A mixture of Meta-/Para-cresol (MPCRE; 58.7%/41.3%, respectively) was evaluated for reproductive toxicity in CD-1 (Swiss) mice using the Reproductive Assessment by Continuous Breeding (RACB) Protocol. Exposure to MPCRE, at levels ranging from a mean of 362 mg/kg/day in the low-dose group (0.25% in feed) to a mean of 1682 mg/kg/day in the high-dose group (1.5% in feed), for 14 weeks of cohabitation, did not significantly affect most measures of reproductive competence, including initial fertility, the proportion of pups born alive, or the sex of pups born alive. However, adjusted the pup weight and the number of live pups per litter (both sexes) were decreased by 5 and 20%, respectively, and cumulative days to the fifth litter were increased by almost three days in the high-dose group compared to controls. F0 body weight and feed consumption, after 16 weeks of MPCRE exposure, were decreased at the 1.0 and 1.5% dose levels, especially in delivering and lactating dams. MPCRE at the 1.5% level decreased body weight and increased kidney and liver weights of F0 animals. Toxicity to reproductive organs at the 1.5% dose level was observed in the form of decreased epididymal and seminal vesicle weights by 10 and 21%, respectively, with no change in testis weight, sperm parameters, or testicular and epididymal histopathology. Crossover mating did not clearly reveal the affected sex. as the only parameter affected (adjusted live pup weight) was decreased if either sex was dosed at the 1.5% level.
Although birth weights of F1 animals were minimally decreased (5.0%) in the high-dose group, MPCRE decreased preweaning growth by 26% and postweaning survival by 39% in the F1 generation. Calculated MPCRE exposure in high-dose F1 animals averaged 2490 mg/kg/day for males and 2939 mg/kg/day for females. Treatment-related clinical signs were reduced size, dehydration, lethargy, and rough coat in the high-dose group. MPCRE at 1.5% in feed had no effect on the reproductive competence of the F1 generation. At both the 1.0 and 1.5% dose level, male body and reproductive organ weights (prostate, seminal vesicles, testes) were decreased. and relative liver and kidney weights were increased, but there were no effects on sperm parameters or histopathology. Female terminal body weights were reduced at the two highest dose levels, as was ovarian weight in all three dosed groups, while kidney and liver weights were increased in all dosed groups. There was no effect of treatment on estrous cyclicity or ovarian. liver, or kidney histopathology.
An MTD for systemic and reproductive toxicity of MPCRE for F0 animals was established at the 1.5% dose level, based on decreased body weight at necropsy, increased relative liver weight, and decreased absolute and relative seminal vesicle weight. An MTD of 1.0% MPCRE for systemic and reproductive toxicity was established for F1 animals, based on decreased body weight, increased relative liver weight, and decreased relative prostate and seminal vesicle weight. In summary, minimal reproductive toxicity was apparent, but only in the presence of significant systemic toxicity.
NTIS # PB92191741