EPAA Annual Conference 2007 Regulatory Acceptance and Implementation of 3Rs approaches Challenges for industry and regul

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

2. Challenges for Industry - global regulatory acceptance Global regulatory acceptance - a must in a globalized world • 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

3. Challenges for industry - the Local Lymph Node Assay • 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

4. 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

5. 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

6. Challenges for industry - Dermal Penetration In Vitro 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

7. Challenges for industry - Dermal Penetration In Vitro • Dermal Penetration In Vitro: Acceptance • EU  accepted  preferred method • U.S.  not accepted Consequence:  Dermal Penetration In Vitrofor registration in EU In addition  Dermal Penetration In Vivofor registration in US

8. Challenges for industry - Studies performed in dogs Studies performed in dogs  mandatory as non-rodent species for agrochemicals  relevant for risk assessment  acute, sub-chronic, chronic (1 year) • chronic dog study: •  OECD 452 32 animals •  risk assessment based on 90 day study feasable •  waiving possible •  Reduction

9. Challenges for industry - Studies performed in dogs • 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

10. 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