Schütze André, Otter Rainer, Modick Hendrik, Langsch Angelika, Brüning Thomas, Koch Holger M
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.
BASF SE, Industrial Petrochemicals Europe, E-CPI/R - H202, 67056, Ludwigshafen, Germany.
Arch Toxicol. 2017 Jan;91(1):179-188. doi: 10.1007/s00204-016-1688-9. Epub 2016 Mar 15.
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.
Hexamoll DINCH（二异壬基环己烷-1,2-二羧酸酯）是一种新型高分子量增塑剂，也是一种非芳香族邻苯二甲酸酯替代品。在这项后续研究中，我们进一步研究了三名男性志愿者口服50毫克（0.552 - 0.606毫克/千克体重）Hexamoll DINCH后的广泛氧化代谢情况。给药后48小时内连续收集尿液样本。采用带标记内标的HPLC-MS/MS进行化学分析。通过碎片类推法和新的标准物质初步鉴定并定量新的代谢物。除了我们之前报道的五种尿液DINCH代谢物外，我们还鉴定出两组广泛氧化的代谢物，其特征为：（a）多个侧链氧化和分解；（b）环己烷环羟基化。新鉴定出的五种羧基化分解代谢物总量占给药剂量的5.12±0.49%。MCHxCH（环己烷-1,2-二羧酸单羧己酯）被鉴定为主要代谢物（2.71±0.34%），因此是DINCH仅次于OH-MINCH（10.7±2.1%）的第二重要的特定代谢物。以环羟基化代谢物形式排泄的量不到1%（鉴定出四种代谢物）。基于一种新的参考标准，我们还可将氧代-MINCH更新为给药剂量的2.6%。这项后续研究将回收剂量的总量从39.2%提高到45.7%，并描述了DINCH的一种新的主要代谢物（MCHxCH），它可作为一种额外的有价值的特定生物标志物，用于未来人体生物监测研究中评估DINCH暴露情况。
