Daily Intravenous Infusion of Busulfan Impurity 5 for 4 Days Is Not Associated With Toxic Effects in the Rat

Abstract

The alkylating agent busulfan is used in conditioning treatment of chronic myelogenous or granulocytic leukemia prior to stem cell transplantations. Its cytotoxic activity results in primary damage or destruction of hematopoietic cells. While the toxicity of busulfan is well investigated, little is known about the toxic effects of its impurities. In this study, the effect of 4-day intravenous infusion (3 h/d) of 4.8 mg/kg/d busulfan and 0.49, 4.9, and 49 mg/kg/d busulfan impurity 5 (4-((methylsulfonyl)oxy)butyl acetate) was investigated in rats. Whereas busulfan elicited myelotoxic and hepatotoxic effects, no toxic effects were observed in animals receiving the impurity at dosages up to 10 times higher than busulfan. The highest impurity dose of 49 mg/kg/d is therefore considered the no-observed-adverse-effect level of busulfan impurity 5.