Evaluation of the Developmental Toxicity of Methacrylonitrile in Sprague-Dawley Rats and New Zealand White Rabbits

Timed-pregnant Sprague-Dawley (CD) outbred rats and New ZealandWhite rabbits were dosed by gavage with methacrylonitrile (MACR)in distilled water during major organogenesis. Rats were dosedon Gestational Days (GD) 6 through 15 (0, 5, 25, or 50 mg MACR/kg/day)and rabbits on GD 6 through 19 (0, 1, 3, or 5 mg MACR/kg/day).Maternal clinical status was monitored daily during treatment.At termination (GD 20, rats; GD 30, rabbits), confirmed-pregnantfemales (25–26 per group, rats; 17–22 per group,rabbits) were evaluated for clinical status and gestationaloutcome; each live fetus was examined for external, visceral,and skeletal malformations. In rats, no treatment-related maternalclinical signs or mortality were observed, nor was there anyadverse effect on maternal body weight or food or water consumption.At necropsy, absolute, relative, and adjusted maternal liverweight was increased at the mid- and high-dose groups, an effectthat may be indicative of induction of hepatic enzymes ratherthan toxicity. In the absence of any indication of maternaltoxicity, the no-observed-adverse-effect level (NOAEL) for maternaltoxicity in this study was 50 mg MACR/kg/day. The NOAEL fordevelop mental toxicity in rats was also 50 mg MACR/kg/day.There was no effect of treatment on postimplantation loss, meanfetal body weight per litter, or morphological development.In rabbits, maternal mortality and clinical signs were not doserelated. Maternal food consumption, body weight, and liver weightwere not adversely affected by treatment. Thus, the maternalNOAEL was 5 mg MACR/kg/day. Maternal toxicity, including death,was observed 7.5 mg/kg/day in preliminary studies. The developmentalNOAEL was also 5 mg MACR/kg/day. There was no adverse effectof treatment on postimplantation loss or fetal body weight.A significant decrease in the percentage male fetuses per litterwas observed, although there was no effect on total live littersize, suggesting that the reduction in the ratio of live malefetuses in the high-dose group was not biologically significant.MACR had no adverse effect on morphological development. Insummary, oral administration of MACR to rats and rabbits duringorganogenesis, at doses that did not cause persistent maternaltoxicity (50 mg MACR/kg/day, rats; 5 mg MACR/kg/day, rabbits),also did not cause any adverse developmental effects.