What does “success” look like in compliance check decisions by the European Chemicals Agency? The curious cases of accepted read-across adaptations_suppl1

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. Plain language summaryThis study analyzed the outcomes of the “compliance checks” on the data submitted by chemical manufacturers or importers for approval by the European Chemicals Agency. We focused on the instances when adaptations to required tests were proposed. Specifically, we analyzed cases where “read-across” was used to avoid animal tests otherwise required by the European Union’s REACH regulation. Instead of new tests, registrants may use results from similar chemicals if scientific justification is strong. This study found that, although read-across was used very frequently, only about 7.5% of such adaptation proposals were found to be satisfactory. The accepted cases relied on clear evidence of similarity in metabolism or strong supporting toxicological data, especially about how the chemicals behave in the body. This work sheds light on why few read-across arguments succeed, providing examples of strong justifications. We conclude that while successful read-across may replace animal testing, better justifications are needed.