Comparison of the acute hematotoxicity of 2-butoxyethanol in male and female F344 rats

Administration of 2-butoxyethanol (BE) to rodents causes acute hemolytic an emia, and metabolic activation of BE to butoxyacetic acid (BAA) is required for the development of this effect. Recent studies have shown that female rats treated with BE exhibit a variety of histopathologic lesions that are absent in males and many of these lesions are attributed to the hemolytic e ffects of BE. Current studies were designed to compare the acute hematotoxi city of BE in male and female F344 rats. Rats were treated with 250 mg BE/k g body weight or water (control; 5 ml/kg) by gavage. At 4, 8, or 24 h after dosing, rats were anesthetized, blood was collected by cardiac puncture, a nd various blood parameters were measured. BE resulted in a time-dependent swelling of erythrocytes as evidenced by an early increase in hematocrit (H ct) and mean cell volume (MCV) in male rats. In contrast, increased Hct in female rats did not accompany an increase in MCV. It is likely that hemolys is was so severe at 4h that Hct exhibited a decline in female rats at that time point. Subsequently, red blood cell (RBCs), hemoglobin concentration ( Hgb), and Hct declined as hemolysis progressed. However, the onset of BE-in duced hemolysis was faster in female compared to male rats. These effects w ere also associated with a significant increase in the spleen weight to bod y weight ratio. Blood smears were also prepared and morphological changes e valuated by light microscopy included stomatocytosis, spherocytosis, and sc histocytosis. Furthermore, aggregation of RBCs in female rats as evidenced by increased formation of rouleaux was observed at 24 h after BE administra tion. These effects were observed earlier and more frequently in female rat s. No differences in the sensitivity of RBCs obtained from male and female rats and exposed to butoxyacetic acid (BAA) in vitro was observed as determ ined by measuring the packed cell volume. In conclusion, these data suggest that female rats are more sensitive to hemolysis and morphological alterat ions of erythrocytes induced by BE during the first 24 h after exposure com pared to males. It is likely that the greater sensitivity of female rats to BE effects on RBCs may account for the reported development of thrombosis and tissue infarction in female rats.