Ethyl t-butyl ether: review of reproductive and developmental toxicity

Ethyl t-butyl ether (ETBE) is a motor fuel oxygenate used in reformulated gasoline. Knowledge of developmental and reproductive toxicity potential of ETBE is critical for making informed decisions about acceptance and regulations. This review discusses toxicology studies providing information about effects on reproduction and the conceptus. Seven GLP-compliant studies following widely accepted protocols have focused specifically on developmental and reproductive toxicity (DART) in rats and rabbits exposed to ETBE by gavage with doses up to 1,000 mg/kg body weight/day, the limit specified in standardized test guidelines. Other repeat-dose general toxicology studies have administered ETBE to rodents for up to 180 days, and included reproductive organ weights, histology, or other indications of reproductive system structure or function. DART potential of the main ETBE metabolite t-butyl alcohol and class-related MTBE has also been studied. More GLP-compliant studies exist for evaluating ETBE using well-established, currently recommended protocols than are available for many other chemicals used today. The database for determining ETBE DART potential is adequate, although not all study details are currently easily accessible for peer-review. ETBE does not appear to be selectively toxic to reproduction or embryofetal development in the absence of other manifestations of general toxicity. Studies using recommended methods for sample preservation and analysis have shown no targeted effect on the reproductive system. No embryofetal effects were observed in rabbits. Early postnatal rat pup deaths show no clear dose-response and have largely been attributed to total litter losses with accompanying evidence of maternal neglect or frank maternal morbidity.