For definition of Groups, see Preamble Evaluation.
Supplement 7: (1987) (p.59)
Chem. Abstr. Name: Bis(chloromethyl)ether
Chem. Abstr. Name: Chloromethyl methyl ether (technical-grade)
A. Evidence for carcinogenicity to humans (sufficient)
Numerous epidemiological studies [ref: 1-9] and case reports [ref: 10-13] from around the world have demonstrated that workers exposed to chloromethyl methyl ether and/or bis(chloromethyl)ether have an increased risk for lung cancer. Among heavily exposed workers, the relative risks are ten fold or more. Risks increase with duration and cumulative exposure. Histological evaluation indicates that exposure results primarily in lung cancer of the small-cell type [ref: 8]. Maximal relative risks appear to occur 15-20 years after first exposure [ref: 6], and latency is shortened among workers with heavier exposure [ref: 5,11].
B. Evidence for carcinogenicity to animals (sufficient)
Bis(chloromethyl)ether produced tumours at the site of its administration to mice after exposure by inhalation [ref: 1,14], skin application [ref: 1] or subcutaneous injection [ref: 1,15] and was an initiator of mouse skin tumours [ref: 15]; it also increased the incidence of lung tumours after its subcutaneous administration [ref: 1]. In rats, it produced tumours of the respiratory tract (lung tumours and nasal-cavity carcinoma) after exposure by inhalation [ref: 14,16-18].
Chloromethyl methyl ether produced local sarcomas in mice after its subcutaneous administration and was an initiator of mouse skin tumours [ref: 1]; in rats and hamsters, the technical grade produced a low incidence of tumours of the respiratory tract after exposure by inhalation [ref: 19].
C. Other relevant data
A slight increase in the incidence of chromosomal aberrations was observed in peripheral lymphocytes of workers exposed to bis(chloromethyl)ether or chloromethyl methyl ether in the preparation of ion-exchange resins [ref: 20].
Bis(chloromethyl)ether did not cause chromosomal aberrations in bone-marrow cells of rats treated in vivo. It induced unscheduled DNA synthesis in human fibroblasts in vitro and was mutagenic to bacteria [ref: 20].
Chloromethyl methyl ether enhanced virus-induced transformation of Syrian hamster embryo cells and was mutagenic to bacteria [ref: 20].
Bis(chloromethyl)ether and chloromethyl methyl ether (technical grade) are carcinogenic to humans (Group 1).
For definition of the italicized terms, see Preamble Evaluation.
Also see previous evaluation: Vol. 4 (1974)
1. IARC Monographs, 4, 231-238, 239-245, 1974
2. Albert, R.E., Pasternack, B.S., Shore, R.E., Lippmann, M., Nelson, N. & Ferris, B. (1975) Mortality patterns among workers exposed to chloromethyl ethers - a prelimary report. Environ. Health Perspect., 11, 209-214
3. DeFonso, L.R. & Kelton, S.C., Jr (1976) Lung cancer following exposure to chloromethyl methyl ether. An epidemiological study. Arch. environ. Health, 31, 125-130
4. Pasternack, B.S., Shore, R.E. & Albert, R.E. (1977) Occupational exposure to chloromethyl ethers. A retrospective cohort mortality study (1948-1972). J. occup. Med., 19, 741-746
5. Pasternack, B.S. & Shore, R.E. (1981) Lung cancer following exposure to chloromethyl ethers. In: Chwat, M. & Dror, K., eds, Proceedings of the International Conference on Critical Current Issues in Environmental Health Hazards, Tel-Aviv, Israel, pp. 76-85
6. Weiss, W. (1982) Epidemic curve of respiratory cancer due to chloromethyl ethers. J. natl Cancer Inst., 69, 1265-1270
7. McCallum, R.I., Woolley, V. & Petrie, A. (1983) Lung cancer associated with chloromethyl methyl ether manufacture: an investigation at two factories in the United Kingdom. Br. J. ind. Med., 40, 384-389
8. Weiss, W. & Boucot, K.R. (1975) The respiratory effects of chloromethyl methyl ether. J. Am. med. Assoc., 234, 1139-1142
9. Weiss, W., Moser, R. & Auerbach, O. (1979) Lung cancer in chloromethyl ether workers. Am. Rev. respir. Dis., 120, 1031-1037
10. Sakabe, H. (1973) Lung cancer due to exposure to bis(chloromethyl)ether. Ind. Health, 11, 145-148
11. Weiss, W. & Figueroa, W.G. (1976) The characteristics of lung cancer due to chloromethyl ethers. J. occup. Med., 18, 623-627
12. Reznik, G., Wagner, H.H. & Atay, Z. (1977) Long cancer following exposure to bis(chloromethyl)ether: a case report. J. environ. Pathol. Toxicol., 1, 105-111
13. Bettendorf, U. (1977) Occupational lung carcinoma after inhalation of alkylating agents. Dichlorodimethyl ether, monochlorodimethylether and dimethylsulphate (Ger.). Dtsch. med. Wochenschr., 102, 396-398
14. Leong, B.K.J., Kociba, R.J. & Jersey, G.C. (1981) A lifetime study of rats and mice exposed to vapors of bis(chloromethyl)ether. Toxicol. appl. Pharmacol., 58, 269-281
15. Zajdela, F., Croisy, A., Barbin, A., Malaveille, C., Tomatis, L. & Bartsch, H. (1980) Carcinogenicity of chloroethylene oxide, an ultimate reactive metabolite of vinyl chloride, and bis(chloromethyl)ether after subcutaneous administration and in intiation-promotion experiments in mice. Cancer Res., 40, 352-356
16. Dulak, N.C. & Snyder, C.A. (1980) The relationship between the chemical reactivity and the inhalation carcinogenic potency of direct-acting chemical agents (Abstract No. 426). Proc. Am. Assoc. Cancer Res., 21, 106
17. Kuschner, M., Laskin, S., Drew, R.T., Cappiello, V. & Nelson, N. (1975) Inhalation carcinogenicity of alpha halo ethers. III. Lifetime and limited period inhalation studies with bis(chloromethyl)ether at 0.1 ppm. Arch. environ. Health, 30, 73-77
18. Leong, B.K.J., Kociba, R.J., Jersey, G.C. & Gehring, P.J. (1975) Effects of repeated inhalation of parts per billion of bis(chloromethyl)ether in rats (Abstract No. 131). Toxicol. appl. Pharmacol., 33, 175
19. Laskin, S., Drew, R.T., Cappiello, V., Kuschner, M. & Nelson, N. (1975) Inhalation carcinogenicity of alpha halo ethers. II. Chronic inhalation studies with chloromethyl methyl ether. Arch. environ. Health, 30, 70-72
20. IARC Monographs, Suppl. 6, 119-120, 159-160, 1987
See Also: Toxicological Abbreviations Griseofulvin (IARC Summary & Evaluation, Supplement7, 1987) Griseofulvin (IARC Summary & Evaluation, Volume 10, 1976) Griseofulvin (IARC Summary & Evaluation, Volume 79, 2001)