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 major tranquilizer (antipsychotic), was evaluated for toxic and teratogenic effects in timed-pregnant CD-1 mice which were matched for body weight across treatment groups on gestational day 0. CPZ (0, 2.5, 5, 15 or 30 mg/kg/day, po) in distilled water was administered in a volume of 0.01 ml per gram of body weight on gd 6 through 15. Females were weighed and observed daily during treatment and at 1 and 4 hours post-dosing for clinical signs of toxicity. At sacrifice on gd 17, a total of 24-29 dams (i.e. , confirmed-pregnant females) per treatment group were evaluated. The gravid uterus of 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, crusted secretions around the eyes and mouth, and hypothermia. Maternal mortality was 17% (5/29) 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 17 maternal body weight was decreased across treatment groups in a doserelated manner. Maternal body weight for dams treated with 5.0 mg/kg/day CPZ was below controls only on gd 11, while dams treated with 15 or 30 mg/kg/day CPZ exhibited body weights below controls on gd 11, 15 and 17. 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 gestation and during the treatment period were significantly decreased in dams treated with 15 or 30 mg/kg/day CPZ. Absolute weight gain and gravid uterine weight were both significantly decreased below controls for the 30 mg/kg/day CPZ group. Absolute maternal liver weight was decreased and relative maternal liver weight was increased in a dose-related manner. The percentage per litter of resorbed, nonlive (i.e., dead plus resorbed) or affected (i.e., nonlive or malformed) fetuses increased across dose groups, and each was significantly elevated in the 30 mg/kg/day CPZ group. In addition, the proportion of litters with one or more nonlive or affected fetuses was elevated above the control group for each CPZ treatment group.
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 males and females equally affected on this measure. Fetal body weight was significantly below controls for both sexes in litters from dams treated with CPZ, 15 or 30 mg/kg/day. The percentage of fetuses malformed per litter and the proportion of litters with one or more malformed fetuses increased significantly with increasing dose. The incidence of malformations was significantly increased above controls in the high-dose group (30 mg/kg/day CPZ) which exhibited an average incidence of 13.70% malformed fetuses; malformations occurred in 8/18 (44%) litters and included open eye, cleft palate, hydronephrosis, missing rib(s), or fused ribs. In contrast, the control group had an average incidence of 1.14% malformed fetuses per litter, and 3/27 (11.11%) litters contained one or more malformed fetuses.
In conclusion, CPZ (0, 2.5, 5, 15 or 30 mg/kg/day, po) administered on gd 6 through 15, produced dose-related maternal and fetal toxicity, increased prenatal mortality, and increased the incidence of malformations in CD-1 mice. No evidence for a teratogenic effect was seen except at doses which produced significant maternal and fetal toxicity.