Bioassay of 3-(chloromethyl) pyridine hydrochloride for possible carcinogenicity.
A bioassay of 3-(chloromethyl)pyridine hydrochloride for possible carcinogenicity was conducted by administering the test chemical by gavage to Fischer 344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were administered 3-(chloromethyl)pyridine hydrochloride in a vehicle of distilled water three times per week at one of the following doses, either 75 or 150 mg/kg body weight for the rats and either 100 or 200 mg/kg body weight for the mice. The low-dose rats were dosed for 103 weeks and the low-dose mice for 102 weeks. Because of early deaths in the high-dose animals, the high-dose rats were dosed for only 83 weeks and the high-dose mice for only 81 weeks. Controls consisted of groups of 20 rats and 20 mice of each sex which were administered the vehicle only for 104 weeks. All surviving rats and mice were killed at 104 weeks. Mean body weights of the male and female rats were lower in the dosed groups than in the corresponding control groups, and the depressions in weight were dose related. At the termination of the administration of the test chemical to the high-dose groups of rats, the mean body weights of these groups recovered rapidly. The mean body weights of the male mice were unaffected by the administration of the chemical; those of the females were only slightly affected. Mortality was generally higher in the dosed groups of rats and mice than in the corresponding control groups and was dose related in all tests except those using the female mice; however, sufficient numbers of animals of each species and sex were at risk for the development of late-appearing tumors. In rats, proliferative squamous-cell lesions of the forestomach were observed in the dosed males (carcinomas: high-dose 1/50; papillomas: low-dose 1/47; high-dose 2/50; hyperplasias: low-dose 1/47, high-dose 2/50) and the dosed females (carcinomas: high-dose 1/48), but not in the male or female vehicle controls. The results of the Fischer exact test were not significant for squamous-cell papillomas or carcinomas. However, comparison of the incidence of these tumors in the high-dose males with that in 99 historical vehicle controls shows that the probability that three or more such tumors did not occur by chance, given that none have been observed in the controls in this laboratory, is P=0.014. In mice, squamous-cell papillomas or carcinomas of the forestomach occurred in the low- and high-dose groups of each sex, but not in the corresponding control groups. The incidence in the high-dose males was significantly higher (P=0.025) than that in the control males (males: vehicle controls 0/19; low-dose 2/43; high dose 10/47 [21%]; females: vehicle controls 0/19, low-dose 1/45, high-dose 5/48 [10%]). Comparison of the incidences of these tumors in the high-dose males and females with those observed in the corresponding control groups of 100 historical vehicle controls of each sex shows that the probability that their occurrence was not due to chance is P<0.001. Also, a life-table analysis of the incidence in males indicated a significant (P=0.003) increase in tumors over the period of observation (58 weeks to 104 weeks) in relation to an increase in dose. Although the incidence of squamous-cell papillomas and carcinomas in male and female rats was significant only in males compared with historical vehicle controls, these tumors are of the same type as those appearing at the same site in male and female mice. Because these tumors are rare and not found in controls, and because they were found in dosed animals of both species, they are considered to be related to administration of the test chemical by gavage. It is concluded that under the conditions of this bioassay, 3-(chloromethyl)pyridine hydrochloride was carcinogenic in male Fischer 344 rats and B6C3F1 mice of both sexes, producing papillomas and carcinomas at the site of topical application, the stomach.