Metabolism and urinary excretion kinetics of di(2-ethylhexyl) adipate (DEHA) in four human volunteers after a single oral dose

Abstract

Di(2-ethylhexyl) adipate (DEHA) is used as a substitute for the reprotoxic phthalate plasticizer di(2-ethylhexyl) phthalate (DEHP). This study reports the first quantitative data on human in vivo DEHA metabolism and urinary metabolite excretion with the aim of providing tools for DEHA exposure and risk assessments. After DEHA was administered to four healthy volunteers (107-164 μg/kg body weight (bw)), urine samples were continuously and completely collected for 48 h and analyzed for the specific oxidized monoester metabolites mono-2-ethyl-5-hydroxyhexyl adipate (5OH-MEHA), mono-2-ethyl-5-oxohexyl adipate (5oxo-MEHA), and mono-5-carboxy-2-ethylpentyl adipate (5cx-MEPA), as well as for the non-specific hydrolysis product adipic acid (AA) using stable isotope dilution analysis. AA was confirmed as a major (urinary excretion fraction (F_UE): 10-40%), yet non-specific DEHA metabolite. 5cx-MEPA was the major specific DEHA metabolite with an F_UE of 0.20% (range: 0.17-0.24%). F_UEs for 5OH-MEHA and 5oxo-MEHA were 0.07% (0.03-0.10%) and 0.05% (0.01-0.06%), respectively. The three specific metabolites were excreted with two concentration maxima (t_max1 = 1.5-2.3 h, t_max2 = 3.8-6.4 h). Elimination half-lives (t_1/2, calculated after the second t_max) for 5cx-MEPA were calculated between 2.1-3.8 h. The majority (98-100%) of metabolites was excreted within 24 h. The F_UE of 5cx-MEPA was applied to demonstrate its applicability for calculating daily intakes based on urinary metabolite levels from three pilot populations. Daily intakes were generally far below the tolerable daily intake (TDI) for DEHA (300 μg/kg bw/day). The highest daily intake (114 μg/kg bw/day) was calculated in individuals after consuming food that had been wrapped in DEHA containing cling film.

Keywords: DEHA; Di(2-ethylhexyl) adipate; Human biomonitoring; Metabolism; Oral dose; Plasticizer.