skin_absorption-penetration

1 Chapter No. 5: Skin absorption / penetration Walter Diembeck1, Chantra Eskes2, Jon R. Heylings3, Gill Langley4, Vera Rogiers5, Johannes J. M. van de Sandt6, Valérie Zuang2 1Beiersdorf A.G., Hamburg, Germany; 2ECVAM-JRC, Ispra, Italy; 3Syngenta CTL, Alderley Park, Macclesfield, UK; 4Dr Hadwen Trust, Hitchin, Herts, UK; 5SCCNFP, V.U.B., Brussels, Belgium; 6TNO Nutrition and Food Research, Zeist, The Netherlands 1. Current data requirements and current tests 1.1. For cosmetic ingredients 1.1.1. Data required from the cosmetic ingredients suppliers: skin absorption testing of chemicals is normally not required by the chemical dangerous substances legislation. For cosmetics, however, companies will require skin absorption data from ingredient suppliers, in particular in the case of “actives”, e.g. colourants, preservatives, uv filters, substances with limitatations in concentration and site of application. In this case, skin absorption data must be available in the safety dossier (PIR required by the 6th Amendment) presented by the industry to the SCCNFP. 1.1.2. Data required from the cosmetic industry: skin absorption data, in particular of “actives”, must be provided in the safety dossier (PIR) for all ingredients (6th Amendment). 1.2. For cosmetic finished products: normally no absorption/penetration data required but the above mentioned tests for the ingredients must have been performed using relevant formulations (close to market product). The worst case situation should be taken into consideration (see: updated version of “Basic criteria for the in vitro assessment …”, SCCNFP (2003)). 1.3. Available human tests and/or data: skin absorption studies in human volunteers can be performed in cases of low toxicity of cosmetic ingredient/product, but often no human data are available. In vitro testing is preferably carried out on excised pig or human skin, according to OECD Guideline 428. Only these data are acceptable. In vitro rodent skin absorption data is considered to be irrelevant (see: updated version of “Basic criteria for the in vitro assessment …”, SCCNFP (2003)). For in vivo testing of chemicals in experimental animals, see OECD Guideline 427 “Skin absorption: in vivo method” (adopted in May 2002). 2. Inventory of alternative methods currently available 2.1 Alternatives to test skin absorption / penetration 2.1.1 State of the art: see ?? OECD Skin Absorption: In vivo Method. Organization for Economic Cooperation and Development (OECD), Environment Directorate, OECD 2 Guideline for the Testing of Chemicals, Guideline 427, Paris (adopted in May 2002, official publication in Febr. 2004)) [rat protocol only] ?? OECD Skin Absorption: In vitro Method. Organization for Economic Cooperation and Development (OECD), Environment Directorate, OECD Guideline for the Testing of Chemicals, Guideline 428, Paris (adopted in May 2002, official publication in Febr. 2004) [either flow-through or static diffusion cells, excised pig or human skin] ?? OECD Guidance Document for the Conduct of Skin Absorption Studies. Organization for Economic Cooperation and Development (OECD), Environment Directorate, OECD Environmental Health and Safety Publications, Series on Testing and Assessment No. 28, Paris (adopted in May 2002, official publication in Febr. 2004) ?? Diembeck W., Beck H., Benech-Kieffer F., Courtellemont P., Dupuis J., Lovell W., Paye M., Spengler J. and Steiling W.. Test guidelines for in vitro assessment of dermal absorption and percutaneous penetration of cosmetic ingredients. Food and Chemical Toxicology, 37, 191-205 (1999) ?? “Cosmetic Ingredients: Guidelines for Percutaneous Absorption/Penetration”, COLIPA, Brussels (1995) ?? Technical Guidance Document on Risk Assessment in support of Commission Directive 93/67/EEC on Risk Assessment for new notified substances, Commission Regulation (EC) No 1488/94 on Risk Assessment for existing substances and Directive 98/8/EC of the European Parliament and of the Council concerning the placing of biocidal products on the market. Doc. EUR 20418 EN/1, European Communities (2003) ?? ECETOC Percutaneous absorption. European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), Monograph No 20, Brussels (1993) ?? EPA (United States Environmental Protection Agency) Proposed rule for in vitro dermal absorption rate testing of certain chemicals of interest to occupational safety and health administration. Federal Register, Volume 64, Number 110, June 9 (1999) ?? Howes D., Guy R., Hadgraft J., Heylings J., Hoeck U., Kemper F., Maibach H., Marty J-P., Merk H., Parra J., Rekkas D., Rondelli I., Schaefer H., Täuber U. and Verbiese N. Methods for assessing percutaneous absorption, ECVAM Workshop Report No. 13. Alternatives To Laboratory Animals (ATLA) 24, 81-106 (1996) ?? Regulatory Toxicology and Pharmacology 31, 53-58 (2000). Sanco/222/2000 Guidance Document on Dermal Absorption European Commission, Health and Consumer Protection Directorate-General Doc. Sanco/222/2000 rev 6, of 27 November 2002 3 ?? SCCNFP/0167/99, Final : Basic Criteria for the in vitro assessment of percutaneous absorption of cosmetic ingredients, adopted by the SCCNFP during the 8th plenary meeting of 23 June 1999 ?? “Guidelines for in vitro methods to assess percutaneous absorption of cosmetic ingredients” in “Notes of Guidance for testing of cosmetic ingredients for their safety evaluation”, SCCNFP/0321/00 Final (2000) ?? SCCNFP/.../03, Updated basic criteria for the in vitro assessment of dermal absorption of cosmetic ingredients,discussed by the SCCNFP at subgroup meeting 10 September 2003, on the agenda of the plenary of 20 October 2003 ?? SCCNFP/Š/03, Final : Notes of Guidance for Testing of Cosmetic Ingredients for Their Safety Evaluation, 5th revision, on the agenda of the plenary meeting of 20 October, 2003 ?? Schaefer H. and Redelmeier T.E. Skin Barrier, Principles of Percutaneous Absorption, Karger, Basel (1996) 3. Identified areas or endpoints with no validated / “valid” alternative methods available: ?? standardized repeat topical dosing in vitro protocols currently not available. Some experience exists with repeat dosing designs within limited experimental time (24-48 h) ?? skin absorption/penetration in combination with metabolism 4. Conclusions and foreseeable timetable (to achieve complete animal replacement) In vivo endpoint: ?? test substance on (= residue) and within skin layers (stratum corneum, epidermis, dermis), in systemic circulation (= receptor fluid in vitro) after topical application ?? covered by alternative method (except metabolism, repeat dosing) Purpose: ?? reduction (OECD in vivo and in vitro guidelines, together with the guidance document, have been accepted in parallel at the same time) ?? replacement of single dose studies (no metabolism) Status: accepted (by OECD [2002] (in parallel with in vivo test), SCCNFP [2000] Validation authority: no formal validation (sufficient and convincing historical data) Regulatory authority: OECD, EC Area of application: chemicals in general (liquids, solutions, emulsions, no gases) 4 Recommendations: ?? screening test (= full replacement) ?? part of a tiered strategy (= partial replacement) Estimated time to have the method validated (ESAC endorsement): no peer reviewed validation foreseen (in vitro test already accepted by EC and OECD regulation) 5. References see 2.1.1 Remarks In principal the in vitro test can be seen as a full alternative to the in vivo test in most cases. However, the quality of submitted in vitro data is still not always satisfying with respect to documentation and technical aspects although the SCCNFP has published basic criteria [1999, 2003] and OECD [2000] a guidance document for this kind of study in addition to the respective guidelines. Many labs do still seem to need time (months – years) to improve special skills which are a prerequisite for general acceptance of this type of in vitro test. Walter Diembeck, Hamburg, December 15, 2003