1. Safety of Ingredients and Formulations Raman Govindarajan, MD, PhD. Regional Director, Medical and Scientific Affairs Johnson and Johnson Asia Pacific

2. Basics of Formulations Water phase Oil phase O/W emulsions W/O emulsions Complex emulsions Emulsifiers and co emulsifiers Water based formulations Oil based formulations Solid formulations – soaps, lip products Devices & others – toothbrushes, floss, intimate hygiene products

3. Basics of Formulations all ingredients have a function! Structurants including water Fragrances Color Preservatives Benefit agents (Humectants, barrier protectants, moisturizers, cleansers – chemical and physical, pigmentation modifiers, antimicrobials, vitamins, naturals (plant microbe, animal derived), sunscreens, dyes, hair growth/ prevention/ removal, antiaging agents, cellulite, agents for special skins – sensitive skin/ atopic skin. A word on impurities!!

4. Formulation Stability Implications for safety Implications for sensory profile of product Physical stability Chemical stability Stability testing Microbial stability

5. Types of use Leave on formulations Wash off formulations Wipe off formulations Washes Lubricants Safety implications

6. Banned ingredients/ Negative list Sources of negative lists – country legislation Reasons for being on negative list –Human Safety (acute, subacute toxicity, accumulation, carcinogenicity, chronic toxicity –Environmental safety –Impurities Fragrances – levels and negative list Colors – negative list Route of use – relationship to toxicity

7. Levels in a formulation Nature of use of a formulation determines levels that can be permitted safely Number of reasonable uses per day, unreasonable use is possible. Area of use – eye lashes, underarm, genital areas, face, oral Age of use – babies, aged, pregnant and nursing

8. Levels of risk Hazard vs risk Risk assessment –Factors – age, exposure, toxicity data. Safety factor considerations Allowance for reasonable misuse

9. Toxicology assessment components Mutagenicity, Irritation – acute, subacute, chronic, cumulative, mucous membrane irritation Sensitization Phototoxic/ photoallergic Systemic toxicity Carcinogenicity Embryotoxicity/ teratogenicity Reproductive toxicity

10. Mutagenicity What is mutagenicity – mutations/ changes in DNA What are the implications How to detect mutagenic chemicals –Bacterial tests –In vitro (cells) tests –Animal tests

11. Irritation What is irritation –Types of irritation Acute, subacute, intermittent, chronic, cumulative How does one detect irritant materials –Exaggerated tests Differentiating irritation from allergy Mucous membrane irritation

12. Sensitization (Allergy) The immune system – antibodies and cell mediated immune system – functions Immune memory Antigenic similarities – eg vaccines Antigenic determinants The process of allergy – skin –Sensitization and challenge response Testing for sensitization –Animal tests –Human patch tests

13. Phototoxicity & Photoallergy UV absorbing materials Chemical change due to UV Localised effects –Toxicity and allergy Rarely photomutagenicity Testing for phototoxicity and photoallergy –Protein binding tests (in vitro) –Animal tests

14. Systemic toxicity Percutaneous absorption –Determinants of absorption Epidermal barrier (intercellular lipids), penetration enhancers, reservoir effects, in tissue metabolism, blood flow. –Entry into systemic blood pool – detoxification in the liver/ sequestration. Metabolism and excretion – urine, breath, sweat, feces. End organ localization -local organ levels can be higher than blood levels –Determinants of tissue specific toxicity –Blood brain barrier Detection of organ toxicity – functional and structural – 40 tissue studies

15. Specialized forms of toxicity Embryotoxicity Teratogenicity Carcinogenicity Metabolic toxicity Hemato toxicity Reproductive toxicity Undetermined toxicity – the risks – specialised populations/ genetics, age groups, pregnancy, lactation, diseases, diet …… the need for post marketing surveillance.

16. Evaluating safety 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

17. Evaluating safety of naturals In principle standards should be no different from that of single molecules Take history of use into consideration Remember they are mixtures –Different climatic conditions can change chemistry of extracts – is there a reasonable fingerprint Levels and concentrations used