Bioassay of chloropicrin for possible carcinogenicity.
A bioassay of technical-grade chloropicrin for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. Chloropicrin in corn oil was administered 5 days a week by gavage, at either of two dosages, to groups of 50 male and 50 female animals of each species. Time-weighted average dosages of 25 mg/kg/day for low dose male rats and 20 mg/kg/day for low dose female rats were administered during weeks 1 through 33, then administered cyclically (1 dose-free week followed by 4 weeks of administration) from weeks 34 through 78. Time-weighted average dosages of 26 mg/kg/day for high dose male rats and 22 mg/kg/day for high dose female rats were administered from weeks 1 through 17, weeks 31 through 33, and cyclically (1 dose-free week followed by 4 weeks of administration) during weeks 34 through 78. Time-weighted average dosages of 66 and 33 mg/kg/day, respectively, for male and female mice were administered for 78 weeks. These dosing regimens were followed by observation periods of 32 weeks for rats and 13 weeks for mice. For each species, 20 animals of each sex were placed on test as vehicle controls. These animals were gavaged with corn oil. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not gavaged. A high incidence of early death was observed among chloropicrin-dosed rats. Deaths among dosed rats occurred as early as week 1 for females and week 6 for males. Median survival was week 48 for high dose males, week 54 for low dose males, week 70 for high dose females and week 59 for low dose females. Statistical tests indicate a positive association between chloropicrin dosage and mortality of rats. No neoplasms were observed at higher incidences in dosed than control rats. In rats of both sexes, incidences of adenoma of the pituitary and of adenocarcinoma or fibroadenoma of the mammary gland were higher in control groups than dosed groups. It is likely that most dosed rats did not survive long enough to be at risk from late-appearing tumors. A rapid decrease in survival after the first year of the study was observed among high dose mice of both sexes. Survival of high dose male mice decreased from 80 percent in week 54 to 26 percent in week 90. Survival of high dose female mice decreased from 82 percent in week 54 to 36 percent in week 90. Statistical tests indicated a positive association between chloropicrin dosage and mortality of mice. In chloropicrin-dosed mice, proliferative lesions of the squamous epithelium of the forestomach included two carcinomas and a papilloma. Although these tumors were uncommon in control animals, statistical analysis did not demonstrate that they were related to administration of chloropicrin. Other proliferative lesions of the forestomach occurring at an increased incidence in dosed mice were acanthosis and hyperkeratosis. No statistically significant increase of tumor incidence was observed in mice. The bioassay of chloropicrin using Osborne-Mendel rats did not permit an evaluation of carcinogenicity because of the short survival time of dosed animals. The bioassay of chloropicrin using B6C3F1 mice did not provide conclusive statistical evidence for the carcinogenicity of this compound.