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.
Chlorpromazine HCl, a widely used tranquilizer and antipsychotic agent, was evaluated for toxic and teratogenic effects in timed-pregnant F-344 rats. CPZ (0, 5, 15, 30 and 45 mg/kg/day, po) in distilled water was administered in a volume of 5 ml per kilogram of body weight on gestational days 6 through 15. Females were weighed and observed during daily treatment and at I and 4 hours post-dosing for clinical signs of toxicity. At sacrifice on gd 20, a total of 22-27 dams (i.e., confirmed-pregnant females) per treatment group were evaluated. The gravid uterus for each dam was weighed and the number of implantation sites, and live, dead or resorbed fetuses were recorded. All live fetuses were weighed and examined for external, visceral and skeletal malformations.
During CPZ treatment, dams exhibited clinical signs including sedation, rough or erect coat, weight loss and lacrimation. The maternal mortality rate was 4% (1/28) for the high-dose group and 0% for all other dose groups. Maternal body weight on gd 6 (i.e. , prior to the initiation of treatment) did not differ significantly among treatment groups. On gd 11, 15 and 20 maternal body weight was decreased across treatment groups in a dose-related manner with 30 and 45 mg/kg/day CPZ dams exhibiting body weights significantly below vehicle controls. Measures of maternal weight gain (i.e., weight gain during treatment, weight gain during gestation and absolute weight gain) as well as gravid uterine weight were also decreased in a dose-related manner. Maternal weight gain during the treatment period was significantly below controls for dams treated with 5, 15, 30 or 45 mg/kg/day CPZ. Absolute weight gain was significantly below controls for the 15, 30 and 45 mg/kg/day CPZ groups. Gestational weight gain and gravid uterine weight were below controls for the 30 and 45 mg/kg/day CPZ groups. Absolute maternal liver weight was decreased in a dose-related manner and was significantly below controls for the 30 and 45 mg/kg/day CPZ groups, but relative maternal liver weight did not differ among treatment groups. The percentage per litter of resorbed, nonlive (i.e., dead plus resorbed) or affected (i.e. , nonlive plus malformed) fetuses increased across dose groups, and each was significantly elevated in both the 30 and 45 mg/kg/day CPZ groups. In addition, the proportion of litters with one or more resorptions was elevated for the 15, 30 and 45 mg/kg/day CPZ groups, and the proportion of litters with one or more nonlive or affected fetuses was elevated above the control group for the 30 and 45 mg/kg/day CPZ treatment groups.
Among those litters containing live fetuses, there were no differences among dose groups in the number of live fetuses per live litter or in the proportion of males per live litter. Average fetal body weight per live litter was reduced in a dose-related manner, with CPZ 5, 15, 30 and 45 mg/kg/day litters significantly below controls; males and females were equally affected on this measure. The percentage of fetuses malformed per litter and the proportion of litters with one or more malformed fetuses did not differ significantly among treatment groups. In conclusion, CPZ (0, 5, 15, 30 or 45 mg/kg/day, po) administered on gd 6 through 15, produced dose-related maternal and fetal toxicity, and increased prenatal mortality, but failed to increase the incidence of malformations in F-344 rats.