German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Strasse 8-10, 10589, Berlin, Germany.
Arch Toxicol. 2024 Nov;98(11):3659-3671. doi: 10.1007/s00204-024-03835-x. Epub 2024 Aug 17.
Mono-n-hexyl phthalate (MnHexP) is a primary metabolite of di-n-hexyl phthalate (DnHexP) and other mixed side-chain phthalates that was recently detected in urine samples from adults and children in Germany. DnHexP is classified as toxic for reproduction category 1B in Annex VI of Regulation (EC) 1272/2008 and listed in Annex XIV of the European chemical legislation REACH; thereby, its use requires an authorisation. Health-based guidance values for DnHexP are lacking and a full-scale risk assessment has not been carried out under REACH. The detection of MnHexP in urine samples raises questions about the sources of exposure and concerns of consumer safety. Here, we propose the calculation of a provisional oral tolerable daily intake value (TDI) of 63 µg/kg body weight/day for DnHexP and compare it to intake levels corresponding to levels of MnHexP found in urine. The resulting mean intake levels correspond to less than 0.2% of the TDI, and maximum levels to less than 5%. The TDI was derived by means of an approximate probabilistic analysis using the credible interval from benchmark dose modelling of published ex vivo data on reduced foetal testosterone production in rats. Thus, for the dose associated to a 20% reduction in testosterone production, a lower and upper credible interval of 14.9 and 30.0 mg/kg bw/day, respectively, was used. This is considered a conservative approach, since apical developmental endpoints (e.g. changed anogenital distance) were only observed at higher doses. In addition, we modelled various scenarios of the exposure to the precursor substance DnHexP from different consumer products, taking measured contamination levels into account, and estimated systemic exposure doses. Of the modelled scenarios including the application of sunscreen (as a lotion or pump spray), the use of lip balm, and the wearing of plastic sandals, and considering conservative assumptions, the use of DnHexP-contaminated sunscreen was highlighted as a major contributing factor. A hypothetical calculation using conservative assumptions for the latter resulted in a margin of safety in relation to the lower credible interval of 3267 and 1007 for adults and young children, respectively. Most importantly, it was found that only a fraction of the TDI is reached in all studied exposure scenarios. Thus, with regard to the reported DnHexP exposure, a health risk can be considered very unlikely.
单正己基邻苯二甲酸酯（MnHexP）是邻苯二甲酸二正己酯（DnHexP）和其他混合侧链邻苯二甲酸酯的主要代谢物，最近在德国成年人和儿童的尿液样本中检测到。DnHexP 被归类为生殖毒性类别 1B，并在法规（EC）1272/2008 的附件 VI 中列出，并在欧洲化学法规 REACH 的附件 XIV 中列出；因此，其使用需要授权。目前缺乏针对 DnHexP 的基于健康的指导值，并且在 REACH 下尚未进行全面的风险评估。尿液样本中 MnHexP 的检测引发了对接触源的关注和对消费者安全的担忧。在这里，我们提出计算 DnHexP 的暂定口服耐受每日摄入量值（TDI）为 63 µg/kg 体重/天，并将其与尿液中发现的 MnHexP 水平相对应的摄入量水平进行比较。由此产生的平均摄入量水平不到 TDI 的 0.2%，最大摄入量水平不到 5%。TDI 是通过使用基于可信区间的近似概率分析得出的，该可信区间来自于已发表的体外数据，这些数据表明大鼠胎儿睾酮生成减少。因此，对于与睾酮生成减少 20%相关的剂量，使用了分别为 14.9 和 30.0 mg/kg bw/天的较低和较高可信区间。这被认为是一种保守的方法，因为只有在较高剂量下才观察到顶端发育终点（例如，改变肛生殖器距离）。此外，我们还模拟了来自不同消费品的前体物质 DnHexP 的各种暴露情景，考虑了测量的污染水平，并估计了系统暴露剂量。在所模拟的情景中，包括使用防晒霜（作为乳液或喷雾泵）、使用唇膏和穿着塑料凉鞋，并且考虑到保守的假设，使用受 DnHexP 污染的防晒霜被突出为主要因素。对于后者，使用保守假设进行的假设计算结果表明，相对于成人和幼儿的较低可信区间，安全系数分别为 3267 和 1007。最重要的是，在所有研究的暴露情景中，仅达到 TDI 的一小部分。因此，就报告的 DnHexP 暴露而言，可以认为健康风险极不可能。
