Ortho-cresol (OCRE), one of three isomers of cresol which are used in the wood preservative creosote and as disinfectants, solvents, and cleaners, was evaluated for reproductive toxicity in CD-1 (Swiss) mice using the Reproductive Assessment by Continuous Breeding Protocol (RACB). Exposure to OCRE at levels ranging from a mean of 66 mg/kg/day in the low-dose group (0.05% in feed) to a mean of 660 mg/kg/day in the high-dose group (0.5% in feed) for 14 weeks of cohabitation did not significantly affect measures of reproductive competence, including initial fertility, mean number of litters per pair, live litter size, the proportion of pups born alive, or adjusted live pup weight. A small but significant non-dose-related increase (two to three days) in cumulative days to litter was observed in the three treated groups. F0 body weight and feed and water consumption, after 16 weeks of OCRE exposure, were not adversely affected by treatment. Treatment had no effect on body or liver, kidney, or testis weight at necropsy, with the exception of a decrease in absolute but not relative kidney weight among females in the high-dose group. No treatment-related testicular histopathology was observed.
OCRE at a dose level of 0.5% in feed did not adversely affect preweaning growth or survival in the F1 generation, nor was there an effect of this dose level on feed or water consumption in the F1 generation. Calculated exposure averaged 773 and 1128 mg/kg/day for adult F1 males and females, respectively. No treatment-related clinical signs were noted. OCRE at 0.5% in feed had no effect on the reproductive competence of the F1 generation. There was no effect of treatment on male body weight or liver, epididymis. kidney, prostate, seminal vesicle, or testis weight, sperm parameters, or histopathology. Female terminal body weight was slightly reduced, but there was no effect on organ weight, vaginal cytology. or liver, kidney, or ovarian histopathology.
In summary, exposure to OCRE in feed at dose levels as high as 0.5% had no significant adverse effect on reproductive competence in F0 or F1 mice. However, the maximum tolerated dose (MTD) was not reached, because no evidence of generalized toxicity was noted for the F0 generation at 0.5% OCRE, and only minimal evidence of generalized toxicity was noted for F1 females at 0.5% OCRE. Although the MTD was not reached for the F0 generation, data from Task 1 suggested that the animals could not have tolerated higher doses for the length of exposures in Tasks 2 and 3. The 0.2% dose level was the no adverse effects level (NOAEL) for both reproductive and general toxicity in both generations. These data indicate that OCRE is not a reproductive toxicant to either F0 or F1 mice under the conditions of this study (i.e., up to 1230 mg/kg/day).