Metabolism of the plasticizer and phthalate substitute diisononyl-cyclohexane-1,2-dicarboxylate (DINCH®) in humans after single oral doses

Abstract

Hexamoll(®) DINCH(®) (diisononyl-cyclohexane-1,2-dicarboxylate) is a new high-molecular-weight plasticizer and a phthalate substitute. In this study, the metabolism of DINCH(®) was investigated by oral dosage of three male volunteers with approximately 50 mg Hexamoll(®) DINCH(®) (resulting in individual doses between 0.552 and 0.606 mg/kg body weight). Their urine samples were consecutively collected over 48 h. In analogy to di-iso-nonylphthalate (DINP) metabolism, we quantified the simple monoester mono-isononyl-cyclohexane-1,2-dicarboxylate (MINCH) and its secondary oxidized metabolites with HPLC-MS/MS via isotope dilution analysis. Additionally, we quantified the unspecific full breakdown product, cyclohexane-1,2-dicarboxylic acid (CHDA), via standard addition. All postulated metabolites were present in all samples analyzed. The unspecific CHDA was identified as the major urinary metabolite representing 23.7 % of the dose as the mean of the three volunteers (range 20.0-26.5 %). 14.8 % (11.3-16.7 %) of the dose was excreted as monoesters with oxidative modifications, in particular OH-MINCH 10.7 % (7.7-12.9 %), oxo-MINCH 2.0 % (1.5-2.6 %) and carboxy-MINCH 2.0 % (1.8-2.3 %). Less than 1 % was excreted as the simple monoester MINCH. In sum, 39.2 % (35.9-42.4 %) of the DINCH(®) dose was excreted as these metabolites in urine within 48 h. Over 90 % of the metabolites investigated were excreted within 24 h after application. The secondary oxidized metabolites, with elimination half-times between 10 and 18 h, proved to be apt and specific biomarkers to determine DINCH(®) exposure. With this study, we provide reliable urinary excretion factors to calculate DINCH(®) intakes based on these metabolites in environmental and occupational studies.

Environmental exposure to the plasticizer 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH) in US adults (2000—2012)

“…In a recent study, three human volunteers, who were orally administered DINCH, excreted 23.7% of DINCH as the non-specific metabolite cyclohexane-1,2-dicarboxylic acid, 2% as MONCH, 10.7% as MHNCH and 2% as MCOCH (Koch et al, 2013a). These data suggest that the metabolism of DINCH is different from that of phthalates because, unlike DINCH, DEHP and DINP mostly excrete as their oxidative metabolites (Koch and Calafat, 2009 Chromatographic separation and mass spectra of three DINCH metabolites from human urine (this work) and DINCH-dosed rat urine (Silva et al, 2012).…”

“…Thus, some metabolites have been used as exposure biomarkers for DEHP (e.g., MECPP) and DINP (e.g., MCOP) Silva et al, 2006a). Similarly, MHNCH, MCOCH, and MONCH are unique DINCH metabolites and as such can be used as biomarkers of DINCH exposure (Koch et al, 2013b;Silva et al, 2012).…”

“…But at high doses, thyroid hyperplasia and signs of renal toxicity have been reported in rats (EFSA, 2006). Several oxidative metabolites of DINCH have been identified in DINCH-dosed rats (Silva et al, 2012) and have been used as biomarkers of exposure to DINCH in humans (Koch et al, 2013b;Schutze et al, 2012). In this study, we measured three of these oxidative metabolites: cyclohexane-1,2-dicarboxylic acid-monocarboxy isooctyl ester (MCOCH), cyclohexane-1,2-dicarboxylic acid-mono(oxo-isono-nyl) ester (MONCH), and cyclohexane-1,2-dicarboxylic acid-mono (hydroxy-isononyl) ester (MHNCH) (Fig.…”

Parabens in 24h urine samples of the German Environmental Specimen Bank from 1995 to 2012

“…Conversely, this means that similar urinary levels of MeP and BuP would point to much higher actual intakes of BuP than of MeP. Thus, to reliably extrapolate from urinary paraben levels to doses actually taken up metabolite conversion factors are urgently needed (Wittassek et al, 2011;Koch and Calafat, 2009;Koch et al, 2012aKoch et al, , 2013) making a comparison with health based benchmark levels possible. To meet these ends, we are currently performing human metabolism studies to derive key toxikokinetic data and urinary metabolite conversion factors for several parabens.…”

Non-phthalate plasticizers in German daycare centers and human biomonitoring of DINCH metabolites in children attending the centers (LUPE 3)

“…The metabolism of DINCH in humans was investigated in a study with three male volunteers (Koch et al, 2013). Cyclohexane-1,2-dicarboxylic acid was identified as the major but unspecific urinary metabolite, representing a 23.7% mean of the given dose of the three volunteers, while 10.7% was excreted after oxidation as OH-MICH, 2.0% as oxo-MINCH (1.5-2.6%), and 2.0% as cx-MINCH.…”