Toxicity Studies of 1,3-Diphenylguanidine (CAS No. 102-06-7) Administered in Feed to F344/N Rats and B6C3F1 Mice.
1,3-Diphenylguanidine (DPG) has been used as a primary and secondary accelerator in the vulcanization of rubber. Exposure to 1,3-diphenylguanidine may occur as a result of dermal contact during rubber manufacture or from contact with the finished products. DPG is poorly absorbed through skin. Therefore, to evaluate the toxicity associated with systemic exposure, 2-week and 13-week toxicology studies were conducted by administering DPG in feed to groups of male and female F344/N rats and B6C3F1 mice. Genetic toxicity was also evaluated in Salmonella typhimurium and in the micronucleus erythrocyte assay in peripheral blood from male and female mice. During 2-week studies, rats and mice received feed containing 0, 250, 500, 750, 1,500, or 3,000 ppm 1,3-diphenylguanidine. All rats and mice survived to the end of the study. Feed consumption and mean body weights of groups of rats that received 750, 1,500, or 3,000 ppm were lower than controls. No compound-related gross lesions were observed at the end of the study. The final mean body weight of female mice that received 3,000 ppm was 6% lower than the controls at the end of the study; however, no other effects attributable to chemical exposure were observed in mice. Based on these results the same exposure concentrations (0, 250, 500, 750, 1,500, and 3,000 ppm) were selected for the 13-week study; because of the poor palatability of the 750 ppm or higher dosed feed in rats, concentrations greater than 3,000 ppm were not considered appropriate. Six male rats and all female rats that received feed containing 3,000 ppm died or were killed moribund before the end of the 13-week study. Final mean body weights and feed consumption of male and female rats that received 1,500 or 3,000 ppm were lower than controls throughout the study. The values of several hematologic parameters were significantly different from the controls in groups of rats that received 1,500 or 3,000 ppm; however, these differences were attributable to reduced nutrient intake as a result of reduced feed consumption. Lower total serum protein, cholesterol, triglyceride, and creatinine concentrations were also considered to be the consequence of reduced nutrient intake. Alkaline phosphatase activity and bile acid concentrations were greater than the controls in most groups exposed to DPG and were considered to be an indication of cholestasis. Secretory depletion of the seminal vesicles and prostate gland, epididymal hypospermia, spermatogenic arrest, and significant reductions in the absolute weights of the prostate gland, seminal vesicles, and testis were observed in male rats in the 3,000 ppm group. Uterine hypoplasia characterized by a reduction in uterine size due to thinner and less developed endometrium was observed in female rats that received diets containing 750 ppm or greater. The mean length of the estrous cycle was greater in female rats that received 750 or 1,500 ppm feed than in the controls. All mice survived to the end of the 13-week study. Mean body weights of males and females that received feed containing 750, 1,500, or 3,000 ppm were lower than the controls. Reduced organ weights relative to control for mice that received 1,500 or 3,000 ppm were related to low body weights of these groups. In mice that received 3,000 ppm sperm motility was reduced and the number of spermatid heads was greater than for control males, and the estrous cycle length in females was longer than that of the controls. 1,3-Diphenylguanidine was tested for mutagenicity in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 with and without S9 metabolic activation enzymes. No mutagenic activity was observed in the absence of S9. With S9, positive responses were observed in strains TA98 and TA100, and an equivocal response was observed in strain TA1537. Results of a peripheral blood micronucleus test in B6C3F1 mice were concluded to be negative in males and equivocal in females. In summary, consumption of feed containing 1,3-diphenylguanidine for 2 weeks or 13 weeks was not associated with any histologic response which could be attributed to chemical exposure. Instead the observed changes were indicative of reduced nutrient intake and are consistent with similar changes observed in other studies of feed restricted rats and mice.