Overview on Current Status of Alternative Methods and Testing Approaches for Skin Corrosion Testing

Chapter

Abstract

The area of skin corrosion represents one of the pioneering areas for the validation of alternative test methods, in which replacement alternatives have been validated and adopted in the regulation as early as 2000 in the European Union and in 2004 at the OECD level. Current internationally agreed approaches recommend the use of Integrated Approach for Testing and Assessment (IATA) that allow to replace or minimize to the extent possible the use of in vivo animal testing while ensuring human safety (OECD Guidance document No. 203, 2014). The IATA comprises in a sequential way (1) the use of existing information, physico-chemical properties and non-testing methods, (2) a weight-of-evidence evaluation of the existing data and (3) if needed, the conduct of prospective testing. When combined within tiered testing strategies in either a top-down or a bottom-up approach for predicting the potential skin irritation and corrosion hazard of a test chemical, the currently validated and adopted in vitro methods for skin irritation and corrosion can replace the traditional in vivo Draize rabbit test (OECD, OECD guidelines for the testing of chemicals No. 404, 2015).

According to the United Nations Globally Harmonized System (UN GHS) for classification, skin corrosives are classified as category 1, and where required by a competent authority (and in case data are sufficient), in one of the three subcategories 1A, 1B and 1C (UN, Globally harmonized system of classification and labelling of chemicals (GHS), 2015). Another system used to classify corrosive substances is described in the UN model regulations for the transport of dangerous goods, in which packaging groups are assigned to skin corrosives (referred to as PG I, II and III) (UN, Volume I – Part 2. Classification, 2015). Skin corrosion effects as defined by the UN GHS classification system and by the UN transport packaging groups can be predicted by the following scientific valid in vitro test methods that have been internationally adopted:
  • The rat skin transcutaneous electrical resistance (TER) test (OECD guidelines for the testing of chemicals No. 430, 2015), which allows discriminating skin corrosives from non-corrosives but does not allow subcategorization of corrosive effects.

  • The reconstructed human epidermal (RhE) models (OECD guidelines for the testing of chemicals No. 431, 2016) including the commercially available EpiSkin™ Standard Model (SM), the EpiDerm™ Skin Corrosion Test (SCT), the SkinEthic™ RhE and the epiCS® test method. In addition to discriminating corrosives from non-corrosives, these test methods also allow the discrimination between subcategory 1A and a combination of subcategories 1B-and-1C but were not adopted for the discrimination between subcategories 1B and 1C due to the limited data set of well-known in vivo corrosive subcategory 1C chemicals.

  • The in vitro membrane barrier test method (OECD guidelines for the testing of chemicals No. 435, 2015), including the commercially available Corrositex® test, which allows, in addition to the discrimination of corrosives from non-corrosives, the discrimination of all skin corrosives under the three UN GHS subcategories, i.e. 1A, 1B and 1C, even though its applicability is limited to test chemicals that are compatible with the assay and, in the EU, it was considered valid only to acids, bases and their derivates.

The applicability domain and the ability of the test methods to provide information on subcategorization play an important role in the choice of test method to be used. When limitations and domain of these in vitro tests are adequately considered, these tests can provide, together with the adopted test method for skin irritation (OECD guidelines for the testing of chemicals No. 439, 2015), sufficient information for the decision on potential of the substance to cause skin irritation and/or corrosion.

Animal testing should be used only as a last resort when discrimination between optional subcategories 1B and 1C for chemicals outside of the applicability domain of OECD TG 435 is required, or the test chemical cannot be tested with the in vitro test methods currently adopted by the OECD due to limitations or non-applicability. However, if additional testing is required, the OECD IATA should be considered in which other in vitro skin corrosion test methods not yet adopted by the OECD are suggested to be used in a weight-of-evidence manner to resolve specific optional or subcategorization issues (OECD Guidance document No. 203, 2014). This is the case for example of the EpiSkin™ test method for which the original prediction model (not adopted due to the limited data set of well-known in vivo corrosive subcategory 1C chemicals) may be considered in a weight-of-evidence approach to distinguish between the subcategories 1B from 1C. In addition, an extended exposure period of 4 h is recommended for the EpiDerm™ SCT for testing fatty amine derivatives (characterized as cationic surfactants) which were found to have a tendency to be under-predicted with the test methods falling within the OECD TG 431 (Houthoff et al., Toxicol In Vitro 29:1263–1267, 2015; see Chap.  9).

References

  1. 1.
    EC. Regulation No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products. Off J Eur Union. 2009; L342:59–209.Google Scholar
  2. 2.
    EC. Regulation 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. 2006; L396:1–849.Google Scholar
  3. 3.
    EC. Regulation No 2016/863 of 31 May 2016 amending Annexes VII and VIII to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) as regards skin corrosion/irritation, serious eye damage/eye irritation and acute toxicity. Off J Eur Union. 2016; L144:27–31.Google Scholar
  4. 4.
    EC. Regulation No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. Off J Eur Union. 2008; L353:1–1355.Google Scholar
  5. 5.
    EC. Regulation 2016/918 of 19 May 2016 amending, for the purposes of its adaptation to technical and scientific progress, Regulation (EC) No 1272/2008 of the European Parliament and of the Council on classification, labelling and packaging of substances and mixtures. Off J Eur Union. 2016; L156:1–103.Google Scholar
  6. 6.
    EC. Directive No 2010/63/EU of the European Parliament and of the council of 22 September 2010 on the protection of animals used for scientific purposes. Off J Eur Union. 2010; L276:33.Google Scholar
  7. 7.
    OECD guidelines for the testing of chemicals No. 404. Acute dermal irritation/corrosion. Paris, France: Organisation for Economic Cooperation and Development. Originally adopted in 1981. 2015. Available at: http://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788. Accessed 10 May 2016.
  8. 8.
    OECD Guidance Document No. 203: integrated approached to testing and assessment for skin irritation/corrosion. Environment, health and safety publications, series on testing and assessment. Organisation for Economic Cooperation and Development, Paris. 2014. Available at: http://www.oecd.org/env/ehs/testing/series-testing-assessment-publications-number.htm. Accessed 25 Apr 2016.
  9. 9.
    United Nations (UN). Globally harmonized system of classification and labelling of chemicals (GHS). Sixth revised edition. Part 3: Health hazards – chapter 3.2 skin corrosion/irritation. New York, USA, and Geneva, Switzerland: United Nations. p. 125–136. 2015. Available at: http://www.unece.org/fileadmin/DAM/trans/danger/publi/ghs/ghs_rev06/English/ST-SG-AC10-30-Rev6e.pdf. Accessed 25 Apr 2016.
  10. 10.
    Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Ther. 1944;82:377–90.Google Scholar
  11. 11.
    ECHA. Guidance on the application of the CLP criteria. Guidance to regulation EC N. 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures. Version 4.1. Chapter 3.2. Skin corrosion/irritation. 2015. Available at: https://echa.europa.eu/documents/10162/13562/clp_en.pdf. Accessed 26 Apr 2016.
  12. 12.
    UN. Volume I – Part 2. Classification. Recommendations on the transport of dangerous goods – model regulations. Nineteenth revised edition. 2015. Available at: http://www.unece.org/trans/danger/publi/unrec/rev19/19files_e.html. Accessed 26 Apr 2015.
  13. 13.
    EC. Directive No 2001/59/EC of 6 August 2001 adapting to technical progress for the 28th time Council Directive 67/548/EEC on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances. Off J Eur Communities. 2001;L225:1–333.Google Scholar
  14. 14.
    EC. Directive No 1999/45/EC of the European Parliament and of the Council of 31 May 1999 concerning the approximation of laws, regulations and administrative provisions of the Member States relating to the classification, packaging and labelling of dangerous preparations. Off J Eur Communities. 1999;L200:1–68.Google Scholar
  15. 15.
    ECHA. Guidance on information requirements and chemical safety assessment. Chapter R.7a: endpoint specific guidance. Version 4.0. Subchapter R.7.2. Skin corrosion/irritation, serious eye damage/eye irritation and respiratory tract corrosion/irritation, p. 168–199. 2015. Available at: http://echa.europa.eu/documents/10162/13632/information_requirements_r7a_en.pdf. Accessed 25 Apr 2016.
  16. 16.
    Alépée N, Grandidier MH, Tornier C, Cotovio J. An integrated testing strategy for in vitro skin corrosion and irritation assessment using SkinEthic™ Reconstructed Human Epidermis. Toxicol In Vitro. 2015;29:179–1792.Google Scholar
  17. 17.
    OECD. Guidance Document No. 34: validation and international acceptance of new or updated test methods for hazard assessment. In: Environmental health and safety monograph series on testing and assessment. 2005. Available at: http://www.oecd.org/env/ehs/testing/series-testing-assessment-publications-number.htm. Accessed 10 May 2016.
  18. 18.
    EpiSkin™ SM (2011). INVITTOX protocol No. 118. EpiSkin™ skin corrosivity test. Available at: https://eurl-ecvam.jrc.ec.europa.eu/validation-regulatory-acceptance/skin-corrosion-docs/EpiSkin_INVITOX%20protocol%20corrosivity%20test_OECD.pdf. Accessed 10 May 2016.
  19. 19.
    Botham PA, Chamberlain M, Barratt MD, Curren RD, Esdaile DJ, Gardiner JR, Gordon VC, Hildebrand B, Lewis RW, Liebsch M, Logemann P, Osborne R, Ponec M, Régnier J-F, Steiling W, Walker AP, Balls M. A prevalidation study on in vitro skin corrosivity testing. The report and recommendations of ECVAM workshop 6. ATLA. 1995;23:219–55.Google Scholar
  20. 20.
    Fentem JH, Archer GEB, Balls M, Botham PA, Curren RD, Earl LK, Esdaile DJ, Holzhütter HG, Liebsch M. The ECVAM international validation study on in vitro tests for skin corrosivity. 2. Results and evaluation by the Management Team. Toxicol In Vitro. 1998;12:483–524.CrossRefGoogle Scholar
  21. 21.
    Liebsch M, Traue D, Barrabas C, Spielmann H, Uphill P, Wilkins S, Wiemann C, Kaufmann T, Remmele M, Holzhütter HG. The ECVAM prevalidation study on the use of EpiDerm for skin corrosivity testing. ATLA. 2000;28:371–401.PubMedPubMedCentralGoogle Scholar
  22. 22.
    EC. Annex I to Directive No 2000/33/EC adapting to technical progress for the 27th time Council Directive 67/548/EEC on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances. Off J Eur Communities. 2000; L136:91–97.Google Scholar
  23. 23.
    EC. Regulation No 440/2008 of 30 May 2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH). Off J Eur Union. 2008; L142:1–739.Google Scholar
  24. 24.
    OECD guidelines for the testing of chemicals No. 430. In vitro skin corrosion: transcutaneous electrical resistance test (TER). Paris, France: Organisation for Economic Cooperation and Development. 2015 (originally adopted in 2004). Available at: http://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788. Accessed 10 May 2016.
  25. 25.
    OECD guidelines for the testing of chemicals No. 435. In vitro membrane barrier test method for skin corrosion. Paris, France: Organisation for Economic Cooperation and Development. 2015 (originally adopted in 2006). Available at: http://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788. Accessed 10 May 2016.
  26. 26.
    OECD guidelines for the testing of chemicals No. 431. In vitro skin corrosion: reconstructed human epidermis (RHE) test method. Paris, France: Organisation for Economic Cooperation and Development. 2016 (originally adopted in 2004). Available at: http://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788. Accessed 10 May 2016.
  27. 27.
    ESAC. Statement on the scientific validity of the EPISKIN™ test (an in vitro test for skin corrosivity). ATLA. 1998;26:277–80.Google Scholar
  28. 28.
    ESAC. Statement on the application of the Epiderm™ human skin model for skin corrosivity testing. ATLA. 2000;28:365–6.Google Scholar
  29. 29.
    ESAC. Statement on the application of the SkinEthic™ human skin model for skin corrosivity testing. 2006. Available at: http://ecvam.jrc.ec.europa.eu/ under “Publications”, “ESAC statements”. Accessed 18 Sep 2009.
  30. 30.
    Kandárová H, Liebsch M, Spielmann H, Genschow E, Schmidt E, Guest R, Whittingham A, Warren N, Gamer A, Remmele M, Kaufmann T, Wittmer E, De Wever B, Rosdy M. Assessment of the SkinEthic reconstituted human epidermis for skin corrosion testing according to OECD guideline 431. Toxicol In Vitro. 2006;20:547–59.CrossRefGoogle Scholar
  31. 31.
    OECD Guidance Document No. 219: performance standards for the assessment of proposed similar or modified in vitro reconstructed human epidermis (RHE) test methods for skin corrosion testing as described in TG 431. OECD environmental health and safety publications, series on testing and assessment. 2015. Available at: http://www.oecd.org/env/ehs/testing/series-testing-assessment-publications-number.htm. Accessed 10 May 2016.
  32. 32.
    ESAC. ESAC statement on the scientific validity of an in vitro test method for skin corrosivity testing. 2009. Available at: http://ecvam.jrc.ec.europa.eu/ under “Publications”, “ESAC statements”. Accessed 18 Sep 2009.
  33. 33.
    Desprez B, Barroso J, Griesinger C, Kandárová H, Alépée N, Fuchs HW. Two novel prediction models improve predictions of skin corrosive sub-categories by test methods of OECD Test Guideline No. 431. Toxicol In Vitro. 2015;29:2055–80.CrossRefGoogle Scholar
  34. 34.
    OECD Guidance Document No. 190: summary document on the statistical performance of methods in OECD test guideline 431 for sub-categorisation. Environment, health, and safety publications, series on testing and assessment. Organisation for Economic Cooperation and Development, Paris. 2013. Available at: http://www.oecd.org/env/ehs/testing/series-testing-assessment-publications-number.htm. Accessed 10 May 2016.
  35. 35.
    ESAC. Statement on the scientific validity of the rat skin transcutaneous electrical resistance (TER) test (an in vitro test for skin corrosivity). ATLA. 1998;26:275–7.Google Scholar
  36. 36.
    ESAC. Statement on the application of the CORROSITEX® assay for skin corrosivity testing. ATLA. 2001;29:96–7.Google Scholar
  37. 37.
    NIH. Corrositex®: an in vitro test method for assessing dermal corrosivity potential of chemicals. NIH Publication No. 99-4495. Research Triangle Park, NC: NIEHS; 1999.Google Scholar
  38. 38.
    Alépée N, Grandidier MH, Cotovio J. Sub-categorisation of skin corrosive chemicals by the EpiSkin™ reconstructed human epidermis skin corrosion test method according to UN GHS: revision of OECD test guideline 431. Toxicol In Vitro. 2014;28:131–45.CrossRefGoogle Scholar
  39. 39.
    Alépée N, Rober C, Tornier C, Cotovio J. The usefulness of the validated SkinEthic™ RHE test method to identify skin corrosive UN GHS subcategories. Toxicol In Vitro. 2014;28:616–25.CrossRefGoogle Scholar
  40. 40.
    EpiDerm™ SCT. SOP version MK-24-007-0024. Protocol for: in vitro EpiDerm™ skin corrosion test (EPI-200-SCT), for use with MatTek corporation’s reconstructed human epidermal model EpiDerm. 2012. Available at: https://eurl-ecvam.jrc.ec.europa.eu/validation-regulatory-acceptance/skin-corrosion-docs/EpiDerm%20EPI-200-SCT%20%20Protocol%20MK-24-007-0024.pdf. Accessed 10 May 2016.
  41. 41.
  42. 42.
    epiCS® 4.1. SOP version in vitro skin corrosion: human skin model test epidermal skin test epiCS® CellSystems. 2012. Available at: http://cellsystems.de/files/epiCS/SOP-epiCS-skin-corrosion.pdf. Accessed 10 May 2016.
  43. 43.
    Eskes C, Detappe V, Koeter H, Kreysa J, Liebsch M, Zuang V, Amcoff P, Barroso J, Cotovio J, Guest R, Hermann M, Hoffmann S, Masson P, Alepee N, Arce LA, Bruschweiler B, Catone T, Cihak R, Clouzeau J, D’Abrosca F, Delveaux C, Derouette JP, Engelking O, Facchini D, Frohlicher M, Hofmann M, Hopf N, Molinari J, Oberli A, Ott M, Peter R, Sa-Rocha VM, Schenk D, Tomicic C, Vanparys P, Verdon B, Wallenhorst T, Winkler GC, Depallens O. Regulatory assessment of in vitro skin corrosion & irritation data within the European framework: workshop recommendations. Regul Toxicol Pharmacol. 2012;62:393–403.CrossRefGoogle Scholar
  44. 44.
    OECD guidelines for the testing of chemicals No. 439. In vitro skin irritation: reconstructed human epidermis test method. Paris, France: Organisation for Economic Cooperation and Development. 215 (originally adopted in 2010). Available at: http://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788. Accessed 10 May 2016.
  45. 45.
    Alépée N, Barroso J, De Smedt A, De Wever B, Hibatallah J, Klaric M, Mewes KR, Millet M, Pfannenbecker U, Tailhardat M, Templier M, McNamee P. Use of HPLC/UPLC-spectrophotometry for detection of formazan in in vitro Reconstructed Human Tissue (RhT)-based test methods employing the MTT-reduction assay to expand their applicability to strongly coloured test chemicals. Toxicol In Vitro. 2015;29:741–61.CrossRefGoogle Scholar
  46. 46.
    Alépée N, Hibatallah J, Klaric M, Mewes KR, Pfannenbecker U, McNamee P. Assessment of cosmetic ingredients in the in vitro reconstructed human epidermis test method EpiSkin™ using HPLC/UPLC-spectrophotometry in the MTT-reduction assay. Toxicol In Vitro. 2016;33:105–17.CrossRefGoogle Scholar
  47. 47.
    Houthoff E, Rugen P, Hart D. Predictability of in vitro dermal assays when evaluating fatty amine derivatives. Toxicol In Vitro. 2015;29:1263–7.CrossRefGoogle Scholar
  48. 48.
    TER. DB-ALM Protocol No. 115. SOP on the rat skin transcutaneous electrical resistance (TER) test. 2008. Available at: https://eurl-ecvam.jrc.ec.europa.eu/validation-regulatory-acceptance/skin-corrosion-docs/115.pdf. Accessed 11 May 2016.
  49. 49.
    Corrositex. DB-ALM protocol No. 116. SOP on the Corrositex® continuous time monitor assay. 2008. Available at: https://eurl-ecvam.jrc.ec.europa.eu/validation-regulatory-acceptance/skin-corrosion-docs/116.pdf. Accessed 11 May 2016.

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.SeCAM Services and Consultation on Alternative MethodsMagliasoSwitzerland
  2. 2.Swiss Federal Office of Public HealthBernSwitzerland

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