Pre- and postnatal development of rats following concomitant intrauterine exposure to propoxyphene and chlordiazepoxide.

The pre- and postnatal effects of the combined oral administration of propoxyphene (PPX, 100 mg/kg/day) and chlordiazepoxide (CDX, 25, 50 or 100 mg/kg/day) were evaluated in Wistar rats in separate experiments by dosing on days 6 through 21 of pregnancy. The controls were given either an aqueous gum tragacanth solution or PPX alone. Maternal toxicity, as evident from death or reduction in body weight, was observed in dams given PPX + 100 mg/kg/day CDX, although previous studies with CDX alone showed no maternal toxicity [5]. PPX alone was well tolerated by the mothers and produced neither any detrimental effects on litter size, litter or pup weights, nor any visceral or skeletal anomalies. Treatment with the two largest doses of CDX + PPX was associated with a high incidence of resorptions, a significant reduction in fetal weight, increased incidence of runts, retarded ossification of skull bones, and a variety of sternal defects. In the postnatal study, PPX alone did not affect pup survival or growth, whereas the combined dosing of PPX and CDX resulted in delayed delivery, increase in stillbirths, reduction in birth weight and a high neonatal mortality compared to pups in the control groups. Pentobarbital sleeping time remained unaltered in 11 to 12-week old offspring of dams given PPX alone. However, in 11 to 12-week old progeny exposed in utero to 25 mg/kg CDX + PPX, the pentobarbital sleeping time was significantly prolonged in males but shortened in females, suggesting that prenatal exposure to PPX + CDX caused a sex-related reversal to pentobarbital hypnosis in mature rats.