Jump to main content.


Carbon tetrachloride (CASRN 56-23-5)

IRIS
List of IRIS Substances




view QuickView

Main Contents

Go

0020

Carbon tetrachloride; CASRN 56-23-5

Health assessment information on a chemical substance is included in IRIS only after a comprehensive review of chronic toxicity data by U.S. EPA health scientists from several Program Offices and the Office of Research and Development. The summaries presented in Sections I and II represent a consensus reached in the review process. Background information and explanations of the methods used to derive the values given in IRIS are provided in the Background Documents.

STATUS OF DATA FOR Carbon tetrachloride

File First On-Line 01/31/1987

Category (section)
Status
Last Revised
Oral RfD Assessment (I.A.) on-line 06/01/1991
Inhalation RfC Assessment (I.B.) no data  
Carcinogenicity Assessment (II.) on-line 06/01/1991

_I.  Chronic Health Hazard Assessments for Noncarcinogenic Effects

_I.A. Reference Dose for Chronic Oral Exposure (RfD)

Substance Name — Carbon tetrachloride
CASRN — 56-23-5
Last Revised — 06/01/1991

The oral Reference Dose (RfD) is based on the assumption that thresholds exist for certain toxic effects such as cellular necrosis. It is expressed in units of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Please refer to the Background Document for an elaboration of these concepts. RfDs can also be derived for the noncarcinogenic health effects of substances that are also carcinogens. Therefore, it is essential to refer to other sources of information concerning the carcinogenicity of this substance. If the U.S. EPA has evaluated this substance for potential human carcinogenicity, a summary of that evaluation will be contained in Section II of this file.

__I.A.1. Oral RfD Summary

Critical Effect
Experimental Doses*
UF
MF
RfD

Liver lesions

Subchronic Rat
Gavage Study

Bruckner et al., 1986

NOAEL: 1 mg/kg/day
(converted to 0.71
mg/kg/day

LOAEL: 10 mg/kg/day
(converted to 7.1
mg/kg/day)
1000
  
1
  
7E-4
mg/kg/day
  

*Conversion Factors: 1 mg/kg/day (NOAEL) x 5/7 = 0.71 mg/kg/day (5 day/week dosing regimen)

__I.A.2. Principal and Supporting Studies (Oral RfD)

Bruckner, J.V., W.F. MacKenzie, S. Muralidhara, R. Luthra, G.M. Kyle and D. Acosta. 1986. Oral toxicity of carbon tetrachloride: Acute, subacute and subchronic studies in rats. Fund. Appl. Toxicol. 6(1): 16-34.

Male Sprague-Dawley rats were given 1, 10, or 33 mg carbon tetrachloride/kg/day by corn oil gavage, 5 days/week for 12 weeks. Liver lesions, as evidenced by mild centrilobular vacuolization and statistically significant increases in serum sorbitol dehydrogenase activity, were observed at the 10 and 33 mg/kg/day dosesm in a dose-related manner. Therefore, the LOAEL was established at 10 mg/kg/day (converted to 7.1 mg/kg/day) and the NOAEL was 1 mg/kg/day (converted to 0.71 mg/kg/day).

__I.A.3. Uncertainty and Modifying Factors (Oral RfD)

UF — UF allows for interspecies and intrahuman variability and extrapolation from subchronic to chronic duration of exposure.

MF — None

__I.A.4. Additional Studies/Comments (Oral RfD)

A 1983 draft of the Bruckner et al. (1986) study was used as the basis for the RfD by the RfD Work Group at a 05/20/1985 verification meeting. When this study was subsequently published (Bruckner et al., 1986), no change to the verified value was required.

Subchronic studies in mice gavaged with carbon tetrachloride in corn oil (Condie et al., 1986; Hayes et al., 1985) support the critical effect and the magnitude of the NOAEL and LOAEL found in the rat studies. Additional studies (Alumot et al., 1976; NCI, 1976) in rats lend moderate support to the choice of a NOAEL in the chosen rat study.

__I.A.5. Confidence in the Oral RfD

Study — High
Database — Medium
RfD — Medium

The principal study was well conducted and good dose-response was observed in the liver, which is the target organ for carbon tetrachloride toxicity; thus, high confidence was assigned. Four additional subchronic studies support the RfD, but reproductive and teratology endpoints are not well investigated; thus, the database rates a medium confidence. Medium confidence in the RfD follows.

__I.A.6. EPA Documentation and Review of the Oral RfD

Source Document — U.S. EPA, 1985

Public review of RfD following ODW proposal of RMCL in June 1984.

Science Advisory Board review of RfD on January 14, 1986.

Other EPA Documentation — None

Agency Work Group Review — 05/20/1985

Verification Date — 05/20/1985

__I.A.7. EPA Contacts (Oral RfD)

Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).

Top of page


_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)

Substance Name — Carbon tetrachloride
CASRN — 56-23-5

Not available at this time.

Top of page


_II.  Carcinogenicity Assessment for Lifetime Exposure

Substance Name — Carbon tetrachloride
CASRN — 56-23-5
Last Revised — 06/01/1991

Section II provides information on three aspects of the carcinogenic assessment for the substance in question; the weight-of-evidence judgment of the likelihood that the substance is a human carcinogen, and quantitative estimates of risk from oral exposure and from inhalation exposure. The quantitative risk estimates are presented in three ways. The slope factor is the result of application of a low-dose extrapolation procedure and is presented as the risk per (mg/kg)/day. The unit risk is the quantitative estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m air breathed. The third form in which risk is presented is a drinking water or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. The rationale and methods used to develop the carcinogenicity information in IRIS are described in The Risk Assessment Guidelines of 1986 (EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries developed since the publication of EPA's more recent Proposed Guidelines for Carcinogen Risk Assessment also utilize those Guidelines where indicated (Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to Section I of this IRIS file for information on long-term toxic effects other than carcinogenicity.

_II.A. Evidence for Human Carcinogenicity

__II.A.1. Weight-of-Evidence Characterization

Classification — B2; probable human carcinogen

Basis — Carcinogenicity in rats, mice, and hamsters

__II.A.2. Human Carcinogenicity Data

Inadequate. There have been three case reports of liver tumors developing after carbon tetrachloride exposure. Several studies of workers (Milham, 1976; Blair et al., 1979) who may have used carbon tetrachloride have suggested that these workers may have an excess risk of cancer.

__II.A.3. Animal Carcinogenicity Data

Sufficient. Carbon tetrachloride has produced hepatocellular carcinomas in rats, mice, and hamsters, the species evaluated to date.

Hepatocellular carcinomas developed in Osborne-Mendel, Japanese, and Wistar rats, but not Sprague-Dawley or Black rats, following s.c. injection of carbon tetrachloride. Hyperplastic nodules were noted in Buffalo rats treated s.c. (Reuber and Glover, 1967a,b, 1970). Sensitivity varied among strains, and trends in incidence appeared inversely related to severity of cirrhosis.

Fifty Osborne-Mendel rats/sex were administered carbon tetrachloride by corn oil gavage at 47 and 94 mg/kg/injection for males and 80 and 159 mg/kg for females 5 times/week for 78 weeks. At 110 weeks, only 7/50 high-dose males and 14/50 high-dose females survived; 14/50 low-dose males and 20/50 low-dose females survived. The incidence of hepatocellular carcinomas was increased in animals exposed to carbon tetrachloride as compared with pooled colony controls. The apparent decrease in the incidence of hepatocellular carcinomas in high-dose female rats compared with the low-dose females (1/14 vs. 4/20, respectively) was attributed by the authors to increased lethality before tumors could be expressed (NCI, 1976a,b, 1977).

In this same study, using the same dosing schedule, male and female B6C3F1 mice received 1250 or 2500 mg/kg carbon tetrachloride. The incidences of hepatocellular carcinomas in males were 5/77, 49/49, and 47/48 in the control, low- and high-dose groups, respectively, and 1/80, 40/40, and 43/45 in the control, low- and high-dose groups, respectively.

Carbon tetrachloride administered by gavage has also been shown to produce neoplastic changes in livers of five additional strains of mice (C3H, A, Y, C, and L) (Andervont, 1958; Edwards, 1941; Eschenbrenner and Miller 1943; Edwards and Dalton, 1942; Edwards et al., 1942). In the last study, 56 male and 19 female L mice, which have a low incidence of spontaneous hepatomas, were treated with 0.1 mL of 40% carbon tetrachloride 2 or 3 times/week over 4 months, for a total of 46 treatments. Animals were killed 3 to 3.5 months after the last treatment. The combined hepatoma incidence of treated male mice was 47% (7/15 vs. 2/71 in the untreated male controls); treated females showed and incidence of 38% (3/8 vs. 0/81 in the untreated female controls).

As part of a larger study of liver carcinogens, Della Porta et al. (1961) treated Syrian golden hamsters (10/sex/dose) with carbon tetrachloride by gavage, weekly for 30 weeks. For the first 7 weeks, 0.25 mL of 0.05% carbon tetrachloride in corn oil was administered; this dose was halved for the remainder of the exposure period. All animals were observed for an additional 25 weeks. All of the 10 hamsters that were killed or dying between weeks 43 and 55 had liver cell carcinomas, compared with 0 in controls.

__II.A.4. Supporting Data for Carcinogenicity

Carbon tetrachloride was not mutagenic to either S. typhimurium or E. coli (McCann et al., 1975; Simmon et al., 1977; Uehleke et al., 1976). At low concentrations, carbon tetrachloride did not produce chromatid or chromosomal aberrations in an epithelial cell line derived from rat liver (Dean and Hodson-Walker, 1979). In vivo unscheduled DNA synthesis assays have likewise been negative in male Fischer 344 rats (Mirsalis and Butterworth, 1980; Mirsalis et al., 1982). Carbon tetrachloride produced mitotic recombination and gene conversion in S. cerevisiae, but only at concentrations which reduced viability to 10% (Callen et al., 1980). Carbon tetrachloride may be metabolized to reactive intermediates capable of binding to cellular nucleophilic macromolecules. Negative responses in bacterial mutagenicity assays may have been due to inadequate metabolic activation in the test systems.

Top of page


_II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure

__II.B.1. Summary of Risk Estimates

Oral Slope Factor — 1.3E-1 per (mg/kg)/day

Drinking Water Unit Risk — 3.7E-6 per (ug/L)

Extrapolation Method — Linearized multistage procedure, extra risk

Drinking Water Concentrations at Specified Risk Levels:

Risk Level
Concentration
E-4 (1 in 10,000)
3E+1 ug/L
E-5 (1 in 100,000)
3E+0 ug/L
E-6 (1 in 1,000,000)
3E-1 ug/L

__II.B.2. Dose-Response Data (Carcinogenicity, Oral Exposure)

Tumor Type — Hepatocellular carcinomas/hepatomas
Test Animals — various, see table
Route — gavage
Reference — several, see table

Administered
Dose (mg/day)
Human Equivalent
Dose(mg/kg)/day
Tumor
Incidence
Unit Risk
per (ug/L)
Reference
Hamster/Syrian, male and female
  0 0 0/80 3.4E-5 Della
  0.95 1.02 10/19 Porta et
al., 1961
Mouse/L, male and female
  0 0 2/152 9.4E-6 Edwards
  15 2.3 34/73 et al.,1942
Mouse/B6C3F1, male and female
  0 0 6/157 1.8E-6 NCI,
  21 55.4 89/89 1976a,b,
  42 110.8 90/93 1977
Rat/Osborne-Mendel:
M, F 0 0 0/37 3.1E-7 NCI,
M 11 4.5 2/45 1976a,b,
F 18 7.4 4/46 1977
M 21 8.7 2/47
F 36 14.9 1/30

__II.B.3. Additional Comments (Carcinogenicity, Oral Exposure)

A geometric mean was calculated from the unit risks derived from the four data sets above. Della Porta et al. (1961) did not report controls in this study, but did give incidence rate for vehicle controls in an earlier study. Animal doses are TWA.

The unit risk should not be used if the water concentration exceeds 3E+3 ug/L, since above this concentration the unit risk may not be appropriate.

__II.B.4. Discussion of Confidence (Carcinogenicity, Oral Exposure)

The studies used were all deficient in some respect, precluding the choice of any one study as most appropriate. For all studies, data from males and females were combined because of the small sample sizes. In the first and second studies (Della Porta et al., 1961; Edwards et al., 1942) one dose was tested. Della Porta et al. (1961) did not report concurrent control incidence. In the NCI (1976a,b) studies, tumor incidence in the mice was virtually 100%, and goodness-of-fit criteria were not satisfied for the multistage model. Tumor incidence in rats in these studies was higher at low doses, presumably because early mortality at higher doses precluded tumor formation. The studies lacked pharmacokinetic data. However, a common biological mechanism, cell death and regeneration, leading to development of the same tumor type, was suggested by observations in all the studies. Since the risk estimates from these data (across 3-4 species and strains) only vary by 2 orders of magnitude, a geometric mean was derived as the risk estimate to accommodate the several study deficiencies.

Top of page


_II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure

__II.C.1. Summary of Risk Estimates

Inhalation Unit Risk — 1.5E-5 per (ug/cu.m)

Extrapolation Method — Linearized multistage procedure, extra risk

Air Concentrations at Specified Risk Levels:

Risk Level
Concentration
E-4 (1 in 10,000) 7E+0 ug/cu.m
E-5 (1 in 100,000) 7E-1 ug/cu.m
E-6 (1 in 1,000,000) 7E-2 ug/cu.m

__II.C.2. Dose-Response Data for Carcinogenicity, Inhalation Exposure

The inhalation risk estimates were calculated from the oral exposure data in Section II.B.2.

__II.C.3. Additional Comments (Carcinogenicity, Inhalation Exposure)

Inhalation risk was calculated assuming an air intake of 20 cu.m/day and 40% absorption rate by humans (U.S. EPA, 1984). This absorption coefficient was based on 30% inhalation in monkeys, and 30% and 57-65% inhalation in humans. A range of estimates of unit risk for inhalation exposures for the four studies cited above was determined, with 1.5E-5 per (ug/cu.m) calculated as the geometric mean for the unit risk.

The unit risk should not be used if the air concentration exceeds 7E+2 ug/cu.m, since above this concentration the unit risk may not be appropriate.

__II.C.4. Discussion of Confidence (Carcinogenicity, Inhalation Exposure)

See II.B.4.

Top of page


_II.D. EPA Documentation, Review, and Contacts (Carcinogenicity Assessment)

__II.D.1. EPA Documentation

Source Document — U.S. EPA, 1984

The 1984 Health Assessment Document for Carbon Tetrachloride received Agency and external review.

__II.D.2. EPA Review (Carcinogenicity Assessment)

Agency Work Group Review — 11/12/1986, 12/04/1986

Verification Date — 12/04/1986

__II.D.3. EPA Contacts (Carcinogenicity Assessment)

Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (FAX) or hotline.iris@epa.gov (internet address).

Top of page


_III.  [reserved]
_IV.  [reserved]
_V.  [reserved]


_VI.  Bibliography

Substance Name — Carbon tetrachloride
CASRN — 56-23-5
Last Revised — 10/01/1992

_VI.A. Oral RfD References

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.

Bruckner, J.V., S. Muralidhara, R. Luthra, G.M. Kyle, W.F. MacKenzie and D. Acosta. 1983. Oral toxicity of carbon tetrachloride: Acute, subacute and subchronic studies in rats. University of Georgia, Athens, GA. (Draft)

Bruckner, J.V., W.F. MacKenzie, S. Muralidhara, R. Luthra, G.M. Kyle and D. Acosta. 1986. Oral toxicity of carbon tetrachloride: Acute, subacute and subchronic studies in rats. Fund. Appl. Toxicol. 6(1): 16-34.

Condie, L.W., R.D. Laurie, T. Mills, M. Robinson and J.P. Bercz. 1986. Effect of gavage vehicle on hepatotoxicity of carbon tetrachloride in CD-1 mice: Corn oil versus Tween-60 aqueous emulsion. Fund. Appl. Toxicol. 7(2): 199-206.

NCI (National Cancer Institute). 1976. Report on the Carcinogenesis Bioassay of Chloroform. Carcinogenesis Program, Division of Cancer Cause and Prevention. March 1.

U.S. EPA. 1985. Drinking Water Criteria Document for Carbon Tetrachloride. Office of Drinking Water, Washington, DC. PB86-118155.

Top of page


_VI.B. Inhalation RfC References

None

Top of page


_VI.C. Carcinogenicity Assessment References

Andervont, H.B. 1958. Induction of hepatomas in strain C3H mice with 4-o- tolylazo-o-toluidine and carbon tetrachloride. J. Natl. Cancer Inst. 20(2): 431-438.

Blair, A., P. Decoufle and D. Grauman. 1979. Causes of death among laundry and dry cleaning workers. Am. J. Public Health. 69(5): 508-511.

Callen, D.F., C.R. Wolf and R.M. Philpot. 1980. Cytochrome P-450 mediated genetic activity and cytoxicity of seven halogenated aliphatic hydrocarbons in Saccharomyces cerevisiae. Mutat. Res. 77: 55-63.

Dean, B.J. and G. Hodson-Walker. 1979. An in vitro chromosome assay using cultured rat-liver cells. Mutat. Res. 64: 329-337.

Della Porta, G., B. Terracini and P. Shubik. 1961. Induction with carbon tetrachloride of liver cell carcinomas in hamsters. J. Natl. Cancer Inst. 26(4): 855-863.

Edwards, J.E. and H.A. Dalton. 1942. Induction of cirrhosis of the liver and of hepatomas in mice with carbon tetrachloride. J. Natl. Cancer Inst. 3: 19-41.

Edwards, J.E., W.E. Heston and H.A. Dalton. 1942. Induction of the carbon tetrachloride hepatoma in strain L. mice. J. Natl. Cancer Inst. 3: 297-301.

Eschenbrenner, A.B. and E. Miller. 1943. Studies on hepatomas size and spacing of multiple doses in the induction of carbon tetrachloride hepatomas. J. Natl. Cancer Inst. 4: 385-388.

McCann, J., E. Choi, E. Yamasaki and B.N. Ames. 1975. Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals. Proc. Natl. Acad. Sci. 72: 5135-5139.

Milham, S. 1976. Neoplasia in the wood and pulp industry. Ann. New York Acad. Sci. 271: 294-300.

Mirsalis, J.C. and B.E. Butterworth. 1980. Detection of unscheduled DNA synthesis in hepatocytes isolated from rats treated with genotoxic agents: An in vivo-in vitro assay for potential carcinogens and mutagens. Carcinogenesis. 1: 621-625.

Mirsalis, J.C., C.K. Tyson and B.E. Butterworth. 1982. Detection of genotoxic carcinogens in the in vivo-in vitro hepatocyte DNA repair assay. Environ. Mutagen. 4: 553-562.

NCI (National Cancer Institute). 1976a. Report on the Carcinogenesis Bioassay of Chloroform. National Cancer Institute, Bethesda, MD. March.

NCI (National Cancer Institute). 1976b. Carcinogenesis Bioassay of Trichloroethylene. National Cancer Institute Carcinogenesis Technical Report Series, No. 2. NCI-CG-TR-2. February.

NCI (National Cancer Institute). 1977. Bioassay of 1,1,1-Trichlorethane for Possible Carcinogenicity. National Cancer Institute Carcinogenesis Technical Report Series, No. 3. NCI-CG-TR-3. January.

Reuber, M.D. and E.L. Glover. 1967a. Hyperplastic and early neoplastic lesions of the liver in buffalo strain rats of various ages given subcutaneous carbon tetrachloride. J. Natl. Cancer Inst. 38(6): 891-899.

Reuber, M.D. and E.L. Glover. 1967b. Cholangiofibrosis in the liver of Buffalo strain rats injected with carbon tetrachloride. Br. J. Exp. Pathol. 48(3): 319-322.

Reuber, M.D. and E.L. Glover. 1970. Cirrhosis and carcinoma of the liver in male rats given subcutaneous carbon tetrachloride. J. Natl. Cancer Inst. 44(2): 419-427.

Simmon, V.F., K. Kauhanen and R.G. Tardiff. 1977. Mutagenic activity of chemicals identified in drinking water. In: Progress in Genetic Toxicology, D. Scott, B.A Bridges and F.H. Sobels, Ed. Elsevier/North-Holland Biomedical Press, New York. p. 249-258.

Uehleke, H., H. Greim, M. Kramer and T. Werner. 1976. Covalent binding of haloalkanes to liver constituents, but absence of mutagenicity on bacteria in a metabolizing test system mutation. Research. 38: 114.

U.S. EPA. 1984. Health Assessment Document for Carbon Tetrachloride. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. EPA 600/8/82-001F.

Top of page


_VII.  Revision History

Substance Name — Carbon tetrachloride
CASRN — 56-23-5

Date
Section
Description
03/01/1988 I.A.1. Dose conversion clarified
03/01/1988 I.A.2. Principal study corrected
03/01/1988 I.A.4. Text added
03/01/1988 I.A.4. Text revised
03/01/1988 I.A.6. Verification and meeting dates changed
03/01/1988 II.A.2. Text corrected
03/01/1988 II.B.4 Confidence statement revised
03/01/1988 II.C.4. Confidence statement revised
03/01/1988 III.A. Health Advisory added
06/30/1988 I.A.7. Primary contact changed
12/01/1989 I.A.4. Corrected citation year for Condie et al.
12/01/1989 VI. Bibliography on-line
06/01/1990 IV.A.1. Area code for EPA contact corrected
06/01/1990 IV.F.1. EPA contact changed
08/01/1990 III.A.2. Uncertainty factor text corrected
08/01/1990 III.A.10 Primary contact changed
01/01/1991 II. Text edited
01/01/1991 II.C.1. Inhalation slope factor removed (global change)
03/01/1991 I.A.7. Primary contact changed
06/01/1991 I.A. Text edited
06/01/1991 II. Text edited
06/01/1991 IV.B.1. EPA contact changed
06/01/1991 IV.B.2. EPA contact changed
08/01/1991 VI.C. Blair et al., 1979 and Milham, 1976 references added
01/01/1992 IV. Regulatory actions updated
04/01/1992 IV.A.1. CAA regulatory action withdrawn
10/01/1992 VI.C. Missing reference added
04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information.
01/12/2000 I., II. This chemical is being reassessed under the IRIS Program.

Top of page


_VIII.  Synonyms

Substance Name — Carbon tetrachloride
CASRN — 56-23-5
Last Revised — 01/31/1987

Top of page

Recent Additions | Newsroom | Search IRIS | IRIS Home | NCEA Home | ORD Home


Jump to main content.