{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:37:32Z","timestamp":1787024252036,"version":"build-2736575974"},"reference-count":38,"publisher":"Japanese Society of Toxicology","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Toxicol. Sci."],"published-print":{"date-parts":[[2019]]},"DOI":"10.2131\/jts.44.23","type":"journal-article","created":{"date-parts":[[2019,1,7]],"date-time":"2019-01-07T18:07:57Z","timestamp":1546884477000},"page":"23-34","source":"Crossref","is-referenced-by-count":10,"title":["The dermal sensitization threshold (DST) approach for mixtures evaluated as negative in &lt;i&gt;in vitro&lt;\/i&gt; test methods; mixture DST"],"prefix":"10.2131","volume":"44","author":[{"given":"Taku","family":"Nishijo","sequence":"first","affiliation":[{"name":"Safety Science Research Laboratories, Kao Corporation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Miyazawa","sequence":"additional","affiliation":[{"name":"Safety Science Research Laboratories, Kao Corporation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazutoshi","family":"Saito","sequence":"additional","affiliation":[{"name":"Safety Science Research Laboratories, Kao Corporation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Otsubo","sequence":"additional","affiliation":[{"name":"Safety Science Research Laboratories, Kao Corporation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Mizumachi","sequence":"additional","affiliation":[{"name":"Safety Science Research Laboratories, Kao Corporation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Sakaguchi","sequence":"additional","affiliation":[{"name":"Safety Science Research Laboratories, Kao Corporation"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"898","reference":[{"key":"1","doi-asserted-by":"crossref","unstructured":"Antignac, E., Nohynek, G.J., Re, T., Clouzeau, J. and Toutain, H. (2011): Safety of botanical ingredients in personal care products\/cosmetics. Food Chem. Toxicol., <b>49<\/b>, 324-341.","DOI":"10.1016\/j.fct.2010.11.022"},{"key":"2","doi-asserted-by":"crossref","unstructured":"Api, A.M., Basketter, D.A., Cadby, P.A., Cano, M.-F., Ellis, G., Gerberick, G.F., Griem, P., McNamee, P.M., Ryan, C.A. and Safford, R. (2008): Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Regul. Toxicol. Pharmacol., <b>52<\/b>, 3-23.","DOI":"10.1016\/j.yrtph.2007.10.008"},{"key":"3","doi-asserted-by":"crossref","unstructured":"Ashikaga, T., Sakaguchi, H., Sono, S., Kosaka, N., Ishikawa, M., Nukada, Y., Miyazawa, M., Ito, Y., Nishiyama, N. and Itagaki, H. (2010): A comparative evaluation of <i>in vitro<\/i> skin sensitisation tests: the human cell-line activation test (h-CLAT) versus the local lymph node assay (LLNA). Altern. Lab. Anim., <b>38<\/b>, 275-284.","DOI":"10.1177\/026119291003800403"},{"key":"4","doi-asserted-by":"crossref","unstructured":"Ashikaga, T., Yoshida, Y., Hirota, M., Yoneyama, K., Itagaki, H., Sakaguchi, H., Miyazawa, M., Ito, Y., Suzuki, H. and Toyoda, H. (2006): Development of an in vitro skin sensitization test using human cell lines: the human Cell Line Activation Test (h-CLAT). I. Optimization of the h-CLAT protocol. Toxicol. In Vitro, <b>20<\/b>, 767-773.","DOI":"10.1016\/j.tiv.2005.10.012"},{"key":"5","doi-asserted-by":"crossref","unstructured":"Basketter, D. and Safford, B. (2016): Skin sensitization quantitative risk assessment: A review of underlying assumptions. Regul. Toxicol. Pharmacol., <b>74<\/b>, 105-116.","DOI":"10.1016\/j.yrtph.2015.11.013"},{"key":"6","doi-asserted-by":"crossref","unstructured":"Basketter, D.A., Clapp, C., Jefferies, D., Safford, B., Ryan, C.A., Gerberick, F., Dearman, R.J. and Kimber, I. (2005): Predictive identification of human skin sensitization thresholds. Contact Dermat., <b>53<\/b>, 260-267.","DOI":"10.1111\/j.0105-1873.2005.00707.x"},{"key":"7","doi-asserted-by":"crossref","unstructured":"Basketter, D.A., Natsch, A., Ellis, G., Api, A.M., Irizar, A., Safford, B., Ryan, C. and Kern, P. (2018): Interspecies assessment factors and skin sensitization risk assessment. Regul. Toxicol. Pharmacol., <b>97<\/b>, 186-188.","DOI":"10.1016\/j.yrtph.2018.06.018"},{"key":"8","doi-asserted-by":"crossref","unstructured":"Basketter, D.A., Evans, P., Fielder, R.J., Gerberick, G.F., Dearman, R.J. and Kimber, I. (2002): Local lymph node assay - validation, conduct and use in practice. Food Chem. Toxicol., <b>40<\/b>, 593-598.","DOI":"10.1016\/S0278-6915(01)00130-2"},{"key":"9","doi-asserted-by":"crossref","unstructured":"Bil, W., Schuur, A.G., Ezendam, J. and Bokkers, B.G. (2017): Probabilistic derivation of the interspecies assessment factor for skin sensitization. Regul. Toxicol. Pharmacol., <b>88<\/b>, 34-44.","DOI":"10.1016\/j.yrtph.2017.05.015"},{"key":"10","doi-asserted-by":"crossref","unstructured":"Dumont, C., Barroso, J., Matys, I., Worth, A. and Casati, S. (2016): Analysis of the Local Lymph Node Assay (LLNA) variability for assessing the prediction of skin sensitisation potential and potency of chemicals with non-animal approaches. Toxicol. In Vitro, <b>34<\/b>, 220-228.","DOI":"10.1016\/j.tiv.2016.04.008"},{"key":"11","doi-asserted-by":"crossref","unstructured":"Emter, R., Ellis, G. and Natsch, A. (2010): Performance of a novel keratinocyte-based reporter cell line to screen skin sensitizers <i>in vitro.<\/i> Toxicol. Appl. Pharmacol., <b>245<\/b>, 281-290.","DOI":"10.1016\/j.taap.2010.03.009"},{"key":"12","doi-asserted-by":"crossref","unstructured":"Felter, S.P., Robinson, M.K., Basketter, D.A. and Gerberick, G.F. (2002): A review of the scientific basis for uncertainty factors for use in quantitative risk assessment for the induction of allergic contact dermatitis. Contact Dermat., <b>47<\/b>, 257-266.","DOI":"10.1034\/j.1600-0536.2002.470502.x"},{"key":"13","doi-asserted-by":"crossref","unstructured":"Felter, S.P., Ryan, C.A., Basketter, D.A., Gilmour, N.J. and Gerberick, G.F. (2003): Application of the risk assessment paradigm to the induction of allergic contact dermatitis. Regul. Toxicol. Pharmacol., <b>37<\/b>, 1-10.","DOI":"10.1016\/S0273-2300(02)00021-1"},{"key":"14","unstructured":"Hoffmann, S. (2015): LLNA variability: an essential ingredient for a comprehensive assessment of non-animal skin sensitization test methods and strategies. ALTEX, <b>32<\/b>, 379-383."},{"key":"15","doi-asserted-by":"crossref","unstructured":"Jaworska, J.S., Natsch, A., Ryan, C., Strickland, J., Ashikaga, T. and Miyazawa, M. (2015): Bayesian integrated testing strategy (ITS) for skin sensitization potency assessment: a decision support system for quantitative weight of evidence and adaptive testing strategy. Arch. Toxicol., <b>89<\/b>, 2355-2383.","DOI":"10.1007\/s00204-015-1634-2"},{"key":"16","doi-asserted-by":"crossref","unstructured":"Keller, D., Krauledat, M. and Scheel, J. (2009): Feasibility study to support a threshold of sensitization concern concept in risk assessment based on human data. Arch. Toxicol., <b>83<\/b>, 1049-1060.","DOI":"10.1007\/s00204-009-0460-9"},{"key":"17","first-page":"8","year":"2010","unstructured":"Kern, P.S., Gerberick, G.F., Ryan, C.A., Kimber, I., Aptula, A. and Basketter, D.A. (2010): Local lymph node data for the evaluation of skin sensitization alternatives: a second compilation. Dermatitis, <b>21<\/b>, 8-32.","journal-title":"Dermatitis","ISSN":"https:\/\/id.crossref.org\/issn\/1710-3568","issn-type":"print"},{"key":"18","unstructured":"Kiken, D.A. and Cohen, D.E. (2002): Contact dermatitis to botanical extracts. Am. J. Contact Dermat., <b>13<\/b>, 148-152."},{"key":"19","doi-asserted-by":"crossref","unstructured":"Kimber, I., Dearman, R.J., Basketter, D.A., Ryan, C.A., Gerberick, G.F., McNamee, P.M., Lalko, J. and Api, A.M. (2008): Dose metrics in the acquisition of skin sensitization: thresholds and importance of dose per unit area. Regul. Toxicol. Pharmacol., <b>52<\/b>, 39-45.","DOI":"10.1016\/j.yrtph.2008.01.010"},{"key":"20","doi-asserted-by":"crossref","unstructured":"Kimber, I., Gerberick, G.F. and Basketter, D.A. (2017): Quantitative risk assessment for skin sensitization: success or failure? Regul. Toxicol. Pharmacol., <b>83<\/b>, 104-108.","DOI":"10.1016\/j.yrtph.2016.11.020"},{"key":"21","doi-asserted-by":"crossref","unstructured":"Koster, S., Leeman, W., Verheij, E., Dutman, E., van Stee, L., Nielsen, L.M., Ronsmans, S., Noteborn, H. and Krul, L. (2015): A novel safety assessment strategy applied to non-selective extracts. Food Chem. Toxicol., <b>80<\/b>, 163-181.","DOI":"10.1016\/j.fct.2015.03.010"},{"key":"22","doi-asserted-by":"crossref","unstructured":"Kroes, R., Renwick, A.G., Cheeseman, M., Kleiner, J., Mangelsdorf, I., Piersma, A., Schilter, B., Schlatter, J., van Schothorst, F., Vos, J.G. and W\u00fcrtzen, G.; European branch of the International Life Sciences Institute. (2004): Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet. Food Chem. Toxicol., <b>42<\/b>, 65-83.","DOI":"10.1016\/j.fct.2003.08.006"},{"key":"23","doi-asserted-by":"crossref","unstructured":"Lalko, J. and Api, A.M. (2006): Investigation of the dermal sensitization potential of various essential oils in the local lymph node assay. Food Chem. Toxicol., <b>44<\/b>, 739-746.","DOI":"10.1016\/j.fct.2005.10.006"},{"key":"24","doi-asserted-by":"crossref","unstructured":"Magnusson, B. and Kligman, A.M. (1969): The identification of contact allergens by animal assay. The guinea pig maximization test. J. Invest. Dermatol., <b>52<\/b>, 268-276.","DOI":"10.1038\/jid.1969.42"},{"key":"25","doi-asserted-by":"crossref","unstructured":"Nishijo, T., Miyazawa, M., Saito, K., Otsubo, Y., Mizumachi, H. and Sakaguchi, H. (2019): Sensitivity of KeratinoSens<sup>TM<\/sup> and h-CLAT for detecting minute amounts of sensitizers to evaluate botanical extracts. J. Toxicol. Sci., <b>44<\/b>, 13-21.","DOI":"10.2131\/jts.44.13"},{"key":"26","unstructured":"OECD. (2012): The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins Part 1: Scientific Evidence. Series on Testing and Assessment No. 168. http:\/\/www.oecd.org\/officialdocuments\/publicdisplaydocumentpdf\/?cote=env\/jm\/mono(2012)10\/part1&amp;doclanguage=en"},{"key":"27","unstructured":"OECD. (2015): OECD Guidelines for the Testing of Chemicals. Test No. 442D: In Vitro Skin Sensitization: ARE-Nrf2 Luciferase Test Method. http:\/\/www.oecd-ilibrary.org\/environment\/test-no-442d-in-vitro-skin-sensitisation_9789264229822-en"},{"key":"28","unstructured":"OECD. (2016): OECD Guidelines for the Testing of Chemicals. Test No. 442E: In Vitro Skin Sensitization: human Cell Line Activation Test (h-CLAT). http:\/\/www.oecd-ilibrary.org\/environment\/test-no-442e-in-vitro-skin-sensitisation_9789264264359-en"},{"key":"29","doi-asserted-by":"crossref","unstructured":"Otsubo, Y., Nishijo, T., Miyazawa, M., Saito, K., Mizumachi, H. and Sakaguchi, H. (2017): Binary test battery with KeratinoSens\u2122 and h-CLAT as part of a bottom-up approach for skin sensitization hazard prediction. Regul. Toxicol. Pharmacol., <b>88<\/b>, 118-124.","DOI":"10.1016\/j.yrtph.2017.06.002"},{"key":"30","doi-asserted-by":"crossref","unstructured":"Roberts, D.W. and Api, A.M. (2018): Chemical applicability domain of the local lymph node assay (LLNA) for skin sensitisation potency. Part 4. Quantitative correlation of LLNA potency with human potency. Regul. Toxicol. Pharmacol., <b>96<\/b>, 76-84.","DOI":"10.1016\/j.yrtph.2018.04.022"},{"key":"31","unstructured":"Rulis, A.M. (1986): De minimis and the threshold of regulation. In: Food protection technology (Felix, C.W., ed.), pp.29-37, Lewis Publishers, Chelsea."},{"key":"32","doi-asserted-by":"crossref","unstructured":"Safford, R.J. (2008): The Dermal Sensitisation Threshold- a TTC approach for allergic contact dermatitis. Regul. Toxicol. Pharmacol., <b>51<\/b>, 195-200.","DOI":"10.1016\/j.yrtph.2008.02.010"},{"key":"33","doi-asserted-by":"crossref","unstructured":"Safford, R.J., Api, A.M., Roberts, D.W. and Lalko, J.F. (2015): Extension of the Dermal Sensitisation Threshold (DST) approach to incorporate chemicals classified as reactive. Regul. Toxicol. Pharmacol., <b>72<\/b>, 694-701.","DOI":"10.1016\/j.yrtph.2015.04.020"},{"key":"34","doi-asserted-by":"crossref","unstructured":"Safford, R.J., Aptula, A.O. and Gilmour, N. (2011): Refinement of the Dermal Sensitisation Threshold (DST) approach using a larger dataset and incorporating mechanistic chemistry domains. Regul. Toxicol. Pharmacol., <b>60<\/b>, 218-224.","DOI":"10.1016\/j.yrtph.2011.03.009"},{"key":"35","unstructured":"SCCS. (2016): Notes of Guidance for the Testing of Cosmetic Ingredients and their Safety Evaluation, 9th revision, SCCS\/1564\/15, revision of 25 April 2016, http:\/\/ec.europa.eu\/health\/scientific_committees\/consumer_safety\/docs\/sccs_o_190.pdf"},{"key":"36","unstructured":"SCCS. (2018): Opinion on Skin Sensitisation Quantitative Risk Assessment for Fragrance Ingredients (QRA2) Submission I (SCCS\/1589\/17) https:\/\/ec.europa.eu\/health\/sites\/health\/files\/scientific_committees\/consumer_safety\/docs\/sccs_o_211.pdf"},{"key":"37","doi-asserted-by":"crossref","unstructured":"Takenouchi, O., Fukui, S., Okamoto, K., Kurotani, S., Imai, N., Fujishiro, M., Kyotani, D., Kato, Y., Kasahara, T., Fujita, M., Toyoda, A., Sekiya, D., Watanabe, S., Seto, H., Hirota, M., Ashikaga, T. and Miyazawa, M. (2015): Test battery with the human cell line activation test, direct peptide reactivity assay and DEREK based on a 139 chemical data set for predicting skin sensitizing potential and potency of chemicals. J. Appl. Toxicol., <b>35<\/b>, 1318-1332.","DOI":"10.1002\/jat.3127"},{"key":"38","doi-asserted-by":"crossref","unstructured":"Urbisch, D., Mehling, A., Guth, K., Ramirez, T., Honarvar, N., Kolle, S., Landsiedel, R., Jaworska, J., Kern, P.S., Gerberick, F., Natsch, A., Emter, R., Ashikaga, T., Miyazawa, M. and Sakaguchi, H. (2015): Assessing skin sensitization hazard in mice and men using non-animal test methods. Regul. Toxicol. Pharmacol., <b>71<\/b>, 337-351.","DOI":"10.1016\/j.yrtph.2014.12.008"}],"container-title":["The Journal of Toxicological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jstage.jst.go.jp\/article\/jts\/44\/1\/44_23\/_pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,11,13]],"date-time":"2019-11-13T13:38:38Z","timestamp":1573652318000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jstage.jst.go.jp\/article\/jts\/44\/1\/44_23\/_article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019]]},"references-count":38,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019]]}},"URL":"https:\/\/doi.org\/10.2131\/jts.44.23","relation":{},"ISSN":["0388-1350","1880-3989"],"issn-type":[{"value":"0388-1350","type":"print"},{"value":"1880-3989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019]]}}}