Dose-dependent uptake, distribution, and elimination of inhaled n-hexane in the Fischer-344 rat

Abstract

n-Hexane-induced neuropathy is thought to be mediated through metabolism to 2,5-hexanedione (2,5HD), but there is no information on target tissue concentrations of 2,5HD after inhalation exposure to a range of n-hexane vapor concentrations. Male Fischer-344 rats were exposed to 500, 1000, 3000, and 10,000 ppm n-hexane in the air. n-Hexane and its metabolites methyl- n-butyl ketone (MBK), 2,5-dimethylfuran (DMFU), 2,5HD, 2-hexanol, and 1-hexanol were quantified by GC MS in several tissues at time intervals during and following a single 6-hr exposure to n-hexane. Urinary metabolites were quantified following a single n-hexane exposure. n-Hexane concentrations achieved an apparent steady state within 2 hr in all tissues. Peak blood concentrations of n-hexane were 1, 2, 8, and 21 μg/ml and peak sciatic nerve concentrations were 12, 48, 130, and 430 μg/g at 500, 1000, 3000, and 10,000 ppm, respectively. The half-lives of n-hexane and MBK were on the order of 1 to 2 hr in all tissues except the kidneys ( t 1 2 = 5 to 6 hr ). The data showed a complex relationship between n-hexane exposure and peak concentrations of the remaining metabolites. Tissue concentrations of 2,5HD, the metabolite of greatest toxicological interest, were not proportional to dose. Highest 2,5HD concentrations were found following exposure to 1000 ppm n-hexane in the blood, kidneys, and sciatic nerve (6.1, 55, and 25 μg/g, respectively). The data indicated that the metabolism and elimination of n-hexane were dependent upon exposure concentration. Consequently, n-hexane exposure concentration cannot be directly correlated with tissue 2,5HD concentrations, and severity of neuropathy may not be directly related to n-hexane exposure concentration.