Developmental Toxicity Study withN-Methyldiethanolamine by Repeated Cutaneous Application to CD Rats

Abstract

Timed pregnant CD rats were dosed cutaneously with aqueous N-methyldiethanolamine (MDEA) daily from gestational day (gd) 6 to 15, inclusive. Dosages employed were 0, 250, 500, and 1000 mg/kg/day and were selected on the basis of maternal toxicity responses determined from a range-finding study. Observations for maternal toxicity included body weight, food consumption, and clinical signs. Prior to scheduled necropsy on gd 21, blood was obtained for hematological study. At necropsy, liver and kidney, which are putative target organs of ethanolamine toxicity, were weighed. Fetuses were evaluated for body weight, and for external, visceral, and skeletal anomalies. Severe skin irritation characterized by necrosis, ecchymoses, exfoliation, crusting, excoriation, erythema, and edema was noted in dams receiving 1000 mg/kg/day during the dosing period. Exfoliation, crusting, necrosis, and erythema persisted subsequent to the dosing period, but by sacrifice on gd 21, substantial repair of the dosing site had occurred. In dams receiving 500 mg/kg/day less severe skin irritation was noted, but no local irritation was seen at the dosage of 250 mg/kg/day. There were no effects on maternal body weight; gestational weight gain; food consumption; or liver, kidney, or gravid uterine weights at any of the MDEA-dosed groups. Dams from the 1000 mg/kg/day group had decreases in erythrocyte count, hemoglobin, and hematocrit. There were no effects on any gestational parameters, and no increases in the total number of malformations or variations (external, visceral, or skeletal) by category or individually. In conclusion, rat dams showed dose-dependent skin irritation following repeated cutaneous application of MDEA during pregnancy. In addition, maternal toxicity was also present as anemia in dams receiving 1000 mg/kg/day. Despite maternal toxicity, there was no evidence of developmental effects. The no-observed-adverse effect level was 250 mg/kg/day for maternal toxicity, and at or above 1000 mg/kg/day for embryofetal toxicity and teratogenicity.