Urine 4-heptanone: a beta-oxidation product of 2-ethylhexanoic acid from plasticisers

4-Heptanone is a common volatile constituent of human urine and is of unkno wn origin. We hypothesised that it arises from in vivo beta -oxidation of 2 -ethylhexanoic acid (EHA) from plasticisers, similar to formation of 3-hept anone from valproic acid. We investigated urine from individuals with norma l and increased plasticiser exposure. Using GC/MS, solvent-extracted organi c acids were analysed as trimethylsilyl (TMS) derivatives and heptanone wit h headspace solid-phase microextraction. We identified 3-oxo-2-ethylhexanoi c acid, the beta -oxidation product of EHA, as an enol in ah samples. This is the first report of its TMS mass spectrum. We also found 2-ethyl-1,6-hex anedioic acid and 5-hydroxyEHA, omega- and omega -1-oxidation products of E HA, respectively, and 2-ethylhexanoylglucuronide, but only in trace amounts in some plasticiser samples. These compounds have not been reported in hum an urine, nor has the TMS mass spectrum of 5-hydroxyEHA. The median concent rations of 3-oxoethylhexanoic acid and total 4-heptanone of seven plasticis er samples were around 30-175-fold higher than normal samples. 4-Heptanone was barely detectable and 3-oxoethylhexanoic acid was not increased in an e ighth plasticiser sample, from a baby with deficiency of 2-methylbranched-c hain acyl-CoA dehydrogenase. beta -Oxidation is a major catabolic pathway o f EHA in man, and might be involved in the metabolism of other branched-cha in drugs and environmental pollutants. (C) 2001 Elsevier Science B.V. All r ights reserved.