Commercial-grade methyl heptyl ketone (5-methyl-2-octanone) neurotoxicity: Contribution of 5-nonanone

Abstract

Methyl heptyl ketone (MHK) was the only one of a series of commercial-grade, aliphatic solvents tested (i.e., diisoamyl ketone, diisobutyl ketone, methyl isoamyl ketone, di- n-propyl ketone, and n-heptane) that produced toxic neuropathy in laboratory rats. The neuropathy produced by MHK was clinically and morphologically identical to that previously reported for n-hexane, methyl n-butyl ketone (M nBK), and 2,5-hexanedione. GC-MS analyses of MHK revealed that it was a mixture of approximately 72% 5-methyl-2-octanone (5M2O), 12% 5-nonanone, 0.8% M nBK, and 15.2% C 7–C 10 ketones and alkanes. Experimentation with purified samples of 5M2O and 5-nonanone resulted in clinical neurotoxicity with 5-nonanone at doses 4.3 times higher than in the commercial mixture. Neurotoxicity was not produced with 5M2O. By combining 5M2O and 5-nonanone in the same proportion as in MHK, the degree of neurotoxicity seen with MHK was reproduced, suggesting that 5M2O potentiates 5-nonanone approximately sixfold. When an equimolar dose of methyl ethyl ketone (MEK) was substituted for 5M2O, little or no potentiation was observed. These findings suggest that MEK, a potentiator of n-hexane and M nBK neurotoxicity, is not a universal potentiator for this type of toxic neuropathy. Serum analyses of rats given MHK showed concentrations of M nBK that could only be accounted for by the metabolic transformation of 5-nonanone to M nBK. Thus commercial-grade MHK neurotoxicity appears principally to be due to the neurotoxic properties of 5-nonanone potentiated by 5M2O. Metabolic studies confirmed the in vivo conversion of 5-nonanone to 2,5-nonanedione, M nBK, and 2,5-hexanedione, the latter of which is the most active neurotoxic metabolite of n-hexane and M nBK. The neurotoxicities of n-hexane, M nBK, and 5-nonanone are linked by virtue of their metabolism to a γ-diketone, 2,5-hexanedione.