Center for Primary Care and Public Health (Unisanté), University of Lausanne, Route de la Corniche 2, Epalinges, Lausanne 1066, Switzerland; Swiss Center for Applied Human Toxicology (SCAHT), Basel, Switzerland.
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance - Institute of the Ruhr-University Bochum (IPA), Bochum, Germany.
Toxicol Lett. 2024 Oct;400:104-112. doi: 10.1016/j.toxlet.2024.08.002. Epub 2024 Aug 10.
Alternative plasticizers such as diisononyl-1,2-cyclohexanedicarboxylate (DINCH), di(2-ethylhexyl) terephthalate (DEHTP), and di(2-ethylhexyl) adipate (DEHA) are progressively replacing phthalates in many consumer and professional products because of adverse effects on reproduction associated with some phthalates. Human exposures to these phthalate substitutes can occur through ingestion, skin absorption and inhalation. Skin uptake can lead to greater concentration at the target organs compared to ingestion because the skin exposure route bypasses the first-pass effect. Skin absorption studies are almost absent for these alternative plasticizers. We therefore wanted first, to characterize skin absorption of a mixture containing DINCH, DEHA and DEHTP in vitro using a flow-through diffusion cell system with ex vivo human skin, quantifying their respective monoester metabolites (mono-isononyl-cyclohexane-1,2-dicarboxylate (MINCH), mono-2-ethylhexyl adipate (MEHA), mono-2-ethylhexyl terephthalate (MEHTP), respectively); second, to validate these results by exposing five human volunteers to this mixture on their forearm and quantifying the corresponding urinary metabolites (including the monoesters and their oxidation products). Our study showed that two of these alternative plasticizers, DEHTP and DINCH, did not permeate skin showing as quantifiable metabolite levels in vitro and only traces of DEHA were quantified as its monoester metabolite, MEHA. Permeation coefficient (Kp) 0.06 and 55.8*10 cm/h for neat and emulsified DEHA, respectively, while the permeation rate (J) remained low for both (0.005 and 0.001 µg/cm/h, respectively). Participants exposed to a mixture of these three plasticizers did not have noteworthy urinary concentrations of their respective metabolites after 24 hours post-application. However, the alternative plasticizer mixture was completely absorbed after six hours post-application on the forearms of the human volunteers, and the urinary elimination curves showed a slight increase after 24 hours post-application. Further studies on skin absorption of these substances should follow the urinary elimination kinetics of these metabolites more than 24 hours post-application. We also recommend quantifying the parent compounds in the in vitro diffusion experiments.
替代增塑剂，如邻苯二甲酸二异壬酯（DINCH）、邻苯二甲酸二（2-乙基己基）酯（DEHTP）和己二酸二（2-乙基己基）酯（DEHA），由于某些邻苯二甲酸酯对生殖的不良影响，正在逐渐取代许多消费和专业产品中的邻苯二甲酸酯。人们可以通过摄入、皮肤吸收和吸入接触到这些邻苯二甲酸酯替代品。与摄入相比，皮肤吸收会导致目标器官的浓度更高，因为皮肤暴露途径绕过了首过效应。对于这些替代增塑剂，几乎没有皮肤吸收研究。因此，我们首先希望使用带有离体人皮肤的流通扩散细胞系统，体外表征含有 DINCH、DEHA 和 DEHTP 的混合物的皮肤吸收情况，定量分析其各自的单酯代谢物（单异壬基环己烷-1,2-二羧酸酯（MINCH）、单-2-乙基己基己二酸酯（MEHA）、单-2-乙基己基对苯二甲酸酯（MEHTP））；其次，通过在五名志愿者前臂暴露于该混合物并定量分析相应的尿代谢物（包括单酯及其氧化产物）来验证这些结果。我们的研究表明，其中两种替代增塑剂，DEHTP 和 DINCH，没有穿透皮肤，在体外没有可量化的代谢物水平，只有痕量的 DEHA 被量化为其单酯代谢物 MEHA。纯态和乳化态的 DEHA 的渗透系数（Kp）分别为 0.06 和 55.8*10 cm/h，而渗透速率（J）则保持较低水平（分别为 0.005 和 0.001 µg/cm/h）。参与者在应用后 24 小时内，尿液中未检测到这三种增塑剂混合物各自代谢物的显著浓度。然而，在志愿者前臂应用六小时后，替代增塑剂混合物完全被吸收，尿液消除曲线在应用后 24 小时后略有增加。在应用后 24 小时以上，应根据这些代谢物的尿消除动力学进一步研究这些物质的皮肤吸收情况。我们还建议在体外扩散实验中定量分析母体化合物。
