Embryo-Fetal Developmental Toxicity of Compounded Diphenhydramine Hydrochloride and Caffeine Formulation Tested on Pregnant SD Rats

Embryonic-fetal developmental toxicity of compounded diphenhydramine hydrochloride (DH) and caffeine formulation has been studied by intragastric administration to pregnant SD rats. Between days 6 and 15 of pregnancy, SD rats in different groups received a low-, medium-, and high-dose of binary formulation containing DH and caffeine (DHC), a single-medication formulation containing DH, or a single-medication formulation containing caffeine. No animal deaths or clinical toxicity manifestations related to these treatments were observed in any test group. Three test groups treated with DHC formulation, as well as the DH group, showed no apparent drug influence on the body weight of pregnant rats. However, the use of caffeine alone had an impact on the body weight gain of pregnant rats (P < 0.05), which indicated maternal toxicity. The single use of caffeine alone had an impact on the food intake during pregnancy, and the food intake was recovered after medication discontinuation (P < 0.05). Except for the caffeine group, the three compounded formulation dose groups and the DH group exhibited no apparent embryonic toxicity (P > 0.05). Besides, the administration of caffeine to pregnant rats (144 mg/kg) caused fetal toxicity and influenced fetal sternal development (P < 0.05). The low, medium, and high doses of compounded DHC formulation and the single-medication DH formulation caused neither adverse reactions in pregnant rats nor impeded embryonic and fetal development. However, a single-medication formulation containing caffeine at a dose of 144 mg/kg caused toxicity to pregnant rats as well as to embryonic and fetal development.