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DISCLAIMER
This document has been reviewed 1n accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement 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
tetrachlorlde. 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-line literature searches of the
TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The basic litera-
ture searched supporting this document Is current up to May, 1987. Secon-
dary 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. 1980a. Ambient Water Quality Criteria Document for
Carbon Tetrachlorlde. Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Water Regulations and
Standards, Washington, DC. EPA 440/5-80-026. NTIS PB81-117376.
U.S. EPA. 1983a. Reportable Quantity Document for Carbon Tetra-
chlorlde. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Emergency and Remedial Response, Wash-
ington, DC.
U.S. EPA. 1983b. Review of Toxlcologlc Data In Support of Evalua-
tion for Carcinogenic Potential of Carbon Tetrachlorlde. Prepared
by the Office of Health and Environmental Assessment, Carcinogen
Assessment Group, Washington, DC for the Office of Solid Waste and
Emergency Response, Washington, DC.
U.S. EPA. 1984a. Health Assessment Document for Carbon Tetra-
chlorlde. Office of Health and Environmental Assessment, Environ-
mental Criteria and Assessment Office, Cincinnati, OH. EPA
600/8-82-001F. NTIS PB 85-124196.
U.S. EPA. 1985a. Assessment of the Mutagenlc Potential of Carbon
Dlsulflde, Carbon Tetrachlorlde, Dlchloromethane, Ethylene
DIchloMde, and Methyl Bromide: A Comparative Analysis In Relation
to Ethylene Dlbromlde. Office of Health and Environmental Assess-
ment, Reproductive Effects Assessment Group, Washington, DC.
U.S. EPA. 1986b. Integrated Risk Information System (IRIS). Risk
estimate for carcinogens: Carbon Tetrachlorlde. Online. (Verifi-
cation date: 12/04/86). Office of Health and Environmental Assess-
ment, Environmental Criteria and Assessment Office, Cincinnati, OH.
111
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The Intent In these assessments 1s to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
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.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, 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 llfespan).
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 assumed. Animal data used for RFD$ 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. These
values are developed for both Inhalation (RfD$i) and oral (RfD$o)
exposures.
The RfD (formerly AIC) 1s similar 1n concept and addresses chronic
exposure. 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 llfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfD can also be derived for the noncardnogenlc health effects of compounds
which are also carcinogenic. The RfD 1s route-specific and estimates
acceptable exposure for either oral (RfDg) or Inhalation (RfDj) with the
Implicit assumption that exposure by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development Is explained In U.S.
EPA (1984b).
For compounds for which there 1s sufficient evidence of carclnogenldty
q-|*s have been computed, 1f appropriate, based on oral and Inhalation data
1f available. For a discussion of risk assessment methodology for
carcinogens refer to U.S. EPA (1980b). Since cancer 1s a process that Is
not characterized by a threshold, any exposure contributes an Increment of
risk.
1v
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
An oral RfD of 7xlO~4 mg/kg/day for carbon tetrachlorlde can be
derived based on a NOAEL of 1 mg/kg/day, a conversion factor of 5/7, and an
uncertainty factor of 1000 (to allow for Interspecles and Intrahuman
variability and extrapolation from subchronlc to chronic duration of
exposure) In a subchronlc gavage study In rats by Bruckner et al. (1986).
This value has been verified by the EPA RfD Workgroups (U.S. EPA, 1986b).
An oral RfD$ of 7xlO"3 mg/kg/day can be also be derived from the same
study.
Animal oral bloassay data In three species (rats, mice, hamsters)
Indicate that carbon tetrachlorlde Is a hepatic carcinogen. Human data are
limited and equivocal. U.S. EPA (1984a) has used data from the following
for quantitative cancer risk estimation purposes: Delia Porta et al.
(1961); Edwards et al. (1942); NCI (1976) (both rat and mouse). Using these
data, the geometric mean of the upper limit unit risk estimates Is
3.7xlO~* (vg/lT1 with a corresponding slope factor (q-|*) of
1.3X10'1 (mg/kg/day)~*.
U.S. EPA (1986b) estimated a slope factor for Inhalation exposure of
5.2xlO~2 (mg/kg/day)"1 using an Inhalation absorption factor of 40% and
the slope factor of l.SxlO'1 (mg/kg/day)'1 derived from the oral data.
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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. Or. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball was the 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
Human Health 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 the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Trlna Porter
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. SUBCHRONIC REFERENCE DOSE (RfDs)
6.2. REFERENCE DOSE (RfO)
6.3. CARCINOGENIC POTENCY (q]*)
6.3.1. Oral
6.3.2. Inhalation
REFERENCES
Page
, , , 1
, , 4
. . . 4
, , 5
7
, , 7
. . . 7
, , 8
9
. . . 9
. . . 9
, , , 14
. . . 14
, , . 15
, . . 15
. . . 18
. . . 18
. . . 19
. . . 19
, , . 22
. . . 22
. . . 24
. . . 26
. . . 28
. . 28
. . . 28
. . . 28
. . . 28
. . . 29
. . . 30
APPENDIX: Summary Table for Carbon Tetrachlorlde 42
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LIST OF TABLES
No.
1-1
4-1
5-1
Title
Selected Physical and Chemical Properties and Half-lives
of Carbon Tetrachlorlde
Incidence of Liver Tumors In Mice Treated by Gavage with
Carbon Tetrachlorlde 1n Corn 011, 5 Days/Week for 78 Weeks. . .
Current Regulatory Standards and Criteria for Carbon
Tetrachlorlde
Paae
2
23
27
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LIST OF ABBREVIATIONS
ALP Alkaline phosphatase
BCF B1oconcentrat1on factor
bw Body weight
CS Composite Score
PEL Frank-effect level
LDH Lactate dehydrogenase
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
ppm Parts per million
RfD Reference dose
RfDj Inhalation reference dose
RfOg Oral reference dose
RfD$ Subchronlc reference dose
RfD$i Subchronlc Inhalation reference dose
RfD$o Subchronlc oral reference dose
SGOT Serum glutamlc oxaloacetlc transamlnase
SGPT Serum glutamlc pyruvlc transamlnase
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
UDS Unscheduled DNA synthesis
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.
Carbon tetrachlorlde 1s extremely stable and persistent 1n the lower
atmosphere and troposphere. The primary fate process of this compound Is
diffusion Into the stratosphere. Once In the stratosphere, 1t Is photolyzed
by shorter wavelength, higher energy ultraviolet light, eventually forming
phosgene as the principal degradation product (U.S. EPA, 1984a). Estimates
of the atmospheric half-life of carbon tetrachlorlde range from 18 years to
60-100 years (U.S. EPA, 1984a). It has been estimated that >90% of tropo-
spherlc carbon tetrachlorlde will eventually reach the stratosphere
(Callahan et al., 1979). The persistence of carbon tetrachlorlde In the
atmosphere Indicates that this compound may be transported long distances
from Its emission source. Global distribution of carbon tetrachlorlde 1n
air Is reported to be nearly uniform (U.S. EPA, 1984a).
Carbon tetrachlorlde dissolved 1n water does not photodegrade or oxidize
In any measurable amounts. Volatilization 1s the primary removal mechanism
for carbon tetrachlorlde from water (U.S. EPA, 1984a). Although carbon
tetrachlorlde 1s relatively Upophlllc, there 1s Uttle tendency for this
compound to bloaccumulate 1n aquatic or marine organisms (Neeley et al.,
1974).
The half-life of carbon tetrachlorlde 1n soil was not located 1n the
available literature; however, evaporation 1s expected to be the predominant
loss mechanism from the soil surface. This compound 1s resistant to
blodegradatlon In subsurface soils (Wilson and Wilson, 1985). Based on the
0039H -1- 01/26/89
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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:
Solubility 1n
Mater:
Organic solvent:
Octanol/water partition
coefficient:
BCF:
Half-lives In
A1r:
Water:
halogenated aliphatic
hydrocarbon
153.82
90 mm Hg at 20°C
757 mg/l at 25°C
mlsclble
676
(recommended value)
537
30 1n blueglll
(Lepomls macrochlrus)
17 1n fathead minnow
(Plmephales promelas)
71
18-100 years
0.3-3 days In river
30-300 days In lake
Callahan et al., 1979
Banerjee et al., 1980
HSDB, 1988
Hansch and Leo, 1985
Banerjee et al., 1980
U.S. EPA, 1980a
Velth et al., 1979
Sabljlc, 1984
U.S. EPA, 1984a
Zoeteman et al., 1980
0039H
-2-
01/26/89
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observed slow blodegradatlon of chloroform (Wilson et al., 1983), carbon
tetrachloMde Is expected to blodegrade even slower because of the addi-
tional chlorine substitution In this compound. Consequently, carbon tetra-
chlorlde Is expected to leach Into groundwater. This has been confirmed by
Page (1981), who detected carbon tetrachloMde with a 64% frequency 1n
groundwater. Upon entering groundwater, carbon tetrachlorlde will be
persistent. The half-life of this compound 1n groundwater 1s estimated to
range from 30-300 days (Zoeteman et al., 1980).
0039H -3- 01/26/89
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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
gastrointestinal tract of humans were located 1n the available literature.
It would be anticipated, however, that carbon tetrachlorlde Is well absorbed
from the gastrointestinal tract of humans since 1t Is readily absorbed from
the gastrointestinal tract of animals, and there are many accounts of human
poisoning resulting from Ingestlon of carbon tetrachlorlde. A number of
Investigators (Seawrlght and McLean, 1967; Marchand et al., 1970; Reddrop et
al., 1981) have studied the extent of absorption of orally administered
doses of carbon tetrachlorlde by measuring the excretion of radlolabeled
parent compound and metabolites In the expired air as a function of time
following administration of the compound. Typically, the percentage of
absorption of an orally administered dose of carbon tetrachlorlde determined
In this fashion Is between 65 and 86%. Seawrlght and Mclean (1967) treated
male rats with radlolabeled carbon tetrachlorlde (4000 mg/kg) by 1ntra-
gastrlc administration. It was calculated (U.S. EPA, 1985b) from the amount
of radioactivity found In the exhaled air over a 24-hour period that >65% of
the administered dose was absorbed from the gastrointestinal tract.
Marchand et al. (1970) administered radlolabeled carbon tetrachlorlde (3200
mg/kg) to male rats by IntragastMc Intubation, and measured exhaled radio-
activity for a period of up to 10 hours following dosing. Of the adminis-
tered radlolabeled carbon, 83% was found 1n the exhaled air 10 hours after
dosing, which led to the conclusion that at least 83% of the dose was
absorbed from the gastrointestinal tract over the 10-hour period (U.S. EPA,
1985b). Using a similar method of monitoring radioactivity In the exhaled
0039H -4- 03/13/89
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air, Reddrop et al. (1981) reported that absorption of carbon tetrachloMde
from the gastrointestinal tract of male rats given 2000 mg/kg was at least
60% over a 6-hour period following dosing.
In an early study, Robblns (1929) Investigated absorption of carbon
tetrachlorlde from the gastrointestinal tract of dogs. He reported that
"considerable quantities" 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 gastrointestinal tract may vary from species to species. They
observed more rapid gastrointestinal absorption 1n rabbits than 1n dogs.
Nielsen and Larsen (1965) determined that both the rate and the amount of
carbon tetrachlorlde absorbed from the gastrointestinal tract were Increased
by concurrent 1ngest1on of fat or alcohol.
2.2. INHALATION
Although there are many cases of human overexposure to carbon tetra-
chlorlde vapor, there are few quantitative studies of pulmonary absorption
of carbon tetrachlorlde 1n humans. Lehmann and Schmldt-Kehl (1936)
estimated that absorption across the lung was -60% In humans based on the
difference In carbon tetrachlorlde concentration In Inhaled and exhaled air.
Few studies on pulmonary absorption In experimental animals were found.
Nielsen and Larsen (1965) stated that carbon tetrachlorlde 1s "readily
absorbed" through the lungs but did not specify the species studied (U.S.
EPA, 1980a). 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/l
carbon tetrachlorlde 1n air. Peak blood concentrations of ~35 or ~38 mg/8.
were attained after -300 minutes of exposure. McColllster et al. (1951)
0039H -5- 01/26/89
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studied the absorption of carbon tetrachlorlde following Inhalation 1n
monkeys. Three female monkeys were exposed to radlolabeled carbon tetra-
chlorlde (290 mg/m3) for 139-300 minutes. By determining the difference
1n concentration of the compound In the Inhaled and exhaled air, absorption
was calculated to be -30.4% of the total amount of carbon tetrachlorlde
Inhaled at any average absorption rate of 0.022 mg carbon tetrachlor1de/kg/
minute.
0039H -6- 01/26/89
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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 Ingestlon of carbon tetrachloMde are available, but no reports of
subchronlc toxldty from Ingestlon of the compound In man were located In
the available literature. Delia Porta et al. (1961) treated groups of 10
male and 10 female Syrian golden hamsters by gavage with 12.26 mg/week
carbon tetrachlorlde 1n corn oil for 30 weeks (-12.3 mg/kg/day). Before
treatment was completed, 50% of the hamsters of each sex died. The
survivors all developed hepatocellular carcinoma within the next 13 weeks.
Several recent studies have examined the effects of subchronlc oral
administration of carbon tetrachlorlde 1n rats and mice (Bruckner et al.,
1986; Condle et al., 1986; Hayes et al., 1986). Bruckner et al. (1986)
dosed groups of ~15 male Sprague-Dawley rats with carbon tetrachlorlde In
corn oil by gavage at levels of 1, 10 or 33 mg/kg, 5 times/week for 12
weeks. The toxldty of carbon tetrachlorlde was found to be dose-dependent.
A dose of 1 mg/kg produced no apparent adverse effects, whereas 10 mg/kg
produced a slight but significant Increase 1n sorbltol dehydrogenase activ-
ity and 33 mg/kg produced marked hepatotoxldty 1n the form of cirrhosis.
Condle et al. (1986) studied the effects of the vehicle (corn oil versus
Tween-60) on the subchronlc toxldty of carbon tetrachlorlde In CD-I mice.
Carbon tetrachlorlde was administered by gavage at doses of 1.2, 12 or 120
mg/kg once dally, 5 days/week for 90 days. Carbon tetrachlorlde was more
toxic when administered In corn oil. The NOAEL for carbon tetrachlorlde
administered 1n corn oil was 1.2 mg/kg and the corresponding NOAEL for
carbon tetrachlorlde administered In Tween-60 was 12 mg/kg. A greater
0039H -7- 01/26/89
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degree of hepatotoxlclty, as measured by serum enzyme levels and hlstopatho-
loglc changes, was also observed In mice treated with 12 and 120 mg/kg of
carbon tetrachloMde when corn oil was the vehicle than when Tween-60 was
the vehicle.
Hayes et al. (1986) administered carbon tetrachlorlde 1n corn oil by
gavage to groups of 20 male and 20 female CD-I mice. The doses used were
12, 120, 540 and 1200 mg/kg and the mice were dosed for 90 consecutive days.
A NOAEL was not observed In this study. A generally dose-related Increase
In serum enzyme levels (LDH, SGPT, SGOT and ALP) was observed In both sexes
at all dose levels. Relative liver and spleen weights were Increased at all
dosage levels 1n both sexes and relative thymus weights were Increased at
>540 mg/kg/day 1n both sexes. Liver damage was observed at all doses 1n
both sexes, with the severity and Intensity of the lesions Increasing In a
dose-related fashion.
3.1.2. Inhalation. Prendergast et al. (1967) performed two studies of
subchronlc Inhalation exposure 1n animals. In the first experiment, 15
Hartley guinea pigs and monkeys were exposed to 80 ppm (503 mg/m3) carbon
tetrachlorlde 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. All the animals showed a body weight loss. In the second
experiment, several species of animals were exposed to either 1 or 10 ppm (6
or 63 mg/m3) carbon tetrachlorlde 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, flbroblastlc proliferation and collagen deposi-
tion. Rats, monkeys and rabbits at 10 ppm also experienced depressed growth
rates and similar hlstopathologlcal liver lesions, but no mortality.
0039H -8- 01/26/89
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No mortality or gross signs of toxlclty occurred In 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 1n rats. No
changes were noted 1n hematologlc or hlstologlc parameters In any of the
species tested.
3.2. CHRONIC
3.2.1. Oral. Pertinent da.ta regarding chronic exposure of man to carbon
tetrachlorlde were not located In the available literature. A 2-year study
of the toxldty of carbon tetrachlorlde was performed by Alumot et al.
(1976) who administered the compound 1n the diets of rats at levels of 0, 80
or 200 ppm. Taking Into account the amount of food consumed and the loss of
carbon tetrachlorlde from the food before consumption, a dietary level of
200 ppm provided a dally dose of carbon tetrachlorlde of 10-18 mg/kg bw. At
this dose level (10-18 mg/kg/day), the authors found no biochemical abnor-
malities attributable to carbon tetrachlorlde exposure, and this dose level
was Indicated to be a NOAEL over a 2-year period. The study was, however,
criticized by U.S. EPA (1985b) because of the high Incidence of respiratory
Infection In the experimental animals.
3.2.2. Inhalation. NIOSH (1975) provided an 1n-depth discussion of the
pathology of chronic Inhalation exposure of carbon tetrachlorlde 1n man;
however, since exposure data are lacking, It 1s not useful In risk assess-
ment. The U.S. EPA (1983a) summarized human studies that are more relevant
to risk assessment (see Section 4.1.). 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 (31-736 mg/m3), with
peak exposures up to a maximum of 1680 ppm (10,570 mg/m3). Of 77 workers
0039H -9- 01/26/89
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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
tetrachlorlde.
Moeller (1973) evaluated the effects of chronic occupational exposure to
carbon tetrachlorlde on several ophthalmologlc Indices. A cohort of 46
workers was exposed from 1 hour/week to 1 hour/day to an unspecified concen-
tration of carbon tetrachlorlde 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 1n color
perception. Further Information comparing the control groups and the
exposed groups was not presented 1n the available review.
Barnes and Jones (1967) reported an Investigation of 27 workers In a
plant manufacturing polyfluorohydrocarbons for refrigerators from carbon
tetrachlorlde and hydrofluoric add. This manufacturing process 1s
virtually an automated and enclosed system, but carbon tetrachlorlde has to
be delivered by road tanker, discharged Into the receiving tanks, and the
pipes and tanks need periodic maintenance, repairs and cleaning. It 1s on
these occasions that the worker becomes exposed. However, Information
concerning the age, sex, job history and exposure levels of the workmen was
not provided 1n this reported. Elevated urinary uroblllnogen In 6/16 and
0039H -10- 03/13/89
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elevated urine protein 1n 3/16 carbon tetrachlorlde-exposed workers were
observed, whereas all 11 unexposed workers were tested negative for both
tests. Microscopic and macroscopic examination of the urine for cells and
casts were negative although a trace of albumen occurred 1n two. Therefore,
the authors concluded that kidney damage was not observed In this study.
Zinc turbidity and average thymol turbidity tests were elevated 1n exposed
workers (5.0 units for zinc turbidity and 4.0 units for thymol turbidity)
compared with controls (1.0 units and 0.6 units, respectively). Carbon
tetrachlorlde-exposed workers also experienced elevated serum blllrubln
(average 1.36, range 0.45-4.0) and slightly elevated SGOT (average 37.3,
range 25-48), compared with controls [0.46 (range 0.20-0.60) for serum
blllrubln and 32.7 (range 27-38) for SGOT, respectively]. Therefore, the
authors concluded that liver damage was a feature In exposed workmen. Rabes
(1972) associated significant elevations 1n serum Iron and glutamlc dehydro-
genase with occupational exposure for >5 years to unspecified concentrations
of carbon tetrachloMde.
Adams et al. (1952) exposed guinea pigs and rats to 5, 10, 25, 50, 100,
200 or 400 ppm (31, 63, 157, 315, 629, 1258 or 2516 mg/m3) carbon tetra-
chlorlde for 7 hours/day, 5 days/week for up to 184 exposures over a period
of 258 days. The numbers of animals Involved Initially 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 tetrachloMde.
Mortality among guinea pigs was high 1n the 200 ppm group and >50% died
In the 400 ppm group. Survivors had elevated kidney and liver weights,
0039H -11- 03/13/89
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fatty degeneration and cirrhosis of the liver. Guinea pigs showed hepato-
megaly at all concentrations tested, moderate hepatic fatty degeneration at
>10 ppm and moderate liver cirrhosis at >25 ppm. At 400 ppm, >50% of the
rats died. Hepatomegaly was observed In all exposed rats, but liver
cirrhosis was not detected at exposure concentrations <50 ppm.
In another part of the study, two rabbits of each sex were exposed to
10, 25, 50 or 100 ppm carbon tetrachlorlde 7 hours/day, 5 days/week (Adams
et a!., 1952). Exposure to 25 ppm, 178 times (248 days) resulted 1n moderate
fatty liver degeneration and cirrhosis. At 50 and 100 ppm, decreased growth
rate, Increased kidney weights and Increased blood clotting time (Indicative
of liver damage) were observed.
Adams et al. (1952) also exposed groups of two monkeys to 25, 50 or 100
ppm carbon tetrachlorlde by the same schedule 148-198 times (~30-4Q weeks).
No abnormal findings were reported In monkeys exposed to 25 ppm. Exposure
to 50 ppm resulted In weight loss and exposure to 100 ppm resulted In "some
Indications of microscopic liver 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 degen-
eration was not noted until concentrations reached 10 ppm. For this study,
5 ppm carbon tetrachlorlde In 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 (0, 315, 629, 1258 or 2516
mg/m3) carbon tetrachlorlde 8 hours/day, 4-6 days/week for periods of up
to 321 days; however, because all guinea pigs exposed to >100 ppm died by 94
days of age, the experiment was redesigned. In the second trial, groups of
15 or 16 guinea pigs were exposed to 25, 50, 100 or 200 ppm carbon tetra-
chlorlde for 8 hours/day, 5 days/week for a total of 10.5 months. A group
0039H -12- 03/13/89
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of 7 unexposed guinea pigs served as controls. All animals 1n the second
trial were provided with a high calcium diet. In the 0, 25, 50, 100 and 200
ppm exposed groups, 0/7, 12/15, 9/16, 11/16 and 11/15 guinea pigs died,
respectively. In addition to the usual hepatic pathology, optic nerve
degeneration was noted 1n 1 or 2 guinea pigs In each exposure group. Fatty
degeneration of the ocular muscles was observed In 3-6 guinea pigs In each
exposed group.
Groups of 24 Wlstar rats were exposed to 0, 50, 100, 200 or 400 ppm
carbon tetrachlorlde for 8 hours/day, 5 days/week for 10.5 months (Smyth and
Smyth, 1935; Smyth et al., 1936). No significant Increase 1n mortality was
observed. Liver degeneration, regeneration and cirrhosis were observed 1n
rats exposed to >50 ppm carbon tetrachlorlde. Degeneration of the myelln
sheath of the sciatic nerve and degenerative changes In ocular muscles, as
well as unspecified kidney damage, were also observed In rats exposed to >50
ppm carbon tetrachlorlde.
Smyth and Smyth (1935) and Smyth et al. (1936) also exposed four monkeys
to 50 ppm and three monkeys to 200 ppm carbon tetrachlorlde 8 hours/day, 5
days/week for 93-231 days. Nerve tissue appeared normal in all 50 ppm
exposed monkeys; however, two of the monkeys exposed to 200 ppm showed
damage to the sciatic nerve. Cloudy swelling of the kidney and fatty
changes In the liver were noted 1n rats exposed to >50 ppm. A 28-day
recovery period demonstrated the reversible nature of these mild liver and
kidney changes.
Carbon tetrachlorlde has been found to cause effects primarily on the
liver, kidney and central nervous system (Smyth and Smyth, 1935; Smyth et
al., 1936). Effects on the central nervous system are usually rapid and the
most common effects are headache, dizziness, vomiting and nausea (Barnes and
0039H -13- 03/13/89
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Jones, 1967). In severe cases, stupor or coma can occur. However, these
effects are often reversible except In severe cases when permanent damage to
nerve cells can occur. The principal clinical signs of liver Injury
following exposure to carbon tetrachloMde are swollen and tender liver,
elevated levels of hepatic enzymes In the serum, elevated serum blllrubln
levels and decreased serum levels of liver proteins. Repeated or chronic
exposure often leads to flbrosls or cirrhosis (Adams et al., 1952; Smyth and
Smyth, 1935; Smyth et al., 1936). Nephritis and nephrosls are also common
effects following exposure to carbon tetrachlorlde with ollguria or anurla
developed within hours to days after exposure (Smetana, 1939). Both hepatic
and renal effects following carbon tetrachlorlde exposure are generally
reversible because both organs can repair damaged cells and replace dead
tissue (Adams et al., 1952; Smyth and Smyth, 1935; Smyth et al., 1936).
In experimental animals, guinea pigs have been found to be more
sensitive to the toxic effects of carbon tetrachlorlde than are rats or
monkeys (Smyth and Smyth, 1935; Smyth- et al., 1936; Adams et al., 1952).
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. No reports were located on developmental and reproductive
effects 1n humans following oral exposure to carbon tetrachlorlde. Twenty-
nine pregnant rats were administered, by gavage, 0.6-0.9 cc/day carbon
tetrachlorlde during gestation (Wilson, 1954). Marked maternal toxldty and
total resorptlon of fetuses 1n some animals were observed, but no terato-
genlc effects or other adverse effects were apparent In surviving offspring.
Administration of carbon tetrachlorlde In the diet of rats does not appear
to affect their reproductive capacity. The reproductive activity of male
and female rats fed 80 or 200 ppm In the diet over a 2-year period was
generally unaffected by the treatment (Alumot et al., 1976).
0039H -14- 03/13/89
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3.3.2. Inhalation. No reports were located regarding developmental and
reproductive effects 1n humans following Inhalation exposure to carbon
tetrachlorlde. Schwetz et al. (1974) exposed groups of Sprague-Dawley rats
to 300 or 1000 ppm carbon tetrachlorlde for 7 hours/day on days 6-15 of
gestation. Maternal weight loss and clear maternal hepatotoxlclty were
observed; however, no effect on conception, number of Implants or number of
resorptlons was apparent. A significant decrease In body weights and
crown-rump lengths was found In fetuses from dams exposed to either 300 or
1000 ppm (1887-6291 mg/m3) 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, although fetal toxldty was observed. Adams et al. (1952)
noted moderate to marked degeneration of testlcular germinal epithelium In
rats exposed repeatedly to >200 ppm of carbon tetrachlorlde.
3.4. TOXICANT INTERACTIONS
In the early 1900s, carbon tetrachlorlde was used as an anthelmlntlc,
particularly against hookworm, In both humans and animals. Sm1ll1e and
Pessoa (1923) studied severe carbon tetrachlorlde-lnduced toxlclty In two
alcoholics In a group of 34 persons treated with carbon tetrachlorlde for
ancylostomlasls. Since then, other Investigators (Guild et al., 1958;
McGuIre, 1932; Smetana, 1939; Gray, 1947) have observed that chronic alcohol
1ngest1on exacerbates carbon tetrachlorlde-lnduced toxldty resulting from
single medicinal doses, von Oettlngen (1964) reported that habitual users
or occasional users of alcoholic beverages became more seriously 111 when
exposed to carbon tetrachlorlde than those who do not drink alcohol.
0039H -15- 03/13/89
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Tralger and Plaa (1971) Investigated the potentlatlon of carbon
tetrachlorlde toxlclty by methanol, ethanol and Uopropanol 1n rats. The
activity of SGPT was monitored to evaluate hepatotoxldty. All three
alcohols potentiated the toxlclty of carbon tetrachlorlde, with Isopropanol
being the most potent. Maximum potentlatlon was observed when alcohols were
administered 18 hours before carbon tetrachlorlde exposure. Neither carbon
tetrachlorlde nor the alcohols alone elevated SGPT levels. We1 et al.
(1971) Investigated the potentlatlon of carbon tetrachlorlde-lnduced hepato-
toxldty by ethanol and cold. 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 tetrachlorlde-lnduced
toxlclty. The authors postulated that the ethanol could release noreplneph-
rlne which 1n turn Increased the susceptibility of the liver to carbon
tetrachlorlde. Cornish and Adefuln (1966) reported that ethanol Ingestlon
potentiated the toxldty of subsequent exposure to carbon tetrachlorlde.
Sixteen to eighteen hours after pretreatment with a single dose of ethanol
(5 g/kg), rats were exposed to carbon tetrachlorlde vapor (100 or 1000 ppm)
for 2 hours. Twenty-four hours after exposure, SGOT activities 1n the
ethanol-pretreated rats were 2.4- and 8.5-fold higher than 1n control rats
(not given ethanol) at the 100 and 1000 ppm exposure levels, respectively.
Alcohol Ingestlon was suspected to play a significant role In the
toxlclty of carbon tetrachlorlde from nonmedlclnal exposure (Abbott and
Miller, 1948), particularly when renal failure occurred. The ACGIH (1986b)
suggested that ethanol and other substances (e.g., barbiturates and poly-
chlorinated blphenyls) Increase the toxldty of carbon tetrachlorlde by
Inducing the synthesis of one or more mlcrosomal enzymes Involved 1n the
metabolic activation of carbon tetrachlorlde.
0039H -16- 03/13/89
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Hafeman and Hoekstra (1977) reported that rats given a diet supplemented
with vitamin E, selenium and methlonlne were protected against carbon
tetrachlorlde-lnduced toxldty. By monitoring the evolution of ethane, a
peroxldatlon product of certain unsaturated fatty acids, these authors
concluded that methlonlne, vitamin E and selenium protected against carbon
tetrachlorlde-lnduced llpld peroxldatlon, probably by maintaining Intra-
cellular glutathlone and glutathlone peroxldase.
0039H -17- 03/13/89
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4. CARCINOGENICITY
4.1. HUMAN DATA
A few cases of liver cancer associated with exposure to carbon tetra-
chloMde have been reported, but no epldemlologlcal studies useful for risk
assessment were located 1n the available literature. Slmler et al. (1964)
reported the case of a fireman who developed epHhelloma of the liver 4
years after being acutely poisoned by carbon tetrachloMde. Tracey and
Sherlock (1968) suggested that hepatocellular carcinoma 1n a 59-year-old man
was developed 7 years after a 5-day exposure to carbon -tetrachlorlde, which
was used to clean his rug. The man did not Ingest alcohol after exposure to
carbon tetrachlorlde, but had Ingested It before exposure. Blair et al.
(1979) reported 87 cancer deaths In a group of 330 laundry and dry cleaning
workers 1n which 67.9 cancer deaths would have been expected. The malignant
neoplasms reported Included lung, cervical and liver cancers, and leukemia.
The proportionate mortality ratio [PMR = (obsverved death/expected
death)xlOO] for deaths associated with malignant neoplasms was 128 and
statistically significant (x2=6.423, 1 degree of freedom, significant at
p<0.05). However, 1t Is difficult to conclude that the elevated PMR Is
Indicative of an excess risk of cardnogenldty In this study. One of the
compounding factors of the paper was that the causes of death 1n workers
group was compared with that of U.S. population deaths, Instead of another
working population to control for the "healthy worker effect."
Additionally, concurrent exposure to other workroom chemicals precluded
attributing the observed Increase 1n cancer Incidence to carbon
tetrachlorlde alone. Therefore, one can only conclude from this study that
there 1s a need for additional work on this occupational group to clarify
the Issue raised.
0039H -18- 03/17/89
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4.2. BIOASSAYS
4.2.1. Oral. Sufficient evidence for the carclnogenldty of carbon
tetrachlorlde 1n laboratory animals exists In the available literature.
Many early studies, although too short In duration to be useful for risk
assessment, demonstrated the hepatocardnogenldty of carbon tetrachlorlde.
Edwards (1941) administered by gavage 0.1 ml of a 40% carbon tetrachlorlde
solution In 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, followed by
cirrhosis and eventually hepatomas 1n C«H mice. Hepatomas were found In
126/143 C3H and all 54 A-stra1n mice. Delia Porta et al. (1961) treated
five Syrian golden hamsters of each sex with 30 weekly doses of 6.25-12.5
yl (10-20 mg) carbon tetrachlorlde. Liver cell carcinomas were found 1n
all hamsters (five/sex) that survived >10 weeks after the end of treatment.
Edwards et al. (1942) performed a study with Inbred L mice, a strain
with an extremely low rate of spontaneous hepatomas, 2.5-3.5 months or
3.5-7.5 months of age at the start of the experiment. Mice, 8-39/group,
were treated by gavage with 46 doses of carbon tetrachlorlde (0.1 mil of a
40% solution of carbon tetrachloMde/dose) over a 4-month period and were
killed and necropsled 3-3.5 months after the last treatment. Hepatomas
developed In 7/15 younger male mice (47%), 21/39 older male mice (54%), 3/8
younger females (38%) and 3/11 older females (27%), In comparison with 2/152
(1%) 1n untreated mice. Therefore, strain L male and female mice were
highly susceptible to the Induction of hepatomas by carbon tetrachlorlde,
and male mice were slightly more susceptible than female mice.
Edwards and Dalton (1942) Investigated the Induction of cirrhosis of the
liver and hepatomas In mice following exposure to high-dose, low-dose and
limited treatment with carbon tetrachlorlde. For high-dose treatment,
0039H -19- 03/17/89
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strains C3H, A, Y and C (1-5 months of age) were given 0.1 ml of a 40%
solution of carbon tetrachlorlde In olive oil by gavage 2 or 3 times/week
for a total number of 23-58 treatments. Incidences of hepatoma as well as
cirrhosis were significantly Increased 1n all four strains of mice. For
low-dose treatment, 58 strain A female mice were given 0.1 ml of 5% carbon
tetrachlorlde 1n olive oil, by gavage, 3 times/week for 2 months. The total
dose of carbon tetrachlorlde administered In the low-dose treatment group
(0.125-0.145 ml) 1s comparable to the total dose used In the high-dose
treatment group (0.120 ml). The Incidences of hepatoma, as well as
cirrhosis, were significantly Increased In the low-dose group. The tumors
of the liver observed were morphologically similar in both high- and
low-dose treatment groups. Limited treatment Involved dosing of strain A
mice with 0.04, 0.01 or 0.005 ml of carbon tetrachlorlde (21-62
mice/group, 1-3 treatments/animal). No hepatoma was observed In animals
exposed to limited dose.
Eschenbrenner and Miller (1944) administered 30 doses of 0.16, 0.32,
0.64, 1.27 or 2.54 g carbon tetrachlor1de/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 1n the five groups, respectively, but a
majority of tumors at each dose level occurred In groups treated every 3 or
4 days. In a later study, Eschenbrenner and Miller (1946) demonstrated that
single gavage doses of 12.5 »il/kg, but not 6.25 yl/kg would cause liver
cell necrosis 1n both male and female strain A mice. Administration of
6.25, 12.5, 25 or 50 pl/kg/day for 120 days resulted 1n hepatoma formation
1n mice exposed to >12.5 yl/day. Other mice were given 30 doses of 25, 50
or 100 pi/kg at 4-day Intervals. Microscopic examination revealed small
hepatomas 1n 2/10 mice given 25 pi/kg. Grossly visible tumors were
0039H -20- 03/17/89
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present In the higher dosed groups. These Investigators theorized that the
necrotlzlng action of carbon tetrachloMde on the liver was an Important
factor In the development of a carcinogenic response.
NIOSH (1975) and U.S. EPA (1980a) discussed other short-term carclno-
genlclty studies with carbon tetrachlorlde, but since they provide no
additional Information and are not useful for risk assessment, they are not
Included here.
In an NCI-sponsored bloassay {NCI, 1976; Welsberger, 1977), groups of 50
male and 50 female Osborne-Mendel rats were treated by gavage 5 days/week
with carbon tetrachlorlde In corn oil (47 or 94 mg/kg for males, or 80 or
160 mg/kg for females) for 78 weeks. Vehicle control groups consisting of
100 males and 100 females were maintained. Observations were continued for
33 additional weeks following cessation of treatment. Survival data
Indicate that excessive mortality occurred In high-dose female rats by 78
weeks and 1n high-dose male rats at termination. Although a slight Increase
1n the Incidence of hepatocellular carcinomas was noted In both males and
females, a clear dose-related response could not be demonstrated.
Mice were also Included In the NCI (1976) bloassay. Groups of 50 male
and 50 female B6C3F1 mice were treated by gavage with 1250 or 2500 mg carbon
tetrachlorlde 1n 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/sex. All mice were necropsled. By the end of the 78-week exposure
period, most carbon tetrachlorlde-exposed mice died. Most carbon tetra-
chlorlde-treated mice had hepatocellular carcinomas (95-100%). 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
0039H -21- 03/17/89
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found at 48 and 26 weeks In the low- and high-dose groups, respectively.
Few hepatocellular tumors were seen 1n vehicle-treated mice. The Incidences
of hepatocellular carcinomas are presented 1n Table 4-1.
4.2.2. Inhalation. Few data concerning cardnogenlclty of carbon tetra-
chlorlde from Inhalation exposure were located In the available literature.
Costa et al. (1963) exposed albino rats to unspecified concentrations of
atmospheric carbon tetrachlorlde for up to 7 months. Rats were killed
serially from 2-10 months after the beginning of exposure. Of the 30 rats
that survived to termination, 12 had adenodrrhosls and 10 had liver nodules
measuring up to 1 cm, which were microscopically diagnosed as Incipient or
established hepatocellular carcinomas. Established carcinomas were found 1n
five Hvers and Incipient carcinomas were found In five others.
4.3. OTHER RELEVANT DATA
Few pertinent data regarding the mutagenlclty of carbon tetrachlorlde
were located In the available literature. Kraemer et al. (1974) found no
mutagenlclty In either the Salmonella typh1mur1um or Escherlchla coll
reversion tests. Details of the experimental protocol were not available.
IARC (1979) also reported a lack of mutagenlclty In S. typhlmurlum strains
TA100, TA1535, TA1538 (McCann and Ames, 1976; McCann et al., 1975; Uehleke
et al., 1976; Uehleke et al., 1977) and E_. coll (Uehleke et al., 1976,
1977). Studies In which the mutagenlclty of carbon tetrachlorlde was tested
under conditions that controlled for volatility of the compound were also
negative. Simmon et al. (1977) used a desiccator to expose plates of
bacteria to carbon tetrachlorlde vapor, and observed no mutagenlc activity.
Barber et al. (1981) tested carbon tetrachlorlde for mutagenlc activity In
Salmonella strains TA1535, TA1537, TA1538, TA98 and TA100 using both a
standard assay system (In which volatilization was not prevented) and a
closed Incubation system that prevented the escape of volatilized carbon
0039H -22- 03/17/89
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TABLE 4-1
Incidence of Liver Tumors 1n Mice Treated by Gavage with
Carbon TetrachloMde 1n Corn Oil 5 Days/Week for 78 Weeks*
Dose Carcinomas
Hales
Control
Matched 2/19 (11%)
Pooled 5/77 (6%)
1250 mg/kg/day 49/49 (100%)
2500 mg/kg/day 47/48 (98%)
Females
Control
Matched 1/20 (5%)
Pooled 1/80 (1%)
1250 mg/kg/day 40/40 (100%)
2500 mg/kg/day 43/45 (96%)
*Source: NCI, 1976
NR = Not reported
0039H . -23- 03/17/89
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tetrachlorlde. Carbon tetrachloMde was not mutagenlc In either the
standard or closed Incubation system.
Assays using S. typhlmurlum and E_. coll to assess the mutagenlclty of a
compound often use an exogenous mammalian liver S-9 activation system to
metabolize the compound to Us active form. The yeast Saccharomyces
cerevlslae strain 07 contains an endogenous cytochrome p-450 dependent mono-
oxygenase activation system, and Callen et al. (1980) used this yeast to
demonstrate that carbon tetrachlorlde was mutagenlc and caused gene cross-
over and mltotlc recombination. Callen et al. (1980) suggested that because
of the presence of an endogenous activation system this yeast system was
more sensitive than some of the other 1_n vitro test systems.
Dean and Hodson-Walker (1979) found that carbon tetrachlorlde did not
Induce chromosome damage In cultured rat liver cells. M1rsal1s and
Butterworth (1980) reported that there was no UDS In hepatocytes Isolated
from rats following oral exposure to carbon tetrachlorlde (10 or 100 mg/kg).
Craddock and Henderson (1978) also reported that carbon tetrachlorlde did
not cause DNA repair (UDS) 1n hepatocytes Isolated from animals exposed to
4000 mg/kg. In their most recent study, M1rsal1s et al. (1982) reported
that combinations of carbon tetrachlorlde doses (up to 400 mg/kg) and
exposure times (up to 48 hours) which resulted 1n liver toxldty were
negative with respect to UDS.
4.4. WEIGHT OF EVIDENCE
There 1s sufficient evidence 1n mice, rats and hamsters to designate
carbon tetrachlorlde as a hepatic carcinogen In animals. Brief exposures
have led to flbroblastlc proliferation and hlstopathologlcal liver abnormal-
ities (Prendergast et al., 1967), while prolonged exposure (NCI, 1976; We1s-
burger, 1977) results 1n a very high Incidence of hepatocellular carcinoma.
0039H -24- 08/09/89
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The few case reports associated with carbon tetrachlorlde provide Inade-
quate evidence to confirm human carclnogenldty. Only one epldemlologlc
study (Blair et al., 1979) was found 1n the available literature. Blair et
al. (1979) observed 87 cancer deaths 1n a cohort of 330 exposed workers In
which 67.9 cancer deaths would have been expected. Concurrent exposure to
other chemicals precluded ascribing the observed Increase In cancer Inci-
dence to carbon tetrachlorlde alone. On the basis of the guidelines adopted
by the U.S. EPA (1986a) for evaluating the overall weight of evidence for
carclnogenldty to humans, carbon tetrachlorlde Is classified as a Group B2
— Probable Human Carcinogen. This Is consistent with the earlier analysis
by U.S. EPA (1986b).
0039H -25- 05/04/89
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.5. REGULATORY STANDARDS AND CRITERIA
ACGIH (1986a,b) and U.S. EPA (1980a) have established regulatory stan-
dards for carbon tetrachloMde (Table 5-1).
IRIS (U.S. EPA, 1986b) lists a verified RfDQ of 7x10"* mg/kg/day for
carbon tetrachlorlde based on a NOAEL of 1 mg/kg/day 1n a subchronlc gavage
study 1n rats by Bruckner et al. (1986). The IRIS report reflects an
analysis by the U.S. EPA (1985b) Office of Drinking Water.
0039H -26- 03/17/89
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TABLE 5-1
Current Regulatory Standards and Criteria for Carbon Tetrachlorlde
Criterion
Value
Reference
TLV
NIOSH celling level
to prevent cancer
Japan and most
European nations
Most eastern
European nations
Maximum contaminant
level 1n drinking
water
5 ppm (30 mg/m3)
2 ppm (12.6 mg/m3)
10 ppm
3-7.5 ppm
0.005 mg/l
ACGIH, 1986a,b
ACGIH, 1986b
ACGIH, 1986b
ACGIH, 1986b
U.S. EPA, 1987
Ambient water
criteria associated
with cancer risk:
10'7
10'«
10"5
consumption of
6.5 q fish only
0.69 yg/1
6.94 yg/l
69.4 wg/l
2 l water +
6.5 q fish
0.04 yg/l
0.40 jig/l
4.0 yg/l
U.S. EPA, 1980b
0039H
-27-
03/17/89
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
Bruckner et al. (1986) dosed groups of -15 male Sprague-Dawley rats with
carbon tetrachloride 1n corn oil by gavage (1, 10 or 33 mg/kg/day, 5
days/week for 12 weeks). Liver lesions, as evidenced by mild centrllobular
vacuollzatlon and statistically significant Increases In serum sorbltol
dehydrogenase activity, were observed at the 10 and 33 mg/kg/day doses. A
NOAEL of 1 mg/kg/day was observed In this study. An RfOg of 7xlO~3
mg/kg/day can be derived based on a NOAEL of 1 mg/kg/day, a conversion
factor of 5/7 (to adjust for 5 days/week dosing regimen) and an uncertainty
factor of 100 (to allow for Interspecles and Intrahuman variability).
6.2. REFERENCE DOSE (RfD)
An oral RfD of 7xlO~4 mg/kg/day can be calculated based on a NOAEL of
1 mg/kg/day 1n a subchronlc gavage study by Bruckner et al. (1986). In
addition to the conversion factor of 5/7 and an uncertainty factor of 100 as
discussed 1n Section 6.1., another uncertainty factor of 10 was applied to
adjust for extrapolation from subchronlc to chronic duration of exposure.
This RfD value was verified by the U.S. EPA RfD Workgroup on 12/04/86.
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. Carbon tetrachloride Is classified as a Group 82, probable
human carcinogen, based on sufficient animal weight of evidence and
Inadequate human weight of evidence. The Carcinogen Assessment Group, as
described 1n U.S. EPA (1984a), used data from the Delia Porta et al. (1961)
(hamster), Edwards et al. (1942) (mouse) and NCI (1976) (both rat and mouse)
studies for risk assessment purposes. Since the studies used were deficient
1n some respect for quantitative purposes, precluding the choice of any one
study as most appropriate, the geometric mean of the upper limit unit risk
0039H -28- 08/01/89
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estimates (3.7x10 «) from four data sets has been calculated for unit risk
corresponding to drinking water containing 1 vg/i. Assuming human
consumption of 2 I of water/day and a human body weight of 70 kg, a slope
factor of I.SOxlO'1 (mg/kg/day)"1 can be calculated from the unit risk
of 3.7xlO~« (yg/l)'1 for the oral route. U.S. EPA (1984a) contains
an 1n-depth explanation of the rationale applied and the calculations
employed. This value has been verified and 1s available on IRIS (U.S. EPA,
1987).
6.3.2. Inhalation. U.S. EPA (1987) adopted the oral slope factor of
l.SxlO'1 (mg/kg/day)"1 and an Inhalation absorption factor of 0.4, based
on pharmacoklnetlc data evaluated by U.S. EPA (1984a), to estimate a slope
factor for Inhalation exposure. Applying the Inhalation absorption factor
of 0.4 to the oral slope factor of l.SxlO"1 (mg/kg/day)'1 results In an
Inhalation slope factor of 5.2xlO~2 (mg/kg/day)'1.
0039H -29- 08/01/89
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7. REFERENCES
Abbott, G.A. and M.J. Miller. 1948. Carbon tetrachlorlde poisoning — A
report on ten cases at the U.S. Marine Hospital, Seattle, WA, since 1937.
Pub. Health Rep. 63: 1619-1624. (Cited 1n NIOSH, 1975)
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986a.
Threshold Limit Values and Biological Exposure Indices for 1986-1987.
Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986b.
Documentation of the Threshold Limit Values and Biological Exposure Indices,
5th ed. Cincinnati, OH.
Adams, E.M., H.C. Spencer, V.K. Rowe, D.O. McColHster and D.D. Irish.
1952. Vapor toxldty of carbon tetrachlorlde determined by experiments on
laboratory animals. Arch. Ind. Hyg. Occup. Med. 6: 50-66. (Cited In U.S.
EPA, 1980a, 1983a)
Alumot, E., E. Nachtoml, E. Mandel and P. Holsteln. 1976. Tolerance and
acceptable dally Intake of chlorinated fumlgants In the rat diet. Food
Cosmet. Toxlcol. 14: 105-110.
Banerjee, S., S.H. Yalkowsky and S.C. Valvanl. 1980. Mater solubility and
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