Developmental toxicity evaluation of inhaled 2-ethoxyethanol acetate in Fischer 344 rats and New Zealand white rabbits

Abstract

Pregnant Fischer 344 rats and New Zealand white rabbits were exposed to 2-ethoxyethanol acetate (EEA; CAS No. 111–159) vapor by inhalation on Gestational Days 6 through 15 (rats) or 6 through 18 (rabbits) at concentrations of 0, 50, 100, 200, or 300 ppm, 6 hr/day. The animals were terminated on Gestational Day 21 (rats) or 29 (rabbits) and fetuses were examined for external, visceral, and skeletal malformations and variations. In rabbits, exposure to 100–300 ppm resulted in maternal toxicity: decreased weight gain at 100–300 ppm, clinical signs at 200–300 ppm, alterations in hematology at 100–300 ppm, reduced gravid uterine weight at termination at 200–300 ppm, and elevated absolute liver weight at 300 ppm. Developmental toxicity was observed at 100–300 ppm: an increased incidence of totally resorbed litters at 200–300 ppm, an increase in nonviable fetuses at 300 ppm, and a decrease in viable implants (live fetuses) per litter at 200–300 ppm. The incidence of fetal malformations (external, visceral, and skeletal) was increased at 200–300 ppm. The incidence of total malformations was 100% at 300 ppm and significantly increased at 200 ppm. Reduced fetal ossification was observed at 100–300 ppm. In rats, exposure to 100–300 ppm also resulted in maternal toxicity: reduced weight gain and reduced food consumption at 200–300 ppm and elevated relative liver weight and alterations in hematology at 100–300 ppm. Absolute maternal liver weight was increased at all EEA exposure concentrations; relative liver weight was increased at 100–300 ppm. Developmental toxicity was observed at 100–300 ppm: increased nonviable implantations/litter (300 ppm), reduced fetal body weight/litter (200–300 ppm), and increased incidence of external (300 ppm), visceral, and skeletal (100–300 ppm) variations indicative of toxicity. The incidence of visceral, skeletal, and total malformations was increased at 200–300 ppm. In conclusion, in both species, inhalation exposure to EEA during organogenesis produced maternal toxicity at 100–300 ppm and developmental toxicity at 100–300 ppm, including teratogenicity at 200–300 ppm. At 50 ppm in both species, there was no evidence of maternal or developmental toxicity, including teratogenicity.