Carisoprodol: Reproductive Assessment by Continuous Breeding in Swiss Mice

Abstract

Carisoprodol: Reproductive Assessment by Continuous Breeding in Swiss Mice. Grizzle, T. B., George J. D., Fail, P. A., and Heindel, J. J. (1995). Fundam. Appl. Toxicol.24, 132-139.Carisoprodol (CARI), a commonly prescribed neuromuscular relaxant, was evaluated for reproductive toxicity in Swiss CD-1 mice using the Reproductive Assessment by Continuous Breeding (RACB) protocol. Male and female mice were given CARI in corn oil suspension by daily garage at doses of 0, 300, 750, and 1200 mg/kg body wt/day. Clinical signs of general toxicity in F0 animals included sedation, primarily in the high-dose group during the first week of exposure, and reduced body weight in high-dose females. CARI administration for 14 weeks did not affect the ability of the F0, animals to produce litters. However, decreases in proportion of pups born alive (4%) and absolute (5%) and adjusted live pup weight (7%) were observed at 1200 mg/kg CARI when compared to controls. In a crossover mating trial to determine the affected sex, there were no significant differences in the measured reproductive parameters. CARI at the high close increased the proportion of time spent in proestrus and estrus, but cycle length was unaffected. At F0 necropsy (Week 27 of treatment), all sperm parameters were normal. Right epididymis and liver weights, relative to body weight, were increased (12 and 23%, respectively) over the control group for high-dose males. A mating trial to determine the fertility and reproductive competence of the F1 generation showed no effect of CARI on indices of mating, pregnancy, or fertility, the proportion of F2 pups born alive, the sex ratio of live F2 pups, live F2 pup weight, or gestation length. However, decreases in the number of F2 pups per litter (22%) and adjusted live F2 pup weight (80%) were observed in the high-dose group. Indications of generalized toxicity in the F1 generation included decreased survival through Postnatal Day 21 at 750 (5%) and 1200 (9%) mg/kg CARI, and transiently decreased body weights during postnatal development and as adults for males and females at all dose levels. At necropsy, there was no effect of treatment on the relative weight of any male or female reproductive organs; testicular spermatid concentration was reduced at all levels of CARI. Relative liver weight was increased for females at 300 mg/kg and for males and females at both 750 and 1200 mg/kg. In summary. CARI produced generalized toxicity and moderate effects on the reproductive processes of F0 and F1 generation Swiss mice during chronic exposures of up to 1200 mg/kg/day.