820K87104
CARBON TETRACHLORIDE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for One-day, Ten-day, Longer-term
(approximately 7 years, or 10% of an individual's lifetime) and Lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any one of these models is able to predict risk more accurately than another.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
-------
Carbon Tetrachloride March 31, 1987
-2-
This Health Advisory (HA) is based on information presented in the
Office of Drinking Water's Health Effects Criteria Document (CD) for carbon
tetrachloride (U.S. EPA, 1985a). The HA and CD formats are similar for easy
reference. Individuals desiring further information on the toxicological
data base or rationale for risk characterization should consult the CD. The
CD is available for review at each EPA Regional Office of Drinking Water
counterpart (e.g., Water Supply Branch or Drinking Water Branch), or for a
fee from the National Technical Information Service, U.S. Department of
Commerce, 5285 Port Royav Rd., Springfield, VA 22161, PB #85-118155/AS.
The toll-free number is 1800) 336-4700; in the Washington, D.C. area:
(703) 487-4650.
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 56-23-5
Structural Formula
Cl
I
C1-C-C1
I
Cl
Synonyms
0 Methane tetrachloride, tetrachloromethane, CC14, perchloroethane.
Uses
0 The major use of CC14 is in the production of chlorofluorocarbons,
which are used as refrigerants, foam-blowing agents and solvents.
Carbon tetrachloride also is used in fumigants, as a solvent in
metal cleaning and in manufacture of paints and plastics (Rams,
et al., 1979). It is being replaced in grain fumigation by other
registered pesticides (U.S. EPA, 1980a).
Properties (U.S. EPA, 1985a)
Chemical Formula CC14
Molecular Weight 153.8
Physical State Colorless liquid
Boiling Point 76.5°C
Melting Point -23°C
Density d|° 1.594
Vapor Pressure 115.2 mm Hg at 25°C
Water Solubility 800 mg/L
Taste Threshold not available
Odor Threshold 0.52 mg/L (Amoore and Hautala, 1983)
Conversion Factor 6.4 mg/m^ = 1 ppm
-------
Carbon Tetrachloride March 31, 1987
-3-
Occurrence
Carbon tetrachloride (CC14) is a synthetic chemical with no natural
sources (U.S. EPA, 1983).
Production of CC14 was approximately 600 million Ibs in 1983 (U.S.ITC,
1983). Carbon tetrachloride also is produced as a by-product of the
manufacture of a number of other chlorinated materials.
Current major sources of CC14 released to the environment are from
accidental releases from production and uses. Previously, large
amounts of CC14 were released from its use as a solvent. Most of the
releases of CC14 occur to the atmosphere by evaporation because of
its high volatility. Some CC14 may be released to the environment
during the disposal of wastes in landfills or surface waters. The
majority of releases will occur in the areas near its production and
use (U.S. EPA, 1983).
Carbon tetrachloride released to: (1) the environment is fairly stable;
(2) the air, degrades slowly; (3) surface waters, migrates to the
atmosphere in a few days or weeks; and (4) the land, does not sorb
onto soil and migrates readily to ground water. Carbon tetrachloride
is expected to remain in ground water for months to years. Unlike
more highly chlorinated compounds, CC14 does not bioaccumulate in
individual animals or food chains (U.S. EPA, 1979).
Carbon tetrachloride occurs ubiquitously in the air but at concen-
trations of less than 10 ppt. Carbon tetrachloride is a fairly rare
contaminant in ground and surface waters, with higher levels found in
ground water. The Agency estimates that less than 1% of all ground
waters derived drinking water systems have levels of CC14 greater
than 0.5 ug/L and less than 0.2 % greater than 5 mg/L (U.S. EPA, 1983).
Very limited information is available on the occurrence of carbon
tetrachloride in food. In the past, CC14 has been used as a grain
fumigant and low levels have been reported to occur in some foods from
this use (U.S. EPA, 1983).
The major source of exposure to CC14 is from contaminated air. Water
and food are only a minor sources.
III. PHARMACOKINETICS
Absorption
Carbon tetrachloride is absorbed readily from the gastrointestinal
tract, the respiratory tract and the skin. About 60% of an oral dose
(1600 mg/kg) was absorbed by rats within six hours (Reddrop et al.,
1981), and 65 to 86% of oral doses of 2,000-4,000 mg/kg were absorbed
by rats within 24 hours (Paul and Rubinstein, 1963; Seawright and
McLean, 1967; Marchand et al., 1970).
-------
Carbon Tetrachloride March 31, 1987
-4-
Absorption from the lung has been reported as about 30% in monkeys
exposed to 290 mg CCl4/m3 for 139, 344 or 300 minutes (McCollister
et al., 1952).
° Bruckner et al. (1986a) assessed potential effects of different vehicles
on the pharmacokinetics of CC14. Fasted 200 g male Sprague-Dawley
rats with indwelling arterial cannulas received 25 mg/kg 0014 by
gavage: in corn oil; as an aqueous emulsion; in water; and as pure
undiluted chemical. A 25 mg/kg dose was given intravenously for
calculation of bioavailability. Serial blood samples were taken and
analyzed for 0014. Peak concentrations of CC14 in the blood were
reached within 8 minutes after dosing in the emulsion and saturated
water groups. These peak levels were slightly higher than in the
pure CC14 group and substantially higher than in the corn oil group.
There was evidence of later secondary peaks of lesser magnitude in
the corn oil group. The absolute bioavailability for the emulsion
and saturated water groups was higher than for the corn oil and pure
chemical groups, and comparable to the intravenous group.
Distribution
0 Carbon tetrachloride appears to be distributed to all major organs
following absorption (U.S. EPA, 1985a). Carbon tetrachloride has been
found in fat, liver, blood, brain, kidney and muscle, with particularly
high concentrations in fat. Carbon tetrachloride reaches maximal
concentrations in most tissues at approximately two to four hours
following intragastric administration (Marchand et al., 1970).
Metabolism
0 Carbon tetrachloride metabolism occurs primarily in the liver. The
first step is thought to be formation of a trichloromethyl radical in
the cytochrome heme moiety. This trichloromethyl radical undergoes a
variety of reactions, including hydrogen abstraction to form chloro-
form, dimerization to form hexachloroethane and addition to cellular
molecules. Further metabolism of the heme-bound trichloromethyl
radical is postulated to result in the eventual formation of carbonyl
chloride (phosgene) (Shah et al., 1979 with an in vitro study with
rat liver).
0 After a single oral dose of CC14 in Wistar rats, Bini et al. (1975)
proposed that the trichloromethyl free radical was the main metabolite
of CC14 after they found chloroform and hexachloroethane as metabolites
in the rats. Fowler (1969) found these metabolites in rabbits given
CC14 orally. McCollister et al. (1951) detected labeled carbon
dioxide exhaled by monkeys exposed to 14C-CC14 by inhalation.
Excretion
Carbon tetrachloride and its volatile metabolites are excreted pri-
marily in exhaled air and also in the urine and feces (U.S. EPA,
1985a). Elimination of orally ingested CC14 occurs with an estimated
half-time of four to six hours, and most of an oral dose is excreted
-------
Carbon Tetrachloride March 31, 1987
-5-
within one to two days. No reports were located regarding the tissue
accumulation and retention of CC14 during chronic exposure.
IV. HEALTH EFFECTS
Humans
0 The effects of CC14 exposure in humans are similar to effects seen
in animals, with the liver, kidney and lungs being most sensitive.
0 Single oral doses of 2.5 to 15 mL (57 to 343 mg/kg) are usually
without effect, although changes may occur in liver and kidney
(U.S. EPA, 1985a). Some individual adults suffer adverse effects
(including death) from ingestion of as little as 1.5 mL (34 mg/kg),
and 0.18 to 0.92 mL may be fatal in children (29 to 150 mg/kg)
(U.S. EPA, 1985a).
0 Inhalation exposure also results in central nervous system depression
and renal and hepatic damage (U.S. EPA, 1985a). No ill effects
result from three hours of exposure to 63 mg/rn3, but 70 minutes of
exposure to 2,309 mg/m3 may produce liver effects. High levels
(1,500 mg/m3) may produce severe poisoning and death.
Animals
Short-term Exposure
0 Carbon tetrachloride is toxic to animals, with oral LDso values ranging
from 1,000 to 12,800 mgAg (U.S. EPA, 1985a).
0 The tissue most affected by CC14 is the liver. Using release of
liver enzymes into serum and histological examination as end-points,
single oral doses (in corn oil) of 40 mg CCl4/kg did not produce
adverse effects, while doses of 80 mgAg °r higher did in male Sprague-
Dawley rats (Bruckner et al., 1986b). Numerous studies have found
that oral doses ranging from about 100 to 4,000 mg/kg produce fatty
infiltration, loss of cytochrome P-450 and other enzymes, inhibition
of protein synthesis and histological alterations in the liver. When
damage is severe, hepatocellular necrosis may result, but the effects
observed following lower doses are largely reversible (U.S. EPA, 1985a).
0 Kidney and lung also are affected following oral exposure to CC14
(U.S. EPA, 1985a). Single doses of about 4,000 mg/kg result in lesions
of the renal proximal tubule in rats and pulmonary Clara cells and
endothelial cells in rats and/or mice. These changes also appear to
be reversible when damage is not too severe.
0 Bruckner et al. (1986b) found hepatotoxic effects (increased serum
enzymes, pathology) in rats given CC14 in corn oil at daily doses of
20 mg/kg and higher by gavage for 9 days in an 11-day study.
-------
Carbon Tetrachloride March 31, 1987
-6-
0 Hayes et al. (1986) observed hepatotoxicity (increased serum enzymes,
increased organ weight) in male and female CD-1 mice given 0014 in
corn oil by gavage at doses of 625, 1,250 or 2,500 mg/kg for 14
consecutive days.
0 The objective of a study by Kim et al. (1986) was to assess the
influence of dosing vehicles on the acute hepatotoxicity of 0014.
Fasted 200 g male Sprague-Dawley rats were given 0, 10, 25, 50,
100, 250, 500, 1,000 or 2,000 mg CCl^/kg by gavage in: corn oil;
as an aqueous emulsion; as the undiluted chemical; and in the 10 and
25 mg/kg doses only in water. Blood and liver samples were taken
24 hrs after dosing for measurement of serum and microsomal enzymes.
Pathological examination of liver samples was also conducted. Dose-
dependent increases in serum enzyme levels and pathological changes,
and dose-dependent decreases in microsomal P-450 and glucose-6-
phosphatase activity were observed in each vehicle group. CC14 was
less hepatotoxic at each dosage level when given in corn oil than
when given as an emulsion or as the pure chemical. CC14 in corn oil
was also less toxic than CC14 in water at the 10 and 25 mg/kg doses.
Long-term Exposure
0 The effects of longer-term exposure to CC14 are similar to the effects
of short-term exposure: the liver is the most sensitive tissue,
showing fatty infiltration, release of liver enzymes, inhibition of
cellular enzyme activities, inflammation and, ultimately, cellular
necrosis (U.S. EPA, 1985a).
0 Rats exposed by gavage to 0014 in corn oil at doses of 1 mg/kg
5 days/week for 12 weeks did not show measurable adverse effects,
while doses of 10 or 33 mg/kg resulted in enzyme release, centri-
lobular vacuolization and necrosis in liver (Bruckner et al., 1986b).
0 Condie et al. (1985) investigated the effects of a corn oil vehicle
as well as Tween-60 on the subchronic hepatotoxicity of carbon
tetrachloride (0014). Male and female CD-1 mice were given 0, 1.2,
12 and 120 mg/kg CC14 by gavage in either corn oil as a solution or
1 % Tween-60 as a suspension once daily for five consecutive days per
week for 90 days. Hepatotoxicity was greater in the corn oil vehicle
groups of mice than in the Tween-60 groups. Significant increases in
serum enzyme activities were detected in the 12 mg/kg CC14 corn oil
male and female groups but not in the corresponding Tween-60 groups.
When comparing the serum enzyme activities in the high dose groups,
there were dramatic increases in both the male and female corn oil
groups as compared to the corresponding Tween—60 groups. Liver and
liver/body weights were significantly greater in each high dose
group. Histopathological findings indicated that hepatocellular
changes occurring during the administration of CC14 at the 12 mg/kg
(hepatocellular cytomegaly, fat and necrosis) and 120 mg/kg (necrosis
and fat) dose levels were more frequently observed when CC14 was
given in corn oil than when it was administered in Tween-60. The
experimental findings indicate that the corn oil vehicle lowered the
no-observed-adverse-effect level (NOAEL) from CC14 exposure by an
-------
Carbon Tetrachloride March 31, 1987
-7-
order of magnitude (from 12 mgA<3 to 1-2 n»g/kg) compared to the
Tween-60 vehicle and also enhanced the hepatotoxicity of CC14 in the
high dose treatment groups.
0 Hayes et al. (1986) reported hepatotoxic effects (increased serum
enzymes, increased organ weight, pathological lesions) in male and
female CD-1 mice given CC14 in corn oil by gavage at doses of 12,
120, 540 or 1,200 mgA9 f°r 90 consecutive days.
0 Alumot et al. (1976) fed 18 male and 18 female rats (strain not
given) 0, 80 or 200 ppm CC14 in the diet until final sacrifice at two
years. The authors equated 200 ppm to 10-18 mg/kg body weight/day.
No adverse effects from exposure to CC14 were observed. However,
tissues were not examined microscopically, liver weights were not
taken, and survival was below 50% at 21 months. In an earlier 6-week
study, Alumot et al. (1976) found no effect with 22 mg/kg and
increased lipid and triglyceride in liver with 40 and 76 mg/kg. Only
body weight was additionally measured.
0 Prendergast et al. (1967) found hepatotoxicity in guinea pigs, rats,
monkeys, rabbits and dogs exposed to 515 mg CCl4/m3 air eight hours/day,
five days/week for six weeks. Liver effects were also found in these
species after continuous exposure to 61 mg/m3 for 90 days but not to
6.1 mg/m3. After inhalation exposure of Wistar rats to CC14 eight
hours/day, five days/week for ten months, Smyth et al. (1936) found
liver toxicity with levels above 315 mg/m3 and kidney changes with at
least 315 mg/m3 (lowest level tested). Adams et al. (1952) noted
liver damage in Wistar rats, guinea pigs, and rabbits at some inhalation
exposures ranging from 32.5 to 2,600 mg/m3, seven hours/day, five
days/week for 258 days and no observable effect in a Rhesus monkey
similarly exposed to 25 mg/m3 for 212 days, but the study cannot be
adequately assessed from the limited details reported.
Reproductive Effects
0 No reproductive evvects were noted in rats fed diets containing CC14
at 80 and 200 ppm for up to two years (Alumot et al., 1976)
Developmental Effects
0 No evidence was located to demonstrate that CC14 is teratogenic (U.S.
EPA, 1985a). Newborn rats appear to be less sensitive to liver damage
by CC14 than 7-day-old rats (Dawkins, 1963). An intraperitoneal dose
of 2,400 mg/kg has resulted in adverse effects on testicular function
in rats (Chatterjee, 1966).
Mutagenicity
0 No evidence of mutagenic activity for CC14 has been found in bacterial
test systems or in cultured liver cells (U.S. EPA, 1985a), except that
Sina et al. (1983) found CC14 weakly positive at cytotoxic levels in
an alkaline elution/rat hepatocyte assay to measure DNA single-strand
breaks. Increased gene crossover and mitotic recombination were
-------
Carbon Tetrachloride March 31, 1987
-8-
observed in yeast cells exposed to CC14 at 3,300 to 5,400 mg/L buffer
(Callen at al., 1980). Amacher and Zelljadt (1983) concluded CC14 as
positive for cell transformation in Syrian hamster embryo cells.
0 In an in vivo-in vitro hepatocyte DNA repair assay by Mirsalis,
et al. (1985), CC14 failed to induce unscheduled DNA synthesis in
male and female BgC3F'| mice but did significantly elevate hepatic
cell proliferation. The latter effect was also induced by CC14 in
male Fischer 344 rats but at higher doses.
Carcinogenicity
0 Carbon tetrachloride is carcinogenic in animals, producing mainly
hepatic neoplasms. Doses of about 30 mg/kg/day or higher for six
months or longer have been found to produce an increased frequency of
hepatocellular tumors in mice, rats and hamsters (U.S. EPA, 1985a).
0 In an exploratory study of a large number of solvents and cancers in
rubber industry workers, Wilcosky et al. (1984) associated exposure
to carbon tetrachloride with lymphosarcoma and lymphatic leukemia,
but they stressed cautious interpretation because of the modest number
of cases and biases.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Health Advisories (HAs) are generally determined for One-day, Ten-day,
Longer-term (approximately 7 years) and Lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = (NOAEL or LOAEL) x (BW) = mg/Ij ( Ug/Il)
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
One-day Health Advisory
The acute animal study by Bruckner et al. (1986b) has been selected to
serve as the basis for the One-day Health Advisory in the 10-kg child because
' this study clearly defined a one-day NOAEL (40 mgAg) and LOAEL (80 mg/kg)
-------
Carbon Tetrachloride March 31, 1987
-9-
for CC14 based on changes in BUN, GPT, SDH and OCT and histopathological
changes in the liver and kidneys of rats sacrificed 24 hours after dosing.
The abstract report of the study by Kim et al. (1986) does not provide
sufficient details for assessment as a basis for the One-day HA.
The One-day HA for a 10-kg child is calculated as follows:
One-day HA = (40 mg/kg/day) (10 kg) = 4>0 /L (4 000 ug/L)
(100) (1 L/day)
where:
40 mg/kg day = NOAEL based on absence of liver toxicity following
one-day exposure in rats.
1 0 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with ODW/NAS
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed water consumption of a child.
Ten-day Health Advisory
The short-term study by Bruckner et al. (1986b) has been selected to
serve as the basis for the Ten-day HA for the 10-kg child. This study identi-
fied a LOAEL of 20 mgAg/day in rats given 9 doses over 11 days, based on
significant increases in serum enzyme levels and hepatic midzonal vacuolization
by 11 days. Higher doses of CC14 caused even more extensive liver damage.
The 14-day study by Hayes et al. (1986) is not selected because all doses
used were effect levels above those in the Bruckner et al. (1986b) study.
The Ten-day HA for a 10-kg child is calculated as follows:
Ten-day HA = (20 mg/kg/day) (10 kg) (9) = 0.16 mg/L (160 ug/L)
(1,000) (1 L/day) (11)
where:
20 ing/kg/day = LOAEL based on liver toxicity in rats.
9/11 = factor accounting for 9 doses given over 11 days.
10 kg = assumed body weight of a child.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a LOAEL from an animal study.
1 L/day = assumed water consumption of a child.
-------
Carbon Tetrachloride March 31, 1987
-10-
Longer-term Health Advisory
The 12-week study by Bruckner et al. (1986b) has been selected to serve
as the basis for calculation of the Longer-term HA. Bruckner and co-workers
dosed rats with CC14 ^n corn oil by gavage five times weekly for 12 weeks
with doses of 1 , 10 or 33 rngAg* This study identified a NOAEL of 1 mg/kg/day
and a LOAEL of 10 mg/kg day for hepatotoxicity. Condie et al. (1985) obtained
similar results with a NOAEL of 1.2 mg/kg/day and a LOAEL of 12 mg/kg/day in
CD-mice given CC14 in corn oil by gavage five times weekly for 90 days. In
the same study, Condie et al. (1985) found a NOAEL of 12 mgAg/day with CC14
suspended in Tween-60, but these data are not selected for the Longer-Term HA
calculation because of use of a rather insoluble form of CC14 (suspension) as
the method of dosing. The 90-day study by Hayes et al. (1986) is not selected
because a NOAEL was not found, although the LOAEL of 12 mg/kg/day approximates
the 10 mgAg/day LOAEL in the Bruckner et al. (1985) study.
The Longer-term HA for a 10-kg child is calculated as follows:
Longer-term HA = (1 mg/kg/day) (10 kg) (5) = 0.071 mg/L (71 ug/L)
(100) (1 L/day) (7)
where:
1 mg/kg/day = NOAEL based on absence of liver toxicity in rats.
1 0 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
5/7 = factor to account for dosing five days per week.
1 L/day = assumed daily water consumption of a child.
The Longer-term HA for a 70-kg adult is calculated as follows:
Longer-term HA = (1 mg/kg/day) (70 kg) (5) = 0.25 mg/L (250 ug/L)
(100) (2 L/day) (7)
where:
1 mgAg/day = NOAEL based on absence of liver toxicity in rats.
70 kg = assumed body weight of an adult.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
5/7 = factor to account for dosing five days per week.
2 L/day = assumed daily water consumption of an adult.
-------
Carbon Tetrachloride March 31, 1987
-11-
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The 12-week study by Bruckner et al. (1986b) described under Longer-term
Health Advisory is the most appropriate from which to derive the DWEL in that
the available animal toxicity studies with chronic exposure to CC14 are
concluded to be insufficient for use in the DWEL calculation. From these
results, a NOAEL of 1 mg/kg was identified.
The two-year study in rats by Alumot et al. (1976) was not chosen
because the assessment of CCl^ toxicity was deficient with respect to tissue
examination. The inhalation studies by Prendergast et al. (1967), Smyth
et al. (1936), and Adams et al. (1952) were not used since inhalation data
are less desirable for HA development.
Using the NOAEL of 1 mgAg/ the DWEL is derived as follows:
Step 1: Determination of the Reference Dose (RfD)
RfD = (1 mgAg/day) (5) = 0.0007 mgAg/day
(1,000) (7)
where:
= NOAEL based on absence of liver toxicity in rats orally
given CC14 for 90 days.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study
of less-than-lifetime duration.
5/7 = factor to account for dosing 5 days per week.
-------
Carbon Tetrachloride March 31, 1987
-12-
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.0007 ug/kg/day) (70 kg) = 0.025 mg/L (25 ug/L)
(2 L/day)
where:
0.0007 ug/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
Carbon tetrachloride may be classified in Group B: Probable human
carcinogen. The estimated excess cancer risk associated with lifetime exposure
to drinking water containing carbon tetrachloride at 25 ug/L is approximately
8 x 10~5. This estimate represents the upper 95% confidence limit from extrap-
olations prepared by EPA's Carcinogen Assessment Group using the linearized,
multistage model. The actual risk is unlikely to exceed this value, but
there is considerable uncertainty as to the accuracy of risks calculated by
this methodology.
Evaluation of Carcinogenic Potential
0 The IARC (1979) classified carbon tetrachloride as a 2B carcinogen with
sufficient animal evidence and inadequate human evidence.
0 Applying the criteria described in EPA's guidelines for assessment
of carcinogenic risk (U.S. EPA, 1986a), carbon tetrachloride maybe
classified in Group B2: Probable human carcinogen. This category is
for agents for which there is inadequate evidence from human studies
and sufficient evidence from animal studies.
0 U.S. EPA calculated a unit risk estimate (the 95% upper limit by the
linearized multistage model) of 0.37 x 10~^ for a human continuously
exposed to 1 ug CC14 per liter of water (U.S. EPA, 1984). The
corresponding 10"^, 10~^ and 10~4 risks are associated with 0.3, 2.7
and 27 ug/L, respectively.
0 It should be noted that this approach, which involved using the
geometric mean of risk estimates based on four studies, for calculating
unit risk estimates for CC14 is from U.S. EPA (1984) which was reviewed
by the U.S. EPA's Science Advisory Board.
0 There was an attempt to compare risk estimates derived with the
multistage model with other models in U.S. EPA, 1984. Of the studies
used (Delia Porta et al., 1961; Edwards et al., 1942; NCI rat and
mouse, 1976), risk estimates could not be calculated with the Weibull
and log probit models, and a time-to-tumor model was successful only
with the NCI (1976) data which gave 95% upper confidence limits similar
to those obtained with the multistage model. Unit (ingestion of 1 ug
CC14/L water/lifetime) risk estimates (95% upper confidence limits)
with individual studies and the multistage model were 3.4 x 10~^
-------
Carbon Tetrachloride March 31, 1987
-1 3-
(Della Porta et al., 1961), 9.4 x 10~6 (Edwards et al., 1942),
1.8 x 10~6 (NCI mouse, 1976) and 3.1 x 10~7 (NCI rat, 1976). Unit
risk estimates (maximum likelihood estimates) with individual studies
and the multistage model were 2.1 x 10~5 (Delia Porta et al., 1961),
7.1 x 10~6 (Edwards et al., 1942), 1.4 x 10~& (NCI mouse, 1976) and
1.9 x 10~7 (NCI rat, 1976). While recognized as statistically
alternative approaches, the range of risks described by using any of
these modeling approaches has little biological significance unless
data can be used to support the selection of one model over another.
In the interest of consistency of approach and in providing an upper
bound on the potential cancer risk, the EPA has recommended use of
the linearized multistage approach.
VI. OTHER CRITERIA, GUIDANCE AND STANDARDS
0 Data from the animal studies have been used by NAS (1977) and U.S. EPA
(1980b, 1984) to calculate the upper 95% bound on the number of
additional cancer cases that may occur when CC14 is consumed in
drinking water over a 70-year lifetime. By these methods, a 10-6
lifetime excess cancer risk was associated with CC14 in drinking
water at levels of 4.5 ug/L by the NAS (1977), 0.4 ug/L by the U.S.
EPA (1980a) and 0.3 ug/L by the U.S. EPA (1984).
0 The criteria for the U.S. EPA, OHEA and NAS risk calculations differ
in two respects: (1) NAS used the multistage model, while U.S. EPA
used an "improved" multistage model; and (2) NAS used the data set
from the National Cancer Institute (NCI) study in male rats while
U.S. EPA initially used the data set from the NCI study in male mice
(U.S. EPA, 1980b) and subsequently used a geometric mean of four
studies (NCI, 1976 - mice; NCI, 1976 - rats; Edwards et al., 1942 -
mice; and Delia Porta et al., 1961 - hamsters) (U.S. EPA, 1984).
0 Ambient water quality criteria for CC14 calculated by the EPA (U.S.
EPA 1980b) were based on increased lifetime cancer risk estimates of
10-5 (4.0 ug/L), 10-6 (0.40 ug/L), and 10~7 (0.04 ug/L). It is note-
worthy that these estimates were derived by assuming a lifetime con-
sumption of both drinking water (2 L/day) and aquatic species (6.5 g
fish and shellfish/day) taken from waters containing the corresponding
CC14 levels. Specifically, daily CC14 exposure assumptions were as
follows: 94% from ingesting drinking water and 6% from consuming
seafood "fish factor." The corresponding "drinking water only"
concentrations were 4.41, 0.44, and 0.04 ug/L, respectively.
0 Using the carcinogenicity data set and a linear multistage model,
WHO (1984) derived a recommended tentative limit for CC14 of 3 ug/L
as a level which should result in less than one additional cancer
per 100,000 population (10~5) for a lifetime of exposure assuming
daily consumption of two liters of drinking water.
0 The U.S. EPA (1981) and NAS (1980) previously calculated SNARLS
(Suggested No-Adverse-Response Levels) for CC14 in drinking water.
These guidelines are summarized in Table 1.
-------
Carbon Tetrachloride March 31, 1987
-14-
TABLE 1
Summary of Existing Guidelines for CC14
USEPAa
One-day
Seven-dayc
Ten-dayc
Long-term
0.2 mg/L
-
0.02 mg/L
Noned
14 mg/L
2 mg/L
-
Nonee
au.S. EPA (1981) used a LOAEL of 20 mg/kg (Korsrud et al., 1972) as the
basis for their calculations.
t>NAS (1980) used a LOAEL of 400 mgAg (Murphy and Malley, 1969) as the
basis for their calculations.
cln the absence of subacute oral data, the NAS (1980) and U.S. EPA (1981)
calculated 7- and 10-day SNARLS by dividing their one-day values by
7 and 10, respectively.
dThe U.S. EPA (1981) did not calculate a long-term SNARL due to a lack
of acceptable chronic oral exposure data at that time.
eThe NAS (1980) did not determine a long-term SNARL because of NAS policy
at that time not to calculate such values for animal carcinogens.
0 The final RMCL by the U.S. EPA Office of Drinking Water is 0, the
proposed MCL is 5 ug/L, and the practical quantitation level is 5 ug/L
(U.S. EPA, I985e).
0 The U.S. EPA Office of Pesticide Programs has published a notice of
intent to cancel registrations of grain fumigation products containing
CC14 (U.S. EPA, 1986b).
0 The OSHA standard in 10 ppm (TWA), and the ACGIH (1983) has recommended
a TLV of 5 ppm and an STEL of 20 ppm.
0 The U.S. EPA (1985d) has published a notice of intent to list CC14
under Section 112 of the Clean Air Act.
VII. ANALYTICAL METHODS
" Analysis of CC14 is by a purge-and-trap gas chromatographic procedure
used for the determination of volatile organohalides in drinking water
(U.S. EPA, I985b). This method calls for the bubbling of an inert
gas through the sample and trapping CC14 on an adsorbent material.
The adsorbent material is heated to drive off the CC14 onto a gas
chromatographic column. This method is applicable to the measurement
of CC14 over a concentration range of 0.03 to 1500 ug/L. Confirmatory
analysis for carbon tetrachloride is by mass spectrometry (U.S. EPA,
-------
Carbon Tetrachloride March 31, 1987
-15-
1985c). The detection limit for confirmation by mass spectrometry is
0.3 ug/L.
VIII. TREATMENT TECHNOLOGIES
0 Treatment techniques which will remove carbon tetrachloride from
drinking water include granular activated carbon adsorption, boiling,
and aeration (Combs, 1980).
0 Pilot plant studies by EPA's Drinking Water Research Division have
shown consistently that conventional treatment processes (coagulation,
sedimentation, filtration), even when augmented by the addition of pow-
dered activated carbon, provide little removal of carbon tetrachloride.
0 The use of powdered activated carbon was only partially effective at
doses as high as 30 ug/L (Love et al., 1983; Symons et al., 1979;
Lykins et al., 1980).
0 Carbon tetrachloride at a raw water concentration of 12 ug/L treated
using Filtrasorb® 400 granular activated carbon exhibited breakthrough
after three weeks. The empty bed contact time reported was 5 minutes.
When the empty bed contact time was increased to 10 minutes, break-
through occurred at 14 to 16 weeks (Symons, 1978).
0 A full-scale installation investigation conducted by Calgon using twin
granular activated carbon beds in series (EBCT of 130 minutes) reported
that, along with other chemicals, carbon tetrachloride was removed to
below detection from an influent concentration of 73 ug/L (O'Brien
et al., 1981).
0 A study demonstrated that the synthetic resin (Ambersorb XE-340)
removed carbon tetrachloride from treated drinking water with an
effectiveness similar to Filtrasorb® 400 (Symons et al., 1979). It
should be noted that these resins are not commercially available.
0 Boiling also is effective in eliminating carbon tetrachloride from a
solution. Studies have shown that five minutes of vigorous boiling
will remove upwards of 99% of the carbon tetrachloride originally
present (Combs, 1980; Love and Eilers, 1981).
0 Finally, aeration may be used to remove carbon tetrachloride from
water. Laboratory studies conducted by Love et al. (1983) showed
that a diffused air aerator could remove 91% of the carbon tetra-
chloride in the water using a 4:1 air to water ratio.
0 Air stripping is an effective, simple, and relatively inexpensive
process for removing carbon tetrachloride and volatile organics from
water. However, use of this process then transfers the contaminant
directly to the air.stream. When considering use of air stripping as
a treatment process, it is suggested that careful consideration be
given to the overall environmental occurrence, fate, route of exposure,
and various hazards associated with the chemical.
-------
Carbon Tetrachloride March 31, 1987
-16-
IX. REFERENCES
ACGIH. 1983. American Conference of Governmental Industrial Hygienists,
Inc. Documentation of the threshold limit values. 4th ed. Cincinnati.
Adams, E.M., H.C. Spencer, V.K. Rowe, D.D. McCollister and D.D. Irish. 1952.
Vapor toxicity of carbon tetrachloride determined by experiments on
laboratory animals. Arch. Indust. Hyg. Occup. Med. 6:50-66.
Alumot E., E. Nachtomi, E. Mandel and P. Holstein. 1976. Tolerance and
acceptable daily intake of chlorinated fumigants in the rat diet.
Food Cosmet. Toxicol. 14:105-110.
Amacher, D.E., and I. Zelljadt. 1983. The morphological transformation of
Syrian hamster embryo cells by chemicals reportedly nonmutagenic to
Salmonella typhimurium. Carcinogenesis. 4(3):291-296.
Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety:
Odor thresholds compared with threshold limit values and volatilities
for 214 industrial chemicals in air and water dilution. J. Appl. Toxicol.
3:272-290.
Bini, A., G. Vecchi, G. Vivioli, V. Vannini and C. Cessi. 1975. Detection
of early metabolites in rat liver after administration of CC14 and CBrCl3.
Pharmacol. Res. Commun. 7:143-149.
Bruckner, J.V., H.J. Kim, C.E. Dallas, R. Ramanathan, S. Muralidhara and J.M.
Gallo. 1986a. Effect of dosing vehicles on the pharmacokinetics of
orally administered carbon tetrachloride (CC14). Society of Toxicology
1987 Annual Meeting. (In press) (Abstract)
Bruckner, J.V., W.F. MacKenzie, S. Muralidhara, R. Luthra, G.M. Kyle and
D. Acosta. 1986b. Oral toxicity of carbon tetrachloride: acute, sub-
acute and subchronic studies in rats. Fund. Appl. Toxicol. 6:16-34.
Callen, D.F., C.R. Wolfe and R.M. Philpot. 1980. Cytochrome P-450 mediated
genetic activity and cytotoxicity of seven halogenated aliphatic hydro-
carbons in Saccharomyces cerevisiae. Mutation Res. 77:55-63.
Chatterjee, A. 1966. Testicular degeneration in rats by carbon tetrachloride
intoxication. Experientia. 22:394-396.
Combs, W.S. 1980. Removal of chlorinated solvents from water by boiling.
State of Rhode Island and Providence Plantations Dept. of Health, Provi-
dence, RI. (MIMEO)
Condie, L.W., R.D. Laurie, M. Robinson and J.F. Bercy. 1985. Effect of corn
oil gavage on hepatotoxicity of carbon tetrachloride in CD-1 mice.
Fund. Appl. Toxicol. In press.
Dawkins, M.J.R. 1963. Carbon tetrachloride poisoning in the liver of the
newborn rat. J. Pathol. Bacteriol. 85:189-196.
-------
Carbon Tetrachloride March 31, 1987
-17-
Della Porta, G., B. Terracini and P. Shubik. 1961. Induction with carbon
tetrachloride of liver cell carcinomas in hamsters. J. Natl. Cancer
Inst. 26:855-863.
Dobbs, R.A., and J.M. Cohen. 1980. Carbon adsorption isotherms for toxic
organics. EPA 600/880-023, Office of Research and Development, Cincinnati,
OH.
Edwards, J.E., W.E. Heston and A,J. Dalton. 1942. Induction of the carbon
tetrachloride hepatoma in strain L. mice. J. Natl. Cancer Inst.
3:297-301.
Fowler, J.S.L. 1969. Carbon tetrachloride metabolism in the rabbit. Brit.
J. Pharmacol. 37:733-737.
Hayes, J.R., L.W. Condie, Jr., and J.F. Borzelleca. 1986. Acute, 14-day
repeated dosing, and 90-day subchronic toxicity studies of carbon tetra-
chloride in CD-1 mice. Fund. Appl. Toxicol. 7:454-463.
IARC. 1979. International Agency for Research on Cancer. IARC Monographs
on the Evaluation of Carcinogenic Risk of Chemicals to Man. 20:371-399.
Kim, H.J., S. Odend'hal, R. Ramanathan, C.E. Dallas, S. Muralidhara and J.V.
Bruckner. 1986. Effect of oral dosing vehicles on acute hepatotoxicity
of carbon tetrachloride (CC14) in rats. Society of Toxicology 1987
Annual Meeting. (In press) (Abstract)
Korsrud, G.O., H.C. Grice and J.M. McLaughlan. 1972. Sensitivity of several
serum enzymes in detecting carbon tetrachloride-induced liver damage in
rats. Toxicol. Appl. Pharmacol. 22:474-483.
Love, O.T., Jr., and R.G. Eilers. 198T. Treatment for the control of tri-
chloroethylene and related industrial solvents in drinking water. U.S.
EPA, Office of Research and Development, Cincinnati, OH.
Love, O.T., Jr., R.J. Miltner, R.G. Eilers and C.D. Fronk-Leist. 1983.
Treatment of volatile organic compounds in drinking water. U.S. EPA,
Municipal Environmental Research Laboratory. EPA-600/8-83-019.
Lykins, B.W., and J. DeMarco. 1980. An overview of the use of powdered
activated carbon for removal of trace organics in drinking water.
U.S. EPA, Office of Research and Development, Cincinnati, OH. (Draft)
Marchand, C., S. McLean and G.L. Plaa. 1970. The effect of SKF 525A on the
distribution of carbon tetrachloride in rats. J. Pharmacol. Exp. Ther.
174:232-238.
McCollister, D.D., W.H. Beamer, G.J. Atchison and H.C. Spencer. 1951.
The absorption, distribution and elimination of radioactive carbon
tetrachloride by monkeys upon exposure to low vapor concentrations.
J. Pharmacol. Exp. Ther. 102:112-124.
-------
Carbon Tetrachloride March 31, 1987
-18-
Mirsalis, J.C., C.K. Tysn, E.N. Loh, O.K. Spek and J.W. Spalding. 1985.
Induction of hepatic cell proliferation and unscheduled DNA synthesis
in mouse hepatocytes following in vivo treatment. Carcinogenesis.
6:1521-1524.
Murphy, S.D., and S. Malley. 1969. Effect of carbon tetrachloride on induc-
tion of liver enzymes by acute stress or corticosterone. Toxicol.
Appl. Pharmacol. 15:117-130.
NAS. 1977. National Academy of Sciences. Drinking Water and Health.
Volume 1. Safe Drinking Water Committee. National Research Council.
National Academy Press. Washington, D.C. pp. 703-707.
NAS. 1980. National Academy of Sciences. Drinking water and health. Vol. 3.
Safe Drinking Water Committee. Board on Toxicology and Environmental
Health Hazards, Assembly of Life Sciences, National Research Council.
Washington, DC: National Academy of Sciences, pp. 96-98.
NCI. 1976. National Cancer Institute. Report on carcinogenesis bioassay of
chloroform. Bethesda, Maryland: Carcinogenesis Program, Division of
Cancer Cause and Prevention.
O'Brien, R.P., D.M. Jordan and W.R. Musser. 1981. Trace organic removal
from contaminated groundwaters with granular activated carbon. Presented
to: American Chemical Society, Atlanta, GA. March, 1981.
Paul, B.P., and D. Rubinstein. 1963. Metabolism of carbon tetrachloride and
chloroform by the rat. J. Pharmacol. Exptl. Therap. 141:141-148.
Prendergast, J.A., R.A. Jones, L.J. Jenkins and J. Seigel. 1967. Effects on
experimental animals of long-term inhalation of trichloroethylene, carbon
tetrachloride, 1,1,1-trichloroethane, dichlorodifluoromethane, and
1,1-dichloroethylene. Toxicol. Appl. Pharmacol. 10:270-289.
Rams, J.M., M. Pilgrim, S. Rauth, G. Hunt, T. Shannon and K. Slimak. 1979.
Draft report, Level I materials balance: carbon tetrachloride. Prepared
by JRB Associates for Office of Pesticides and Toxic Substances, U.S.
Environmental Protection Agency, Washington, D.C.: U.S. Environmental
Protection Agency. Contract No. 68:01-5793.
Reddrop, C.J., W.Riess and T.F. Slater. 1981. Interactions of carbon tetra-
chloride and promethazine in the rat. II. Elimination of carbon tetra-
chloride and chloroform in expired air as indications of their metabolism
in the intact animal. Biochem. Pharmacol. 30:1449-1455.
Seawright, A.A., and A.E.M. McLean. 1967. The effect of diet on carbon
tetrachloride metabolism. Biochem. J. 105:1055-1060.
Shah, H., S. Hartman and S. Weinhouse. 1979. Formation of carbonyl chloride
in carbon tetrachloride metabolism by rat liver in vitro. Cancer Res.
39:3942-3947.
-------
Carbon Tetrachloride March 31, 1987
-19-
Sina, J.F., C.L. Bean, G.R. Dysart, V.I. Taylor and M.O. Bradley. 1983.
Evaluation of the alkaline elution/rat hepatocyte assay as a predictor
of carcinogenic/rautagenic potential. Mutat. Res. 113:357-391.
Smyth, H.F., H.F. Smyth, Jr. and C.P. Carpenter. 1936. The chronic toxicity
of carbon tetrachloride: Animal exposure and field studies. J. Indust.
Hyg. Toxicol. 18:277-298.
Symons, J.M. 1978. Interim treatment guide for controlling organic contami-
nants in drinking water using granular activated carbon. U.S. EPA,
Office of Research and Development, Cincinnati, OH.
Symons, J.M., J.K. Carswell, J. DeMarco and O.T. Love, Jr. 1979. Removal of
organic contaminants from drinking water using techniques other than
granulated activated carbon alone - a progress report. In: Proceedings,
Practical Applications of Adsorption Techniques in Drinking Water, EPA/
NATO, Challenges of Modern Society, Reston, VA. (In press)
U.S. EPA. 1979. Water related environmental fate of 129 priority pollutants.
Office of Water Planning and Standards. EPA-440/4-79-029.
U.S. EPA. 1980a. U. S. Environmental Protection Agency. Carbon tetrachloride;
Pesticide Programs; rebuttable presumption against registration and
continued registration of certain pesticide products. Federal Register
45(201). Part IV:68534-68584. (Oct. 15).
U.S. EPA. 1980b. U. S. Environmental Protection Agency. Ambient water
quality criteria for carbon tetrachloride. Environmental Protection
Agency. Office of Water Regulations and Standards, Criteria and Standards
Division. Washington, D.C.
U.S. EPA. 1981. U.S. Environmental Protection Agency. Advisory opinion for
carbon tetrachloride. Office of Drinking Water, Washington, D.C.
U.S. EPA. 1983. U.S. Environmental Protection Agency. Carbon tetrachloride
occurrence in drinking water, food, and air. Office of Drinking Water.
U.S. EPA. 1984. U.S. Environmental Protection Agency. Health assessment
document for carbon tetrachloride. Cincinnati, OH: EPA Publ. No.
600/8-82-001F, Environmental Criteria and Assessment Office.
U.S. EPA. I985a. U.S. Environmental Protection Agency. Final draft criteria
document for'carbon tetrachloride. TR-540-131A. Office of Drinking Water.
U.S. EPA. 1985b. U.S. Environmental Protection Agency. Method 502.1.
Volatile halogenated organic compounds in water by purge and trap gas
chromatography. Environmental Monitoring and Support Laboratory, Cincinnati,
Ohio 45268, June 1985.
U.S. EPA. 1985c. U.S. Environmental Protection Agency. Method 524.1.
Volatile organic compounds in water by purge and trap gas chromatography/
mass spectrometry. Environmental Monitoring and Support Laboratory,
Cincinnati, Ohio 45268. June 1985.
-------
Carbon Tetrachloride
March 31, 1987
-20-
U.S. EPA. 1985d. U.S. Environmental Protection Agency. Assessment of carbon
tetrachloride as a potentially toxic air pollutant. Federal Register.
50(156):32621-32627.
U.S. EPA. 1985e. U.S. Environmental Protection Agency. National primary
drinking water regulations; Volatile synthetic organic chemicals; Final
rule and proposed rule. Federal Register 50(219):46880-46933. November 13.
U.S. EPA. 1986a. U.S. Environmental Protection Agency. Guidelines for
carcinogenic risk assessment. Federal Register 51 (1 85): 33992-34003.
September 24.
U.S. EPA. 1986b. U.S. Environmental Protection Agency. Pesticide products
containing carbon tetrachloride; Notice of intent to cancel registrations
and notice of transmittal and availability of draft notice to cancel.
Federal Register. 51(78):15372-15373. April 23.
U.S. ITC. 1983. U.S. International Trade Commission. Synthetic organic
chemicals, United States production. USITC Publication 1422. Washington,
D.C.
Wilkosky, C., H. Checkoway, E.G. Marchall and H.A. Tyroler. 1984. Cancer
mortality and solvent exposures in the rubber industry. Am. Indust.
Hyg. J. 45:809-811.
WHO. 1984. World Health Organization. Guidelines for drinking water quality.
Volume I, Recommendations. EPP/82.39.
------- |