title: 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.
authors.affiliation: Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-University Bochum (IPA), Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Germany. koch@ipa-dguv.de
authors.forename: Holger M
authors.initials: HM
authors.lastname: Koch
authors.forename: André
authors.initials: A
authors.lastname: Schütze
authors.forename: Claudia
authors.initials: C
authors.lastname: Pälmke
authors.forename: Jürgen
authors.initials: J
authors.lastname: Angerer
authors.forename: Thomas
authors.initials: T
authors.lastname: Brüning
mesh_terms: D000284:Administration, Oral; D000328:Adult; D015415:Biomarkers / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D003509:Cyclohexanecarboxylic Acids / Q000493:pharmacokinetics* / Q000652:urine; D003998:Dicarboxylic Acids / Q000493:pharmacokinetics* / Q000652:urine; D006207:Half-Life; D006801:Humans; D008297:Male; D010084:Oxidation-Reduction; D010968:Plasticizers / Q000032:analysis / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry
chemical_list: D015415:Biomarkers; D003509:Cyclohexanecarboxylic Acids; D003998:Dicarboxylic Acids; D010968:Plasticizers; C558012:diisononyl 1,2-cyclohexanedicarboxylic acid