Hazardous Chemical Information System (HCIS)

Carbon tetrachloride

Exposure standard adopted in December 1995

Skin absorption notice: Absorption through the skin may be asignificant source of exposure.

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Carcinogen category notice: Category 2. Probable human carcinogenfor which there is sufficient evidence to provide a strong presumption thathuman exposure might result in the development of cancer. This evidence isgenerally based on appropriate long term animal studies, limitedepidemiological evidence or other relevant information. See Chapter 13:Guidance Note on theInterpretation of Exposure Standards for Atmospheric Contaminants in theOccupational Environment, published by Worksafe Australia.

Documentation notice: NationalOccupational Health and Safety Commission documentation available for thesevalues.

1. SUBSTANCE IDENTIFICATION

2. CHEMICAL AND PHYSICAL PROPERTIES

Carbon tetrachloride is a colourless, non-flammable liquid with a sweetishodour. Its physical and chemical properties include:

3. OCCURRENCE, PRODUCTION AND USE

Currently the major use of carbon tetrachloride is in the production ofchlorofluorocarbons. It also has some minor uses in grain fumigation and asa solvent. Carbon tetrachloride is not manufactured in Australia. Theannual import of carbon tetrachloride is below 9,000 tonnes. This importvolume will decrease significantly, as carbon tetrachloride is listed underthe Ozone Protection Act 1989 (Cwlth) and is to be phased out by theyear 2000.

4. MEASUREMENT TECHNIQUES AND ANALYTICAL METHODS

NIOSH Method 1003 (1) describes a partiallyvalidated method for sampling and analysing airborne levels of carbontetrachloride. The technique involves sampling onto coconut shell charcoal,desorption with carbon disulfide and analysis using gas chromatographycoupled to a flame ionisation detector. The estimated limit of detection is0.01 mg per sample (1).

5. TOXICOLOGY

5.1 Toxicokinetics

Carbon tetrachloride is lipophilic and because of this property CCl4 is absorbed from the skin and gastrointestinal tract as wellas the lungs, although the rate of absorption is different by the separateroutes. CCl4 is slowly eliminated from the body with over 50%being exhaled unchanged (2). Inhalationstudies in monkeys (3) and rats (4,5) show that the highest CCl4concentrations occur in fat, and in tissues with high fat content such asbone marrow, liver, brain and kidney.

CCl4 is metabolised in the liver by a specific type ofcytochrome P-450 to highly reactive metabolites (the trichloromethyl freeradical and phosgene). Metabolically activated CCl4 may bind toboth lipid and protein cellular structures in vivo and in vitro(6). CCl4and its metabolites arereported to be excreted in exhaled air, urine and faeces in animals but thedata are largely unavailable on the excretion of CCl4 in humans.

Studies in animals confirm that liquid CCl4 is absorbedthrough the skin (7), though the absorption ofvapours through the skin is very low.

5.2 Health Effects in Humans

The classical effects of CCl4 poisoning are narcosis, acutehepatic necrosis and acute nephritis (2,8).There are marked individual differences in susceptibility to CCl4.Several factors influencing this variation in toxicity are: concomitantingestion of ethanol; age; obesity and prior existence of renal and hepaticdisease (9). Low level exposure may producenausea, dizziness and vomiting. These symptoms have been reported at aconcentration as low as five ppm, but in general, the exposure data in humansare insufficient and the study designs are inadequate, with a number ofuncontrolled variables. Elkins (10) surveyeda number of dry cleaning plants and reported drowsiness, headache, dizziness,and lassitude in employees exposed to CCl4 for several days at anaverage of 35 ppm (range:10-80 ppm), and vomiting at an average concentrationof 20 ppm (range: five to 40 ppm). In a study in an electrical plant, Rabes(11) reported an increase in serum iron andglutamic dehydrogenase in a group of workers exposed to CCl4 atconcentrations of 6.3-9.5 ppm for three to 27 years. Moller (12) found a high percentage of restricted visualfields in 62 workers using CCl4 for cleaning. The measuredconcentrations of CCl4 in the air were in the range of seven to 10ppm.

Oral exposure produced marked central nervous system (CNS) depression butminimal liver and renal injury (2).

Some individuals may show swelling, itching and blisters following dermalcontact (13). CCl4produces slight irritation of the eyes on direct contact or vapour exposure,but this irritation is usually transient. Smyth et al. (14) reported restricted vision in workers in anumber of plants using CCl4. The exposure levels were estimatedas eight-hour TWA exposures of 7, 10, 10 and 24 ppm with estimated peakexposures of 66, 22, 173 and 232 ppm respectively. Chronic exposure toCCl4 may also cause optic nerve damage and impaired vision.

A physiologically-based pharmacokinetic model (15) for the rat described the concentrations ofCCl4 in adipose tissues where no significant day-to-dayaccumulation in the fat or blood was observed following repeated exposure to100 ppm for either eight or 11.5 hours/day. In contrast, because ofphysiological differences, humans exposed to five ppm for eight hours/daywill show day-to-day increases of CCl4 in the fat and thisaccumulation is more pronounced if the exposure time is increased to 11.5hours/day.

Ingestion of alcohol potentiates CCl4 toxicity. Norwood et al.(16) reported that exposure to 225 ppm ofCCl4 for 15 minutes was fatal in an alcoholic but did not produceany adverse effects in non-alcoholic workers.

5.2.1. Reproductive toxicity

There are no epidemiological studies available on the effects ofCCl4 on human pregnancy or the reproductive system.

5.2.2. Carcinogenicity

The cause of death for 330 deceased laundry and dry cleaning workersexposed to solvents including carbon tetrachloride was established by theproportionate mortality method (17). Theincreased risk of death from malignant neoplasms resulted primarily from anexcess of lung and cervical cancer and slight excess of leukaemia and livercancer. There are also some case reports of people developing hepatoma inassociation with exposure to CCl4 (18,19,20). Though these studies suggest thepossibility of CCl4 being a hepatocarcinogen in humans, theevidence is not conclusive.

5.3 Toxicity in Animals

5.3.1. Acute toxicity

The oral LD50 in rats is 2,800 mg/kg. Four to six hoursexposure to 300 ppm caused 50% mortality in rats (21). In animals exposed to a daily seven hourexposure, five days a week, the maximum vapour concentrations without adverseeffect (NOAEL) were 25 ppm for the monkey, 10 ppm for the rabbit and 5 ppmfor the rat and the guinea pig. The acute toxic effects observed in ratswere depression of the central nervous system at a concentration above 5 ppm,and injury of the liver.

5.3.1. Repeated dose toxicity

Chronic inhalation toxicity of CCl4 was studied by Smyth etal. (14). A group of 16 guinea pigs wereexposed to 25, 50, 100 and 200 ppm CCl4 vapours. Exposure lastedeight hours a day, five days/week for ten and a half months. Theconcentration of 100 ppm caused death attributable to combined hepatic andrenal damage. Hepatic and renal damage was seen at exposure levels of 25ppm.

Many studies are available on the inhalation, oral and dermal toxicity ofCCl4 in species including mice, rats, guinea pigs, hamsters andmonkeys. CCl4 produced hepatic and renal damage of a mild tosevere degree in these species, although there was a species and straindifference in the degree of damage and recovery. Pendergest et al. (22) reported a NOAEL of one ppm in ratschronically exposed to carbon tetrachloride. Paustenbach et al. (5) exposed groups of rats to similarconcentrations of CCl4 for eight hours or 11.5 hours/day for aperiod of one to 10 days, and concluded that even at relatively lowconcentrations, modest changes in the dose regimen, like those involvingunusual work schedules, can have a measurable effect on the distribution ofthe chemical and the degree of toxicity.

Excessive absorption through the skin may produce toxic effects comparableto the effects produced from inhalation or the oral route. In animals,Wahlberg and Boman (23) found that a dose of260 mg/cm2 applied to the skin of guinea pigs resulted in 25%mortality within five days.

5.3.3. Carcinogenicity

A number of experiments has shown that CCl4 is ahepatocarcinogen after long-term oral treatment in many animal species (24,25,26). It also enhances rat and mousehepatocarcinogenesis (27) when administeredconcomitantly with or after other carcinogens. Costa et al. (28) administered CCl4 to rats forseven months and liver tumours were observed as well as cirrhosis. In anexperiment done by Reuber and Glover (29) inmale rats of Japanese, Osborne-Mendel Wistar, Black and Sprague-Dawley strains, hepatocellularcarcinomas as well as hyperplastic nodules and cirrhosis were observed.

Edwards and Dalton (30) and Edwards et al.(31) reported the induction of hepatomas infive strains of mice. In rats CCl4 caused neoplastic nodules andhepatocellular carcinoma of the liver (26).

It is most likely that carbon tetrachloride has an epigenetic mechanism ofcarcinogenesis. In contrast to genotoxic carcinogens, epigenetic carcinogensmay not pose a risk for human development of cancer at low levels of exposureand it is possible to establish 'safe' threshold levels for these chemicalsonce it is established that their mechanism of carcinogenicity is other thangenotoxicity.

5.4 Genotoxicity

Though metabolically activated CCl4 has been found to bindcovalently to lipid and protein both in vivo and in vitro (6), it produced negative results in mutagenicitystudies (32,33,34).

6. CONCLUSION

Excessive absorption of CCl4 results in a clinical complexmanifesting in depression of the CNS followed by hepatic and renal damage.Low level exposure may produce nausea, dizziness and vomiting. Thesesymptoms have been reported at a concentration as low as five ppm.Hepatotoxicity has been shown in workers exposed to CCl4 at alevel as low as five to 10 ppm.

Chronic exposure to CCl4 may also cause optic nerve damage andimpaired vision. Alcohol intake potentiates the hepatotoxicity ofCCl4.

CCl4 is absorbed through the skin and may be absorbed in toxicconcentrations by this route. It may also produce slight eye irritation(exposure level unknown) which is usually transient.

There is sufficient evidence of carcinogenicity of CCl4 inexperimental animals. CCl4 has produced malignant liver tumoursin many species including rat, mouse and hamster through oral administration.

There is inadequate evidence for carcinogenicity of CCl4 inhumans.

7. OVERSEAS EXPOSURE STANDARDS

8. RECOMMENDATION FOR AN EXPOSURE STANDARD

A NOAEL in animals is in the range of one-5 ppm (21,22). In humans, although a LOAEL of aboutfive ppm (10,11) has been reported, there areno epidemiological studies describing a NOAEL. Based on epidemiologicalstudies, it can be concluded that a NOAEL in humans will be less than fiveppm, but the exact level is unknown. A safety factor of 10 is used torecommend a time weighted average exposure standard for carbon tetrachloridebased on a NOAEL of 1 ppm in animals in addition to the fact that adverseeffects have been shown in humans at a level as low as five ppm. TheExposure Standards Expert Working Group recommends a lowering of the exposurestandard to 0.1 ppm (TWA) to prevent subjective symptoms and hepatotoxicity.This recommended exposure standard should be able to take into account thepotentiation of CCl4 toxicity by alcohol and a possibility ofsimultaneous exposure by the dermal route.

The review of the relevant data indicates that CCl4 may be apotential carcinogen to humans, based on the sufficient evidence from animalstudies, and that the mechanism of carcinogenicity is probably epigenetic.It is recommended that it should be classified as a Carcinogen Category 2.Also carbon tetrachloride has a potential for skin absorption in toxicconcentrations and skin notation should be included.

9. ACKNOWLEDGEMENT

This documentation is substantially based upon a treatise prepared by DrKaruna Raja titled 'Review of Toxicity of Carbon Tetrachloride:Recommendation for an Occupational Exposure Standard'. This treatise wassubmitted in partial satisfaction of the requirements for the degree ofMaster of Occupational Health and Safety, University of Sydney.

REFERENCES

1. NIOSH, Hydrocarbons, "Halogenated-method 1003", NIOSH Manual of Analytical Methods, 4th ed., Cincinnati, Ohio, National Institute for Occupational Safety and Health, 1003-1 to 1003-7, 1994.

2. Stewart R D, Boettner E A, Southworth R R, Cerny J C, "Acute Carbon Tetrachloride Intoxication", Journal of American Medical Association, vol 183, 12, 994-997, 1963.

3. McCollister D D, Beamer W H, Atchison G J, Spencer H C, "The Absorption, Distribution and Elimination of Radioactive Carbon Tetrachloride by Monkeys Upon Exposure to Low Vapour Concentrations", Journal of Pharmacology and Experimental Therapeutic, 102, 112-124, 1951.

4. Paustenbach D J, Carlson G P, Christian J E, Born G S, "The Effect of an 11.5 hr/day Exposure Schedule on the Distribution and Toxicity of Inhaled Carbon Tetrachloride in the Rat", Fundamental and Applied Toxicology, 6, 472-483, 1986a.

5. Paustenbach D J, Carlson G P, Christian J E, Born G S, A Comparative: Study of the Pharmacokinetics of Carbon Tetrachloride in the Rat Following Repeated Inhalation Exposures of 8 and 11.5 hr/day, Fundamental and Applied Toxicology, 6, 484-497, 1986b.

6. Rocchi P, Prodi G, Grilli S, Ferreri A M, "In vivo and In vitro Binding of Carbon Tetrachloride with Nucleic Acids and Proteins in Rat and Mouse Liver", International Journal of Cancer, 11, 419-425, 1973.

7. Jakobsen I, Wahlberg J E, Holmberg B O and Johansson G, "Uptake via the Blood and Elimination of 10 Organic Solvents Following Epicutaneous Exposure of Anesthetized Guinea Pigs", Toxicology and Applied Pharmacology, 63, 181-187, 1982.

8. Cornish H H, Ling B P, Barth M L, "Phenobarbital and Organic Solvent Toxicity", American Industrial Hygiene Association Journal, 34, 487-492, 1973.

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10. Elkins H B, "Maximal Allowable Concentrations I. Carbon Tetrachloride", Journal of Industrial Hygiene and Toxicology, Vol 24, 8, 233-235, 1942.

11. Rabes U, "Results of Occupational Medical Examinations of Workers Exposed for Many Years to Carbon Tetrachloride", Wiss Z Univ Halle, 1972, 21,73-80 (as cited in NIOSH criteria document on carbon tetrachloride 1975).

12. Moller K O, "Some Cases of Carbon Tetrachloride Poisoning in Connection with Dry Shampooing and Dry Cleaning with a Survey of the Use and Action of the Substance", Journal of Industrial Hygiene 1933, 15, 418-32 (as cited in NIOSH criteria document on carbon tetrachloride 1975).

13. Taylor H F, "A Case of Hypersensitiveness to Carbon Tetrachloride", Journal of American Medical Association, 1925, 84, 280 (as cited in Toxicological Profile for Carbon Tetrachloride ASTDR 1989).

14. Smyth H F, Smyth H F Jr, Carpenter C P, "The Chronic Toxicity of Carbon Tetrachloride: Animal Exposures and Field Studies", Journal of Industrial Hygiene and Toxicology, 18, 277-298, 1936.

15. Paustenbach D J, Clewe H J M, Gargas M L, Andersen M E, "A Physiologically Based Pharmacokinetic Model for Inhaled Carbontetrachloride", Toxicology and Applied Pharmacology, 96, 191-211, 1988.

16. Norwood W D, Fuqua P A, Scudder B C, "Carbon Tetrachloride Poisoning: More Regulation, More Education Needed", Archives of Industrial Hygiene and Occupational Medicine, 1, 90-100, 1950.

17. Blair A, Decoufle P, Grauman D, "Causes of Death Among Laundry and Dry Cleaning Workers", American Journal of Public Health, vol 69, 5, 508-511, 1979.

18. Tracey J P, Sherlock P, "Hepatoma Following Carbon Tetrachloride Poisoning", New York State Journal of Medicine, 68, 2202-2204, 1968.

19. Simler M, Maurer M, Mandard J C, "Cancer of the Liver Following Cirrhosis due to Carbon Tetrachloride", Strasbourg Medicine, 1964, 15, 910-917 (as cited in NIOSH criteria document on carbon tetrachloride 1975).

20. Johnstone R T, "Occupational Medicine and Industrial Hygiene", St Louis, Mo, C V Mosby Company, 1948, p. l57 (as cited in NIOSH criteria document for carbon tetrachloride, 1975).

21. Adams E M, Spencer H C, Rowe V K, McCollister D D, Irish D D, "Vapour Toxicity of Carbon Tetrachloride Determined by Experiments on Laboratory Animals", Archives of Industrial Hygiene and Occupational Medicine, 6, 50-66, 1952.

22. Prendergast J A, Jones R A, Jenkins L J Jr, Siegel J, "Effects on Experimental Animals of Long Term Inhalation of Trichloroethylene, Carbon Tetrachloride, 1, 1, l-trichloroethane, Dichlorodifluoromethane, and 1, l-dichloroethylene", Toxicology and Applied Pharmacology, 10, 270-289, 1967.

23. Wahlberg J E, Boman A, "Comparative Percutaneous Toxicity of Ten Industrial Solvents in the Guinea Pig", Scandinavian Journal of Work, Environment and Health, 5, 345-351, 1979.

24. Della Porta G, Terracini B, Shubic P, "Induction with Carbon Tetrachloride of Liver-cell Carcinomas in Hamsters", Journal of the National Cancer Institute, vol 26, 4, 855-859, 1961.

25. Eschenbrenner A B and Miller E, "Studies on Hepatomas: Size and Spacing of Multiple Doses in the Induction of Carbon Tetrachloride Hepatomas", Journal of the National Cancer Institute, 4, 385-388, 1944.

26. Weisburger E K, "Carcinogenicity Studies on Halogenated Hydrocarbons", Environmental Health Perspectives, 21, 7-16, 1977.

27. Kanematsu T, "Promoting Effect of CC14 on Azo-dye Hepatocarcinogenesis in Rats", Fukoka Igaku Zasshi 1976, 67, 134-45 (as cited in Dragani et al., 1986).

28. Costa A, Weber G, St Omer F B, "L'adenocirrosi e la Cancrocirrosi Nell' Uomo", Arch de Vecchi Anat Path 1963, 39, 357-407 (as cited in Reuber and Glover, 1970).

29. Reuber M D, Glover E L, "Cirrhosis and Carcinoma of the Liver in Male Rats Given Subcutaneous Carbon Tetrachloride", Journal of the National Cancer Institute, Vol 44, 2, 419-423, 1970.

30. Edwards J E and Dalton A J, "Induction of Cirrhosis of the Liver and of Hepatomas in Mice with Carbon Tetrachloride", Journal of the National Cancer Institute, 3, 19-41, 1942-1943.

31. Edwards J E, Heston W E, and Dalton J E, "Induction of the Carbon Tetrachloride Hepatoma in Strain L Mice", Journal of the National Cancer Institute 1942, 3, 297-301 (as cited in Eschenbrenner and Miller, 1944).

32. Vehlike H, Werner T, Greim H, Kramer M, "Metabolic Activation of Haloalkanes and Tests In Vitro for Mutagenicity", Xenobiotica,7: 393-400, 1977.

33. .Simmon VF, Kauhanen K, Tardiff RG, "Mutagenic Activity of Chemicals Identified in Drinking Water". In Progress in Genetic Toxicology, Elseveir/North-Holland Biomedical Press, New York, 249-258, 1977.

34. Barber ED, Danish WH, Muellar KR, "A Procedure for the Quantitative Measurement of the Mutagenicity of Volatile Liquids in the Ames Salmonella/Microsome Assay", Mutation Research, 90: 31-48, 1981.

Footnotes:

Documentation notice:

Entries carrying a notice for National Occupational Health and SafetyCommission documentation indicate that these substances have been reviewed indetail by the Exposure Standards Expert Working Group and that documentationsupporting the adopted national values is available in the NationalCommission's Documentation of the Exposure Standards [NOHSC:10003(1995)].