Clariant Produkte (Deutschland) GmbH, Am Unisyspark 1, 65843, Sulzbach, Germany.
Scientific Consultancy-Animal Welfare, Neubiberg, Germany.
Arch Toxicol. 2021 Mar;95(3):853-881. doi: 10.1007/s00204-020-02967-0. Epub 2021 Jan 18.
This article presents the outcomes of higher-tier repeated-dose toxicity studies and developmental and reproductive toxicity (DART) studies using Wistar rats requested for methyl paraben and propyl paraben under the European Union chemicals legislation. All studies revealed no-observed adverse effects (NOAELs) at 1000 mg/kg body weight/day. These findings (absence of effects) were then used to interpolate the hazard profile for ethyl paraben, further considering available data for butyl paraben. The underlying read-across hypothesis (all shorter-chained linear n-alkyl parabens are a 'category' based on very high structural similarity and are transformed to a common compound) was confirmed by similarity calculations and comparative in vivo toxicokinetics screening studies for methyl paraben, ethyl paraben, propyl paraben and butyl paraben. All four parabens were rapidly taken up systemically following oral gavage administration to rats, metabolised to p-hydroxybenzoic acid, and rapidly eliminated (parabens within one hour; p-hydroxybenzoic acid within 4-8 h). Accordingly, for ethyl paraben, the NOAELs for repeated-dose toxicity and DART were interpolated to be 1000 mg/kg body weight/day. Finally, all evidence was evaluated to address concerns expressed in the literature that parabens might be endocrine disruptors. This evaluation showed that the higher-tier studies do not provide any indication for any endocrine disrupting property. This is the first time that a comprehensive dataset from higher-tier in vivo studies following internationally agreed test protocols has become available for shorter-chained linear n-alkyl parabens. Consistently, the dataset shows that these parabens are devoid of repeated-dose toxicity and do not possess any DART or endocrine disrupting properties.
本文介绍了根据欧盟化学品法规，对甲基对羟基苯甲酸酯和丙基对羟基苯甲酸酯进行的高等级重复剂量毒性研究和发育与生殖毒性（DART）研究的结果。所有研究均在 1000mg/kg 体重/天的剂量下未观察到不良效应（NOAEL）。这些发现（无效应）随后被用于推断对羟基苯甲酸乙酯的危害概况，进一步考虑了对羟基苯甲酸丁酯的可用数据。基于非常高的结构相似性，将所有较短链线性正烷 n-烷基对羟基苯甲酸酯归为“一类”，并转化为一种共同的化合物，这种潜在的从头预测假说（read-across hypothesis）通过对甲基对羟基苯甲酸酯、乙基对羟基苯甲酸酯、丙基对羟基苯甲酸酯和丁基对羟基苯甲酸酯的相似性计算和比较体内毒代动力学筛选研究得到了证实。所有四种对羟基苯甲酸酯经口服灌胃给予大鼠后均迅速被全身吸收，代谢为对羟基苯甲酸，然后迅速消除（对羟基苯甲酸酯在 1 小时内；对羟基苯甲酸在 4-8 小时内）。因此，对于乙基对羟基苯甲酸酯，重复剂量毒性和 DART 的 NOAEL 被推断为 1000mg/kg 体重/天。最后，对文献中表达的关于对羟基苯甲酸酯可能具有内分泌干扰特性的担忧进行了所有证据评估。该评估表明，这些高等级研究没有提供任何关于任何内分泌干扰特性的迹象。这是首次为较短链线性正烷 n-烷基对羟基苯甲酸酯提供符合国际协议测试方案的高等级体内研究综合数据集。一致的是，该数据集表明这些对羟基苯甲酸酯没有重复剂量毒性，也没有任何 DART 或内分泌干扰特性。
