Carcinogenesis Studies of 1,1,1,2-Tetrachloroethane (CAS: 630-20-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Carcinogenesis studies of technical grade 1,1,1,2-tetrachloroethane (>99% pure) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats at doses of 125 or 250 mg/kg body weight and to groups of 50 male and 50 female B6C3F1 mice at doses of 250 or 500 mg/kg. (1,1,1,2-tetrachloroethane is used as a chemical intermediate in the production of trichloroethylene and tetrachloroethylene). Doses were administered five times per week for 103 weeks. Due to chemically induced toxicity, high-dose mice received the chemical for only 65 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. The chemical produced cumulative toxic effects with signs of central nervous system involvement from week 44 forward in the chronic study, resulting in significantly lower survival of high-dose male rats (P=0.001), and possibly decreasing the incidence of late-developing tumors in this group. Mean body weights of dosed and control rats of each sex were similar. Fourteen control, 10 low-dose, and 3 high-dose male rats and 2 control, 5 low-dose, and 8 high-dose female rats were killed accidentally during the study; of these, 11 control and 7 low-dose males died apparently from heat stress during week 62 as a result of a 6-hour elevated temperature (>34 degrees C) in the animal room. Neither hepatocellular neoplastic nodules alone nor hepatocellular carcinomas alone occurred in statistically significant incidences in male rats, but the combined incidence of male rats with either hepatocellular neoplastic nodules or carcinomas occurred with a statistically significant positive trend (P<0.05) in the life table test (controls, 0/49, 0%; low-dose, 1/49, 2%; high-dose, 3/48, 6%). A single hepatocellular carcinoma occurred in the high-dose group. The combined incidence of liver tumors in the high-dose males (3/48, 6%) did not greatly exceed the historical incidences of liver tumors in groups of vehicle controls in other studies at this laboratory (5/243, 2.1%; range 0%-4%). However, reduced survival of the high-dose group in the present study may have reduced the sensitivity of this bioassay for detecting liver tumors. Mineralization of the kidney increased in a dose-related fashion in the male rats (12/48, 19/50, 26/48). Fibroadenomas in the mammary gland of female rats occurred with a statistically significant (P<0.05) increased incidence in the low-dose group as compared with the controls (6/49, 15/49, 7/46). The incidence in the high-dose group was not different than that in the controls. The combined incidence of adenomas, adenocarcinomas, and carcinomas in the pituitary gland of female rats showed a statistically significant (P<0.05) negative trend and the incidence in the high dose group was significantly (P<0.05) less than that in the controls (18/39, 16/45, 7/42). Mean body weight of high-dose mice was less than that of controls after week 20 in males and after week 40 in females. Clinical signs of central nervous system toxicity occurred at week 51 in both sexes of high-dose mice and by week 66 they were dead or moribund and were killed. Survival of low-dose females was also significantly (P<0.05) less than that of controls. The maximum tolerated dose was exceeded in high-dose mice. Inflammation, necrosis, fatty metamorphosis, and hepatocytomegaly were observed in increased incidences in the livers of high-dose male and female mice. The major neoplastic histopathological effects occurred in the liver, where dose-related statistically significant (P<0.05) increases in the incidence of hepatocellular adenomas occurred in both male and female mice: vehicle controls, low-, and high-dose male mice had rates of 13% (6/48), 30% (14/46), and 42%, (21/50); corresponding percentages in female mice were 8% (4/49), 17% (8/46), and 50% (24/48). Evidence for the association between 1,1,1,2-tetrachloroethane and development of hepatocellular carcinomas in mice was limited because of poor survival in the high-dose grouporoethane and development of hepatocellular carcinomas in mice was limited because of poor survival in the high-dose groups. Nevertheless, there was an increased incidence of hepatocellular carcinomas in female mice despite the reduced survival in the dosed groups (controls, 1/49, 2&percnt;; low-dose, 5/46, 11&percnt;; high-dose, 6/48, 13&percnt;). There was no clear effect in male mice. Under the conditions of these studies, 1,1,1,2-tetrachloroethane was not demonstrated to be carcinogenic in F344/N rats, although the observed increase in the proportion of male rats with liver tumors may have been associated with the administration of 1,1,1,2-tetrachloroethane; accidental killing of 27 male and 15 female rats reduced the sensitivity of this bioassay for detecting a carcinogenic response. 1,1,1,2-Tetrachloroethane was carcinogenic for B6C3F1 mice, causing an increased proportion of female mice with hepatocellular carcinomas and an increased proportion of male and female mice with hepatocellular adenomas; the decreased survival in high-dose male and female mice compromised the ability of this bioassay to further determine the presence or absence of a carcinogenic effect and gave clear evidence that these doses were toxic. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Positive Female Mice: Positive