The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings may not have been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. For more information, see the Explanation of Levels of Evidence for Developmental Toxicity. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.
Scopolamine hydrobromide, a naturally occurring anticholinergic drug, was evaluated for toxic and teratogenic effects in timed-pregnant CD rats. Animals were exposed to SCOP in water, by gavage on gestational days 6 through 15. Caesarian sections were performed on gd 20. Prior to initiation of the teratology study, a preliminary study was conducted in order to establish appropriate doses for use in the teratology study. Based on the results of the preliminary study, doses of 0, 10, 100, 450, and 900 mg/kg/day SCOP were administered in the teratology study.
The teratology study was conducted using a two-replicate design, with 12-16 animals assigned to each dose group in each replicate. The second replicate was started (gd 0) 19 days after the first replicate. In each replicate, females were weighed and observed during daily treatment for clinical signs of toxicity. At sacrifice on gd 20, the gravid uterus of each dam was weighed. Following uterine dissection the number and status of uterine implantation sites was recorded. Each live fetus was weighed, sexed, and examined for external, visceral, and skeletal malformations. A total of 21-28 dams (i.e., confirmed-pregnant females) per treatment group were evaluated in the study.
Exposure of timed-pregnant CD rats to SCOP dissolved in distilled water (0, 10, 100, 450, or 900 mg/kg/day) by gavage on gestational days 6 through 15 produced the following results:
Observed maternal or developmental toxicity at 10 mg/kg/day.
At doses greater than or equal to 100 mg/kg/day SCOP, a marginal non-dose-related reduction in fetal body weight, and a marginal non-dose-related increase in the incidence of malformations per litter in the presence of significant dose-related maternal toxicity (reduced maternal body weight and weight gain).
At doses greater than or equal to 450 mg/kg/day, exposure to SCOP was associated with a significant increase in the incidence of short ribs. This effect was observed in the presence of significant maternal toxicity.
- At the doses tested (0, 10, 100, 450, or 900 mg/kg/day SCOP) there was no separation of maternal toxicity from developmental toxicity.
In conclusion, exposure of timed-pregnant CD rats to SCOP at doses up to 900 mg/kg/day on gestational days 6-15 caused no clear evidence of teratogenic response in gd 20 rat fetuses. Marginal evidence of intrauterine growth retardation, and a non-dose-related trend toward an increase in the incidence of malformations was observed only at doses that caused significant maternal toxicity.