Evaluation of the Developmental Toxicity of Ethylene Glycol Aerosol in the CD Rat and CD-1 Mouse by Whole-Body Exposure

Abstract

Evaluation of the Developmental Toxicity of Ethylene Glycol Aerosol in the CD Rat and CD-1 Mouse by Whole-Body Exposure. Tyl, R. W., Ballantyne, B., Fisher, L. C., Fait, D. L., Savine, T. A., Dodd, D. E., Klonne, D. R., and Pritts, I. M. (1995). Fundam. Appl. Toxicol.24, 57-75.Ethylene glycol (EG) is a major industrial chemical, shown to be teratogenic at high doses by gavage in rodents. Since one route of industrial exposure is to the aerosol at high concentrations, timed-pregnant CD rats and CD-1 mice were exposed, whole-body, to a respirable aerosol of EG (mass median aerodynamic diameter, 2.3 μm) on Gestational Days (GD) 6 through 15 for 6 hr per day at target exposure concentrations of 0, 150, 1000, or 2500 mg/m3 (analytical concentrations of 0, 119 ± 13, 888 ± 149, and 2090 ± 244 mg/m3, respectively), with 25 plug-positive animals per species per group. Clinical observations and 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 for mice), maternal animals were evaluated for body weight, liver weight, kidney weight, gravid uterine weight, number of ovarian corpora lutea, 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 malformations and variations. All rat dams survived to scheduled termination. Minimal maternal toxicity was indicated by a significant increase in absolute and relative liver weight at 2500 mg/m3. Food and water consumption, maternal body weights and weight gain, and maternal organ weights (other than liver) were unaffected by exposure. Gestational parameters were unaffected by exposure, including pre- and post-implantation loss, live fetuses/litter, sex ratio, and fetal body weight/litter. There was no treatment-related increase in the incidence of any individual malformation, in the incidence of pooled external, visceral, or skeletal malformations, or in the incidence of total malformations by fetus 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 hind-limb, was observed at 1000 and 2500 mg/m3. All mouse dams survived to scheduled termination. One dam at 2500 mg/m3 was carrying a totally resorbed litter at termination. Maternal toxicity was observed at 1000 and 2500 mg/m3, expressed as reduced body weight and weight gain during and after the exposure period, and reduced gravid uterine weight. (Maternal effects may have been due, in part or in whole, to effects on the conceptuses; see below.) Embryo/fetal toxicity was also observed at 1000 and 2500 mg/m3, expressed as an increase in nonviable implantations/litter, a reduction in viable implantations/litter, and reduced fetal body weights (male, female, and total)/litter. The incidences of individual and pooled external, visceral, and skeletal malformations were increased at 1000 and 2500 mg/m3, as was the incidence of total malformations. Malformations were found in the head (exencephaly), face (cleft palate, foreshortened and abnormal face, and abnormal facial bones), and skeleton (vertebral fusions, and fused, forked, and missing ribs). The incidences of many fetal variations were also increased at 1000 and 2500 mg/m3 (and only a few at 150 mg/m3). The no observable adverse effect level (NOAEL) for maternal toxicity in rats was 1000 mg/m3 (analytical concentration 888 mg/m3) and in mice was 150 mg/m3 (analytical concentration 119 mg/m3). The NOAEL for development toxicity in rats was 150 mg/m3 and in mice was at or below 150 mg/m3, under the conditions of this study. Analysis of EG on the fur of rats and mice during and after the exposure period at 2500 mg/m3 indicated that much of the EG "dose" (∼65-95%) was potentially derived from ingestion after 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 evaluation of the possible role of inhaled EG aerosol alone in teratogenesis requires an exposure regimen which limits or precludes exposure by any other route.