In Vitro Metabolites of Di-2-ethylhexyl Adipate (DEHA) as Biomarkers of Exposure in Human Biomonitoring Applications

Abstract

Di-2-ethylhexyl adipate (DEHA) is a common plasticizer used in food packaging. At high doses, DEHA can cause adverse health effects in rats. Although the potential for human exposure to DEHA is high, no DEHA specific biomarkers are identified for human biomonitoring. Using human liver microsomes, we investigated the in vitro phase I metabolism of DEHA and its hydrolytic metabolite mono-2-ethylhexyl adipate (MEHA) and, for comparison purposes, of the analogous di-2-ethylhexyl phthalate (DEHP) and its hydrolytic metabolite mono-2-ethylhexyl phthalate. We unequivocally identified MEHA, a DEHA specific biomarker, and adipic acid, a nonspecific biomarker, using authentic standards. On the basis of their mass spectrometric fragmentation patterns, we tentatively identified two other DEHA specific metabolites: mono-2-ethylhydroxyhexyl adipate (MEHHA) and mono-2-ethyloxohexyl adipate (MEOHA), analogous to the oxidative metabolites of DEHP. Interestingly, although adipic acid was the major in vitro metabolite of DEHA, the analogous phthalic acid was not the major in vitro metabolite of DEHP. Our preliminary data for 144 adults with no known exposure to DEHA suggests that adipic acid is also the main in vivo urinary metabolite, while MEHA, MEHHA, and MEOHA are only minor metabolites. Therefore, the use of these specific metabolites for assessing the exposure of DEHA may be limited to highly exposed populations.

Identification of di-2-ethylhexyl terephthalate (DEHTP) metabolites using human liver microsomes for biomonitoring applications

“…However, human metabolites of DEHTP are unknown. In vitro studies have been used to identify metabolites of xenobiotic chemicals (Moslemi et al, 1993; Muhitch, 1993; Treadway and Pelkonen, 2006; Zulalian et al, 1993) which can be used as biomarkers of exposure to these chemicals (Silva et al, 2013b). …”

Wastewater-based epidemiology to assess human exposure to personal care and household products – A review of biomarkers, analytical methods, and applications

“…Two additional oxidative metabolites were identified in in vitro studies and proposed, in addition to MEHA, as specific human biomarkers of exposure to DEHA. However, their excretion rates seem to be low and the preliminary results suggested that their application may be limited to the highly exposed populations [ 76 ]. Indeed, a very recent pharmacokinetic study reported mean urinary excretion rates of three oxidized metabolites in humans between 0.05 % and 0.20 % [ 33 ].…”

“… Compound Biomarker Excretion rate (%) a Ref. Di-2-ethylhexyl adipate (DEHA) Mono-2-ethylhexyl adipate (MEHA) NA [ 76 ] b Mono-5-carboxy-2-ethylpentyl adipate (5cx-MEPA) 0.20 (0.17–0.24) [ 33 ] c Mono-2-ethylhydroxyhexyl adipate (5OH-MEHA) 0.07 (0.03–0.10) Mono-(2-ethyl-5-oxohexyl) adipate (5oxo-MEHA) 0.05 (0.01–0.06) Di(2-ethylhexyl) terephthalate (DEHTP) 1-Mono-(2-ethyl-5-carboxyl-pentyl) terephtahalate (5cx-MEPTP) 13.0 (7.0–20.4) [ 79 ] d 1-Mono-(2-ethyl-5-hydroxy-hexyl) terephtahalate (5OH-MEHTP) 1.8 (1.3–2.4) 1-Mono-(2-ethyl-5-oxo-hexyl) terephtahalate (5oxo-MEHTP) 1.0 (0.57–1.6) 1-Mono-(2-carboxyl-methyl-hexyl) terephtahalate (2cx-MEHTP) 0.28 (0.17–0.42) Di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) Cyclohexane-1,2-dicarboxylate-mono-(7-hydroxy-4-methyl) octyl ester (OH-MINCH) 10.7 (7.7–12.9) [ 81 ] d 14.5 (9.2–17.6) [ 82 ] e Cyclohexane-1,2-dicarboxylic mono oxoisononyl ester (oxo-MINCH) 2.0 (1.5–2.6) [ 81 ] d 4.8 (2.9−7.5) [ 82 ] e Cyclohexane-1,2-diarboxylic mono carboxyisononyl ester (cx-MINCH) 2.0 (1.8–2.3) [ 81 ] ...…”

Determination of volatile non intentionally added substances coming from a starch-based biopolymer intended for food contact by different gas chromatography-mass spectrometry approaches

“…Other potential plasticizers detected were 2,3-bis-(2-hydroxyethyl)glucitol and MEOHA (mono-2-ethyloxoexyl adipate). It is worth noting that MEOHA can be considered a proper NIAS, as it was found to be an oxidative metabolite of DEHA (2-ethylexyl adipate), which is widely used as a plasticizer for food contact plastics [49].…”