Carisoprodol (CARI) was evaluated for reproductive toxicity in CD-1 (Swiss) mice using the Reproductive Assessment by Continuous Breeding Protocol (RACB). After a 2 week dose- range-finding study, dose levels for the Task 2 Continuous cohabitation phase were set at 0, 300, 750, and 1500 mg/kg/day, in corn oil gavage. When the high dose killed 2/20 (10%) of males and 4/20 (20%) of females after less than one week exposure, the high dose level was reduced to 1200 mg/kg/day.
During 14 weeks of cohabitation in Task 2, with daily dosing of CARI, there was no effect on the ability of the F0 animals to produce litters. However, the proportion of pups born alive, and absolute and adjusted live pup weight, were decreased in the high-dose group compared to the controls. Evaluation of the control and 1200 mg/kg/day dose groups in the Task 3 crossover mating trail (to identify the affected sex) found no effect of CARI on any measure of reproductive function. At F0 necropsy of controls and 1200 mg/kg/d groups, there was no effect of 1200 mg/kg/day CARI on sperm concentration, motility, or morphology. Relative right epididymis weight was significantly increased over the control group for high-dose males. Additionally, high-dose males exhibited increased relative liver weight. whereas high-dose females exhibited decreased absolute but not relative kidney/adrenal weight, compared to the controls. There was no effect of CARI on F0 estrous cyclicity. No treatment-related histopathology in the kidney, liver, or reproductive organs was observed in either males or females exposed to 1200 mg/kg/day CARI. Indications of generalized toxicity in the F0 animals included tranquilization, primarily in the high-dose group during the first weeks of Task 2, and reduced body weight in high-dose females during Tasks 2 and 3. Mortality (non-gavage related) for the F0 generation was 1/40 (2%). 0/20 (0%), 1/20 (5%), and 9/20 (45%) for males. and 3/40 (7.5%), 1/20 (5%). 1/20 (5%), and 4/20 (20%) for females in the control through high-dose groups.
Task 4, a trial to determine the fertility and reproductive competence of the second generation (F1 animals), was conducted with the final offspring of all groups. There was no effect of CARI on indices of mating, pregnancy. or fertility, the proportion of pups born alive, the sex ratio of live pups, unadjusted live pup weight, or average number of days to litter. The number of pups per litter (females and the sexes combined) was reduced in the high dose group. Adjusted live pup weight was significantly decreased in the mid- and high-dose groups. At F1 necropsy, there was no effect of treatment of the relative weight of any male or female reproductive organs; spermatid head count was significantly reduced at all levels of CARI. Relative liver weight was significantly increased for females at 300 mg/kg/day and for both males and females at both 750 and 1200 mg/kg/day. There were no treatment-related histopathological changes.
Indications of generalized toxicity in the F1 generation included decreased survival of the pups through postnatal day 21 at 750 mg/kg/day CARI (females and sexes combined), 1200 mg/kg/day (sexes combined), and decreased body weight for males at doses of 750 and/or 1200 mg/kg/day, and for females at all dose groups. Only a few animals exhibited transient tranquilization during Task 4.
In summary, despite indications of generalized toxicity, only minimal effects of CARI on the reproductive processes were observed in the F0 generation and their offspring at the doses used in this study.
NTIS# PB92128404