EVALUATION OF THE DEVELOPMENTAL TOXICITY OF ETHYLENE-GLYCOL AEROSOL IN THE CD RAT AND CD-1 MOUSE BY WHOLE-BODY EXPOSURE

Ethylene glycol (EG) is a major industrial chemical, shown to be terat ogenic at high doses by gavage in rodents. Since one route of industri al exposure is to the aerosol at high concentrations, timed-pregnant C D rats and CD-1 mice were exposed, whole-body, to a respirable aerosol of EG (mass median aerodynamic diameter, 2.3 mu m) on Gestational Day s (GD) 6 through 15 for 6 hr per day at target exposure concentrations of 0, 150, 1000, or 2500 mg/m(3) (analytical concentrations of O, 119 +/- 13, 888 +/- 149, and 2090 +/- 244 mg/m(3), respectively), with 25 plug-positive animals per species per group. Clinical observations an d maternal body weights were documented throughout gestation for both species. Maternal food and water consumption was measured in rats only throughout gestation. At scheduled necropsy (GD 21 for rats, GD 18 fo r mice), maternal animals were evaluated for body weight, liver weight , kidney weight, gravid uterine weight, number of ovarian corpora lute a, and status of implantation sites, i.e., resorptions, dead fetuses, live fetuses. Fetuses were dissected from the uterus, counted, weighed , sexed, and examined for external, visceral, and skeletal malformatio ns and variations. All rat dams survived to scheduled termination. Min imal maternal toxicity was indicated by a significant increase in abso lute and relative liver weight at 2500 mg/ m(3). Food and water consum ption, maternal body weights and weight gain, and maternal organ weigh ts (other than liver) were unaffected by exposure. Gestational paramet ers were unaffected by exposure, including pre- and post-implantation loss, live fetuses/litter, sex ratio, and fetal body weight/litter. Th ere was no treatment-related increase in the incidence of any individu al malformation, in the incidence of pooled external, visceral, or ske letal malformations, or in the incidence of total malformations by fet us or by litter. There were no increases in the incidence of external or visceral variations. Evidence of fetotoxicity, expressed as reduced ossification in the humerus, the zygomatic arch, and the metatarsals and proximal phalanges of the hindlimb, was observed at 1000 and 2500 mg/m(3). All mouse dams survived to scheduled termination. One dam at 2500 mg/m(3) was carrying a totally resorbed litter at termination. Ma ternal toxicity was observed at 1000 and 2500 mg/m(3), expressed as re duced body weight and weight gain during and after the exposure period , and reduced gravid uterine weight. (Maternal effects may have been d ue, in part or in whole, to effects on the conceptuses; see below.) Em bryo/fetal toxicity was also observed at 1000 and 2500 mg/m(3), expres sed as an increase in nonviable implantations/litter, a reduction in v iable implantations/litter, and reduced fetal body weights (male, fema le, and total)/litter. The incidences of individual and pooled externa l, visceral, and skeletal malformations were increased at 1000 and 250 0 mg/m(3), as was the incidence of total malformations. Malformations were found in the head (exencephaly), face (cleft palate, foreshortene d and abnormal face, and abnormal facial bones), and skeleton (vertebr al fusions, and fused, forked, and missing ribs). The incidences of ma ny fetal variations were also increased at 1000 and 2500 mg/m(3) (and only a few at 150 mg/m(3)). The no observable adverse effect level (NO AEL) for maternal toxicity in rats was 1000 mg/m(3) (analytical concen tration 888 mg/m(3)) and in mice was 150 mg/m(3) (analytical concentra tion 119 mg/m(3)). The NOAEL for development toxicity in rats was 150 mg/m(3) and in mice was at or below 150 mg/m(3), under the conditions of this study. Analysis of EG on the fur of rats and mice during and a fter the exposure period at 2500 mg/m(3) indicated that much of the EG ''dose'' (similar to 65-95%) was potentially derived from ingestion a fter grooming and/or percutaneous absorption. This contribution of the ingested and/or absorbed chemical could have been sufficient, per se, to produce the teratogenic effects observed in mice. The definitive e valuation of the possible role of inhaled EG aerosol alone in teratoge nesis requires an exposure regimen which limits or precludes exposure by any other route. (C) 1995 Society of Toxicology.