Diphenhydramine HCl, a widely used antihistamine, was evaluated for toxic and teratogenic effects in CD-1 mice. DPH (0, 40, 80, and 160 mg/kg/day, po) in distilled water was administered in a volume of 0.01 ml per gram of body weight on days 6 through 15 of gestation. Dams were weighed and observed daily during treatment for clinical signs of toxicity. At sacrifice on gestational day 17, 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 treatment DPH-treated dams exhibited dose-related clinical signs of toxicity including hyperactivity, weight loss, convulsions and death. Maternal weight gain during the treatment period was significantly reduced for dams treated with 80 or 160 mg/kg/day DPH. In addition, dams receiving the high dose (160 mg/kg/day, DPH) showed significantly decreased maternal body weight on the final day of treatment (i.e., gestational day 15), decreased absolute maternal weight gain during gestation (i.e., not including gravid uterine weight), and decreased average fetal body weight per litter. Although the overall incidence of affected fetuses (i.e., resorbed, dead and malformed) did not increase significantly across treatments, a statistically significant dose-related trend toward increased cleft palate was observed. Although the incidence of cleft palate in the present study was higher than the historical control incidence observed in this laboratory, the incidence was not statistically greater than concurrent controls for any individual treatment group. These results suggest that diphenhydramine hydrochloride may tend to increase the incidence of cleft palate in CD-1 mice, but only at dose levels which produce overt signs of toxicity in the dams.