{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T03:20:31Z","timestamp":1778728831209,"version":"3.51.4"},"reference-count":54,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2016,10,1]],"date-time":"2016-10-01T00:00:00Z","timestamp":1475280000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2016,10,1]],"date-time":"2016-10-01T00:00:00Z","timestamp":1475280000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Regulatory Toxicology and Pharmacology"],"published-print":{"date-parts":[[2016,10]]},"DOI":"10.1016\/j.yrtph.2016.07.007","type":"journal-article","created":{"date-parts":[[2016,7,16]],"date-time":"2016-07-16T15:10:14Z","timestamp":1468681814000},"page":"247-254","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":18,"special_numbering":"C","title":["Chemical applicability domain of the Local Lymph Node Assay (LLNA) for skin sensitization potency. Part 1. Underlying physical organic chemistry principles and the extent to which they are represented in the LLNA validation dataset"],"prefix":"10.1016","volume":"80","author":[{"given":"D.W.","family":"Roberts","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.M.","family":"Api","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G.","family":"Patlewicz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T.W.","family":"Schultz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.yrtph.2016.07.007_bib1","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s00204-011-0693-2","article-title":"Alternative (non-animal) methods for cosmetics testing: current status and future prospects","volume":"85","author":"Adler","year":"2011","journal-title":"Arch. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib2","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.taap.2014.12.013","article-title":"Predicting chemically-induced skin reactions. Part II: QSAR models of skin permeability and the relationships between skin permeability and skin sensitization","volume":"284","author":"Alves","year":"2015","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib3","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1002\/etc.34","article-title":"Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment","volume":"29","author":"Ankley","year":"2010","journal-title":"Environ. Toxicol. Chem."},{"key":"10.1016\/j.yrtph.2016.07.007_bib4","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1021\/tx0601004","article-title":"Mechanistic applicability domains for nonanimal-based prediction of toxicological end points: general principles and application to reactive toxicity","volume":"19","author":"Aptula","year":"2006","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib5","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/0300-483X(95)03132-Y","article-title":"Structure activity relationships in skin sensitization using the murine local lymph node assay","volume":"10","author":"Ashby","year":"1995","journal-title":"Toxicology"},{"key":"10.1016\/j.yrtph.2016.07.007_bib6","series-title":"Allergic Contact Dermatitis. The Molecular Basis (","first-page":"81","article-title":"Hapten-protein interactions","author":"Barratt","year":"1997"},{"key":"10.1016\/j.yrtph.2016.07.007_bib7","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/S0278-6915(96)00059-2","article-title":"The local lymph node assay: a viable alternative to currently accepted skin sensitization tests","volume":"34","author":"Basketter","year":"1996","journal-title":"Food Chem. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib8","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0278-6915(99)00112-X","article-title":"Threshold for classification as a skin sensitizer in the local lymph node assay: a statistical evaluation","volume":"37","author":"Basketter","year":"1999","journal-title":"Food Chem. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib9","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1034\/j.1600-0536.2000.042006344.x","article-title":"Use of the local lymph node assay for the estimation of relative contact allergenic potency","volume":"42","author":"Basketter","year":"2000","journal-title":"Contact Dermat."},{"key":"10.1016\/j.yrtph.2016.07.007_bib10","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0278-6915(01)00130-2","article-title":"Local lymph node assay \u2013 validation, conduct and use in practice","volume":"40","author":"Basketter","year":"2002","journal-title":"Food Chem. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib11","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1046\/j.1365-2230.2003.01247.x","article-title":"Contact allergy: the local lymph node assay for the prediction of hazard and risk","volume":"28","author":"Basketter","year":"2003","journal-title":"Clin. Exp. Dermatol"},{"key":"10.1016\/j.yrtph.2016.07.007_bib12","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1600-0536.2008.01444.x","article-title":"Nothing is perfect, not even the local lymph node assay: a commentary and the implications for REACH","volume":"60","author":"Basketter","year":"2009","journal-title":"Contact Dermat."},{"key":"10.1016\/j.yrtph.2016.07.007_bib13","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1001\/archderm.1965.01600080079017","article-title":"Delayed contact hypersensitivity in the Guinea pig","volume":"91","author":"Buehler","year":"1965","journal-title":"Arch. Dermatol"},{"key":"10.1016\/j.yrtph.2016.07.007_bib14","doi-asserted-by":"crossref","first-page":"774","DOI":"10.3891\/acta.chem.scand.05-0774","article-title":"The partition of organic compounds between higher alcohols and water","volume":"5","author":"Collander","year":"1951","journal-title":"Acta. Chem. Scand."},{"key":"10.1016\/j.yrtph.2016.07.007_bib15","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s00420-002-0418-1","article-title":"Occupational skin-disease data in Europe","volume":"76","author":"Diepgen","year":"2003","journal-title":"Int. Arch. Occup. Environ. Health"},{"key":"10.1016\/j.yrtph.2016.07.007_bib16","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1007\/s004200050407","article-title":"The epidemiology of occupational contact dermatitis","volume":"72","author":"Diepgen","year":"1999","journal-title":"Int. Arch. Occup. Environ. Health"},{"key":"10.1016\/j.yrtph.2016.07.007_bib17","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1111\/j.0105-1873.2005.00683.x","article-title":"Hapten-protein binding: from theory to practical application in the in\u00a0vitro prediction of skin sensitization","volume":"53","author":"Divkovic","year":"2005","journal-title":"Contact Dermatis"},{"key":"10.1016\/j.yrtph.2016.07.007_bib18","series-title":"Allergic Contact Dermatitis to Simple Chemicals. A Molecular Approach","author":"Dupuis","year":"1982"},{"key":"10.1016\/j.yrtph.2016.07.007_bib19","unstructured":"EC (2006). EC. Regulation (EC) No 1907\/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999\/45\/EC and repealing Council Regulation (EEC) No 793\/93 and Commission Regulation (EC) No 1488\/94 as well as Council Directive 76\/769\/EEC and Commission Directives 91\/155\/EEC, 93\/67\/EEC, 93\/105\/EC and 2000\/21\/EC. Off J Eur Union, L396\/1 of 30.12.2006. Commission of the European Communities."},{"issue":"L342","key":"10.1016\/j.yrtph.2016.07.007_bib20","first-page":"59","article-title":"EC. Regulation (EC) No 1223\/2009 of the European parliament and the council of 30 November 2009 on cosmetic products","volume":"2009","author":"EC","year":"2009","journal-title":"Off. J. Eur. Union"},{"key":"10.1016\/j.yrtph.2016.07.007_bib21","series-title":"Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.7a: Endpoint Specific Guidance","author":"ECHA","year":"2015"},{"key":"10.1016\/j.yrtph.2016.07.007_bib22","article-title":"Is skin penetration a determining factor in skin sensitization potential and potency? Refuting the notion of a LogKow threshold for Skin Sensitization","author":"Fitzpatrick","year":"2016","journal-title":"J.\u00a0Appl. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib23","article-title":"What determines skin sensitization potency: myths, maybes and realities. The 500 molecular weight cut-off: an updated analysis","author":"Fitzpatrick","year":"2016","journal-title":"J.\u00a0Appl. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib24","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S1046-199X(00)90027-7","article-title":"Local lymph node assay: validation assessment for regulatory purposes","volume":"11","author":"Gerberick","year":"2000","journal-title":"Am. J. Contact Dermat."},{"key":"10.1016\/j.yrtph.2016.07.007_bib25","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.ymeth.2006.07.006","article-title":"Local lymph node assay (LLNA) for detection of sensitization capacity of chemicals","volume":"41","author":"Gerberick","year":"2007","journal-title":"Methods"},{"key":"10.1016\/j.yrtph.2016.07.007_bib26","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/0378-4274(95)03356-P","article-title":"The expanding role of quantitative structure-activity relationships (QSAR) in toxicology","volume":"79","author":"Hansch","year":"1995","journal-title":"Toxicol. Lett."},{"key":"10.1016\/j.yrtph.2016.07.007_bib27","series-title":"Intermolecular and Surface Forces","author":"Israelachvili","year":"1991"},{"key":"10.1016\/j.yrtph.2016.07.007_bib28","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1002\/jat.2869","article-title":"Bayesian integrated testing strategy to assess skin sensitization potency: from theory to practice: integrated testing strategy to assess skin sensitization potency","volume":"33","author":"Jaworska","year":"2013","journal-title":"J.\u00a0Appl. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib29","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1007\/s00204-015-1634-2","article-title":"Bayesian integrated testing strategy (ITS) for skin sensitization potency assessment: a decision support system for quantitative weight of evidence and adaptive testing strategy","volume":"89","author":"Jaworska","year":"2015","journal-title":"Arch. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib30","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1002\/jat.1146","article-title":"A\u00a0future approach to measuring relative skin sensitising potency: a proposal","volume":"26","author":"Jowsey","year":"2006","journal-title":"J.\u00a0Appl. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib31","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0300-483X(94)90193-7","article-title":"The local lymph node assay: developments and applications","volume":"93","author":"Kimber","year":"1994","journal-title":"Toxicology"},{"key":"10.1016\/j.yrtph.2016.07.007_bib32","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1093\/occmed\/kql039","article-title":"Incidence by occupation and industry of work-related skin diseases in the United Kingdom, 1996-2001","volume":"56","author":"McDonald","year":"2006","journal-title":"Occup. Med."},{"key":"10.1016\/j.yrtph.2016.07.007_bib33","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/jid.1969.42","article-title":"The identification of contact allergens by animal assay. The guinea pig maximisation test","volume":"52","author":"Magnusson","year":"1969","journal-title":"J.\u00a0Invest. Dermatol"},{"key":"10.1016\/j.yrtph.2016.07.007_bib34","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1021\/tx1002707","article-title":"Chemical basis for the extreme skin sensitization potency of (E)-4-(Ethoxymethylene)-2-phenyloxazol-5(4H)-one","volume":"23","author":"Natsch","year":"2010","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib35","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1021\/tx2003678","article-title":"Relating skin sensitizing potency to chemical reactivity: reactive Michael acceptors inhibit NF-jB signaling and are less sensitizing than SNAr- and SN2- reactive chemicals","volume":"24","author":"Natsch","year":"2011","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib36","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1093\/toxsci\/kfu229","article-title":"Predicting skin sensitizer potency based on in\u00a0vitro data from keratinoSens and kinetic peptide binding: global versus domain-based assessment","volume":"143","author":"Natsch","year":"2015","journal-title":"Toxicol. Sci."},{"key":"10.1016\/j.yrtph.2016.07.007_bib37","series-title":"The Murine Local Lymph Node Assay: a Test Method for Assessing the Allergic Contact Dermatitis Potential of Chemicals\/Compounds","author":"NIH","year":"1999"},{"key":"10.1016\/j.yrtph.2016.07.007_bib38","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1021\/tx900193s","article-title":"Reduced sensitizing capacity of epoxy resin systems: a structure-activity relationship study","volume":"22","author":"Niklasson","year":"2009","journal-title":"Chem. Res. Toxicol"},{"key":"10.1016\/j.yrtph.2016.07.007_bib39","series-title":"Test Guideline 406. Skin Sensitisation","author":"OECD","year":"1992"},{"key":"10.1016\/j.yrtph.2016.07.007_bib40","series-title":"Test Guideline 429. Skin Sensitisation: Local Lymph Node Assay","author":"OECD","year":"2002"},{"key":"10.1016\/j.yrtph.2016.07.007_bib41","series-title":"The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins Part 1: Scientific Evidence","author":"OECD","year":"2012"},{"key":"10.1016\/j.yrtph.2016.07.007_bib42","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.yrtph.2014.06.001","article-title":"Towards AOP application \u2013 implementation of an integrated approach to testing and assessment (IATA) into a pipeline tool for skin sensitization","volume":"69","author":"Patlewicz","year":"2014","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib43","series-title":"pKa Prediction for Organic Acids and Bases","author":"Perrin","year":"1981"},{"key":"10.1016\/j.yrtph.2016.07.007_bib44","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/0022-5193(82)90199-0","article-title":"The derivation of quantitative correlations between skin sensitisation and physicochemical parameters for alkylating agents and their application to experimental data for sultones","volume":"99","author":"Roberts","year":"1982","journal-title":"J.\u00a0Theor. Biol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib45","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s11743-000-0134-z","article-title":"Aquatic toxicity \u2013 are surfactant properties relevant?","volume":"3","author":"Roberts","year":"2000","journal-title":"J.\u00a0Surfact. Deterg."},{"key":"10.1016\/j.yrtph.2016.07.007_bib46","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1002\/qsar.200390016","article-title":"Mechanisms of action for general and polar narcosis: a difference in dimension","volume":"22","author":"Roberts","year":"2003","journal-title":"QSAR Comb. Sci."},{"key":"10.1016\/j.yrtph.2016.07.007_bib47","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1021\/tx060102o","article-title":"Mechanistic Applicability Domains for Non-Animal Based Prediction of Toxicological Endpoints. QSAR Analysis of the Schiff Base Applicability Domain for Skin Sensitization","volume":"19","author":"Roberts","year":"2006","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib48","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1021\/tx060121y","article-title":"Electrophilic chemistry related to skin sensitization. Reaction mechanistic applicability domain classification for a published data set of 106 chemicals tested in the mouse local lymph node assay","volume":"20","author":"Roberts","year":"2007","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib49","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1002\/jat.1289","article-title":"Determinants of skin sensitisation potential","volume":"28","author":"Roberts","year":"2008","journal-title":"J.\u00a0Appl. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib50","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1021\/tx800431x","article-title":"High throughput kinetic profiling approach for covalent binding to peptides: application to skin sensitization potency of Michael acceptor electrophiles","volume":"22","author":"Roberts","year":"2009","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib51","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1111\/j.1600-0536.2009.01646.x","article-title":"Does the extreme skin sensitisation potency of Benzoquinone result from special chemistry?","volume":"61","author":"Roberts","year":"2009","journal-title":"Contact Dermatatitis"},{"key":"10.1016\/j.yrtph.2016.07.007_bib52","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/j.1600-0536.2012.02160.x","article-title":"What determines skin sensitization potency\u2013myths, maybes and realities. Part 1. The 500 molecular weight cut-off","volume":"68","author":"Roberts","year":"2012","journal-title":"Contact Dermat."},{"key":"10.1016\/j.yrtph.2016.07.007_bib53","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1021\/tx400355n","article-title":"Electrophilic reactivity and skin sensitization potency of SNAr electrophiles","volume":"27","author":"Roberts","year":"2014","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.yrtph.2016.07.007_bib54","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.yrtph.2013.09.007","article-title":"Computer models versus reality: how well do in silico models currently predict the sensitization potential of a substance","volume":"67","author":"Teubner","year":"2013","journal-title":"Regul. Toxicol. Pharmacol."}],"container-title":["Regulatory Toxicology and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0273230016301908?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0273230016301908?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T12:28:03Z","timestamp":1759494483000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0273230016301908"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,10]]},"references-count":54,"alternative-id":["S0273230016301908"],"URL":"https:\/\/doi.org\/10.1016\/j.yrtph.2016.07.007","relation":{},"ISSN":["0273-2300"],"issn-type":[{"value":"0273-2300","type":"print"}],"subject":[],"published":{"date-parts":[[2016,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Chemical applicability domain of the Local Lymph Node Assay (LLNA) for skin sensitization potency. Part 1. Underlying physical organic chemistry principles and the extent to which they are represented in the LLNA validation dataset","name":"articletitle","label":"Article Title"},{"value":"Regulatory Toxicology and Pharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.yrtph.2016.07.007","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2016 Elsevier Inc. All rights reserved.","name":"copyright","label":"Copyright"}]}}