Toxicology and carcinogenesis studies of chlorodibromomethane (greater than 98% pure), a trihalomethane formed after chlorination of water supplies, were conducted by administering this test chemical in corn oil gavage five times per week for 104 weeks to groups of 50 male and 50 female F344/N rats at 0,40, or 80 mg/kg per day and to groups of 50 male and 50 female B6C3F1 mice for 105 weeks at doses of 0, 50, or 100 mg/kg per day. Survival of dosed male and female rats and female mice was comparable to that of the corresponding vehicle control groups. An overdose of chemical was given to low dose male and female mice at week 58; this overdose killed 35 male mice, whereas the female mice were apparently not affected. Because this mortality significantly reduced the number of survivors, the low dose male mouse group was considered to be inadequate for analysis of neoplasms. High dose male mice had lower survival than the vehicle controls (44/50 vs 29/50; P<0.001). At week 82, nine high dose male mice had died; the cause remains unknown. High dose male rats and dosed male and female mice had lower body weights compared with those of the vehicle controls.
Compound-related nonneoplastic lesions were found in the liver and kidney in male and female rats and in male mice in the 13-week studies at the highest dose (250 mg/kg). In the 2-year studies, compound-related toxicity was seen primarily in the livers of male and female rats (fatty metamorphosis and ground-glass cytoplasmic changes) and in the male mice (hepatocytomegaly, necrosis, fatty metamorphosis) and female mice (calcification and fatty metamorphosis). Toxicity was also seen in the kidneys (nephrosis) of male mice and female rats.
Administration of chlorodibromomethane significantly increased the incidence of hepatocellular adenomas (vehicle control, 2/50; low dose, 4/49; high dose, 11/50) and the combined incidences of hepatocellular adenomas or carcinomas (6/50; 10/49; 19/50) in high dose female mice. The incidence of hepatocellular carcinomas (vehicle control, 10/50; high dose, 19/50) was significantly increased in high dose male mice, although the combined incidence of hepatocellular adenomas or carcinomas (vehicle control, 23/50; high dose, 27/50) was marginally significant by the life table test but not by the incidental tumor test.
Negative trends in several common rodent tumors were found in dosed animals in the 2-year studies. These neoplasms included fibroadenomas of the mammary gland in female rats, endometrial stromal polyps of the uterus in female rats, and malignant lymphomas in male mice.
Chlorodibromomethane was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of Aroclor-induced male Sprague-Dawley rat or male Syrian hamster liver S9.
An audit of the experimental data was conducted for the 2-year toxicology and carcinogenesis studies of chlorodibromomethane. No data discrepancies were found that influenced the final interpretations.
Under the conditions of these gavage studies, there was no evidence of carcinogenicity in male or female F344/N rats receiving chlorodibromomethane at doses of 40 or 80 mg/kg five times per week for 104 weeks. Fatty metamorphosis and ground-glass cytoplasmic changes of the liver in male and female F344/N rats were related to administration of chlorodibromomethane. There was equivocal evidence of carcinogenicity for male B6C3F1 mice; chlorodibromomethane caused an increased incidence of hepatocellular carcinomas, whereas the combined incidence of hepatocellular adenomas or carcinomas was only marginally increased. Some evidence of carcinogenicity was observed for female B6C3F1 mice, since chlorodibromomethane caused an increased incidence of hepatocellular adenomas and an increased combined incidence of hepatocellular adenomas or carcinomas.