Conduct and interpretation of a dermal developmental toxicity study with KBR 3023 (a prospective insect repellent) in the Sprague-Dawley rat and Himalayan rabbit

KBR 3023, 1-(1-methyl-propoxycarbonyl)-2-(2-hydroxyethyl)piperidine, a pros pective insect repellent being developed by Bayer Corporation, was evaluate d for developmental toxicity in the Sprague-Dawley rat and Himalayan rabbit . As the intended human usage of the test compound is topical, the test sys tems were exposed to the compound via the dermal route. Specifically, the a nimals were fitted with Elizabethan collars, to reduce the likelihood of or al ingestion, and dermally administered either 0, 50, 200, or 400 mg KBR 30 23/kg (rat), and 0, 50, 100, or 200 mg KBR 3023/kg (rabbit) on gestation da ys 0-19 (rat) and 0-28 (rabbit). Maternal toxicity, as demonstrated by clin ical signs and changes in body weight gain and food consumption during gest ation, was characterized. Animals were sacrificed on gestation day 20 (rat) and 29 (rabbit), at which time fetuses were removed by cesarean section an d a gross maternal necropsy was performed. All fetuses were evaluated for e xternal anomalies. With rats, approximately half of each litter was examine d for visceral effects; the other half underwent a skeletal examination. Wi th rabbits, all fetuses underwent both visceral and skeletal examinations. No effects were observed on maternal body weight gain or food consumption i n either the rat or rabbit. In the rat, dermal effects (scaling/sloughing), were observed at the dose site of all test substance-treated groups from a pproximately gestation day 7 until termination of the study. Also noted wer e an increase in both absolute and relative liver weights in rats in the 40 0-mg/kg dose group. In the rabbit, dermal effects (slight erythema, squamou s and cracked skin) were noted at the dose site of virtually all does admin istered the test compound, from approximately gestation day 7 until termina tion. Also observed in the rabbits was a potentially compound-related incre ase in soft stool, particularly at the highest dose level. In both species, there were no statistically significant effects on any reproductive parame ters, or any embryonic endpoints, including pre/post-implantation loss and resorptions. There were no statistically significant effects on litter size or fetal or placental weights. No test compound-related external, visceral , or skeletal findings were observed. No effect on the individual fetal or litter incidence of total malformations or variations was observed and ther e was no difference in the incidence of malformations between males and fem ales. KBR 3023 Technical, administered as described in these studies, produ ced maternal effects in the rat (liver weight) at a dose of 400 mg/kg, and in the rabbit (soft stool) in the 200-mg/kg dose group. No developmental to xicity was observed at any dose level. (C) 2000 Wiley-Liss, Inc.