title: Bioassay of N-phenyl-p-phenylenediamine for possible carcinogenicity.
abstract: A bioassay of N-phenyl-p-phenylenediamine for possible carcinogenicity was conducted by administering the test chemical in the diet to Fischer 344 rats and B6C3F1 mice. Groups of 50 rats of each sex were administered N-phenyl-p-phenylenediamine at one of two doses, either 600 or 1,200 ppm, for 78 weeks and were then observed for 26 additional weeks. Matched controls consisted of groups of 20 untreated rats of each sex. All surviving rats were killed at 104 weeks. Groups of 50 mice of each sex were initially administered N-phenyl-p-phenylenediamine at one of the following doses, either 2,500 or 5,000 ppm for the males and either 5,000 or 10,000 ppm for the females, for 31 weeks. Because of toxicity of the chemical, the doses were lowered at that time and terminated at 48 weeks. The animals were then observed for 43 additional weeks. Time-weighted average doses during the period of administration were 2,057 or 4,114 ppm for the males and 3,672 or 8,170 for the females. Matched controls consisted of groups of 20 untreated mice of each sex. All surviving mice were killed at 91 weeks. Mean body weights of the dosed rats were only slightly lower than those of the matched controls during the bioassay. Mean body weights of the dosed mice were appreciably lower than those of the matched controls, and mortality was high in the dosed groups prior to the reductionof the doses, particularly in the females. Sufficient numbers of rats and mice of each sex were at risk for the development of late-appearing tumors; however, the shortened period used for administering N-phenyl-p-phenylenediamine to the mice may not have been adequate for determining the carcinogenic potential of the test chemical in this species. In the male and female rats, the incidences of neoplasms in the groups receiving the test chemical were not significantly different from those in the corresponding control groups. In the male mice, the incidence of combined hepatocellular adenomas and carcinomas was significantly higher (P=0.022) in the low-dose group than in the controls, but there was no significant dose-related trend (controls 2/20, low-dose 18/49, high-dose 10/50). Furthermore, since at this laboratory the overall historical incidences of these combined lesions in male mice have been 53/340 (15.6%) and have been as high as 7/20 (35%), these neoplasms could not be established as being compound related. Unusually extensive hepatic inflammation occurred in large numbers of the dosed males (controls 0/20, low-dose 23/49, high-dose 24/50) and in lesser numbers of the dosed females (controls 1/20, low-dose 8/49, high-dose 2/48). It is concluded that under the conditions of this bioassay, N-phenyl-p-phenylenediamine was not carcinogenic for Fischer 344 rats or for B6C3F1 mice.