Developmental phase-specific and dose-related teratogenic effects of ethylene glycol monomethyl ether in CD-1 mice

Several animal species have shown a teratogenic response to inhaled or ingested ethylene glycol monomethyl ether (EGME). The present study examined the developmental phase specificity and dose-response characteristics of EGME-induced embryotoxicity. Pregnant CD-1 mice (vaginal plug positive day = gestation Day [gd]0) received multiple or single doses of EGME by gavage between gd 7 and 14. Fetuses were examined on gd 18 for external and skeletal malformations. EGME was not maternally toxic after multiple doses of 250 mg/kg or a single administration of up to 500 mg/kg. EGME induced embryotoxicity as manifested by reduced gd 18 fetal weights and increased resorptions. The observed malformations were specifically related to the developmental stage at the time of exposure. Exencephaly resulted after EGME exposure between gd 7 to 10 whereas paw anomalies (syndactyly, oligodactyly, and stunted digit No. 1) predominated during later stages of development. Paw anomalies were maximal after administration on gd 11, and forepaws exhibited greater susceptibility than hindpaws. The no observed effect dose for the induction of digit malformations after a single administration of EGME on gd 11 was 100 mg/kg. At 175 mg EGME/kg digit anomalies were induced without any concurrent reduction in fetal body weight while at 250 mg/kg and above, digit anomalies occurred concurrently with reduced fetal body weight.