1. Preclinical Safety Assessment of Cosmetics & Toiletries Raman Govindarajan, MD, PhD. Regional Director Medical and Scientific Affairs Johnson and Johnson Asia Pacific

2. Preclinical Safety Assessment Outline: Cosmetic & Toiletry Products Safety Review of Cosmetic Ingredients Safety Review of Active Ingredients and Products

3. Preclinical Safety Assessment Cosmetic & Toiletry Products Cosmetics – least regulated Companies bear the burden of proof on the safety of cosmetic products

4. Preclinical Safety Assessment Sources of Safety Information for Cosmetic Ingredients Cosmetic Ingredient Review (CIR) - CTFA Prohibited Ingredients and other Hazardous Substance – FDA California Proposition 65 List - California EPA List of Suspected Carcinogens - NTP Federal Insecticide, Fungicide and Rodenticide Act - EPA

5. Preclinical Safety Assessment Sources of Safety Information for Cosmetic Ingredients Industry Guidelines to Restrict Ingredient Usage - IFRA Approved Colorant list (limited) - FDA Endocrine Disruptor Screening Program - EPA Voluntary Children’s Health Chemical Evaluation Program – EPA COLIPA - EU Pubmed - Toxnet

6. Preclinical Safety Assessment Toxicity/Preclinical Safety Review Single Dose Study: IV, IP, Dermal, Oral Multiple Dose Study: Subacute, Subchronic, Chronic Organ toxicity – structural and functional Carcinogenicity Study: Dermal, Oral

7. Toxicology: Fundamentals Special Toxicity Studies Ocular Irritation Dermal Irritation/Sensitization Photo-Irritation/Sensitization Reproductive Tests, Embryo toxicity, teratology tests Mutagenicity Tests

8. Preclinical Safety Assessment Additional Studies to support claims Genital/Mucus Membrane Irritation Test Ocular Irritation (Draize, TEP) Test Comedogenicity Test

9. Preclinical Safety Assessment Other information required to access safety Skin Absorption Data Toxicokinetics/Pharmacokinetics Data

10. Safety testing of ingredients and formulations Is there a need to test formulations if ingredients are safe –Interactions during processing – pH, temperature –Interaction within formulation – impurities –Interaction within the body –Interaction with other products used Misuse, overuse, unintended use

11. Preclinical Safety Assessment Safety Evaluation for External Color Additives [From 21 CFR Ch.1 Subpart C, 70.40 (4-1-99)] Safety factor should be 100 to 1 (based on NOEAL in most sensitive species) Safety of external color additives will be determined by : Acute Oral Toxicity Primary Irritation /Contact Sensitization Subacute Dermal Toxicity on intact/abraded skin Dermal Carcinogenicity

13. Non animal test methods In vitro testing Human testing –On satisfactory data being available only

14. Preclinical Safety Assessment/US Most naturals have established long safe use history via oral route Not enough safety information with ocular and dermal exposure Safety issues are mostly related to irritation /sensitization and photo-irritation /sensitization Batch to batch variation FIFRA and California Prop 65 Safety Review of Naturals-Containing Products

15. Preclinical Safety Assessment/US Dependent on the intended use of the enzyme (cosmetic, food, laundry detergent) Potential exposure route under normal or accidental contact (oral, eye, skin, inhalation) Major health effects associated with enzymes are related to irritation and sensitization Safety Review of Enzyme-Containing Products