{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T20:29:53Z","timestamp":1786998593139,"version":"build-2736575974"},"reference-count":46,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,3,1]],"date-time":"2025-03-01T00:00:00Z","timestamp":1740787200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T00:00:00Z","timestamp":1738195200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Regulatory Toxicology and Pharmacology"],"published-print":{"date-parts":[[2025,3]]},"DOI":"10.1016\/j.yrtph.2025.105776","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T04:42:00Z","timestamp":1738039320000},"page":"105776","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":7,"special_numbering":"C","title":["Comprehensive extractables and leachables sensitization analysis and practical application of a risk-based approach to sensitization assessment for parenteral drug products"],"prefix":"10.1016","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9613-940X","authenticated-orcid":false,"given":"Patricia","family":"Parris","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraldine","family":"Whelan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martyn L.","family":"Chilton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Beaumont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Burild","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uma","family":"Bruen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Callis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Graham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Kovalova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melisa","family":"Masuda-Herrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Wors\u00f8e","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anissa","family":"Alami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Bercu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dvir","family":"Doron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Dusenbury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Troy","family":"Griffin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jedd","family":"Hillegass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Johann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes","family":"Koenig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Macho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Martirosyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kobi","family":"Oded","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constan\u00e7a Porredon","family":"Guarch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Schmitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brad","family":"Stanard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Tien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Udovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen T.","family":"Cruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Nagao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.yrtph.2025.105776_bib1","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1097\/DER.0000000000000304","article-title":"Fragrances categorized according to relative human skin sensitization potency","volume":"28","author":"Api","year":"2017","journal-title":"Dermatitis"},{"key":"10.1016\/j.yrtph.2025.105776_bib2","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1021\/tx050075m","article-title":"Skin sensitization: reaction mechanistic applicability domains for structure-activity relationships","volume":"18","author":"Aptula","year":"2005","journal-title":"Chem Res Toxicol"},{"key":"10.1016\/j.yrtph.2025.105776_bib48","doi-asserted-by":"crossref","first-page":"113469","DOI":"10.1016\/j.ijheh.2020.113469","article-title":"How to assess respiratory sensitization of low molecularweight chemicals?","volume":"225","author":"Arts","year":"2020","journal-title":"Int J Hyg Environ Health"},{"key":"10.1016\/j.yrtph.2025.105776_bib3","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1289\/ehp.9310162","article-title":"Mechanistic relationship among mutagenicity, skin sensitization, and skin carcinogenicity","volume":"101","author":"Ashby","year":"1993","journal-title":"Environ Health Perspect"},{"key":"10.1016\/j.yrtph.2025.105776_bib4","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1097\/DER.0000000000000003","article-title":"Categorization of chemicals according to their relative human skin sensitizing potency","volume":"25","author":"Basketter","year":"2014","journal-title":"Dermatitis"},{"key":"10.1016\/j.yrtph.2025.105776_bib5","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1111\/j.1600-0536.2007.01141.x","article-title":"The local lymph node assay and the assessment of relative potency: status of validation","volume":"57","author":"Basketter","year":"2007","journal-title":"Contact Dermatitis"},{"key":"10.1016\/j.yrtph.2025.105776_bib6","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.yrtph.2016.08.011","article-title":"Assessing safety of extractables from materials and leachables in pharmaceuticals and biologics - current challenges and approaches","volume":"81","author":"Broschard","year":"2016","journal-title":"Regul Toxicol Pharmacol"},{"key":"10.1016\/j.yrtph.2025.105776_bib7","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1002\/jat.3448","article-title":"A quantitative in silico model for predicting skin sensitization using a nearest neighbours approach within expert-derived structure-activity alert spaces","volume":"37","author":"Canipa","year":"2017","journal-title":"J Appl Toxicol"},{"key":"10.1016\/j.yrtph.2025.105776_bib8","doi-asserted-by":"crossref","DOI":"10.1016\/j.yrtph.2022.105200","article-title":"Updating the Dermal Sensitisation Thresholds using an expanded dataset and an in silico expert system","volume":"133","author":"Chilton","year":"2022","journal-title":"Regul Toxicol Pharmacol"},{"key":"10.1016\/j.yrtph.2025.105776_bib9","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.yrtph.2018.03.015","article-title":"Making reliable negative predictions of human skin sensitisation using an in silico fragmentation approach","volume":"95","author":"Chilton","year":"2018","journal-title":"Regul Toxicol Pharmacol"},{"key":"10.1016\/j.yrtph.2025.105776_bib47","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.tox.2015.04.010","article-title":"Thresholds in chemical respiratory sensitisation","volume":"333","author":"Cochrane","year":"2015","journal-title":"Toxicology"},{"key":"10.1016\/j.yrtph.2025.105776_bib10","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1080\/17460441.2018.1437141","article-title":"Tools to investigate and avoid drug-hypersensitivity in drug development","volume":"13","author":"Corsini","year":"2018","journal-title":"Expert Opin Drug Discov"},{"key":"10.1016\/j.yrtph.2025.105776_bib11","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1016\/j.tiv.2015.04.012","article-title":"Optimization of the THP-1 activation assay to detect pharmaceuticals with potential to cause immune mediated drug reactions","volume":"29","author":"Corti","year":"2015","journal-title":"Toxicol In Vitro"},{"key":"10.1016\/j.yrtph.2025.105776_bib12","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/j.1600-0536.2009.01582.x","article-title":"Formaldehyde-releasers: relationship to formaldehyde contact allergy. Contact allergy to formaldehyde and inventory of formaldehyde-releasers","volume":"61","author":"de Groot","year":"2009","journal-title":"Contact Dermatitis"},{"key":"10.1016\/j.yrtph.2025.105776_bib13","article-title":"Potency values from the local lymph node assay: application to classification, labelling and risk assessment","year":"2008","journal-title":"ECETOC Document No. 46. 14. Page 18. Brussels"},{"key":"10.1016\/j.yrtph.2025.105776_bib14","series-title":"Guidance on the Application of the CLP Criteria. Guidance to Guidance to Regulation (EC) No 1272\/2008 on Classification, Labelling and Packaging (CLP) of Substances and Mixtures","year":"2024"},{"key":"10.1016\/j.yrtph.2025.105776_bib16","doi-asserted-by":"crossref","first-page":"204","DOI":"10.3389\/fphar.2016.00204","article-title":"In vitro models to evaluate drug-induced hypersensitivity: potential test based on activation of dendritic cells","volume":"7","author":"Galbiati","year":"2016","journal-title":"Front Pharmacol"},{"key":"10.1016\/j.yrtph.2025.105776_bib17","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1021\/acs.chemrestox.0c00320","article-title":"Mapping chemical respiratory sensitization: how useful are our current computational tools?","volume":"34","author":"Golden","year":"2021","journal-title":"Chem Res Toxicol"},{"key":"10.1016\/j.yrtph.2025.105776_bib18","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s40629-020-00127-5","article-title":"Hypersensitivity reactions to biologics (part II): classifications and current diagnostic and treatment approaches","volume":"29","author":"G\u00fclsen","year":"2020","journal-title":"Allergo journal international"},{"key":"10.1016\/j.yrtph.2025.105776_bib19","series-title":"International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)","year":"2023"},{"key":"10.1016\/j.yrtph.2025.105776_bib20","series-title":"ICH Quality Risk Management Q9(R1) Final Version Adopted on 18 January 2023","year":"2023"},{"key":"10.1016\/j.yrtph.2025.105776_bib21","doi-asserted-by":"crossref","first-page":"237","DOI":"10.5731\/pdajpst.2022.012819","article-title":"Characterizing extractables and leachables chemical space to support in silico toxicological hazard assessments","volume":"78","author":"Johnson","year":"2024","journal-title":"PDA Journal of Pharmaceutical Science and Technology"},{"key":"10.1016\/j.yrtph.2025.105776_bib22","series-title":"Drug Hypersensitivity","first-page":"140","article-title":"Non-clinical testing approaches for drug development: possibilities and limitations","author":"Kawabata","year":"2007"},{"key":"10.1016\/j.yrtph.2025.105776_bib23","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1080\/009841098159141","article-title":"Assessment of the skin sensitization potential of topical medicaments using the local lymph node assay: an interlaboratory evaluation","volume":"53","author":"Kimber","year":"1998","journal-title":"J Toxicol Environ Health A"},{"key":"10.1016\/j.yrtph.2025.105776_bib24","first-page":"213","article-title":"The impact of vehicle on assessment of relative skin sensitization potency of 1,4-dihydroquinone in the local lymph node assay","volume":"10","author":"Lea","year":"1999","journal-title":"Am J Contact Dermat"},{"key":"10.1016\/j.yrtph.2025.105776_bib25","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1001\/jama.1979.03300120030019","article-title":"Contact dermatitis to neomycin sulfate","volume":"242","author":"Leyden","year":"1979","journal-title":"JAMA"},{"key":"10.1016\/j.yrtph.2025.105776_bib26","doi-asserted-by":"crossref","DOI":"10.1016\/j.yrtph.2023.105335","article-title":"Semiquantitative sensitization safety assessment of extractable and leachables associated with parenteral pharmaceutical products","volume":"138","author":"Liu","year":"2023","journal-title":"Regul Toxicol Pharmacol"},{"issue":"5","key":"10.1016\/j.yrtph.2025.105776_bib28","doi-asserted-by":"crossref","first-page":"369","DOI":"10.5731\/pdajpst.2021.012693","article-title":"Development of duration-based non-mutagenic thresholds of toxicological concern (TTC) relevant to parenteral extractables and leachables (E&ls)","volume":"76","author":"Masuda-Herrera","year":"2022","journal-title":"PDA J Pharm Sci Technol"},{"key":"10.1016\/j.yrtph.2025.105776_bib27","doi-asserted-by":"crossref","DOI":"10.1016\/j.yrtph.2023.105494","article-title":"Harmonisation of read-across methodology for drug substance extractables and leachables (E&Ls)","volume":"145","author":"Masuda-Herrera","year":"2023","journal-title":"Regul Toxicol Pharmacol"},{"key":"10.1016\/j.yrtph.2025.105776_bib29","doi-asserted-by":"crossref","first-page":"2738","DOI":"10.1016\/j.vaccine.2013.03.071","article-title":"Pharmacokinetic modeling as an approach to assessing the safety of residual formaldehyde in infant vaccines","volume":"31","author":"Mitkus","year":"2013","journal-title":"Vaccine"},{"key":"10.1016\/j.yrtph.2025.105776_bib31","article-title":"Test No. 429: skin sensitisation: local lymph node assay","volume":"vol. 4","year":"2010"},{"key":"10.1016\/j.yrtph.2025.105776_bib32","series-title":"Guideline No. 497: Defined Approaches on Skin Sensitisation","year":"2021"},{"key":"10.1016\/j.yrtph.2025.105776_bib33","series-title":"Test No. 406: Skin Sensitisation","year":"2022"},{"key":"10.1016\/j.yrtph.2025.105776_bib34","doi-asserted-by":"crossref","DOI":"10.1016\/j.yrtph.2020.104802","article-title":"Considerations when deriving compound-specific limits for extractables and leachables from pharmaceutical products: four case studies","volume":"118","author":"Parris","year":"2020","journal-title":"Regul Toxicol Pharmacol"},{"key":"10.1016\/j.yrtph.2025.105776_bib36","first-page":"1","article-title":"Framework for sensitization assessment of extractables and leachables in pharmaceuticals","author":"Parris","year":"2022","journal-title":"Critical Reviews in Toxicology"},{"issue":"4","key":"10.1016\/j.yrtph.2025.105776_bib35","doi-asserted-by":"crossref","first-page":"399","DOI":"10.5731\/pdajpst.2022.012811","article-title":"Sensitization assessment of extractables and leachables in pharmaceuticals: ELSIE database analysis","volume":"78","author":"Parris","year":"2023","journal-title":"PDA J Pharm Sci Technol"},{"key":"10.1016\/j.yrtph.2025.105776_bib37","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1111\/j.1600-0749.1989.tb00231.x","article-title":"Metabolism of 4-hydroxyanisole: identification of major urinary excretory products","volume":"2","author":"Pavel","year":"1989","journal-title":"Pigment Cell Res"},{"key":"10.1016\/j.yrtph.2025.105776_bib38","article-title":"Safety thresholds and best demonstrated practices for extractables and leachables in parenteral drug products (intravenous, subcutaneous, and intramuscular)","year":"2021","journal-title":"Product Quality Research Institute"},{"key":"10.1016\/j.yrtph.2025.105776_bib39","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.yrtph.2015.03.001","article-title":"Principles for identification of high potency category chemicals for which the dermal sensitisation threshold (DST) approach should not be applied","volume":"72","author":"Roberts","year":"2015","journal-title":"Regul Toxicol Pharmacol"},{"key":"10.1016\/j.yrtph.2025.105776_bib40","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1080\/15569520701212258","article-title":"Extrapolating local lymph node assay EC3 values to estimate relative sensitizing potency","volume":"26","author":"Ryan","year":"2007","journal-title":"Cutan Ocul Toxicol"},{"key":"10.1016\/j.yrtph.2025.105776_bib41","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.yrtph.2008.02.010","article-title":"The Dermal Sensitisation Threshold\u2014a TTC approach for allergic contact dermatitis","volume":"51","author":"Safford","year":"2008","journal-title":"Regul Toxicol Pharmacol"},{"key":"10.1016\/j.yrtph.2025.105776_bib42","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.yrtph.2011.03.009","article-title":"Refinement of the Dermal Sensitisation Threshold (DST) approach using a larger dataset and incorporating mechanistic chemistry domains","volume":"60","author":"Safford","year":"2011","journal-title":"Regul. Toxicol Pharmacol."},{"key":"10.1016\/j.yrtph.2025.105776_bib46","unstructured":"Scientific Committee on Consumer Safety (SCCS), 2012. Opinion on 1,2,4-Trihydroxybenzene COLIPA n\u00b0 A33. SCCS\/1452\/11 Adopted at 17th plenary meeting of 11 December 2012."},{"key":"10.1016\/j.yrtph.2025.105776_bib43","year":"2023"},{"key":"10.1016\/j.yrtph.2025.105776_bib44","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1016\/j.jaci.2019.07.046","article-title":"Deriving individual threshold doses from clinical food challenge data for population risk assessment of food allergens","volume":"144","author":"Westerhout","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"10.1016\/j.yrtph.2025.105776_bib45","series-title":"Skin Sensitization in Chemical Risk Assessment","article-title":"Inter-organization Programme for the Sound management of chemicals","year":"2008"}],"container-title":["Regulatory Toxicology and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0273230025000066?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0273230025000066?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T02:39:50Z","timestamp":1740623990000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0273230025000066"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3]]},"references-count":46,"alternative-id":["S0273230025000066"],"URL":"https:\/\/doi.org\/10.1016\/j.yrtph.2025.105776","relation":{},"ISSN":["0273-2300"],"issn-type":[{"value":"0273-2300","type":"print"}],"subject":[],"published":{"date-parts":[[2025,3]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Comprehensive extractables and leachables sensitization analysis and practical application of a risk-based approach to sensitization assessment for parenteral drug products","name":"articletitle","label":"Article Title"},{"value":"Regulatory Toxicology and Pharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.yrtph.2025.105776","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2025 The Authors. Published by Elsevier Inc.","name":"copyright","label":"Copyright"}],"article-number":"105776"}}