EPAA Annual Conference 2007 Regulatory Acceptance and Implementation of 3Rs approaches Challenges for industry and regulators Dr. Hennicke Kamp BASF Aktiengesellschaft

Global regulatory acceptance - a must in a globalized world Challenges for Industry - global regulatory acceptance Industry acts globally products usually sold in different regions product safety has to satisfy regional demands studies for safety assessment have to be accepted in these regions (preferably globally) international guidelines (OECD, ICH,...) Consequence If different testing requirements exist in different regions requirements will need to be addressed different tests will be conducted for different regions duplication of efforts and unnecessary use of animals

Local Lymph Node Assay (LLNA) OECD 429 sensitization animal test performed in mice replaces tests in guinea pigs Refinement, potential reduction Test principle repeated application of test substance (ear) measurement of cell proliferation in local lymph node incorporation of radioactively labeled substrates cell number in lymph node Challenges for industry - the Local Lymph Node Assay

Challenges for industry - the Local Lymph Node Assay Local Lymph Node Assay: Acceptance EU accepted UK assessment of pooled values from 4 animals mandatory accepted in EU U.S. assessment of individual animals (5 - 6) study protocol not permitted in UK requirement of positive control Consequence LLNA cannot be conducted in UK if data needed for registration in US LLNA performed using more animals for U.S. compared to EU

Challenges for industry - the Local Lymph Node Assay Local Lymph Node Assay: agrochemical formulations LLNA originally not developed for formulations scientifically sound for formulations protocol for aqueous formulations developed by ECPA group (BASF, Bayer, DOW, Syngenta) EU accepted in EU preferred for formulations U.S. not accepted Buhler test (guinea pig) preferred for formulations (not accepted in EU) Consequence: LLNA for formulations for registration in EU guinea pig test performed for registration in US more animal testing instead of less

Dermal Penetration In Vitro OECD 428 Test substance penetration via skin explanted skin Replacement Test principle application of test substance on skin surface measurement of test substance penetrating through the skin Challenges for industry - Dermal Penetration In Vitro

Challenges for industry - Dermal Penetration In Vitro Dermal Penetration In Vitro : Acceptance EU accepted preferred method U.S. not accepted Consequence: Dermal Penetration In Vitro for registration in EU In addition Dermal Penetration In Vivo for registration in US

Studies performed in dogs mandatory as non-rodent species for agrochemicals relevant for risk assessment acute, sub-chronic, chronic (1 year) Challenges for industry - Studies performed in dogs chronic dog study: OECD animals risk assessment based on 90 day study feasable waiving possible Reduction

Chronic dog study - waiving: Acceptance EU waiving accepted not mandatory in revised 91/414 U.S. waiving possible after case-by-case discussion (U.S. EPA) California: waiving not possible Brazil, Japan: situation unclear Consequence: study performed for worldwide registration Challenges for industry - Studies performed in dogs

Conclusion global acceptance of methodologies is important for industry examples where alternative approaches are not accepted in some regions: Local Lymph Node Assay Dermal Penetration In Vitro Studies performed in dogs not only a transatlantic issue acceptance of negative results of alternative methods big impact on animal welfare prerequisite: high negative predictivity