicity,
or other effects.
I. INTRODUCTION
This profile is based on the Ambient Water Quality Criteria
Document for Chlorinated Naphthalenes (U.S. EPA, 1979b).
2-Chloronaphthalene (C,QH-C1; molecular weight 162) is a
crystalline solid with a melting point of 61°C and a boiling
point of 256°C. Its density at 16°C is 1.27. It is insoluble in
»
water and soluble in many organic solvents (Weast; 1972 and
Hardie, 1964).
-------
A review of the production range (includes importation)
statistics for 2-chloronaphthalene (CAS. No. 91-58-7) which is
listed in the inital TSCA Inventory (1979a) has shown that
between 1,000 and 9,000 pounds of this chemical were
produced/imported in 1977.jV
Monochloronaphthalenes and mixtures of mono- and dichloro-
naphthalenes have been used for chemical-resistant gauge fluids
and instrument seals, as heat exchange fluids, high-boiling
specialty solvents (e.g., for solution polymerization), color
dispersions, engine crankcase additives to dissolve sludges and
'gums, and as ingredients in motor tuneup compounds. Monochloro-
naphthalene was formerly used as a wood preservative (Dressier,
1979).
II. EXPOSURE
1
A. Environmental Fate
Polychlorinated naphthalenes do not occur •' jturally in the
environment. Potential environmental accumulation can occur
around points of manufacture of the compounds or products
containing them, near sites of disposal of polychorinated
naphthalene-containing wastes, and, because polychlorinated
This production range information does not include any
production/importation data claimed as confidential by the
person(s) reporting for the TSCA inventory, nor does it ,
include any information which would compromise Confidential
Business Information. The data submitted for the TSCA
Inventory, including production range information, are subject
to the limitations contained in the Inventory Reporting
Regulations (40 CFR 710).
-------
biphenyls (PCBs) are to some extent contaminated by polychlori-
nated naphthalenes (Vos _et_ _al_. 1970; Bowes et al. 1975) near
sites of heavy PCB contamination.
Because polychlorinated naphthalenes are relatively insol-
uble in water, they are not expected to migrate far from their
point of disposition. The use of mono- and dichlorinated naphtha-
lenes as an engine oil additive and as a polymerization solvent
in the fabric industry suggests possible contamination of soil or
water.
Walker and Wiltshire (1955) found that soil bacteria when
first grown on naphthalene could also grow on 1-chloronaph-
thalene, producing a diol and chlorosalicylic acid. Canonica et
al. (1957) found similar results for 2-chloronaphthalene. Okey
and Bogan (1965) studied the utilization of chlorinated sub-
strates by activated sludge and found that naphthalene was
degraded at a fairly rapid rate, while 1-and 2-chloronaphthalenes
were handled more slowly.
Ruzo ^t_ _al^. (1975) studied the photodegradatiori of 2-chloro-
naphthalene in methanol. The major reaction pathways seen were
dechlorination and dimerization. Jaffe and Orchin (1966) indi-
cated that any 2-chloronaphthalene present at the surface of
water could be degraded by sunlight to naphthalene. In the
aquatic environment, 2-chloronaphthalene can exist as a surface
film, be adsorbed by sediments, or accumulated by biota.
-------
B. Bioconcentration
Monochlorinated naphthalenes appear to bioconcentrate in the
aquatic environment. Adult grass shrimp (Palaemonetes pugio)
were exposed to a mixture of mono- and dichloro naphthalenes for
15 days. The concentration of chloronaphthalenes detected in the
shrimp was 63 times that of the experimental environment. When
removed from the contaminated environment, however, the concen-
tration in the shrimp returned to virtually zero within 5 days
(Green and Neff, 1977).
Erickson £t_\al_- (1978a) reported a higher relative biocon-
centration of the lower chlorinated naphthalenes in the fruit of
apple trees grown on contaminated soil. The soil was found to
have a polychlorinated naphthalene level of 190 ug/kg of which
1.6 ug/kg consisted of monochloronaphthalenes. While the apples
grown on this soil had only 90 ug/kg of polychlorinated naphtha-
lenes, the level of monochloronaphthalene was 62 ug/kg.
C. Environmental Occurrence
2-Chloronaphthalene has been identified as a pollutant in a
variety of industries, e.g. organic chemical, rubber, power
generation, and foundries (U.S. EPA, 1979c).
Chlorinated naphthalenes have been found more consistently
in air and soil samples than in associated rivers and streams
(Erickson _et_ _al_., 1978b). The air samples contained mainly the
mono-, di- and trichlorinated naphthalenes, while soil contained
#
mostly the tri-, tetra- and pentachlorinated derivatives.
To date polychlorinated naphthalenes have not been identi-
fied in either drinking water or market basket food. The Food
and Drug Administration has had polychlorinated naphthalene
-------
monitoring capability for foods since 1970, but has not reported
their occurrence in food (U.S. EPA, 1975).
III. PHARMACOKINETICS
Ruzo et al. (1976b) reported the presence of 2-chloronaph-
thalene in the brain, kidney, and liver of pigs six hours after
injection. Small concentrations of 3-chloro-2-naphthol, a
metabolite , were seen in the kidney and liver with large amounts
occurring in the urine and bile. The metabolism of some chlori-
nated napthalenes proceeds through an epoxide mechanism (Ruzo et
al. 1975, 1976ab; Chu _et_ _al_. , 1977ab) .
IV. HEALTH EFFECTS
A. Teratogenicity, Mutagenicity, and Carcinogenicity
No information was located on the carcinogenicity, muta-
genicity, or teratogenicity of polychlorinated naphthalenes.
If an epoxide is formed as an intermediate in the metabolism
of 2-chloronaphthalene, it could react with cellular macromole-
cules. Binding might occur with.protein, RNA, and DMA resulting
in possible cytotoxicity, mutagenicity, oncogenicity, or other
effects (Garner, 1976; Heidelberger, 1973;.Wyndham and Safe,
1978).
B. Other Toxity
In man, the first disease recognized as being associated
0
with occupational exposure to higher polychlorinated naphthalenes
was chloracne. Occurrence of this disease was associated with
the manufacture or use of polychloronaphthalene-treated electri-
cal cables. Kleinfeld _et_ ^1_. (1972) noted that workers at
-590-
-------
an electric coil manufacturing plant had no cases of chloracne
while using a mono- and dichloronaphthalene mixture. When a
tetra-/pentachlorinated naphthalene mixture was substituted for
the original mixture, 56 of the 59 potentially exposed workers
developed chloracne within a "short" time.
The lower chlorinated naphthalenes appear to have low acute
toxicity. Mixtures of mono-/dichloronaphthalenes and tri-/tetra-
chloronaphthalenes at 500 mg/g in a mineral oil suspension
applied to the skin of the human ear caused no response over a
30-day period. A mixture of penta-/hexachloronaphthalenes given
under the same conditions caused chloroacne (Shelley and Kligman,
1957).
The oral LD50 for rats and mice is 2078 mg/kg and 886 mg/kg
respectively (NIOSH, 1978). No mortality or illness was reported
in rabbits given 500 mg/kg orally (Cornish and Block, 1958).
V. AQUATIC EFFECTS
The LC50 (ppb) of a mixture of 60% mono- and 40% dichloro-
naphthalenes in grass shrimp (Palaemonetes pugio)is as follows:
72-hr 96-hr
post larval stage - 449
adult 370 325
(Green and Neff, 1977)
VI. EXISTING GUIDELINES
»
There are no existing guidelines for 2-chloronaphthalene.
-------
BIBLIOGRAPHY
Bowes, G. W. j5t_ _a_l_. 1975. Identification of chlorinated diben-
zofurans in American polychlorinated biphenyls. Nature 256, 305.
(as cited in U.S. EPA, 1979b).
Canonica, L. _et_ _al_. 1957. Products of microbial oxidation of
some substituted naphthalenes. Rend. 1st. Lombardo Sci. 91, 119-
129 (Abstract).
Cornish H.H., and W.D. Block. 1958. Metabolism of chlorinated
naphthalenes. J. Biol. Chem. 231, 583. (as cited in U.S. EPA,
1979b).
Chu, I., et _al_. 1977a. Metabolism and tissue distribution of
(1, 4, 5,8-^C)-l, 2-dichloronaphthalene in rats. Bull. Environ.
Contain. Toxicol. 18, 177. (as cited in U.S. EPA, 1979b).
Chu, I., et al. 1977b. Metabolism of chloronaphthalenes. J.
Agric. Food Chem. 25, 881. (as ' jted in U.S. EPA, 1979b).
Dressier, H. 1979. Chlorocarbons and chlorohydrocarbons:
chlorinated naphthalenes. In. Standen A. ed. Kirk-Othmer
Encyclopedia of Chemical Technology, 3rd ed. New York: John Wiley
and Sons, Inc.
Erickson, M.D., et al. 1978a. Sampling and analysis for
polychlorinated naphthalenes in'he environment J. Assoc. Off.
Anal. Chem. 61, 1335. (as cited-'in U.S. EPA, 1979b).
Erickson, M.D., et_ _al_. 1978b. "^velopment of methods for
sampling and analysis of polychlorinated naphthalenes in ambient
air. Environ. Sci. Tech. 12(8), 927-931.
Garner, R.C. 1976. The role of epoxides in bioactivation and
carcinogenesis. In; Bridges, J. W. and L. F. Chasseaud, eds.
Progress in drug metabolism, Vol. 1. New York: John Wiley and
Sons. pp. 77-128.
Green, F. A., Jr. and J. M. Neff. 1977. Toxicity, accumulation,
and release of three polychlorinated naphthalenes (Halowax 1000,
1013, and 1099) in postlarval and adult grass shrimp,
Palaemonetes pugio. Bull. Environ. Contam. Toxicol. 14, 399.
Hardie, D.W.F. 1964. Chlorocarbons and chlorohydrocarbons:
chlorinated naphthalenes. In: Kirk-Othmer Encyclopedia of
Chemical Technology. 2nd ed. John Wiley and Sons. Inc., New York.
Heidelberger, C. 1973. Current trends in carcinogenesis. Proc.
Fed. Am. Soc. Exp. Biol. 32,2154-2161.
Jaffe, H. H. and M. Orchin. 1966. Theory and aplication of
ultraviolet spectroscopy. Wiley Pub. New York> 624pp.
-------
Kleinfeld, M. , et al_- 1972. Clinical effects of chlorinated
naphthalene exposure. J. Occup. Med. _14_, 377-379. (as cited in
U.S. EPA, 1979b).
National Institute of Occupational Safety and Health. 1978.
Registry of Toxic Effects of Chemical Substances. DHEW Publ. No.
79-100.
Okey, R. W. and R. H. Bogan. 1965. Apparent involvement of
electronic mechanisms in limiting microbial metabolism of
pesticides. J. Water Pollution Contr. Fedr. 37, 692.
Ruzo, L.O., _et_ _al_. 1975. Hydroxylated metabolites of chlo-
rinated naphthalenes (Halowax 1031) in pig urine. Chemosphere 3,
121-123.
Ruzo, L. O. , _et_ al_. 1976a. Metabolism of chlorinated
naphthalenes. . J. Agric. Food Chem. 24, 581-583.
Ruzo, L.O., et al. 1976b. Uptake and distribution of
chloronaphthalenes and their metabolities in pigs. Bull.
Environ. Contam. Toxicol. 16(2), 233-239.
Shelley, W. B., and A. M. Kligman. 1957. The experimental
production of acne by penta-and hexachloronaphthalenes. A.M.A.
Arch'. Derma to 1. 7j, 689-695. (as cited in U.S. EPA, 1979b) .
U.S. EPA. 1975. Environmental Hazard Assessment Report:
Chlorinated Naphthalenes. (EPA 560/8-75-001).
U.S. EPA. 1979a. Toxic Substances Control Act Chemical
Substance Inventory, Production Statistics for Chemicals on the
Non-Confidential Initial TSCA Inventory, .
U.S. EPA.- 1979b. Ambient Water Quality Criteria: Chlorinated
Naphthalenes. PB-292-426.
U.S. EPA. Unpublished data obtained from the U.S. EPA
Environmental Research Laboratory, Athens, Georgia, February 22,
1979c.
Vos, J.G., et al. 1970. Identification and toxicological evalu-
ation of chlorinated dibenzofurans and chlorinated naphthalenes
in two commercial polychlorinated biphenyls. Food Cosmet.
Toxicol. _§_, 625. (as cited in U.S. EPA,' 1979b)
Walker, N. and G.H. Wiltshire. 1955. The decomposition of 1-
chloro- and 1-bromonaphthalene.by soil bacteria. J. Gen.
Microbiol. 12, 478-483.
-------
Weast, R.C., ed. 1972. CRC Handbook of Chemistry and Physics
CRC Press, Inc., Cleveland, Ohio.
Wyndham, D., and S. Safe. 1978. In vitro metabolism of 4-
ss
-------
No. 50
2-Chloropheno1
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.
-------
2-CHLOROPHENOL
SUMMARY
Insufficient data exist to indicate that 2-chlorophenol
is a carcinogenic agent. 2-Chlorophenol appears to act as a
nonspecific irritant in promoting tumors in skin painting
studies. No information is available on mutagenicity, tera-
togenicity, or subacute and chronic toxicity. 2-Chlorophenol
is a weak uncoupler of oxidative phosphorylation and a con-
vulsant.
2-Chlorophenol is acutely toxic to freshwater fish at
concentrations ranging from 6,590 to 20,170 ug/1. No marine
studies are available. Concentrations greater than 60 ug/1
have been reported to taint cooked rainbow trout flesh in
flavor impairment studies.
-------
I. INTRODUCTION
This profile is based primarily on the Ambient Water
Quality Criteria Document for 2-Chlorophenol (U.S. EPA,
1979) .
2-Chlorophenol (ortho-chlorophenol) is a liquid having
the empirical formula CgH^Cl (molecular weight: 128.56).
It has the following physical/chemical properties (Rodd,
1954; Judson and Kilpatrick, 1949; Sax, 1975; Stecher, 1968;
Henshaw, 1971):
Melting Point: 8.7°C
Boiling Point Range: 175-176°C
Vapor Pressure: 1 mm Hg at 12.1°C
Solubility: Slightly soluble (lg/1)
in water at 25°C and
neutral pH
2-Chlorophenol is a commercially produced chemical used
as an intermediate in the production of higher chlorophenols
and phenolic resins and has been utilized in a process for
extracting sulfur and nitrogen compounds from coal (U.S. EPA,
1979).
2-Chlorophenol undergoes photolysis in aqueous solutions
as a result of UV irradiaton (Omura and Matsuura, 1971;
Joschek and Miller, 1966). Laboratory studies suggest that
microbial oxidation could be a degradation route for 2-chlo-
rophenol (Loos, et al., 1966; Sidwell, 1971; Nachtigall and
Butler, 1974). However, studies performed by Ettinger and
Ruchhoft (1950) on the persistency of 2-chlorophenol in sew-
age and polluted river water indicated that the removal of
«
monochlorophenols requires the presence of an adapted micro-
flora.
-------
II. EXPOSURE
A. Water
The generation of waste from the commercial produc-
tion and use of 2-chlorophenol (U.S. EPA, 1979) and the inad-
vertent synthesis of 2-chlorophenol due to chlorination of
water contaminated with phenol (Aly, 1968: Barnhart and Camp-
bell, 1972; Jolley, 1973; Jolley, et al., 1975) are potential
sources of contamination of water with 2-chlorophenol. How-
ever, no data regarding 2-chlorophenol concentrations in fin-
ished drinking water are available (U.S. EPA, 1979).
B. Food
Information on levels of 2-chlorophenol in foods is
not available. Any contamination of foods is probably indi-
rect as a result of use and subsequent metabolism of phenoxy-
alkanoic herbicides (U.S. EPA, 1979). Although residues of
2,4-dichlorophenol were found in tissues of animals fed 2,4-D
and nemacide containing food (Clark, et al. 1975); Sherman,
et al. 1972), no evidences were cited to indicate the pres-
ence of 2-chlorophenol; moreover, there was no contamination
of 2-chlorophenol in milk and cream obtained from cows fed
2,4-D treated food (Bjerke, et al. 1972).
The potential for airborne exposure to 2-chloro-
phenol in the general environment, excluding occupational ex-
posure, has not been reported (U.S. EPA, 1979).
The U.S. EPA (1979) has estimated the weighted
average bioconcentration factor for 2-chlorophenol and the*
edible portion of fish and shellfish consumed by Americans at
-------
490. This estimate is based on measured steady state biocon-
centration studies in bluegills.
C. Inhalation
Pertinent data regarding concentrations of 2-chloro-
phenol in ambient air could not be found in the available
literature.
III. PHARMACOKINETICS
A. Absorption
Data dealing directly with the absorption of 2-
chlorophenol by humans and experimental animals has not been
found. Chlorophenol compounds are generally considered to be
readily absorbed, as would be expected from their high lipid
solubility and low degree of ionization at physiological pH
(Doedens, 1963; Farquharson, et. al. , 1958 ) . Toxicity studies
indicate that 2-chlorophenol is absorbed through the skin.
B. Distribution
Pertinent data regarding tissue distribution of 2-
chlorophenol was not located in the available literature.
C. Metabolism
Data regarding the metabolism of 2-chlorophenol in
humans was not available (U.S. EPA, 1979). Based on experi-
mental work in two species, it appears that the metabolism of
2-chlorophenol in mammals is similar to that of phenol in
regard to the formation and excretion of sulfate and glucur-
onide conjugates (Von Oettingen, 1949; Lindsay-Smith, et al.
*
1972) Conversion of chlorobenzene to monochlorophenols,
including 2-chlorophenol, has been shown in vitro with rat
If
-6,00-
------- |