title: Additional oxidized and alkyl chain breakdown metabolites of the plasticizer DINCH in urine after oral dosage to human volunteers.
abstract: Hexamoll®DINCH®(diisononyl-cyclohexane-1,2-dicarboxylate) is a new high molecular weight plasticizer and a non-aromatic phthalate substitute. In this follow-up study, we further investigated the extensive oxidative metabolism of Hexamoll®DINCH®after oral dosage of 50 mg to three male volunteers (0.552-0.606 mg/kg body weight). Urine samples were consecutively collected over 48 h post-dose. Chemical analysis was carried out by HPLC-MS/MS with labeled internal standards. New metabolites were tentatively identified and quantified via fragmentation analogies and new standard substances. In addition to the five urinary DINCH metabolites previously reported by us, we identified two groups of extensively oxidized metabolites characterized (a) by multiple side chain oxidation and breakdown and (b) by hydroxylation at the cyclohexane ring. The five newly identified carboxylated breakdown metabolites represented in sum 5.12 ± 0.49 % of the applied dose. MCHxCH (cyclohexane-1,2-dicarboxylic acid mono carboxyhexyl ester) was identified as a major metabolite (2.71 ± 0.34 %) and thus represents the second most important specific metabolite of DINCH after OH-MINCH (10.7 ± 2.1 %). Less than 1 % was excreted as ring-hydroxylated metabolites (four metabolites identified). Based upon a new reference standard, we can also update oxo-MINCH to 2.6 % of the applied dose. This follow-up study increases the total amount of the recovered dose from 39.2 to 45.7 % and describes a new major metabolite (MCHxCH) of DINCH that can be used as an additional valuable and specific biomarker to assess DINCH®exposure in future human biomonitoring 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.
authors.forename: André
authors.initials: A
authors.lastname: Schütze
authors.affiliation: BASF SE, Industrial Petrochemicals Europe, E-CPI/R - H202, 67056, Ludwigshafen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Otter
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.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Modick
authors.affiliation: BASF SE, Industrial Petrochemicals Europe, E-CPI/R - H202, 67056, Ludwigshafen, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Langsch
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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brüning
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
mesh_terms: D000284:Administration, Oral; D000328:Adult; D015415:Biomarkers / Q000652:urine; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity* / Q000652:urine*; D003998:Dicarboxylic Acids / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity* / Q000652:urine*; D004784:Environmental Monitoring / Q000379:methods*; D005500:Follow-Up Studies; D006801:Humans; D006900:Hydroxylation; D008297:Male; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010968:Plasticizers / Q000008:administration & dosage / Q000032:analysis* / Q000378:metabolism / Q000633:toxicity*; D065667:Renal Elimination; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry; D066007:Toxicokinetics
chemical_list: D015415:Biomarkers; D003509:Cyclohexanecarboxylic Acids; D003998:Dicarboxylic Acids; D010968:Plasticizers; C000614745:cyclohexane-1,2-dicarboxylic acid mono carboxyhexyl ester; C558012:diisononyl 1,2-cyclohexanedicarboxylic acid
keywords: DINCH; Excretion fractions; Human biomonitoring; Human metabolism; Phthalate substitute; Urinary metabolites