Further studies on ketone neurotoxicity and interactions.

Ethyl n-butyl ketone (EBK, 3-heptanone) has not been reported to produce neurotoxicity in previous studies when it was given by oral or inhalation routes. In the present study, EBK given by gavage at 2 g/kg/day, 5 days/week for 14 weeks produced a typical central-peripheral distal axonopathy characterized by "giant" axonal swelling and neurofilamentous hyperplasia. This dose approximates the single dose LD50 (2.76 g/kg) of EBK determined by Smyth et al., (J. Ind. Hyg. Toxicol. 31, 60-62, 1949). Large multiple doses (1.5 g/kg/day, 5 days/week, 14 weeks) of methyl ethyl ketone (MEK) given by gavage potentiated EBK neurotoxicity but 5-methyl-2-octanone did not. MEK modestly increased the urinary excretion of two neurotoxic gamma-diketones, 2,5-heptanedione, and 2,5-hexanedione, when MEK was given by gavage with EBK. When rats were exposed to EBK (700 ppm) and MEK (700 or 1400 ppm) in combination by inhalation exposure, serum 2,5-heptanedione levels were increased approximately 2.5 times. This effect was absent at MEK levels of 70 ppm. The serum from rats exposed to EBK or EBK/MEK combinations did not contain 2,5-hexanedione. The toxicity of EBK appears to involve the metabolism of EBK to two neurotoxic gamma-diketones, 2,5-heptanedione and 2,5-hexanedione. Combined EBK/MEK exposure modestly increased gamma-diketone levels in the serum and urine suggesting that MEK potentiates EBK neurotoxicity by stimulating the metabolism of EBK to neurotoxic metabolites. The magnitude of the doses used in the present study to produce neurotoxicity and the absence of neurotoxicity in previous subchronic studies suggest that the neurotoxic hazard of EBK is low.