{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T16:59:13Z","timestamp":1790441953443,"version":"4.1.0"},"reference-count":0,"publisher":"ALTEX Edition","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["ALTEX"],"abstract":"<jats:p>Read-across is the most widely used adaptation to standard information requirements under REACH and is central to efforts to reduce unnecessary animal testing. However, its regulatory acceptance in European Chemicals Agency (ECHA) compliance check (CCH) decisions remains limited. This study systematically examined common deficiencies and trends in reasons that read-across adaptations fail based on publicly available CCH decisions. We reviewed ECHA CCH decisions published from 2010 through 2025, extracted information on read-across type, adaptation study type proposed, source and target substances, and reasons for rejection. The latter were coded using 17 assessment elements related to structural similarity, toxicokinetics, toxicodynamics, substance identity, and supporting data. Among 2,722 analyzed CCH decisions, nearly half contained at least one read-across adaptation, but only 85 read-across hypotheses were deemed acceptable. In contrast, 1,526 rejected read-across hypotheses were identified, most of which used analogue rather than group type of reasoning. Rejections were especially common for higher-tier repeated dose studies. The most frequent deficiencies in proposed adaptations involved unresolved uncertainty in toxicokinetic and toxicodynamic similarity, including limited evidence on bioavailability, metabolite formation, non-common compounds, and endpoint-relevant bridging data. Structural similarity was nearly always part of read-across but was rarely sufficient on its own. These findings show that successful read-across requires more than a plausible similarity argument; it must provide endpoint-specific evidence that residual uncertainty is low enough for regulatory use. Our results identify recurring pitfalls in submissions and support a path toward uncertainty-characterized, NAM-supported read-across that can improve regulatory confidence while reducing potentially unnecessary testing in animals.\nPlain language summaryThis manuscript examines why \u201cread-across\u201d submissions are often not accepted by the European Chemicals Agency during review of chemical registration submissions under European Union\u2019s REACH regulation. Read-across means using data from safety studies from a similar, better-studied chemical to infer potential hazards of a less-studied chemical. The authors reviewed 2,722 public compliance-check decisions from 2010-2025 and found that read-across was widely used, but only 85 read-across proposals were accepted. Rejections were most common for complex animal studies such as repeated-dose and reproductive toxicity tests. The main issues were weak evidence that the chemicals behave similarly in the body, produce similar metabolites, or cause similar biological effects. This study identified recurring weaknesses and showed that successful read-across must be endpoint-specific and address uncertainties. The 3R relevance of this work lies in determining weaknesses in read-across adaptations; if these deficiencies are addressed, then read-across can reduce and potentially replace animal testing.<\/jats:p>","DOI":"10.14573\/altex.2608201","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T16:30:46Z","timestamp":1790440246000},"source":"Crossref","is-referenced-by-count":0,"title":["ECHA writes back: The reasons for rejection of read-across in compliance check decisions by the European Chemicals Agency"],"prefix":"10.14573","author":[{"given":"Hannah M.","family":"Roe","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01f5ytq51","id-type":"ROR","asserted-by":"publisher"}],"name":"Texas A&M University"},{"name":"Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Ball","sequence":"additional","affiliation":[{"name":"The Dow Chemical Company, Horgen, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Han","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01f5ytq51","id-type":"ROR","asserted-by":"publisher"}],"name":"Texas A&M University"},{"name":"Department of Epidemiology and Biostatistics, School of Public Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred","family":"Wright","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04tj63d06","id-type":"ROR","asserted-by":"publisher"}],"name":"North Carolina State University"},{"name":"Departments of Statistics and Biological Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihsueh","family":"Chiu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01f5ytq51","id-type":"ROR","asserted-by":"publisher"}],"name":"Texas A&M University"},{"name":"Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Rusyn","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01f5ytq51","id-type":"ROR","asserted-by":"publisher"}],"name":"Texas A&M University"},{"name":"Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"5675","published-online":{"date-parts":[[2026,9,25]]},"container-title":["ALTEX - Alternatives to Animal Experimentation"],"original-title":[],"link":[{"URL":"https:\/\/www.altex.org\/index.php\/altex\/article\/download\/3255\/3045","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.altex.org\/index.php\/altex\/article\/download\/3255\/3034","content-type":"application\/vnd.openxmlformats-officedocument.spreadsheetml.sheet","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.altex.org\/index.php\/altex\/article\/download\/3255\/3035","content-type":"application\/vnd.openxmlformats-officedocument.spreadsheetml.sheet","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.altex.org\/index.php\/altex\/article\/download\/3255\/3036","content-type":"application\/vnd.openxmlformats-officedocument.spreadsheetml.sheet","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.altex.org\/index.php\/altex\/article\/download\/3255\/3037","content-type":"application\/vnd.openxmlformats-officedocument.spreadsheetml.sheet","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.altex.org\/index.php\/altex\/article\/download\/3255\/3038","content-type":"application\/vnd.openxmlformats-officedocument.spreadsheetml.sheet","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.altex.org\/index.php\/altex\/article\/download\/3255\/3045","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T16:30:47Z","timestamp":1790440247000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.altex.org\/index.php\/altex\/article\/view\/3255"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":0,"URL":"https:\/\/doi.org\/10.14573\/altex.2608201","relation":{},"ISSN":["1868-8551","1868-596X"],"issn-type":[{"value":"1868-8551","type":"electronic"},{"value":"1868-596X","type":"print"}],"subject":[],"published":{"date-parts":[[2026,9,25]]}}}