title: Bioassay of 4,4'-thiodianiline for possible carcinogenicity.
abstract: A bioassay of 4,4'-thiodianiline for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 35 mice of each sex were administered 4,4'-thiodianiline 5 days per week at one of the following doses, either 1,500 or 3,000 ppm for the rats and either 2,500 or 5,000 ppm for the mice. The period of administration of the chemical was 68-72 weeks for the rats and 77 or 79 weeks for the mice, depending on the length of survival time of the animals. Matched controls consisted of groups of 15 untreated rats and 14 untreated mice of each sex. All surviving matched-control rats were killed at 104 weeks; all surviving matched-control mice were killed at 91 weeks. The administration of 4,4'-thiodianiline resulted in marked reduction in mean body weights of the rats and mice of each sex, and all dosed animals died prior to the scheduled end of the study. Tumors of epithelial origin were found in many organs, and all dosed rats except one were affected at one or more sites (males: skin, ear canal, lungs, liver, colon, and thyroid; females: ear canal, lung, liver, thyroid, and uterus). These tumors were not found among any of the matched-control animals. In male rats, several of these neoplastic lesions occurred with statistically significant incidences in one or both of the dosed groups. The incidences of hepatocellular carcinoma (controls 0/15, low-dose 21/33, high-dose 10/33) and of follicular-cell carcinoma of the thyroid (controls 0/15, low-dose 28/33, high-dose 32/33) were significant in each of the groups at P</= 0.014. The combined incidences of squamous-cell carcinoma and squamous-cell papilloma of the ear canal in the low- and high-dose groups of males were both significantly higher (low-dose P=0.001, high-dose P=0.037) than that in the control group (controls 0/15, low-dose 15/33, high dose 8/33). The first such tumor in the high-dose group was observed at 25 weeks. Also in low-dose male rats, squamous-cell papilloma of the skin occurred in 4/33 animals, and squamous-cell carcinoma of the skin in 1/33, but no tumors of either type occurred in the controls. The incidences of these lesions were too low to have statistical significance. The majority of the squamous-cell tumors of the skin were located in one area near the commissure of the mouth. Only one such tumor occurred among the 235 historical-control male rats at this laboratory; thus, the tumors of the skin may be associated with administration of the chemical. Adenocarcinoma of the colon occurred in six low-dose male rats and in one high-dose male rat, but not in any of the controls. This incidence is not statistically significant; however, no such tumors occurred among the 235 historical-control male rats at this laboratory; thus, the tumors of the colon are considered to be related to administration of 4,4'-thiodianiline. In female rats, the incidences of hepatocellular adenoma or carcinoma in the dosed groups were greater than those in the controls, but not statistically significant (controls 0/15, low-dose 6/32, high-dose 3/33). Follicular-cell carcinoma of the thyroid and adenocarcinoma of the uterus occurred in the females administered the test chemical at statistically significant incidences (P<0.001) in both dosed groups (follicular-cell carcinoma: controls 0/14, low-dose 24/33, high-dose 32/32; adenocarcinoma: controls 0/15, low-dose 31/33, high-dose 23/32). Squamous-cell papilloma or carcinoma of the ear canal occurred at increased, but not statistically significant, incidences in female rats (controls 0/15, low-dose 6/33, high-dose 3/33). However, no such tumors occurred among the 235 historical-control female rats at this laboratory; thus, the tumors of the ear canal are considered to be related to administration of the chemical. In mice of each sex, the incidence of hepatocellular carcinoma was statistically significant (P<0.001) in each of the dosed groups (males: controls 1/13, low-dose 32/34, 32/34, high-dose 22/24, females: controls 0/12, low-dose 32/34, high-dose 30/31). In the males, follicular-cell carcinoma of the thyroid occurred at statistically significant incidences (P </= 0.001) in both the low- and high-dose groups (controls 0/14, low-dose 15/33, high-dose 20/23). In the females, the incidence was significant (P=0.002) only at the high dose (controls 0/11, high-dose 15/30); however, when follicular-cell adenoma and carcinoma were combined, the incidences in both the low- and high-dose groups of females were significantly higher (low-dose P=0.025, high-dose P<0.001) than that in the control group (controls 0/11, low-dose 11/33, high-dose 18/30). It is concluded that under the conditions of this bioassay, 4,4'-thiodianiline was carcinogenic for Fischer 344 rats, inducing tumors in the liver, thyroid, colon, and ear canal of male rats, and the thyroid, uterus, and ear canal of female rats. 4,4'-Thiodianiline was carcinogenic for B6C3F1 mice, inducing tumors in the liver and thyroid of both males and females.