{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:14:46Z","timestamp":1788412486657,"version":"build-2803163510"},"reference-count":26,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Cosmetic and quasi\u2010drug ingredients intended for daily use require reliable skin irritation assessment. However, restrictions on animal testing, including the European Union marketing ban for cosmetics tested on animals, have prompted the adoption of reconstructed human epidermis (RhE) assays, such as Organization for Economic Co\u2010operation and Development (OECD) Test Guideline 439 (TG439). Although TG439 identifies Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Category 2 irritants and No Category (non\u2010irritant) chemicals as an alternative to the 4\u2010h rabbit skin irritation test, its ability to predict human responses to 24\u2010h exposure and mild irritation remains limited. This study evaluated the reproducibility of TG439 across six laboratories using LabCyte EPI\u2010MODEL24 and a standardized stepwise dilution design. TG439 was used to determine a \u201cTG439 non\u2010irritant concentration\u201d for 17 test substances. Human 24\u2010h closed patch tests were then performed using stepwise escalation to one\u2010quarter and one\u2010half of this concentration, with predefined stopping criteria to ensure subject safety. Inter\u2010laboratory control results confirmed TG439 reproducibility. Most test substances exhibited Sugai's Irritation Index (S.I.I.) values within the \u201cSafe\u201d or \u201cAcceptable\u201d categories at both test concentrations. However, selected surfactants, cationic preservatives, and hair dye intermediates produced elevated S.I.I. values, requiring discontinuation of concentration escalation and highlighting the importance of predefined stopping criteria. These findings support TG439 as a practical starting point for human irritation testing when combined with a stepwise concentration approach and predefined safety criteria, enabling the ethical translation of in\u00a0vitro findings to human testing and extending TG439\u2010based evaluation beyond \u201charmless ingredients.\u201d<\/jats:p>","DOI":"10.1002\/jat.70428","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T04:24:07Z","timestamp":1788409447000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Stepwise Skin Irritation Assessment Approach Integrating in Vitro Skin Irritation Testing and Human Patch Testing"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8506-9790","authenticated-orcid":false,"given":"Hidefumi","family":"Ikeda","sequence":"first","affiliation":[{"name":"Mandom Corporation  Osaka 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Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriyasu","family":"Imai","sequence":"additional","affiliation":[{"name":"KOS\u00c9 Corporation  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariko","family":"Sugiyama","sequence":"additional","affiliation":[{"name":"General Incorporated Association SSCI\u2010Net  Aichi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4110-5015","authenticated-orcid":false,"given":"Morihiko","family":"Hirota","sequence":"additional","affiliation":[{"name":"Japan Cosmetic Industry Association (JCIA)  Tokyo Japan"},{"name":"Shiseido Brand Value R&amp;D Institute  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Yagami","sequence":"additional","affiliation":[{"name":"Department of Allergology Fujita Health University School of Medicine  Aichi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Ashikaga","sequence":"additional","affiliation":[{"name":"National Institute of Health Sciences  Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105\u20101873.2004.00385.x"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600\u20100625.2000.009003165.x"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600\u20100846.2008.00291.x"},{"key":"e_1_2_8_5_1","volume-title":"Communication from the Commission to the European Parliament and the Council on the animal testing and marketing ban and on the state of play in relation to alternative methods in the field of cosmetics","author":"Commission to the European Parliament and the 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