Kinetics of di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate in blood and of DEHP metabolites in urine of male volunteers after single ingestion of ring-deuterated DEHP

The plasticizer di(2-ethylhexyl) phthalate (DEHP) is suspected to induce antiandrogenic effects in men via its metabolite mono(2-ethylhexyl) phthalate (MEHP). However, there is only little information on the kinetic behavior of DEHP and its metabolites in humans. The toxikokinetics of DEHP was investigated in four male volunteers (28-61 y) who ingested a single dose (645 +/- 20 mu g/kg body weight) of ring-deuterated DEHP (DEHP-D-4). Concentrations of DEHP-D-4, of free ring-deuterated MEHP (MEHP-D-4), and the sum of free and glucuronidated MEHP-D-4 were measured in blood for up to 24 h; amounts of the monoesters MEHP-D-4, ring-deuterated mono(2-ethyl-5-hydroxyhexyl) phthalate and ring-deuterated mono(2-ethyl-5-oxohexyl) phthalate were determined in urine for up to 46 h after ingestion. The bioavailability of DEHP-D-4 was surprisingly high with an area under the concentration-time curve until 24 h (AUC) amounting to 50% of that of free MEHP-D-4. The AUC of free MEHP-D-4 normalized to DEHP-D-4 dose and body weight (AUC/D) was 2.1 and 8.1 times, that of DEHP-D-4 even 50 and 100 times higher than the corresponding AUC/D values obtained earlier in rat and marmoset, respectively. Time courses of the compounds in blood and urine of the volunteers oscillated widely. Terminal elimination half-lives were short (4.3-6.6 h). Total amounts of metabolites in 22-h urine are correlated linearly with the AUC of free MEHP-D-4 in blood, the parameter regarded as relevant for risk assessment. (C) 2012 Elsevier Inc. All rights reserved.