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IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Re-evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide. Lyon (FR): International Agency for Research on Cancer; 1999. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 71.)
Data were last evaluated in IARC (1991).
1. Exposure Data
1.1. Chemical and physical data
1.1.1. Nomenclature
- Chem. Abstr. Services Reg. No.: 124-48-1
- Systematic name: Chlorodibromomethane
1.1.2. Structural and molecular formulae and relative molecular mass
1.1.3. Physical properties (for details, see IARC, 1991)
- (a) Boiling-point: 119–200°C at 99 kPa
- (b) Melting-point: < −20°C
- (c) Conversion factor: mg/m3 = 8.52 × ppm
1.2. Production, use and human exposure
Chlorodibromomethane has limited commercial use but is used industrially as a chemical intermediate. It is found in chlorinated drinking-water as a consequence of the reaction between chlorine, added during drinking-water treatment, and natural organic substances in the presence of bromide. The major route of human exposure is via drinking-water. Chlorodibromomethane is not normally present in untreated water. It is a major component of organohalide emissions from marine algae (IARC, 1991).
2. Studies of Cancer in Humans
No data were available to the Working Group.
3. Studies of Cancer in Experimental Animals
Chlorodibromomethane was tested for carcinogenicity in two-year studies by oral gavage in male and female B6C3F1 mice and Fischer 344 rats and in a lifetime study in CBA × C57BL/6 hybrid mice by administration in the drinking-water. In B6C3F1 mice, it produced a significant increase in the incidence of hepatocellular neoplasms in females and a marginal increase in males. Chlorodibromomethane did not increase the proportion of rats with tumours at any site relative to that in controls. There was no increase in tumour incidence in CBA × C57BL/6 hybrid mice given chlorodibromomethane in the drinking-water (IARC, 1991).
4. Other Data Relevant to an Evaluation of Carcinogenicity and its Mechanisms
4.1. Absorption, distribution, metabolism and excretion
4.1.1. Humans
No data were available to the Working Group.
4.1.2. Experimental systems
Chlorodibromomethane administered in corn oil orally by gavage to rats was eliminated in the expired air as unchanged chlorodibromomethane (approx. 48% of the dose) and CO2 (18%) within 8 h. Only 1% appeared in urine and about 1% was retained in tissues. In contrast, after oral dosing to mice, unchanged chlorodibromomethane in expired air accounted for approximately 12% of the dose and CO2 for approximately 72% within 8 h. About 2% of the dose was excreted in urine and 5% was retained in tissues (IARC, 1991).
4.2. Toxic effects
4.2.1. Humans
No data were available to the Working Group.
4.2.2. Experimental systems
Liver and kidney are target organs in rats and mice for chlorodibromomethane toxicity following oral gavage dosing. In a 13-week study, male and female Fischer 344/N rats and B6C3F1 mice were administered 15–250 mg/kg bw chlorodibromomethane by gavage on five days per week. The highest dose was lethal for 9/10 male and 9/10 female rats and resulted in fatty changes and centrilobular necrosis in the liver and proximal tubule-cell degeneration and regeneration in the kidney. Inflammation and squamous metaplasia were observed in the salivary glands. Mice were less sensitive. Fatty changes of the liver and tubule degeneration of the kidney were observed in 5/10 of the males but not in the females of the highest dose group. In the subsequent carcinogenicity study in which the doses used were 40 or 80 mg/kg bw for rats and 50 or 100 mg/kg bw for mice, fatty changes occurred in the liver of all dose groups, whereas cytomegaly and necrosis of the liver were observed only in the high-dose male mice. Nephrosis was observed in female rats and male mice and follicular-cell hyperplasia of the thyroid gland was observed in female mice in all dose groups (IARC, 1991).
4.3. Reproductive and developmental effects
4.3.1. Humans
No data were available to the Working Group.
4.3.2. Experimental systems
Chlorodibromomethane can cause maternal toxicity in the absence of fetal or embryo toxicity in orally dosed rats. No teratogenic effects have been observed (IARC, 1991).
4.4. Genetic and related effects
4.4.1. Humans
No data were available to the Working Group.
4.4.2. Experimental systems (see Table 1 for references)
Table 1
Genetic and related effects of chlorodibromomethane.
Chlorodibromomethane induced DNA damage and mutation in bacteria. In single studies, it induced gene conversion and aneuploidy, but not mutation, in fungi. It induced chromosomal aberrations, sister chromatid exchanges and mutations in mammalian cell lines and sister chromatid exchanges in cultured human lymphocytes. Sister chromatid exchanges, but not micronuclei, were increased in mice treated in vivo. Unscheduled DNA synthesis was not induced in hepatocytes from rats treated in vivo.
5. Evaluation
No epidemiological data relevant to the carcinogenicity of chlorodibromomethane were available.
There is limited evidence in experimental animals for the carcinogenicity of chlorodibromomethane.
Overall evaluation
Chlorodibromomethane is not classifiable as to its carcinogenicity to humans (Group 3).
6. References
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- Ishidate, M., Jr (1988) Data Book of Chromosomal Aberration Test In Vitro, rev. Ed., Tokyo, Life-Science Information Center, pp. 118–119.
- Khudoley V.V., Mizgireuv I., Pliss G.B. The study of mutagenic activity of carcinogens and other chemical agents with Salmonella typhimurium assays: testing of 126 compounds. Arch. Geschwulstforsch. 1987;57:453–462. [PubMed: 3435224]
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- Nestmann E.R., Lee E.G. Genetic activity in Saccharomyces cerevisiae of compounds found in effluents of pulp and paper mills. Mutat. Res. 1985;155:53–60. [PubMed: 3881665]
- Simmon, V.F., Kauhanen, K. & Tardiff, R.G. (1977) Mutagenic activity of chemicals identified in drinking water. In: Scott, D., Bridges, B.A. & Sobels, F.H., eds, Progress in Genetic Toxicology, Vol. 2, Development in Toxicology and Environmental Science, Amsterdam, Elsevier, pp. 249–258.
- Sofuni T., Honma M., Hayashi M., Shimada H., Tanaka N., Wakuri S., Awogi T., Yamamoto K.I., Nishi Y., Nakadate M. Detection of in vitro clastogens and spindle poisons by the mouse lymphoma assay using the microwell method: interim report of an international collaborative study. Mutagenesis. 1996;11:349–355. [PubMed: 8671759]
- Stocker K.J., Statham J., Howard W.R., Proudlock R.J. Assessment of the potential in vivo genotoxicity of three trihalomethanes: chlorodibromomethane, bromodichloromethane and bromoform. Mutagenesis. 1997;12:169–173. [PubMed: 9175643]
- United States National Toxicology Program (1985) Toxicology and Carcinogenesis Studies of Chlorodibromomethane (CAS No. 124-48-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies) (NTP Technical Report Series No. 282), Research Triangle Park, NC, United States Department of Health and Human Services. [PubMed: 12748697]
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