By: Linna Benardi, S.Si, Apt R&D Director PT KinoCare Era Kosmetindo

1. EXPOSURE TO COSMETICS:CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS By: Linna Benardi, S.Si, Apt R&D Director PT KinoCare Era Kosmetindo

2. I. GENERAL CONSIDERATION

3. Cosmetic Directive 76/768/EEC modified for the 6th time by Directive 93/35/EEC ARTICLE 1 “ A cosmetic product shall mean any substance or preparation intended to be placed in contact with the various external parts of the human body or the mucous membranes of the oral cavity”

4. Cosmetic Directive 76/768/EEC 5TH RECITAL “… products containing substances or preparations intended to be ingested, inhaled, injected or implanted in the human body do not come under the field of cosmetics.”

5. Cosmetics Directive 76/768/EEC modified for the 6th time by Directive 93/35/EEC ARTICLE 2 “Cosmetic products put on the market within the community must not cause damage to human health when applied under normal or reasonably foreseeable condition of use…”

7. In direct contact with skin Applied as such Applied before rinsing COSMETICS Applied after dilution Applied in association with other cosmetics In contact with skin annexes (partition coefficient)

8. The safety assessment needs a case by case approach: Soaps, Shampoos, Bath Preparations… Lotions, Creams, Lipsticks… Sunscreen products… Depilatories… Hair Care Products…

9. In common to all cosmetic products No way of controlling the conditions of use of the cosmetic products Formulas containing number of ingredients Ingredients able to pass in variable amount more or less quickly across the skin Ingredients able to generate adverse effects at given level of systemic exposure

10. Therefore, in cosmetics areaa need for an acceptable margin of safety • Based on the knowledge of the ingredients and their ability to be absorbed by the skin • Covering potential misuse

11. SECONDARY SYSTEMATIC EXPOSURE ACCIDENTAL OCCASIONAL EXPOSURE UNDER NORMAL CONDITIONS OF USE UNDER FORESEEABLE CONDITIONS OF USE

12. IRRITATION RAW MATERIAL FINISHED PRODUCT ALLERGY SYSTEMIC EFFECT

13. Margin of safety = Non observed adverse effect level Systemic exposure dose

14. The assessment of an ingredients by means of the safety margin is not applicable when there is no threshold dose for the harmful effectAllergensCMR substances

15. Non Observed Adverse Effect Level (NOAEL) The No Observed Adverse Effect Level is the outcome of long term toxicity. It is the highest dosage for which no (adverse) effects can be observed. The NOAEL should be expressed as mg/kg bw/day

16. Non Observed Adverse Effect Level (NOAEL) • Obtained from a subchronic toxicity study: • At least 28 days • By oral route • On sensitive species • With appropriate doses

17. Non Observed Adverse Effect Level (NOAEL) • Sometimes it may be relevant to have results from more sensitive information resulting from: • Chronic toxicity • Reproduction toxicity • Carcinogenicity test • Other specific investigations

18. Dose exposure: Amount of substance applied on the skin or mucous membrane The dose is expressed: • As weight (mg or g) • As weight per body weight (ex: mg/kg bw) • As weight per unit of surface (ex: mg/cm2 of skin) • In experimental models as constant dietary concentrations (ppm or mg/kg of food) Exposure dosage: General term comprising of dose, its frequency and duration (ex: mg/kg bw/day)

19. Skin absorption Skin exposure : amount of substance in contact with an unit area of skin for a defined period of time. Percutaneous absorption: passage of substance across the skin without indication of its fate Penetration Permeation Resorption

20. Percutaneous Absorption B ID flux FD A ID Cumulative amount L T Time Using finite dose of substance mimicking the human exposure Using infinite dose of substance allowing to calculate the steady state flux and Kp

21. Percutaneous Absorption Reported as absolute amount of substance penetrating the skin after a certain period (µg/cm2) Reported as percentage of substance penetrating the skin

22. SED: The Systemic Exposure Dosage of a cosmetic ingredients is the amount expected to enter the blood stream. The SED should be expressed per kg bw/day For this definition a mean body weight of 60 kg is commonly accepted

23. CALCULATION OF THE EXPOSURE DOSE (I)

24. The calculation of the in use exposure levels needs a case by case approach considering among others: • Class of cosmetic product • Method of application • Frequency of application • Consumer target group • Site of contact • Total area of skin contact • Duration of contact • Concentration of ingredients in the product • Foreseeable misuse

25. Estimation of consumers exposure to the finished product • Data provided by Colipa • Cosmetic products are gathered into 4 main types: • Oral hygiene and care products • Eye products • Leave on products • Rinse off products

26. Partition coefficient : takes into account rinsing off and dilution of finished products by application on wet skin Ex: Toothpaste Retention coefficient : takes into account the residual part of finished products in direct contact with skin Ex : Shampoo

27. ORAL HYGIENE PRODUCTS

28. EYE PRODUCTS

29. LEAVE ON PRODUCTS

30. RINSE OFF PRODUCTS

31. Maximalized global daily exposure Total oral hygiene products 3.52 g Total eye products 0.05 g Total leave on products 13.50 g Total rinse off products 0.72 g Maximum daily exposure 17.79 g

32. Calculation of The Daily Exposure Dose of Substance Applied to The Skin I (mg/day) = A (g/application) x 103 (mg/g) x C (%) x 10-2 x F (day-1) A (g/application) = amount of finished cosmetic product applied per application C (%) = concentration of ingredients under study in the finished product F (day-1) = frequency of application of the substance

33. CALCULATION OF THE SYSTEMIC EXPOSURE DOSE (SED)

34. CALCULATION OF THE SYSTEMIC EXPOSURE DOSE BASED ON THE PERCENTAGE OF SUBSTANCE PENETRATING THE SKIN SED = I (mg/day) x DAp (%) x 10-2 (mg/kg bw/day) 60 kg bw I (mg/day) = daily dermal exposure to the substance DAp (%) = dermal absorption of the substance expressed in percentage 60 kg bw = default human body weight

35. CALCULATION OF THE SYSTEMIC EXPOSURE DOSE BASED ON THE ABSOLUTE AMOUNT OF SUBSTANCE PENETRATING THE SKIN SED = DAa (µg/cm2) x 10-3 (mg/µg) x SSA (cm2) x F (day-1) (mg/kg bw/day) 60 kg bw DAa (µg/cm2) = dermal absorption of the substance reported as amount (µg)/cm2 SSA (cm2) = surface of skin area expected to be in contact with the cosmetic product 60 kg bw = default human body weight F (day-1) = frequency of application of the substance

36. CALCULATION OF THE MARGIN OF SAFETY (MOS)

37. Margin of Safety = NOAEL (mg/kg bw/day) SED (mg/kg bw/day) • MoS never below 100

38. x Interspecies differences Intraspecies differences Humans Animals 10 10 Dynamics 3.2 Kinetics 4.0 Dynamics 2.5 Kinetics 3.2 x x

39. UV filter example : Isopentyl 4 methoxycinnamate (S27) Margins of safety = NOAEL = o/w : 1667 w/o : 333 SED Based on daily application of 1 mg formulation/cm2 over the entire body surface (1.8 m2) containing at maximum 10% of the active ingredient • Maximum amount of ingredients applied I = 1800 mg/day • Maximum absorption through the skin DAp = o/w : 0.4% or w/o : 2% • Systemic exposure dose : SED = I (mg/day) x DAp (%)/100 o/w : 0.12 mg/kg bw/day 60 kg bw w/o: 0.60 mg/kg bw/day • No observed adverse effect level NOAL = 200 mg/kg bw/day

40. Preservatives : example iodopropynyl butylcarbamate (P91) • Industry proposed to reduce the maximum concentration in products to 0.05% and to restrict its use to eye, non rinse off and rinse off products • Maximum exposure in cosmetic products E = 14.27 g/day resulting from • Eye products : 0.05 g/day • Leave on products : 13.50 g/day • Rinse off products : 0.72 g/day Maximum amount of ingredients daily applied : I = E x 0.05/100 = 7.14 mg/day

41. Preservatives : example iodopropynyl butylcarbamate (P91) Margin of safety = NOAEL = 10 = 156 SED 0.064 Maximum amount of ingredients daily applied : I = 7.14 mg/day Maximum absorption through the skin : Dap = 54% Systemic exposure dose: SED = I (mg/day) x Dap (%)/100 = 0.064 mg/kg w/day 60 kg bw No observed adverse effect level NOAEL = 10 mg/kg bw/day

42. Hair dyes : example : Kardinal rot (B31)Oxidation or Permanent Margin of safety = NOAEL = 5 = 500 SED 0.01 Based on an usage volume of 100 ml containing at maximum 1.25% Maximum amount of ingredients applied : I = 1250 mg Maximum absorption through the skin : A = 0.05% Dermal absorption per treatment : I x A = 0.625 mg Systemic exposure dose : SED = I x A = 0.01 mg/kg bw 60 No observed adverse effect level NOAEL = 5 mg/kg bw

43. Hair dyes : example : Kardinal rot (B31)Semi Permanent Margin of safety = NOAEL = 5 = 685 SED 0.0073 Based on an usage volume of 35 ml containing at maximum 2.5% Maximum amount of ingredients applied : I = 875 mg Maximum absorption through the skin : A = 0.05% Dermal absorption per treatment : I x A = 0.438 mg Systemic exposure dose : SED = I x A = 0.0073 mg/kg bw 60 No observed adverse effect level NOAEL = 5 mg/kg bw

44. Fragrance ingredients : example : musk ketoneThe concentration in the different fragranced cosmetic products was considered case by case

45. Fragrance ingredients : example : musk ketone Margin of safety = NOAEL = 7.5 = 250 SED 0.030 Maximum daily exposure to musk ketone: I = 12.85 mg/day Maximum estimated absorption through the skin : DAp = 14% Systemic exposure dose : SED = I (mg/day) x DAp (%)/100 = 0.030 mg/kg bw/day 60 kg bw No observed adverse effect level NOAEL = 7.5 mg/kg bw/day

46. Calculation of the margin of safety : only applies for ingredients with threshold dose of toxicity

47. Risk characterization when there is no threshold dose of toxicity : Ex : acceptable lifetime cancer risk basing on the dose descriptor T25 from animal studies

48. The dose descriptor T25 is defined as the chronic dose rate (in mg/kg bw) which gives 25% of the animal tumours at a specific tissue site, after corrections for spontaneous incidence, within the life time of that species T25 must be calculated for the most relevant data-set

49. LTCR = Systemic Exposure Dose (mg/kg bw) Human Dose Descriptor (mg/kg bw) The human dose descriptor (HT) is extrapolated from animal dose descriptor (T)

50. Calculation of the HT25 dose descriptor(SCCNFP 25 Sept 2001, Dybing E 1997 and Sanner T 2001) T25 are converted into the corresponding human dose descriptor HT25 by using the following expression in order to take into account the basic metabolic differences between humans and test species : HT25 = T25/ (bw human/bw animal)0.25 (bw human/bw animal)0.25 = 3.6 in the rat (bw human/bw animal)0.25 = 7.0 in the mouse