Shell Global Solutions International B.V., Carel van Bylandtlaan 16, The Hague 2596HR, The Netherlands.
Penman Consulting Ltd., Aspect House, Grove Business Park, Grove, Wantage, Oxon OX12 9FF, U.K.
Chem Res Toxicol. 2022 Aug 15;35(8):1383-1392. doi: 10.1021/acs.chemrestox.2c00089. Epub 2022 Jul 13.
To reduce the number of animals and studies needed to fulfill the information requirements as required by Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) (EC no. 1907/2006), a read-across approach was used to support approximately 30 higher olefins. This study aimed to assess the absorption potential of higher olefins through the gut wall as the experimentally determined bioavailability which would strengthen the read-across hypothesis and justification, reducing the need for toxicity studies on all of the higher olefins. The absorption potential of a series of higher olefins (carbon range from 6 to 28, with five configurations of the double bond) was determined in the in vitro everted rat small intestinal sac model and subsequently ranked. In addition, in silico approaches were applied to predict the reactivity, lipophilicity, and permeability of higher olefins. In the in vitro model, everted sacs were incubated in "fed-state simulated small intestinal fluid" saturated with individual higher olefins. The sac contents were then collected, extracted, and analyzed for olefin content using gas chromatography with a flame ionization detector. The C6 to C10 molecules were readily absorbed into the intestinal sacs. Marked inter-compound differences were observed, with the amount of absorption generally decreasing with the increase in carbon number. Higher olefins with ≥C14 carbons were either not absorbed or very poorly absorbed. In the reactivity simulation study, the reactivity is well described by the position of the double bond rather than the number of carbon atoms. In the lipophilicity and permeability analysis, both parameter descriptors depend mainly on the number of carbon atoms and less on the position of the double bond. In conclusion, these new approach methodologies provide supporting information on any trends or breakpoints in intestinal uptake and a hazard matrix based on carbon number and position of the double bond. This matrix will further assist in the selection of substances for inclusion in the mammalian toxicity testing programme.
为了减少满足注册、评估、授权和限制化学品（REACH）（EC 编号 1907/2006）信息要求所需的动物数量和研究数量，本研究采用了一种读-跨方法来支持大约 30 种高烯烃。本研究旨在评估高烯烃通过肠壁的吸收潜力，作为实验确定的生物利用度，这将加强读跨假设和理由，减少对所有高烯烃进行毒性研究的必要性。通过在体外外翻大鼠小肠囊模型中测定一系列高烯烃（碳范围为 6 至 28，双键有五种构型）的吸收潜力，并对其进行排序。此外，还应用了计算方法来预测高烯烃的反应性、亲脂性和渗透性。在体外模型中，将外翻囊在“进食状态模拟小肠液”中孵育，使个体高烯烃饱和。然后收集囊内容物，提取并使用带有火焰电离检测器的气相色谱法分析烯烃含量。C6 至 C10 分子很容易被吸收到肠囊中。观察到明显的化合物间差异，吸收量通常随着碳数的增加而减少。碳原子数≥C14 的高烯烃要么不被吸收，要么吸收很差。在反应性模拟研究中，双键的位置而不是碳原子数很好地描述了反应性。在亲脂性和渗透性分析中，两个参数描述符主要取决于碳原子数，而双键的位置影响较小。总之，这些新方法提供了关于肠吸收的任何趋势或断点的支持信息，并基于碳数和双键位置提供了危害矩阵。该矩阵将进一步有助于选择物质纳入哺乳动物毒性测试计划。
