Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

Case study on the evaluation of skin sensitization for 23 selected fragrance ingredients using a defined approach based on OECD Guideline 497

  • Hyejin Kim (College of Pharmacy, Dongduk Women's University) ;
  • Kwangsik Park (College of Pharmacy, Dongduk Women's University)
  • Received : 2025.04.12
  • Accepted : 2025.06.17
  • Published : 2025.11.15
⟨ Previous Next ⟩

Abstract

Twenty-three single-ingredient substances, selected from materials labeled as allergens in cosmetic fragrances, were assessed for skin sensitization potential using a defined approach (DA) based on the OECD Guideline 497 Integrated Testing Strategy version 2 (ITSv2). According to the ITSv2, skin hypersensitivity data for these selected substances were integrated. In chemico data (from the Direct Peptide Reactivity Assay, DPRA) and in vitro data (from the human Cell Line Activation Test, h-CLAT) were obtained from existing databases, while in silico data were generated via the automated workflow of the OECD QSAR Toolbox. The DA for skin sensitization, which combines QSAR predictions with DPRA and h-CLAT test results, categorized 17 substances, including 2-benzylideneheptanal, as "Sensitizers"; 5 substances, including 4-methoxybenzyl alcohol, as "Inconclusive"; and citronellol alone was categorized as "Not Classified." The outcomes from the Local Lymph Node Assay (LLNA) for substances identified as skin sensitizers by the DA method demonstrated similar classification patterns to those from DA. These results underscore the necessity of integrating comprehensive in vitro, in chemico, and in silico data for accurate evaluation of potential skin sensitizers. This case study could aid in enhancing the safety assessments of potential skin sensitizers using DA; however, final categorization is subject to validation by regulatory authorities.

Keywords

Acknowledgement

This work was supported from Dongduk Women's University

References

  1. Brites GS, Ferreira I, Sebastião AI, Silva A, Carrascal M, Neves BM, Cruz MT (2020) Allergic contact dermatitis: From pathophysiology to development of new preventive strategies. Pharmacol Res 162:105282. https://doi.org/10.1016/j.phrs.2020.105282
  2. Nishijo T, Api AM, Gerberick GF, Miyazawa M, Roberts DW, Safford RJ, Sakaguchi H (2020) Application of the dermal sensitization threshold concept to chemicals classified as high potency category for skin sensitization assessment of ingredients for consumer products. Regul Toxicol Pharmacol 117:104732. https://doi.org/10.1016/j.yrtph.2020.104732
  3. Bialas I, Zelent-Kraciuk S, Jurowski K (2023) The skin sensitisation of cosmetic ingredients: review of actual regulatory status. Toxics 11(4):392. https://doi.org/10.3390/toxics11040392
  4. OECD (2010) Test No. 429: skin sensitisation: local lymph node assay. OECD guidelines for the testing of chemicals, section 4. OECD Publishing. https://doi.org/10.1787/9789264071100-en
  5. OECD (2020) Test No. 406: skin sensitisation. OECD guidelines for the testing of chemicals, section 4. OECD Publishing. https://doi.org/10.1787/9789264070660-en
  6. Gądarowska D, Kalka J, Daniel-Wójcik A, Mrzyk I (2022) Alternative methods for skin-sensitization. Assess Toxics 10(12):740. https://doi.org/10.3390/toxics10120740
  7. Natsch A, Landsiedel R, Kolle SN (2021) A triangular approach for the validation of new approach methods for skin sensitization. Altex 38(4):669-677. https://doi.org/10.14573/altex.2105111
  8. OECD (2023) Guideline No. 497: defined approaches on skin sensitization. OECD guidelines for the testing of chemicals, section 4. OECD Publishing. https://doi.org/10.1787/b92879a4-en
  9. OECD (2024) Test No. 442C: In chemico skin sensitisation: assays addressing the adverse outcome pathway key event on covalent binding to proteins. OECD guidelines for the testing of chemicals, section 4. OECD Publishing. https://doi.org/10.1787/9789264229709-en
  10. OECD (2024) Test No. 442E: in vitro skin sensitisation: in vitro skin sensitisation assays addressing the key event on activation of dendritic cells on the adverse outcome pathway for skin sensitisation. OECD guidelines for the testing of chemicals, section 4. OECD Publishing. https://doi.org/10.1787/9789264264359-en
  11. Patlewicz GY, Basketter DA, Pease CK, Wilson K, Wright ZM, Roberts DW, Bernard G, Arnau EG, Lepoittevin JP (2004) Further evaluation of quantitative structure-activity relationship models for the prediction of the skin sensitization potency of selected fragrance allergens. Contact Dermat 50(2):91-97. https://doi.org/10.1111/j.0105-1873.2004.00322.x
  12. Na M, Ritacco G, O'Brien D, Lavelle M, Api AM, Basketter D (2021) Fragrance skin sensitization evaluation and human testing: 30-year experience. Dermatitis 32(5):339-352. https://doi.org/10.1097/DER.0000000000000684
  13. EU (2009) Regulation (EC)No 1223/2009 of the European parliament and of the council, of 30 Nov. 2009 on cosmetic product. Off J Eur Union. L342/59. https://health.ec.europa.eu/system/files/2016-11/cosmetic_1223_2009_regulation_en_0.pdf
  14. Kim S, Lee K, Lim M (2022) Characteristics and co-occurrence patterns of fragrance allergens in consumer chemical products. J Env Health Sci 48(4):206-215. https://doi.org/10.5668/JEHS.2022.48.4.206
  15. MFDS (2020) Regulation on precautions for use and labeling of allergic substances in cosmetics: allergenic ingredients among fragrance components. Annex 2
  16. Braeuning C, Braeuning A, Mielke H, Holzwarth A, Peiser M (2018) Evaluation and improvement of QSAR predictions of skin sensitization for pesticides. SAR QSAR Environ Res 29(10):823-846. https://doi.org/10.1080/1062936X.2018.1518261
  17. Alves VM, Muratov E, Fourches D, Strickland J, Kleinstreuer N, Andrade CH, Tropsha A (2015) Predicting chemically-induced skin reactions. Part I: QSAR models of skin sensitization and their application to identify potentially hazardous compounds. Toxicol Appl Pharmacol 284(2):262-272. https://doi.org/10.1016/j.taap.2014.12.014
  18. Kim H, Park J, Lee H, Son J, Park Y, Bae H, Park SY, Lee SH, Seo J, Shin S, Park K (2023) Potency classification of isothiazolinone compounds based on defined approaches of skin sensitization in OECD GL 497. Environ Anal Health Toxicol 38(4):e2023026. https://doi.org/10.5620/eaht.2023026
  19. Natsch A, Ryan CA, Foertsch L, Emter R, Jaworska J, Gerberick F, Kern P (2013) A dataset on 145 chemicals tested in alternative assays for skin sensitization undergoing prevalidation. J Appl Toxicol 33(11):1337-1352. https://doi.org/10.1002/jat.2868
  20. Nukada Y, Ashikaga T, Miyazawa M, Hirota M, Sakaguchi H, Sasa H, Nishiyama N (2012) Prediction of skin sensitization potency of chemicals by human Cell Line Activation Test (h-CLAT) and an attempt at classifying skin sensitization potency. Toxicol In Vitro 26(7):1150-1160. https://doi.org/10.1016/j.tiv.2012.07.001
  21. Ferreira I, Brites G, Silva A, Caramelo F, Oliveiros B, Neves BM, Cruz MT (2023) Development of an in chemico high-throughput screening method for the identification of skin sensitization potential. Arch Toxicol 97(9):2441-2451. https://doi.org/10.1007/s00204-023-03550-z
  22. Natsch A, Gerberick GF (2022) Integrated skin sensitization assessment based on OECD methods (II): hazard and potency by combining kinetic peptide reactivity and the "2 out of 3" defined approach. Altex 39(4):647-655. https://doi.org/10.14573/altex.2201142
  23. Cottrez F, Boitel E, Ourlin JC, Peiffer JL, Fabre I, Henaoui IS, Mari B, Vallauri A, Paquet A, Barbry P, Auriault C, Aeby P, Groux H (2016) SENS-IS, a 3D reconstituted epidermis based model for quantifying chemical sensitization potency: reproducibility and predictivity results from an inter-laboratory study. Toxicol In Vitro 32:248-260. https://doi.org/10.1016/j.tiv.2016.01.007
  24. ECHA (2025) Registered Dossier. https://echa.europa.eu/registration-dossier/-/registered-dossier
  25. Casati S, Asturiol D, Browne P, Kleinstreuer N, Régimbald-Krnel M, Therriault P (2022) Standardisation and international adoption of defined approaches for skin sensitisation. Front Toxicol 4:943152. https://doi.org/10.3389/ftox.2022.943152
  26. Macmillan DS, Chilton ML (2019) A defined approach for predicting skin sensitisation hazard and potency based on the guided integration of in silico, in chemico and in vitro data using exclusion criteria. Regul Toxicol Pharmacol 101:35-47. https://doi.org/10.1016/j.yrtph.2018.11.001
  27. Li H, Bai J, Zhong G, Lin H, He C, Dai R, Du H, Huang L (2019) Improved defined approaches for predicting skin sensitization hazard and potency in humans. Altex 36(3):363-372. https://doi.org/10.14573/altex.1809191
  28. Malloy T, Zaunbrecher V, Beryt E, Judson R, Tice R, Allard P, Blake A, Cote I, Godwin H, Heine L, Kerzic P, Kostal J, Marchant G, McPartland J, Moran K, Nel A, Ogunseitan O, Rossi M, Thayer K, Tickner J, Whittaker M, Zarker K (2017) Advancing alternatives analysis: The role of predictive toxicology in selecting safer chemical products and processes. Integr Environ Assess Manag 13(5):915-925. https://doi.org/10.1002/ieam.1923
  29. Piersma AH, Ezendam J, Luijten M, Muller JJ, Rorije E, van der Ven LT, van Benthem J (2014) A critical appraisal of the process of regulatory implementation of novel in vivo and in vitro methods for chemical hazard and risk assessment. Crit Rev Toxicol 44(10):876-894. https://doi.org/10.3109/10408444.2014.940445. (Erratum. In: Crit Rev Toxicol. 2015;45(9):812. doi:10.3109/10408444.2015.1073501)