Urinary oxidative metabolites of di(2-ethylhexyl) phthalate in humans

Di(2-ethylhexyl) phthalate (DEHP) is added to polyvinyl chloride (PVC) plastics used widely in medical devices and toys to impart flexibility and durability. DEHP produces reproductive and development toxicities in rodents. Initial metabolism of DEHP in animals and humans results in mono(2-ethylhexyl) phthalate (MEHP), which subsequently metabolizes to a wide range of oxidative metabolites before being excreted in urine and feces. We investigated the metabolism of DEHP in humans by identifying urinary oxidative metabolites of DEHP from individuals with urinary MEHP concentrations about 100 times higher than the median concentration in the general US population. In addition to the previously identified DEHP metabolites MEHP, mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono(2-carboxymethylhexyl) phthalate (MCMHP), we also identified for the first time in humans three additional oxidative metabolites, mono(2-ethyl-3-carboxypropyl) phthalate (MECPrP), mono(2-ethyl-4-carboxybutyl) phthalate (MECBP), and mono(2-(1-oxoethyl)hexyl) phthalate (MOEHP) based on their chromatographic behavior and mass spectrometric fragmentation patterns. We also tentatively identified metabolites with two functional groups in the side alkyl chain as isomers of mono(2-hydroxyethyl-4-carboxybutyl) phthalate (MHECBP), mono(2-ethyl-4-oxo-5-carboxypentyl) phthalate (MEOCPP), and mono(2-ethyl-4-hydroxy-5-carboxypentyl) phthalate (MEHCPP). We report the presence of urinary DEHP metabolites in humans that have fewer than eight carbons in the alkyl chain. These metabolites were previously identified in rodents. Although quantitative information is not available, our findings suggest that, despite potential differences among species, the oxidative metabolism of DEHP in humans and rodents results in similar urinary metabolic products.