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Such grouping is usually based on shared structural features and should only be used for the prioritization objectives. However, additional considerations (as well as structural similarity) are needed, e.g., mode of action, metabolic pathways, chemical reaction products and physicochemical properties, when regulatory management measures are considered (such as restriction, harmonized classification and labeling). Guidance documents from the European Chemicals Agency (ECHA) recommend considering toxicokinetic information to enhance the robustness of the grouping; however, examples of this approach are lacking. Therefore, this paper shares findings on chemical grouping based on ADME data generated for multiple esters of salicylic acid. These differ with respect to chain length and branching of the alcohol moiety of salicylic acid ester, resulting in a wide range of lipophilicity (LogP 0.21\u201310.88). Since LogP impacts skin absorption, as well as hydrolysis by carboxylesterases, the bioavailability and thus internal exposure to topically applied salicylate esters can vary considerably. Therefore, we collected skin absorption and metabolism data for 41 salicylates using in vitro testing and in silico models and combined the information to group them according to their potential systemic exposure to the major metabolite, salicylic acid. The results show that, despite a similar general chemical structure, their toxicokinetics vary considerably, indicating the need for better understanding of ADME properties to assess the internal exposure for sound risk assessment.<\/jats:p>","DOI":"10.1007\/s00204-024-03935-8","type":"journal-article","created":{"date-parts":[[2025,1,4]],"date-time":"2025-01-04T22:18:36Z","timestamp":1736029116000},"page":"995-1010","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Grouping of chemicals for safety assessment: the importance of toxicokinetic properties of salicylate esters"],"prefix":"10.1007","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4620-9830","authenticated-orcid":false,"given":"Abdulkarim","family":"Najjar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Gr\u00e9goire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Nicol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Natsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazanin","family":"Golbamaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Boisleve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amaia","family":"Irizar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Wall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angus","family":"Swinscoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Masini-Et\u00e9v\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaushal","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Marie","family":"Api","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Griem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Reis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola J.","family":"Hewitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estefania","family":"Cardamone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,4]]},"reference":[{"key":"3935_CR1","doi-asserted-by":"publisher","first-page":"105735","DOI":"10.1016\/j.tiv.2023.105735","volume":"95","author":"T Brackin","year":"2024","unstructured":"Brackin T, Gayes H, Johnson I, Fox D, Roper C (2024) Skin barrier function for regulatory skin absorption tests and effects on testosterone and sucrose absorption. 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AR is employed by The Procter & Gamble Company. Each affiliation uses one or more of the salicylate esters in cosmetic products. Cosmetics Europe is the trade association for the cosmetics and personal care industry where author EC is employed and author NH provides services as a consultant. None of the authors will benefit financially from this work other than their salaries.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}