A twenty-volunteer study using deuterium labelling to determine the kinetics and fractional excretion of primary and secondary urinary metabolites of di-2-ethylhexylphthalate and di-iso-nonylphthalate

Abstract

This study has obtained estimates of the kinetics and fractional excretion factors of metabolism of DEHP and DINP to their main primary and secondary metabolites. Samples were obtained from an open-label, fixed sequence, single oral dose study in 10 male and 10 female subjects. The dosed substances were deuterated di-2-ethylhexylphthalate (D(4)-DEHP) and di-isononylphthalate (D(4)-DINP) at two dose levels. Urine samples were collected at intervals up to 48 h post-dose. LC-MS/MS was used to measure metabolite concentrations. Excreted amounts were then calculated using urine volumes. Metabolite half-lives were estimated to be 4-8h with more than 90% of metabolites in the first 24h of urine collections and the remainder in the 24-48 h period. The four metabolites of DEHP amounted to 47.1 ± 8.5% fractional excretion on a molar basis. For DINP the identified metabolites totalled 32.9 ± 6.4%. For both DEHP and DINP the metabolites were in the abundance order -monoester<-oxo<-carboxy<-hydroxy. These robust fractional excretion values for the main primary and secondary phthalate metabolites along with estimates of their uncertainty can be used in future surveys of human exposure to DEHP and DINP.