Acute gavage administration of a single dose of 2-butoxyethanol (BE) to male F344/N rats caused severe hemolytic anemia as evidenced by a decrease in the number of circulating red blood cells, hemoglobin concentration, and hematocrit. The hemolytic effects of BE were found to be dose-dependent. BE also caused hemoglobinuria and liver and kidney changes both of which were considered secondary to the hemolytic effects of BE. We have found that BE-toxicity is age related with young rats being significantly less sensitive than older rats. Gavage dosing with 125mg/kg BE for 1 or 2 days resulted in a significant increase in BE hematotoxicity in rats treated for 2 days. However, continued daily administration of BE beyond 2 days resulted in a gradual decrease in the Be-induced hematotoxicity which is indicative of tolerance development. Tolerance was attributed to a decline in the hemolytic effects of BE with multiple dosing. Further, we have investigated the metabolic basis of Be-induced hematotoxicity. Pretreatment of rats with pyrazole has protected rats against Be-induced hematotoxicity, which suggested that metabolic activation via the alcohol dehydrogenase enzyme is a prerequisite for the development of BE toxicity.
