United States
Environmental Protection
Agency
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Research and Development
EPA/600/S8-82/001FApr. 1987
Project Summary
Health Assessment Document
for Carbon Tetrachloride
Cynthia Sonich-Mullin
The Office of Health and Environmen-
tal Assessment (OHEA), in consultation
with an Agency work group, has pre-
pared this hearth assessment to serve
as a "source document" for EPA use.
Originally the hearth assessment was
developed for use by the Office of Air
Quality Planning and Standards; how-
ever, at the request of the Agency Work
Group on Solvents, the assessment
scope was expanded to address multi-
media aspects.
In the development of this assess-
ment document, the scientific literature
has been inventoried, key studies have
been evaluated, and summaries and
conclusions have been prepared so that
the chemical's toxicity and related char-
acteristics are qualitatively identified.
Observed effect levels and dose-
response relationships are discussed
evaluating the potential toxicity of CCI4.
Unit risk estimates for cancer are calcu-
lated to provide a media-specific meas-
ure of toxicity. This information can
then be placed in perspective with ob-
served environmental levels.
This Project Summary was devel-
oped by EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH,
to announce key findings of the re-
search protect that is fully documented
in a separate report of the same title
(see Project Report ordering informa-
tion at back).
Summary
Carbon tetrachloride (CCI4) is a rela-
tively nonpolar compound that is
slightly soluble in water, soluble in alco-
hol and acetone, and miscible in ben-
zene, chloroform and ether. Its density
is 1.59 g/me at 4°C which is greater than
the density of water. Thus, under favor-
able conditions, large amounts spilled
into water may settle and not volatilize.
However, the high vapor pressure of
CCU 015.2 mm Hg at 25°C) favors
volatilization from water to air.
Carbon tetrachloride is produced
commercially from the chlorination of
several chemicals such as methane,
propane, ethane propylene and carbon
disulfide. In 1980, 3.22 x 108 kg were
produced in the United States. A much
smaller amount of CCI4 is generated
during the production of vinyl chloride
and perchloroethylene. The major use
of CCI4 is in the production of chloroflu-
orocarbons. A reduction in the demand
for CCI4 has resulted in a 3.5% decrease
in production over the years 1970-1980.
A continued 1.0% decline in production
is projected each year through 1985.
Carbon tetrachloride can be detected
in the environment using media-
specific analytical methods. Levels de-
tected in the environment are generally
<0.01 mg/ein water, <0.01 mg/m3 in air,
and <0.01 mg/kg in food although
higher levels have been detected in
urban air and grain fumigated with CCI4.
Food products made from this grain
also contain residues of CCI4. Natural
sources of CCI4 are unknown so that
most, if not all CCI4 present in the envi-
ronment can be accounted for by an-
thropogenic activities.
Carbon tetrachloride is extremely sta-
ble in the lower atmosphere and tropo-
sphere; however, once in the strato-
sphere, photodissociation is rapid. Its
presence in the stratosphere is of con-
cern due to its possible contribution to
ozone depletion and subsequent mod!
fication of UV-B radiation flux. The ex-
tent of this contribution cannot pres-
ently be estimated for CCI4 due to
numerous significant uncertainties in
modeling and data. Increased UV-B ra-
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diation studies in the laboratory have
shown adverse effects to a variety of
terrestrial plant species; for example, in
terms of depressed photosynthetic ac-
tivity, reduced growth rate, increased
somatic mutation rates, and inhibition
of seed germination. In laboratory stud-
ies, some aquatic organisms have also
been shown to be adversely affected.
Direct extension of these laboratory
findings to the natural environment
should not be made because of adapt-
ability potential to small changes in LIV-
ES flux. Indirect ecosystem effects asso-
ciated with increases in UV-B radiation
flux have been identified to include
changes in genetic material and possi-
ble alterations in population composi-
tion. However, it is not known if these
laboratory findings apply to the natural
environment due to observed adapta-
tions. The implication of increased UV-B
flux to human populations is that >90%
of skin cancer (other than melanoma) in
the United States is attributed to sun-
light in the UV-B region.
When present in water in dilute con-
centrations, CCI4 is rapidly lost to the
atmosphere by volatilization. However,
large quantities of CC!4 spilled into
water may settle and persist, due to its
high specific gravity, low water solubil-
ity and high chemical stability. In such
cases its presence in ambient water or
drinking water may present a threat to
aquatic ecosystems or human health.
Humans are potentially exposed to
CCI4 through various media. For an
adult male, the typical exposure is esti-
mated at 13 jig/day from inhalation,
9 M-g/day from fluid intake and 4 ^g/day
from food intake. Uptake from air ap-
pears to be the major source of expo-
sure followed by liquids and food. For
this reason, the fate and transport of
CCI4 has been most extensively studied
in air. Information on CCI4 soil contami-
nation is limited; consequently, its con-
tribution to human exposure is uncer-
tain.
Ecological impacts have been moni-
tored to a limited extent in freshwater
and saltwater organisms. Only two
freshwater fish and one invertebrate
species have been acutely tested; a 96-
hour LCgo has been determined as low
as 27.3 mg/e in the bluegill, Lepomis
macrochirus. Chronic toxicity data are
not available. However, reported bio-
concentration factors are <30 so that
tissue residues are insignificant. The
only data on saltwater species deals
with toxicity following acute exposures.
Effects have been identified at levels of
50.0 mg/e. It is noted that the toxic dose
for both freshwater and saltwater spe-
cies can be lower if more sensitive spe-
cies were tested.
In mammals, CCI4 is readily absorbed
from the lungs and gastrointestinal
tract. Absorption also occurs through
the skin but at a much slower rate. Fol-
lowing absorption, CCI4 is distributed to
all major organs. Metabolism of the
compound occurs primarily in the liver
where it is reduced to a trichloromethyl
radical and thought to be further metab-
olized and/or released as a free radical.
Excretion of CCI4 is primarily through
the lungs but also occurs in the urine
and feces. Quantitative estimates are
available only for inhalation absorption
efficiency; these range from 30-65%.
Varying degrees of toxicity have been
reported in humans and animals follow-
ing acute, subchronic and chronic expo-
sures via ingestion, inhalation or der-
mal administration. Such effects can
occur systemically as well as locally. For
example, cirrhosis of the liver has re-
sulted from inhalation and dermal ex-
posures, whereas lung lesions have re-
sulted from oral ingestion. Animals
surviving acute doses have developed a
range of effects such as damage to the
liver, kidney, lung and central nervous
system as well as dermal effects; bio-
chemical alterations were also noted.
Animals receiving subchronic and
chronic doses have developed kidney
and liver damage and, less frequently,
damage to the central nervous system.
It has been observed that exposure to a
higher concentration over a shorter pe-
riod of time produces a greater effect
upon the liver than exposure to a lower
concentration over a longer period of
time, even though the product of time
and concentration is equal in both
cases.
In an attempt to verify the purity of
CCI4 used in the testing protocols of the
studies summarized in this document, it
was observed that CCI4 of impure or
technical grade was not reported; only
the use of pure CCI4 was reported.
Adverse effects recorded for humans
following CCI4 exposure are similar to
those observed in animals. Damage to
the liver, kidney, lungs and central ner-
vous system has been documented in
various case reports. Biochemical alter-
ations have been identified in case re-
ports and one epidemiological study.
Exposure to CCI4 did not produce
skeletal or functional abnormalities but
did result in signs of fetotoxicity. Rats
exposed in utero to CCI4 were noted to
have fatty infiltration of the liver from
days 1-4 after birth. Carbon tetrachlo-
ride has been shown to be transferred
to the neonate through mothers' milk.
Other adverse reproductive effects in-
clude changes in testicular histology
eventually resulting in functional infer-
tility.
Tests of the mutagenicity of CCI4 have
been consistently negative in the
Salmonella assay. A positive mutagenic
response was seen in an assay using
Saccharomyces cerevisiae; however,
there have been problems associated
with this study.
Carbon tetrachloride has been found
to produce (1) carcinogenic or neo-
plastic responses in the liver of six
strains of mice (C3H, B6C3F1, A, Y, C
and L); (2) carcinomas in the liver of
three strains of rat (Osborne-Mendel,
Japanese, Wistar) and hyperplastic
nodules in a fourth rat strain (Buffalo) in
less than lifetime studies; (3) a small but
statistically significant (as compared to
pooled controls) hepatocellular car-
cinoma response in female Osborne-
Mendel rats in lifetime experiments;
and (4) hepatocellular carcinomas in
Syrian golden hamsters.
Case reports of human carcinomas
developing years after a history of high
CCI4 exposures are suggestive of but
not evidence for an association be-
tween human carcinogenic risk and ex-
posure to CCI4. Studies on groups ex-
posed to CCI4 indicate that further
research is necessary.
If the criteria of the International
Agency for Research on Cancer (IARC)
were used, this evidence would be clas-
sified as sufficient in animals and inade-
quate in humans for an overall rating of
28. Estimates of excess human cancer
risk from lifetime exposure to CCI4 have
been extrapolated from the cancer stud-
ies on animals. The recommended
upper limit estimates of unit risk are
from 3.1 x 10~7 to 3.4 x 10~5 for expo-
sure to 1 (xg/f in water and from
1.2 x 10~6 to 1.4 x 10"4for exposure to
in air.
In assessing toxicity, carcinogenic!^
or any other harmful effect, compound!
that react synergistically or antagonist!
cally with CCI4 must be considered
Identified synergistic substances in
elude ethanol, kepone, PCB and PBE
Antagonistic effects have been demon
strated with such compounds as chic
ramphenicol and catechol.
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Conclusions
Carbon tetrachloride may contribute
to the long term, partial destruction of
stratospheric ozone. Several uncertain-
ties in the modeling and data preclude
quantitative estimation of ozone deple-
tion due to CCI4.
Carbon tetrachloride causes damage
to the liver, lungs, kidneys and central
nervous system in humans. These ef-
fects are primarily the result of high oral
or inhalation exposures. Less severe ef-
fects such as biochemical alterations,
nausea and headache result from lower
exposures or are secondary to the
major health hazards attributed to
higher exposures. Similar responses
have been demonstrated in animals.
These animal studies provide useful
dose/response data, are well-defined
and can identify a causal relationship
between the CCI4 insult and the toxic
response. Furthermore, the toxicity
from CCI4 is not only local but also sys-
temic.
Absorption of CCI4 varies with spe-
cies. Based upon both human and ani-
mal data, absorption coefficients of 40%
when route of exposure is via inhalation
and 100% when route of exposure is via
ingestion are recommended.
The potential exists for embryotoxic-
ity, especially in males. Toxic effects
due to CCI4 have been demonstrated in
mammalian fetuses and neonates ex-
posed directly or indirectly via the pla-
centa or mothers' milk, respectively.
Teratogenic effects have not been noted
following CCI4 exposure; however, de-
generative changes in the testes and
subsequent infertility of the offspring
have occurred.
Definitive conclusions concerning
mutagenicity tests cannot be reached.
Carbon tetrachloride did exhibit a posi-
tive mutagenic response in an assay
using Saccharomyces cerevisiae; how-
ever, due to problems associated with
the study and the lack of corroborative
studies, the evidence is not adequate to
conclude whether or not CCI4 is geno-
toxic.
Interactions with other chemicals
must be considered in assessing the po-
tential health hazards of exposure to
CCI4. Chemicals have been identified
that potentiate the effects of CCI4 as well
as those that inhibit the effects of CCI4.
Carcinogenicity of CCI4 has been ob-
served in three animal species. The pri-
mary lesions are hepatic neoplasms.
Cirrhosis, necrosis and cholangiofibro-
sis have also been found and have been
suggested as initial lesions prior to tu-
morigenesis in liver. Human data on
carcinogenicity are restricted to case re-
ports and one preliminary epidemiolog-
ies I study. The animal data provide evi-
dence to indicate that CCI4 is a potential
human carcinogen. The combined evi-
dence of animal and human studies
would fall into IARC classification of 2B
if the IARC criteria were used. The IARC
description of this level of evidence is
that this compound is probably carcino-
genic for humans.
Mechanism of action is an important
issue in the assessment of the potential
carcinogenicity of CCI4 to humans at
low doses.
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This Project Summary was prepared by staff of EPA's Environmental Criteria
and Assessment Office. Cincinnati. OH 45268.
Cynthia Sonich-Multin is the EPA Project Officer (see below).
The complete report, entitled "Health Assessment Document for Carbon
Tetrachloride—Final Report." (Order No. PB85-124 196; Cost: $30.95, subject
to change) will be available only from:
National Technical Information Service
5285 Port Royal Road
Springfield, VA 22161
Telephone: 703-487-4650
The EPA Project Officer can be contacted at:
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Cincinnati, OH 45268
United States
Environmental Protection
Agent*.
Center for Environmental Research
Information
Cincinnati OH 45268
. ,,— \.,OH\0,
Official Business
Penalty for Private Use $300
EPA/600/S8-82/001F
10032*
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