ECVAM Key Area Sensitisation: Overview on Activities Silvia Casati, Chantra Eskes

ECVAM Key Area Sensitisation Refine Reduce Replace Collaboration with industries Support to policies: Cosmetics Directive REACH Task Force input Research Activities Test development Prevalidation/Validation LLNA related activities

Budget: 11 M€ Partners: 28 (including universities, research institutes, industries, SMEs, JRC) Coordinator: Erwin Roggen (Novozymes) Duration: October 2005 – November 2010  Sens-it-iv aims to develop assay systems that model sensitisation, rather than irritation and toxicity of chemicals and proteins.  The innovative aspect of the project is the coordinated and extensive characterisation of the impact of compounds on cell-cell interactions for the identification of the key mechanisms involved in sensitisation. Deliverable In vitro tests and test strategies ready to be validated, allowing the testing of the sensitising potency of existing and new chemical entities for classification and labelling and for the purpose of risk assessment. Sens-it-iv Novel Testing Strategies for In Vitro Assessment of Allergens

WP8: In vitro assay development WP7: Data Management WP9: Technology transfer & Dissemination Technology module (Months 0-60) (Months 0-60) WP1: Compound Selection WP3: DC – T-cell Interactions and biology WP2: EC- DC interactions and biology WP4: Genomics WP5: Proteomics WP6: Metabonomics Science module (Months 0-36) WP10: Project management (Months 0-60) Sens-it-iv Structure

Coordination Board E. Roggen (coordinator) H. Weltzien (vice-coordinator IPR, Financial and legal Officers Steering Committee E. Roggen, S. Casati, O. De Silva D. Basketter, I. Kimber, H. Weltzien Management Team E. Roggen, S. Casati, C. Borrebaeck F. Sallusto, H.J. Thierse, K. Park, C. Helma, S. Gibbs, H. Hermans European Commission WP10 WP9 WP8 WP7 WP6 WP5 WP4 WP3 WP2 WP1 Advisory Committees General Assembly WP1: Chemicals Selection WP1:EC - DC interactions WP3: DC - T-cell interactions WP4: Genomics WP5: Proteomics WP6: Metabonomics WP7:Data Management WP8: In vitro assays development WP9: Technology transfer & dissemination WP10: Project management ECVAM Involvement in Sens-it-iv

Selection of a tutorial set of compounds Repository established in ECVAM and chemicals distribution to other partners Procedures for chemicals handling Extended list of chemicals for subsequent project phases Database under development on physico-chemical properties of compounds and published in vitro and in vivo data (human and animal) Sens-it-iv WP1: 24 Months Achievements

“ Dendritic cells as a tool for a predictive identification of skin sensitization hazard” (2004) “ The relevance of epidermal disposition for sensitisation hazard identification and risk assessment” (2006) “Chemical reactivity measurement and the predictive identification of skin sensitisers” (2007) Skin penetration Protein binding DC activation DC migration DC T CELL DC- T cell interactions Memory T cells EC Others Chemical Respiratory Allergy: Opportunities for Hazard Identification and Characterisation Relevant Workshops

Collaboration with Industries Definition of a set of reference chemicals for methods development and evaluation

The LLNA and REACH Regulation (EC) N. 1907/2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Applies to new and about 30,000 existing substances Annex VII Standard information requirements for substances manufactured or imported in quantities of 1 tonne or more Skin sensitisation: An assessment of the available human, animal and alternative data In vivo testing The LLNA is the first-choice method for in vivo testing Only in exceptional circumstances should another test be used Justification for the use of another test shall be provided

LLNA Performance Standards Modifications to the standard LLNA incorporating non- radioactive endpoints Validation of the standard LLNA for the purposes of measuring relative potency using EC3 values Reduced LLNA Under Peer Review Workshop on: “Alternative Endpoints for the LLNA” Ispra, September 2007 Method under evaluation Peer-review panel being established ESAC statement - April ’07 Inclusion into RIP 3.3 TGD Draft TG submitted to CA LLNA Related Activities

Revised approach of the standard LLNA to reduce animal use in skin sensitisation testing Standard LLNA 3 concencentrations test chemical + vehicle control 4-5 mice/group Reduced-LLNA top concencentration test chemical + vehicle control 4-5 mice/group mice 8-10 mice Does not provide information on potency For risk assessment purposes a standard LLNA should be conducted Reduced-LLNA

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