EPA-540/1-86-039
Office of Emergency and
Remedial Response
Washington DC 20460
Superfund
&EPA
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
HEALTH EFFECTS ASSESSMENT
FOR CARBON TETRACHLORIDE
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EPA/540/1-86-039
September 1984
HEALTH EFFECTS ASSESSMENT
FOR CARBON TETRACHLORIDE
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
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DISCLAIMER
This report has been funded wholly or In part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and 1t has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with carbon
tetrachloMde. All estimates of acceptable Intakes and carcinogenic potency
presented In this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-Hne literature searches of the
Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/OATAL06 data bases.
The basic literature searched supporting this document 1s current up to
September, 1984. Secondary sources of Information have also been relied
upon 1n the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The
following Office of Health and Environmental Assessment (OHEA) sources have
been extensively utilized:
U.S. EPA. 1980b. Ambient Water Quality Criteria for Carbon Tetra-
chlorlde. Environmental Criteria and Assessment Office, Cincin-
nati, OH. EPA-440/5-80-026. NTIS PB 81-117376.
U.S. EPA. 1983b. Reportable Quantity Document for Carbon Tetra-
chlorlde. Prepared by the Environmental Criteria and Assessment
Office, Cincinnati, OH, OHEA for the Office of Solid Waste and
Emergency Response, Washington, DC.
U.S. EPA. 1983c. Review of Toxlcologlc Data 1n Support of Evalua-
tion for Carcinogenic Potential of: Carbon Tetrachlorlde. Prepared
by the Carcinogen Assessment Group, OHEA, Washington, DC for the
Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1984. Health Assessment Document for Carbon Tetrachlo-
rlde. Environmental Criteria and Assessment Office, Cincinnati,
OH. EPA 600/8-82-001F. NTIS PB 85-124196.
The Intent 1n these assessments Is to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer Is not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants 1n ambient air or water where lifetime exposure 1s
111
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assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
The AIC, acceptable Intake chronic, is similar 1n concept to the ADI
(acceptable dally Intake). It 1s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the Hfespan [see U.S. EPA (1980a) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable
exposure for a given route with the Implicit assumption that exposure by
other routes Is Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development 1s explained 1n U.S. EPA (1983a).
For compounds for which there Is sufficient evidence of carclnogenlclty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-|*s have been computed based on oral
and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context the
reader Is referred to the Preface of this document. The preface outlines
limitations applicable to all documents of this series as well as the appro-
priate Interpretation and use of the quantitative estimates presented.
Animal bloassay data 1n three species (rats, mice, hamsters) Indicate
that carbon tetrachlorlde Is a hepatic carcinogen. Human data are limited
and equivocal. The Cancer Assessment Group, as explained In U.S. EPA
(1984), has used data from the following for risk assessment purposes:
Delia Porta et al. (1961); Edwards et al. (1942); NCI (1976) (both rat and
mouse). Since none of these studies were deemed adequate Individually, the
geometric mean of the upper limit unit risk estimates (3.7xlO~6) has been
employed. The corresponding slope estimate (q-|*) is l.SOxlCT1
(mg/kg/day)"1.
A note of caution 1s provided by U.S. EPA (1984). Some evidence Indi-
cates that carbon tetrachlorlde may act via a nongenotoxic mechanism. If
this should be the case, then low-dose risk extrapolation using techniques
developed for agents which presumably act through genotoxicity could
substantially overestimate risk. The reader Is referred to U.S. EPA (1984)
for a thorough discussion of this question. More experimental data are
needed to resolve this Issue.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract NO. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball wasithe Project
Officer. The final documents In this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
7.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
3.4. TOXICANT INTERACTIONS
CARCINOGENICITY
4.1. HUMAN DATA
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
6.3. CARCINOGENIC POTENCY (q-|*)
6.3.1. Oral
6.3.2. Inhalation
REFERENCES
Page
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3
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5
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5
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, . . 9
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APPENDIX: Summary Table for Carbon Tetrachlorlde 32
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LIST OF TABLES
No. Title Page
1-1 Selected Physical and Chemical Properties and Half-lives
of Carbon Tetrachlorlde 2
4-1 Survival of Rats Treated with Carbon Tetrachlorlde 14
4-2 Survival of Mice Treated with Carbon Tetrachlorlde 15
4-3 Liver Tumors 1n Mice 16
5-1 Current Regulatory Standards and Criteria for
Carbon Tetrachlorlde 20
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
BCF Bloconcentratlon factor
bw Body weight
CS Composite score
PEL Frank-effect level
GI Gastrolntetlnal
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
ppm Parts per million
SGOT Serum glutamlc oxaloacetlc transamlnase
SGPT Serum glutamlc pyruvlc transamlnase
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
carbon tetrachlorlde (CAS No. 56-23-5), also known as tetrachloromethane,
are shown In Table 1-1.
The value for the retardation factor for carbon tetrachlorlde 1s esti-
mated on the basis of a comparison of the octanol/water partition coeffi-
cient and water solubility of this compound with chloroform and the
estimated retardation factor of 1.2 for chloroform (Wilson et a!., 1981).
The half-life of carbon tetrachlorlde In soil could not be located 1n
the literature searched; however, evaporation 1s expected to be the predomi-
nant loss mechanism from the soil surface. In subsurface soil, blodegrada-
tlon of carbon tetrachlorlde will probably be a very slow process, as Is
true of chloroform (Wilson et al.t 1983). Therefore, carbon tetrachlorlde
Is expected to leach Into groundwater. This has been confirmed by Page
(1981), who detected carbon tetrachlorlde with a 64% frequency 1n ground-
water.
-1-
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TABLE 1-1
Selected Physical and Chemical Properties and Half-lives
for Carbon TetrachloMde
Properties
Values
Reference
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Octanol/water partition
coefficient:
Soil mobility:
(predicted as retardation
factor for a soil depth of
140 cm and organic carbon
content of 0.087%)
BCF:
Half-lives 1n A1r:
halogenated aliphatic
hydrocarbon
153.82
90 mm Hg at 20°C
757 mg/l at 25°C
437
537
>1.2 (estimated)
Water:
30 1n blueglll
(Lepomls macroschlrus)
17 1n fathead minnow
(Plmephales promelas)
22 years
-50 years
0.3-3 days 1n river
30-300 days 1n lake
Callahan
et al., 1979
Banerjee
et al., 1980
Callahan et
al., 1979
Banerjee et
al., 1980
Wilson
et al., 1981
U.S. EPA,
1980b
Velth
et al., 1979
Singh
et al., 1981
U.S. EPA,
1984
Zoeteman
et al., 1980
-2-
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
No pertinent studies of absorption of carbon tetrachlorlde from the 61
tract of humans were located 1n the available literature. Little Informa-
tion on absorption from the GI tract of experimental animals was available.
In an early study, Robblns (1929) Investigated absorption of carbon tetra-
chlorlde from the GI tract of dogs. He reported that "considerable quanti-
ties" were absorbed from the small Intestine, lesser quantities from the
colon and still lesser quantities from the stomach. Lamson et al. (1923)
suggested that the dynamics and kinetics of absorption from the GI tract may
vary from species to species. They observed more rapid GI absorption In
rabbits than 1n dogs. Nielsen and Larsen (1965) determined that both the
rate and the amount of carbon tetrachlorlde absorption from the GI tract
were Increased by concurrent 1ngest1on of fat or alcohol.
2.2. INHALATION
Pertinent studies of pulmonary absorption of carbon tetrachlorlde In
humans were not located 1n the available literature. Few studies on pulmo-
nary absorption 1n experimental animals were found. Nielsen and Larsen
(1965) stated that carbon tetrachlorlde is "readily absorbed" through the
lungs but the species studied was not reported (U.S. EPA, 1980b). Lehmann
and Hasegawa (1910) showed that the rate of absorption decreased with
duration of exposure. von Oettlngen et al. (1949, 1950) studied blood
concentrations in dogs following exposure to 15 or 20 g/a. in air. Peak
blood concentrations of -35 or -38 mg/8. were attained after -300 minutes
of exposure to 15 or 20 g/a, 1n air, respectively.
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Reports of acute toxldty from accidental, medicinal or
suicidal 1ngest1on of carbon tetrachlorlde are available, but no reports of
subchronlc 1ngest1on 1n man were located In the available literature. One
study of subchronlc oral exposure described the toxldty of carbon tetra-
chlorlde 1n Syrian golden hamsters. U.S. EPA (1983c) discussed the study by
Delia Porta et al. (1961) 1n which groups of 10 male and 10 female Syrian
golden hamsters were treated with 12.26 mg/week carbon tetrachlorlde by
gavage for 30 weeks (-12.3 mg/kg/day). Mortality claimed 50% of the animals
of each sex before treatment was completed. The survivors all developed
hepatocellular carcinoma within the next 13 weeks.
3.1.2. Inhalation. Prendergast et al. (1967) performed two studies of
subchronlc Inhalation exposure In animals. In the first experiment, guinea
pigs and monkeys were exposed to 80 ppm carbon tetrachlorlde for 8 hours/
day, 5 days/week for 6 weeks (30 exposures). Increased mortality (3/15
guinea pigs, 1/3 monkeys) and severe liver damage were reported. In the
second experiment, animals were exposed to either 1 or 10 ppm carbon tetra-
chlorlde continuously for 90 days. At 10 ppm, guinea pigs showed Increased
mortality (3/15 treated vs. 2/314 colony controls), growth depression and
liver enlargement with fatty Infiltration, hepatocytlc degeneration, flbro-
blastlc proliferation and collagen deposition. Rats, monkeys and rabbits
also experienced depressed growth rates and similar hlstopathologlcal liver
lesions, but no mortality occurred 1n these species. No mortality or gross
signs of toxldty occurred 1n guinea pigs, rats, monkeys or rabbits exposed
to 1 ppm carbon tetrachlorlde continuously for 90 days. A depression of
body weight gain was observed only In rats. No changes were noted 1n
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hematologlc or hlstologlc parameters 1n any of the species tested; continu-
ous exposure to 1 ppm carbon tetrachlorlde (6.3 mg/m3) was designated a
LOAEL associated with depression of body weight gain.
3.2. CHRONIC
3.2.1. Oral. Pertinent data regarding chronic exposure of man to carbon
tetrachloMde were not located 1n the available literature. Studies of
chronic exposure of animals to carbon tetrachlorlde were designed to be
cardnogenldty bloassays and, as such, used doses >12.26 mg/week, which
produced 50% mortality 1n Syrian golden hamsters. These studies are, there-
fore, not useful 1n deriving ADIs, and are reviewed 1n Chapter 4.
3.2.2. Inhalation. NIOSH (1975) provides an In-depth discussion of the
pathology of chronic Inhalation exposure of carbon tetrachlorlde 1n man.
These reports are arranged by effects on organ systems and, since exposure
data are lacking, are not useful 1n risk assessment. The U.S. EPA (1983b)
summarized human studies that are more relevant to risk assessment. Smyth
et al. (1936) and Smyth and Smyth (1935) studied the hematology, kidney and
liver function (parameters not clearly specified) and vision of carbon
tetrachlorlde-exposed workers. TWA exposures were estimated to range from
5-117 ppm, with peak exposures up to a maximum of 1680 ppm. Of 77 workers
examined, 9 showed severely restricted visual fields and 26 showed slightly
restricted visual fields. Of 67 men tested, 13 had elevated Icterus
Indices. Hematology, kidney function and other parameters of liver function
showed no significant alteration associated with exposure to carbon tetra-
chlorlde.
Moeller (1973) evaluated the effects of chronic occupational exposure to
carbon tetrachlorlde on several ophthalmologlc Indices. A cohort of 46
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workers was exposed from 1 hour/week to 1 hour/day to an unspecified concen-
tration of carbon tetrachloMde for an average of 7.7 years. Of these
workers, 28 were found to have reduced corneal sensitivity. A group of 62
locksmiths exposed to 6.4-9.5 ppm carbon tetrachlorlde for a minimum of 1-3
hours/day and a control group of 82 unexposed persons were evaluated for
corneal sensitivity and other visual parameters. Of the 62 exposed lock-
smiths, 43 had reduced corneal sensitivity, 4 had subnormal dark adaptation
corneas, 4 had restricted outer limits of white visual fields, 15 had color
limits of the visual field and 7 had Instrument-detectable changes In color
perception. Further Information comparing the control groups and the
exposed groups was not presented 1n the available review.
Barnes and Jones (1967) reported elevated urinary uroblUnogen In 6/16
and elevated urine protein In 3/16 carbon tetrachloMde-exposed workers
compared with 11 unexposed controls. Z1nc turbidity and average thymol
turbidity tests were elevated 1n exposed workers compared with controls.
Carbon tetrachloMde-exposed workers also experienced elevated serum
bH1rub1n and slightly elevated SGOT, compared with controls. Rabes (1972)
associated significant elevations 1n serum Iron and glutamlc dehydrogenase
with occupational exposure for >5 years to unspecified concentrations of
carbon tetrachlorlde.
Adams et al. (1952) exposed guinea pigs and rats to 5, 10, 25, 50, 100,
200 or 400 ppm carbon tetrachlorlde for 7 hours/day, 5 days/week for up to
184 exposures over a period of 258 days. The numbers Initially Involved and
surviving were not specified, but apparently 8-9 guinea pigs of each sex
were tested at each concentration and -15 rats of each sex/group were tested
at dosages >25 ppm, 20 rats of each sex were tested at 10 ppm, and 23
females and 26 males were exposed to 5 ppm carbon tetrachlorlde.
-6-
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Mortality among guinea pigs was high 1n the 200 ppm group and claimed
>50% of the 400 ppm group. Survivors evidenced elevated kidney and Hver
weights, fatty degeneration and cirrhosis of the liver. Guinea pigs showed
hepatomegaly at all concentrations tested, moderately hepatic fatty degener-
ation at >10 ppm and moderate liver cirrhosis at >25 ppm. Mortality also
claimed >50% of the rats exposed to 400 ppm carbon tetrachlorlde. Hepato-
megaly was observed In all exposed rats but liver cirrhosis was not detected
at exposure concentrations <50 ppm.
Concurrently, two rabbits of each sex were exposed to 10, 25, 50 or 100
ppm carbon tetrachlorlde by the same exposure schedule (Adams et al., 1952).
Exposure to 25 ppm, 178 times (248 days) resulted In moderate fatty liver
degeneration and cirrhosis. Additionally, at 50 and 100 ppm, decreased
growth rate, Increased kidney weights and Increased blood clotting time
(Indicative of liver damage) were observed.
Groups of two monkeys were exposed to 25, 50 or 100 ppm carbon tetra-
chlorlde by the same schedule for 148-198 times (-30-40 weeks) (Adams et
al., 1952). No abnormal findings were reported 1n monkeys exposed to 25
ppm. Exposure to 50 ppm resulted 1n weight loss and exposure to 100 ppm
resulted In "some Indications of microscopic Hver change." In this study,
guinea pigs appeared to be the most sensitive species. Moderate (presumably
reversible) hepatomegaly occurred at all exposures tested, but evidence of
fatty degeneration was not noted until concentrations reached 10 ppm. For
this study, 5 ppm carbon tetrachlorlde 1n guinea pigs constituted a LOAEL.
Smyth and Smyth (1935) and Smyth et al. (1936) exposed groups of 22-24
guinea pigs to 0, 50, 100, 200 or 400 ppm carbon tetrachloride 8 hours/day,
4-6 days/week for periods of up to 321 days. All guinea pigs exposed to
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>100 ppm died by 94 days of age, necessitating restructuring of the experi-
ment. In the second trial, groups of 15 or 16 guinea pigs were exposed to
25, 50, 100 or 200 ppm carbon tetrachloride. A group of 7 unexposed guinea
pigs served as controls. Mortality claimed 0/7, 12/15, 9/16, 11/16 and
11/15 of the 0, 25, 50, 100 and 200 ppm-exposed groups, respectively. In
addition to the usual hepatic pathology, optic nerve degeneration was noted
1n 1 or 2 guinea pigs 1n each exposure group. Fatty degeneration of the
ocular muscles was observed 1n 3-6 guinea pigs 1n each exposed group.
Groups of 24 rats were exposed to 0, 50, 100, 200 or 400 ppm carbon
tetrachloride using the same dosage schedule described above for guinea pigs
(Smyth and Smyth, 1935; Smyth et al., 1936). Liver degeneration, regenera-
tion and cirrhosis were observed 1n rats exposed to >50 ppm carbon tetra-
chloride. Degeneration of the myelln sheath of the sciatic nerve and
degenerative changes 1n ocular muscles, as well as some evidence of kidney
damage, were observed sporadically In 50 ppm-exposed rats.
Finally, these Investigators (Smyth and Smyth, 1935; Smyth et al., 1936)
exposed four monkeys to 50 ppm and three monkeys to 200 ppm carbon tetra-
chloMde by the same exposure schedule for 93-231 days. Nerve tissue
appeared normal in all 50 ppm-exposed monkeys. Cloudy swelling of the
kidney and fatty changes in the liver were noted at the 50 ppm level. A
28-day recovery period demonstrated the reversible nature of these mild
liver and kidney changes.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. No reports of teratogenldty in humans or animals orally
exposed to carbon tetrachloride have been found in the available literature.
-8-
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3.3.2. Inhalation. No reports of fetotoxldty In humans associated with
Inhalation of carbon tetrachlorlde have been found In the available litera-
ture. Only one Investigation of fetotoxldty caused by Inhalation exposure
of animals to carbon tetrachlorlde has been found. Schwetz et al. (1974)
exposed groups of Sprague-Dawley rats to 300 or 1000 ppm carbon tetrachlo-
rlde for 7 hours/day on days 6-15 of gestation. A significant decrease In
body weights and crown-rump lengths was found In fetuses from dams exposed
to either 300 or 1000 ppm carbon tetrachlorlde, as compared with controls.
Gross examination revealed no anatomical or developmental anomalies; micro-
scopic examination revealed delayed ossification of the sternebrae. The
authors concluded that carbon tetrachlorlde was not teratogenlc to rats at
these exposures. Assuming that rats weigh 0.35 kg and Inhale 0.26 m3 of
air/day, exposure to 300 ppm carbon tetrachlorlde for 7 hours/day results In
an Intake of 406.7 mg/kg/day.
3.4. TOXICANT INTERACTIONS
Alcohol 1ngest1on has been clearly shown to potentiate the toxlclty of
carbon tetrachlorlde. Tralger and Plaa (1971) Investigated the potentlatlon
of carbon tetrachlorlde toxldty by methanol, ethanol and Isopropanol In
rats. The activity of SGPT was monitored to evaluate hepatotoxldty. All
three alcohols tested potentiated the toxldty of carbon tetrachlorlde, with
Isopropanol being the most potent. Neither carbon tetrachlorlde nor the
alcohols alone elevated SGPT levels. We1 et al. (1971) Investigated the
ability of ethanol and exposure to cold to potentiate hepatotoxldty of
carbon tetrachlorlde In rats. Rats were pretreated with ethanol and sub-
jected for 18 hours to a temperature of 4°C. Elevated SGPT Indicated that
ethanol and exposure to cold potentiated carbon tetrachloMde-lnduced
-9-
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toxldty. von Oettlngen (1964) reported that persons who were habitual
users or occasional users of alcoholic beverages became more seriously 111
than abstainers when exposed to carbon tetrachlorlde.
In the early 1900's, carbon tetrachlorlde was used as an ant1helm1nt1c,
particularly against hookworm, In both humans and animals. SmllUe and
Pessoa (1923) reported on severe carbon tetrachloMde-lnduced toxldty among
two alcoholics 1n a group of 34 persons treated with carbon tetrachlorlde
for ancylostomlasls. Since then, other Investigators (Guild et a!., 1958;
McGuIre, 1932; Smetana, 1939; Gray, 1947) have observed that chronic alcohol
1ngest1on exacerbates carbon tetrachloMde-lnduced toxldty resulting from
single medicinal doses.
Alcohol Ingestlon was suspected to play a significant role In the toxlc-
1ty of carbon tetrachlorlde from nonmedldnal exposure (Abbott and Miller,
1948), particularly where renal failure was a major part of the clinical
picture. The ACGIH (1980) suggested that ethanol and other substances
(e.g., barbiturates and polychloMnated blphenyls) that Induce hepatic
mlcrosomal enzymes enhance the toxldty of carbon tetrachlorlde.
Hafeman and Hoekstra (1977) claimed that vitamin E, selenium and methlo-
nlne offer partial protection from carbon tetrachloMde-lnduced toxldty.
By monitoring the evolution of ethane, a peroxldatlon product of certain
unsaturated fatty adds, these authors concluded that methlonlne, vitamin E
and selenium protected against carbon tetrachlorlde-lnduced I1p1d peroxlda-
tlon, probably by maintaining Intracellular glutathlone and glutathlone
peroxldase.
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4. CARCINOGENICITY
4.1. HUMAN DATA
A few cases of "Mver cancer associated with exposure to carbon tetra-
chlorlde have been reported, but no ep1dem1olog1cal studies from which risk
figures can be derived have been located In the available literature.
Slmler et al. (1964) reported the case of a fireman who developed eplthe-
Homa of the liver 4 years after being acutely poisoned by carbon tetrachlo-
rlde. Tracey and Sherlock (1968) suggested that hepatocellular carcinoma 1n
a 59-year-old man was caused by a 5-day exposure to carbon tetrachlorlde
used to clean his rug. The patient denied Ingesting alcohol since being
exposed to carbon tetrachlorlde, but admitted to having used 1t before the
exposure to carbon tetrachlorlde. Blair et al. (1979) reported 87 cancer
deaths 1n a group of 330 exposed workers 1n which 67.9 cancer deaths would
have been expected. Concurrent exposure to other workroom chemicals
precluded attributing the observed Increase 1n cancer Incidence to carbon
tetrachlorlde alone.
4.2. BIOASSAYS
4.2.1. Oral. Sufficient evidence for the carclnogenlclty of carbon
tetrachlorlde 1n laboratory animals exists 1n the available literature.
Many early studies, although too short 1n duration to be useful for risk
assessment, demonstrated the hepatocarc1nogen1c1ty of carbon tetrachlorlde.
Edwards (1941) administered by gavage 0.1 mj, of a 40% carbon tetrachlorlde
solution 1n olive oil to C3H and A-stra1n mice 2-3 times/week for 23-58
doses. Necropsies performed 2-147 days after the last administration
revealed a progression of events beginning with liver necrosis and followed
by cirrhosis and eventually hepatomas In C3H mice. Hepatomas were found In
126/143 C3H and all 54 A-stra1n mice. Delia Porta et al. (1961) reported
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administrating 30 weekly doses of 6.25-12.5 y9. (10-20 mg) carbon tetra-
chloride to five Syrian golden hamsters of each sex. Liver cell carcinomas
were discovered in all animals (5 of each sex) that survived >10 weeks after
the end of treatment.
Subsequently, C3H and strains A, Y, C and L mice were exposed to carbon
tetrachloride to further elucidate the process of carcinogenesis (Edwards
and Dalton, 1942; Edwards et al., 1942). Small numbers of mice were killed
and necropsied after one or more doses. Liver necrosis and regenerative
processes were observed throughout the study. Atypical mitotic forms such
as triple mitoses were frequent findings. In mice treated for >1 month,
enlarged hepatocytes with small nuclei were concentrated along strands of
fibrous tissue. Hepatic tumors were usually multiple; neither invasion of
blood vessels nor metastases were seen. These authors reported finding no
evidence of tumors in other organs.
Eschenbrenner and Miller (1944) administered 30 doses of 0.16, 0.32,
0.64, 1.27 or 2.54 g carbon tetrachloride/kg bw by gavage to groups of 60
strain A mice. The interval between doses varied from 1-5 days; thus, the
treatment period varied from 30-150 days. The incidence of hepatomas was
23/60, 23/60, 25/59, 32/60 and 33/60 in the five groups, respectively. In a
later study, Eschenbrenner and Miller (1946) demonstrated that single doses
of 12.5 y8./kg, but not 6.25 y9./kg, by gavage would cause liver cell
necrosis in both male and female strain A mice. Administration of 6.25,
12.5, 25 or 50 y8./kg/day for 120 days resulted in hepatoma formation in
mice exposed to >12.5 yi/day. Other mice were given 30 doses of 25, 50 or
100 ya./kg at 4-day intervals. Microscopic examination revealed small
hepatomas in 2/10 mice given 25 yJ./kg. Grossly visible tumors were
-12-
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present in the higher-dosed groups. These Investigators theorized that a
necrotlzlng action of carbon tetrachloride on the liver was an Important
factor in the development of a carcinogenic response.
NIOSH (1975) and U.S. EPA (1980b) discussed short-term carcinogenicity
bioassays involving carbon tetrachloride.
In an NCI-sponsored bioassay (NCI, 1976; Weisberger, 1977), Osborne-
Mendel rats were exposed to 47 or 94 mg/kg (males) or 80 or 160 mg/kg
(females) carbon tetrachloride by gavage for 78 weeks. Observations were
continued for 33 additional weeks. Survival data, summarized in Table 4-1,
indicate that excessive mortality had occurred in high dose rats of either
sex. Although a slight increase in the incidence of hepatocellular carci-
nomas was noted in both males and females, a clear dose-related response
could not be demonstrated.
Mice were also included in the NCI (1976) bioassay. Groups of 50 male
and female 35-day-old mice were treated by gavage with 1250 or 2500 mg
carbon tetrachloride in corn oil/kg bw/day, 5 days/week for 78 weeks.
Observations continued for an additional 13 weeks. Vehicle control groups
consisted of 20 mice of each sex. All mice were subjected to necropsy.
Survival data are presented in Table 4-2. Mortality claimed most carbon
tetrachloride-exposed mice by the end of the 78-week exposure period. Most
carbon tetrachloride-treated mice were discovered to have hepatocellular
carcinomas. The first carcinomas in female mice were found at 16 weeks and
19 weeks in low and high dose groups, respectively. Among male mice, the
first carcinomas were found at 48 and 26 weeks in the low and high dose
groups, respectively. The incidences of hyperplastic nodules and hepato-
cellular carcinomas are presented in Table 4-3.
-13-
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Dose
TABLE 4-1
Survival of Rats Treated with Carbon Tetrachlorlde*
Initial
*Source: NCI, 1976
78 Weeks
110 Weeks
Males
Control
Low
High
Females
Control
Low
High
100
50
50
100
50
50
67 (6754)
34 (68%)
34 (68%)
75 (75%)
38 (76%)
21 (42%)
26 (26%)
14 (28%)
7 (14%)
51 (51%)
20 (40%)
14 (28%)
-14-
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Dose
TABLE 4-2
Survival of Mice Treated with Carbon Tetrachlorlde*
Initial
78 Weeks
91-92 Weeks
Males
Control
Matched
Pooled
Low
High
Females
Control
Matched
Pooled
Low
High
20
77
50
50
20
80
50
50
13 (65%)
53 (69%)
11 (22%)
2 (4%)
18 (90%)
71 (89%)
10 (20%)
4 (8%)
7 (35%)
38 (49%)
0 (0%)
0 (0%)
17 (85%)
65 (81%)
0 (0%)
1 (2%)
*Source: NCI, 1976
-15-
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TABLE 4-3
Liver Tumors 1n Mice*
Dose
Carcinomas
Males
Control
Matched
Pooled
Low
High
2/19 (IT/.)
5/77 (6%)
49/49 (100%)
47/48 (98%)
Females
Control
Matched
Pooled
Low
High
1/20 (5%)
1/80 (1%)
40/40 (100%)
43/45 (96%)
'Source: NCI, 1976
NR = Not reported
-16-
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4.2.2. Inhalation. Little data concerning cardnogenldty of carbon
tetrachloMde from Inhalation exposure have been located 1n the available
literature. Costa et al. (1963) exposed albino rats to unspecified concen-
trations of atmospheric carbon tetrachloMde for up to 7 months. Rats were
killed serially from 2-10 months after the beginning of exposure. Of the 30
rats that completed the experiment, 12 had adenodrrhosls and 10 had liver
nodules measuring up to 1 cm, which were microscopically diagnosed as
Incipient hepatocellular carcinoma.
4.3. OTHER RELEVANT DATA
Scarce pertinent data regarding the mutagenlclty of carbon tetrachlorlde
were located 1n the available literature. Kraemer et al. (1974) found no
mutagenlclty In either the Salmonella typhimurium or Escher1ch1a coll
reversion tests. Details of the experimental protocol were not available.
Likewise, IARC (1979) reported a lack of mutagenlclty in S. typhimurium
strains TA100, TA1535, TA1538 (McCann and Ames, 1976; McCann et al., 1975;
Uehleke et al., 1976) and £. coll (Uehleke et al., 1976).
4.4. WEIGHT OF EVIDENCE
There is sufficient evidence 1n mice, rats and hamsters to designate
carbon tetrachlorlde a potent hepatic carcinogen in animals. Prolonged
exposure (NCI, 1976; Welsburger, 1977) results 1n a very high incidence of
hepatocellular carcinoma.
The few case reports associated with carbon tetrachlorlde provide
limited, but not sufficient, evidence to confirm human carcinogenicity.
Only one epidemlologic study (Blair et al., 1979) was found in the available
literature. Blair et al. (1979) observed 87 cancer deaths in a cohort of
330 exposed workers in which 67.9 cancer deaths would have been expected.
-17-
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Concurrent exposure to other chemicals precluded ascribing the observed
Increase 1n cancer Incidence to carbon tetrachlorlde alone. On the basis of
the criteria proposed by the Carcinogen Assessment Group of the U.S. EPA for
evaluating the overall weight of evidence for carclnogenlclty to humans
(Federal Register, 1984), carbon tetrachlorlde 1s most appropriately
classified as a Group B2 - Probable Human Carcinogen.
-18-
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5. REGULATORY STANDARDS AND CRITERIA
The American Conference of Governmental Industrial Hyglenlsts (ACGIH,
1980, 1983) and the U.S. EPA (1980b) have established regulating standards
for carbon tetrachlorlde as dted 1n Table 5-1.
-19-
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TABLE 5-1
Current Regulatory Standards and Criteria for Carbon Tetrachlorlde
Criterion
TLV
STEL
NIOSH celling level
Value
5 ppm, 30 mg/m3
20 ppm, 125 mg/m3
2 ppm
Reference
ACGIH,
ACGIH,
ACGIH,
1983
1983
1980
to prevent cancer
Japan and most
European nations
Most eastern
European nations
Tolerance 1n food
10 ppm
3-7.5 ppm
exempt
Ambient water
criteria associated
with cancer risk:
10"7
10"6
lO's
consumption of
6.5 g fish only
0.69 yg/8,
6.94 yg/S,
69.4 yg/8.
2 a, water +
6.5 q fish
0.04 yg/8.
0.40 vg/J.
4.0 yg/9.
ACGIH, 1980
ACGIH, 1980
Code of Federal
Regulations,
1982
U.S. EPA, 1980b
-20-
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
Carbon tetrachlorlde 1s amply demonstrated to be carcinogenic 1n animals
and data are sufficient for derivation of a q *. It 1s Inappropriate,
therefore, to calculate an AIS for this chemical.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
Carbon tetrachlorlde 1s amply demonstrated to be carcinogenic 1n animals
and data are sufficient for derivation of a q,*. It Is Inappropriate,
therefore, to calculate an AIC for this chemical.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. The Carcinogen Assessment Group, as described 1n U.S. EPA
i
(1984), used data from the following for risk assessment purposes: Delia
Porta et al. (1961); Edwards et al. (1942); NCI (1976) (both rat and mouse).
Since none of these studies was deemed adequate Individually and no study
could be selected as "best" or "most appropriate", the geometric mean of the
upper limit unit risk estimates (3.7xlO~6) has been calculated for drink-
Ing water containing 1 vg/9.. Assuming human consumption of 2 l of
water/day, a cancer risk of 3.7xlO~6 1s associated with a dose of 2 yg
carbon tetrachlor1de/day. For a 70 kg human, a q * of l.SOxlO'1
(mg/kg/day)"1 can be calculated from the following formula:
q.j* = 70 kg x 3.7xlO~6 * (2xlO~3)
where 3.7xlO~6 1s the risk associated with a dally dose of 2 yg or
2xlO~3mg/day. U.S. EPA (1984) contains an 1n-depth explanation of the
rationale applied and the calculations employed.
6.3.2. Inhalation. Sufficient data regarding the carclnogenlcHy of
carbon tetrachlorlde 1n laboratory animals exposed by Inhalation, from which
to calculate a q * were not located 1n the available literature.
-21-
-------
7. REFERENCES
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ACGIH (American Conference of Governmental Industrial Hygienists). 1983.
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Workroom Environment with Intended Changes for 1983-84. Cincinnati, OH.
Adams, E.M., H.C. Spencer, V.K. Rowe, D.D. McColHster and D.D. Irish.
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Barnes, R. and R.C. Jones. 1967. Carbon tetrachloride poisoning. Am.
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Blair, A., P. Decoufle and D. Grauman. 1979. Causes of death among laundry
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Callahan, M.A., M.W. SUmak, N.W. Gabel, et al. 1979. Water-Related
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Costa, A., G. Weber, F.S.O. Bartolon! and G. Campana. 1963. Experimental
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Edwards, J., et al. 1942. Induction of the carbon tetrachloMde hepatoma
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Hafeman, D.G. and W.G. Hoekstra. 1977. Protection against carbon tetra-
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-24-
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IARC (International Agency for Research on Cancer). 1979. Carbon Tetra-
*
chloride. In.: Some Halogenated Hydrocarbons. IARC Monographs on the Eval-
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-25-
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Moeller, W. 1973. Chronic carbon tetrachloMde poisoning from an ophthal-
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Zoeteman, B.C.J., K. Harmensen, J.B.H.J. Unders, C.F.H. Morra and W.
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APPENDIX
Summary Table for Carbon Tetrachlorlde
ro
I
Carcinogenic
Potency
Inhalation
Oral
Experimental
Species Dose/Exposure Effect
(mg/kg/day)
mice 1250-2500 liver
tumors
Ql*
ND
1.3X10"1
(mg/kg/day) *
Reference
Delia Porta
et al., 1961;
Edwards
et al., 1942;
NCI, 1976;
U.S. EPA, 1984
ND = Not derived
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