Roe Hannah M, Tsai Han-Hsuan D, Ball Nicholas, Oware King D, Han Gang, Chiu Weihsueh A, Rusyn Ivan
Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA.
The Dow Chemical Company, Horgen, Switzerland.
ALTEX. 2025 Jul 28. doi: 10.14573/altex.2505191.
Under the European Union's REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) regulation, the European Chemicals Agency (ECHA) is required to assess the compliance of safety data submitted by chemical registrants. ECHA must check a proportion of registration dossiers for compliance. From 2010 to 2023, 4,854 compliance checks (CCHs) were conducted. When dossiers lack required studies or use inappropriate adaptations, ECHA issues decisions that are publicly available. As of April 2, 2024, 2,311 such decisions have been published. This study systematically analyzed these published CCH decisions, focusing on ECHA's findings of non-compliant REACH registrations and the use of adaptations to standard data requirements. We found that over 70% of published CCH decisions included at least one adaptation, with "read-across" being the most common (48%). Among these, 83 documents contained read-across adaptations with justifications that ECHA deemed plausible. To understand what made these read-across hypotheses acceptable, we evaluated them using 17 assessment elements that capture specific arguments registrants proposed to justify the adaptation. Elements of "acceptable" read-across hypotheses included strong evidence of (i) toxicokinetic similarity between the registered substance and its analogues, and (ii) toxicodynamic similarity, supported by bridging studies. Additional support from in vitro studies and QSAR predictions further strengthened the accepted read-across hypotheses. Overall, this analysis provides insights into what constitutes a successful read-across under REACH data requirements. By identifying and evaluating accepted cases or read-across adaptations, we highlight best practices for establishing scientifically robust justifications for chemical similarity that can meet ECHA's high regulatory standards.
根据欧盟的《化学品注册、评估、授权和限制》（REACH）法规，欧洲化学品管理局（ECHA）需要评估化学品注册者提交的安全数据的合规性。ECHA必须检查一定比例的注册卷宗是否合规。2010年至2023年期间，共进行了4854次合规检查（CCH）。当卷宗缺少所需研究或使用了不适当的改编时，ECHA会发布公开可用的决定。截至2024年4月2日，已发布了2311项此类决定。本研究系统地分析了这些已发布的CCH决定，重点关注ECHA对不符合REACH注册要求的调查结果以及对标准数据要求的改编使用情况。我们发现，超过70%的已发布CCH决定至少包含一项改编，其中“类推法”最为常见（48%）。在这些决定中，83份文件包含了ECHA认为合理的类推法改编及理由。为了解这些类推法假设为何被接受，我们使用17个评估要素对其进行了评估，这些要素涵盖了注册者为证明改编合理性而提出的具体论据。“可接受”的类推法假设要素包括：（i）注册物质与其类似物之间毒代动力学相似性的有力证据，以及（ii）由桥接研究支持的毒效动力学相似性。体外研究和定量构效关系预测的额外支持进一步强化了被接受的类推法假设。总体而言，该分析为REACH数据要求下成功的类推法构成要素提供了见解。通过识别和评估被接受的案例或类推法改编，我们突出了为满足ECHA的高监管标准而建立科学可靠的化学相似性理由的最佳实践。
