exposure to cosmetics: calculation of the safety margin and the acceptable lifetime risk for...

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

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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. I. GENERAL CONSIDERATION. Cosmetic Directive 76/768/EEC modified for the 6 th time by Directive 93/35/EEC. - PowerPoint PPT Presentation

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Page 1: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

EXPOSURE TO COSMETICS:EXPOSURE TO COSMETICS:CALCULATION OF THE SAFETY MARGIN CALCULATION OF THE SAFETY MARGIN

AND THE ACCEPTABLE LIFETIME RISK FOR AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTSCOSMETIC INGREDIENTS

By:By:Linna Benardi, S.Si, AptLinna Benardi, S.Si, Apt

R&D Director PT KinoCare Era R&D Director PT KinoCare Era KosmetindoKosmetindo

Page 2: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

I. GENERAL CONSIDERATIONI. GENERAL CONSIDERATION

Page 3: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Cosmetic Directive 76/768/EEC Cosmetic Directive 76/768/EEC modified for the 6modified for the 6thth time by Directive time by Directive

93/35/EEC93/35/EEC

ARTICLE 1ARTICLE 1“ “ A cosmetic product shall mean any A cosmetic product shall mean any

substance or preparation intended to substance or preparation intended to be placed in contact with the various be placed in contact with the various external parts of the human body or external parts of the human body or the mucous membranes of the oral the mucous membranes of the oral cavity”cavity”

Page 4: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Cosmetic Directive Cosmetic Directive 76/768/EEC76/768/EEC

55THTH RECITAL RECITAL

“… “… products containing substances or products containing substances or preparations intended to be preparations intended to be ingested, inhaled, injected or ingested, inhaled, injected or implanted in the human body do not implanted in the human body do not come under the field of cosmetics.”come under the field of cosmetics.”

Page 5: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Cosmetics Directive 76/768/EEC Cosmetics Directive 76/768/EEC modified for the 6modified for the 6thth time by Directive time by Directive

93/35/EEC93/35/EEC

ARTICLE 2ARTICLE 2

““Cosmetic products put on the market Cosmetic products put on the market within the community must not cause within the community must not cause damage to human health when damage to human health when applied under normal or reasonably applied under normal or reasonably foreseeable condition of use…”foreseeable condition of use…”

Page 6: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Illustrative list by category of cosmetic Illustrative list by category of cosmetic productsproducts

-Creams, emulsions, gels and oils Creams, emulsions, gels and oils (hands, face, feet, etc)(hands, face, feet, etc)-Face Masks (with the exception of Face Masks (with the exception of peeling products)peeling products)-Tinted bases (liquids, pastes, Tinted bases (liquids, pastes, powders)powders)-Make up powders, after-bath Make up powders, after-bath powders, hygienic powders, etcpowders, hygienic powders, etc-Toilet soaps, Deodorant soaps, Toilet soaps, Deodorant soaps, etcetc-Perfumes, Toilet waters and Eau Perfumes, Toilet waters and Eau de Colognede Cologne-Bath and Shower preparation Bath and Shower preparation (salts, foams, oils, gels, etc)(salts, foams, oils, gels, etc)-DepilatoriesDepilatories-Deodorants and Anti PerspirantsDeodorants and Anti Perspirants-Hair Care products:Hair Care products:-Hair tints and bleachesHair tints and bleaches-Products for waxing, Products for waxing, straightening and fixingstraightening and fixing

-Setting productsSetting products-Cleansing products (lotions, Cleansing products (lotions, powders, shampoos)powders, shampoos)-Shaving product (creams, foams, Shaving product (creams, foams, lotion, etc)lotion, etc)-Products for making up and Products for making up and removing make up from the face removing make up from the face and the eyesand the eyes-Products intended for application Products intended for application to the lipsto the lips-Product for care of teeth and the Product for care of teeth and the mouthmouth-Products for nail care and make Products for nail care and make upup-Products for external intimate Products for external intimate hygienehygiene-Sunbathing productsSunbathing products-Product for tanning without sunProduct for tanning without sun-Skin whitening productsSkin whitening products-Anti-wrinkle productsAnti-wrinkle products

Page 7: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

COSMETICS

In direct contact with skin

Applied before rinsing

Applied in association with other cosmetics

In contact with skin annexes (partition

coefficient)

Applied after dilution

Applied as such

Page 8: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

The safety assessment needs a The safety assessment needs a case by case approach:case by case approach:

Soaps, Shampoos, Bath Soaps, Shampoos, Bath Preparations…Preparations…

Lotions, Creams, Lipsticks…Lotions, Creams, Lipsticks… Sunscreen products…Sunscreen products… Depilatories…Depilatories… Hair Care Products…Hair Care Products…

Page 9: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

In common to all cosmetic In common to all cosmetic productsproducts No way of controlling the conditions of use No way of controlling the conditions of use

of the cosmetic productsof the cosmetic products Formulas containing number of Formulas containing number of

ingredientsingredients Ingredients able to pass in variable Ingredients able to pass in variable

amount more or less quickly across the amount more or less quickly across the skinskin

Ingredients able to generate adverse Ingredients able to generate adverse effects at given level of systemic effects at given level of systemic exposureexposure

Page 10: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Therefore, in cosmetics Therefore, in cosmetics areaareaa need for an acceptable margin a need for an acceptable margin of safetyof safety Based on the knowledge of the Based on the knowledge of the

ingredients and their ability to be ingredients and their ability to be absorbed by the skinabsorbed by the skin

Covering potential misuseCovering potential misuse

Page 11: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

UNDER NORMAL CONDITIONS OF USEUNDER NORMAL CONDITIONS OF USE

UNDER FORESEEABLE CONDITIONS UNDER FORESEEABLE CONDITIONS OF USEOF USE

SECONDARY SYSTEMATIC EXPOSURE

ACCIDENTAL OCCASIONAL EXPOSURE

Page 12: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

RAW MATERIAL

FINISHED PRODUCT

SYSTEMIC EFFECT

IRRITATION

ALLERGY

Page 13: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Margin of safety = Margin of safety = Non observed adverse effect Non observed adverse effect levellevel

Systemic exposure doseSystemic exposure dose

Page 14: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

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

effecteffect

AllergensAllergens

CMR substancesCMR substances

Page 15: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Non Observed Adverse Effect Non Observed Adverse Effect Level (NOAEL)Level (NOAEL)

The No Observed Adverse Effect The No Observed Adverse Effect Level is the outcome of long term Level is the outcome of long term toxicity. It is the highest dosage for toxicity. It is the highest dosage for which no (adverse) effects can be which no (adverse) effects can be observed.observed.

The NOAEL should be expressed as The NOAEL should be expressed as mg/kg bw/daymg/kg bw/day

Page 16: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Non Observed Adverse Effect Non Observed Adverse Effect Level (NOAEL)Level (NOAEL)

Obtained from a subchronic toxicity Obtained from a subchronic toxicity study:study: At least 28 daysAt least 28 days By oral routeBy oral route On sensitive speciesOn sensitive species With appropriate dosesWith appropriate doses

Page 17: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Non Observed Adverse Effect Non Observed Adverse Effect Level (NOAEL)Level (NOAEL)

Sometimes it may be relevant to Sometimes it may be relevant to have results from more sensitive have results from more sensitive information resulting from:information resulting from: Chronic toxicityChronic toxicity Reproduction toxicityReproduction toxicity Carcinogenicity testCarcinogenicity test Other specific investigationsOther specific investigations

Page 18: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Dose exposure:Dose exposure:Amount of substance applied on the skin or Amount of substance applied on the skin or mucous membranemucous membraneThe dose is expressed:The dose is expressed:

As weight (mg or g)As weight (mg or g) As weight per body weight (ex: mg/kg bw)As weight per body weight (ex: mg/kg bw) As weight per unit of surface (ex: mg/cm2 As weight per unit of surface (ex: mg/cm2

of skin)of skin) In experimental models as constant dietary In experimental models as constant dietary

concentrations (ppm or mg/kg of food)concentrations (ppm or mg/kg of food)Exposure dosage:Exposure dosage:

General term comprising of dose, its General term comprising of dose, its frequency and duration (ex: mg/kg bw/day)frequency and duration (ex: mg/kg bw/day)

Page 19: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Skin absorptionSkin absorption

Skin exposure : amount of substance in Skin exposure : amount of substance in contact with an unit area of skin for a defined contact with an unit area of skin for a defined period of time.period of time.

Percutaneous absorption: passage of Percutaneous absorption: passage of substance across the skin without indication substance across the skin without indication of its fateof its fate

PenetrationPenetration PermeationPermeation ResorptionResorption

Page 20: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Percutaneous AbsorptionPercutaneous Absorption Using finite dose of substance Using finite dose of substance

mimicking the human exposuremimicking the human exposure Using infinite dose of substance Using infinite dose of substance

allowing to calculate the steady state allowing to calculate the steady state flux and Kpflux and Kp

flux

ID

FD

B

A

L

ID

T Time

Cumulative amount

Page 21: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Percutaneous AbsorptionPercutaneous Absorption Reported as absolute amount of Reported as absolute amount of

substance penetrating the skin after substance penetrating the skin after a certain period (µg/cma certain period (µg/cm22))

Reported as percentage of substance Reported as percentage of substance penetrating the skinpenetrating the skin

Page 22: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

SED:SED: The Systemic Exposure Dosage of a The Systemic Exposure Dosage of a

cosmetic ingredients is the amount cosmetic ingredients is the amount expected to enter the blood stream. expected to enter the blood stream. The SED should be expressed per kg The SED should be expressed per kg bw/daybw/day

For this definition a mean body For this definition a mean body weight of 60 kg is commonly weight of 60 kg is commonly acceptedaccepted

Page 23: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

CALCULATION OF THE EXPOSURE CALCULATION OF THE EXPOSURE DOSE (I)DOSE (I)

Page 24: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

The calculation of the in use exposure The calculation of the in use exposure levels needs a case by case approach levels needs a case by case approach considering among others:considering among others:

Class of cosmetic productClass of cosmetic product Method of applicationMethod of application Frequency of applicationFrequency of application Consumer target groupConsumer target group Site of contactSite of contact Total area of skin contactTotal area of skin contact Duration of contactDuration of contact Concentration of ingredients in the Concentration of ingredients in the

productproduct Foreseeable misuseForeseeable misuse

Page 25: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Estimation of consumers Estimation of consumers exposure to the finished exposure to the finished productproduct Data provided by ColipaData provided by Colipa Cosmetic products are gathered into Cosmetic products are gathered into

4 main types:4 main types: Oral hygiene and care productsOral hygiene and care products Eye productsEye products Leave on productsLeave on products Rinse off productsRinse off products

Page 26: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Partition coefficient : takes into Partition coefficient : takes into account rinsing off and dilution of account rinsing off and dilution of finished products by application on finished products by application on wet skinwet skinEx: ToothpasteEx: Toothpaste

Retention coefficient : takes into Retention coefficient : takes into account the residual part of finished account the residual part of finished products in direct contact with skinproducts in direct contact with skinEx : ShampooEx : Shampoo

Page 27: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

ORAL HYGIENE PRODUCTSORAL HYGIENE PRODUCTSProduct TypeProduct Type

Total amount Total amount per per

application application (g)(g)

Frequency of Frequency of application application

per dayper dayPartition (%)Partition (%) Exposure per Exposure per

day (g)day (g)

ToothpasteToothpaste 1.401.40 22 1717 0.480.48

MouthwashMouthwash 10.0010.00 33 1010 3.003.00

LipstickLipstick 0.010.01 44 100100 0.040.04

TotalTotal          3.523.52

Page 28: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

EYE PRODUCTSEYE PRODUCTSProduct TypeProduct Type

Total amount Total amount per per

application application (g)(g)

Frequency of Frequency of application application

per dayper dayPartition (%)Partition (%) Exposure per Exposure per

day (g)day (g)

Eye make upEye make up 0.0100.010 22 100100 0.0200.020

MascaraMascara 0.0250.025 11 100100 0,0250,025

LinerLiner 0.0050.005 11 100100 0.0050.005

TotalTotal          0.0500.050

Page 29: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

LEAVE ON PRODUCTSLEAVE ON PRODUCTS

Product TypeProduct TypeTotal amount Total amount

per per application application

(g)(g)

Frequency of Frequency of application application

per dayper dayPartition (%)Partition (%) Exposure per Exposure per

day (g)day (g)

Face CreamFace Cream 0.80.8 22 100100 1.601.60General General CreamCream 1.21.2 22 100100 2.402.40Body LotionBody Lotion 8.08.0 11 100100 8.008.00Deodorant Deodorant (roll on)(roll on) 0.50.5 11 100100 0.500.50Hair Styling Hair Styling 5.05.0 22 1010 1.001.00TotalTotal          13.5013.50

Page 30: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

RINSE OFF PRODUCTSRINSE OFF PRODUCTS

Product TypeProduct TypeTotal amount Total amount

per per application application

(g)(g)

Frequency of Frequency of application application

per dayper dayPartition (%)Partition (%) Exposure per Exposure per

day (g)day (g)

Make Up Make Up RemoverRemover 2.52.5 22 1010 0.500.50Shower GelShower Gel 5.05.0 22 11 0.100.10ShampooShampoo 8.08.0 11 11 0.080.08Hair Hair ConditionerConditioner 14.014.0 0.280.28 11 0.040.04TotalTotal          0.720.72

Page 31: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Maximalized global daily Maximalized global daily exposureexposure

Total oral hygiene products Total oral hygiene products 3.52 g3.52 g Total eye products Total eye products 0.05 g0.05 g Total leave on products Total leave on products 13.50 g13.50 g Total rinse off products Total rinse off products 0.72 g0.72 g

Maximum daily exposure Maximum daily exposure 17.79 g17.79 g

Page 32: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Calculation of The Daily Exposure Calculation of The Daily Exposure Dose of Substance Applied to The Dose of Substance Applied to The

SkinSkin

A (g/application) = amount of finished A (g/application) = amount of finished cosmetic product applied per applicationcosmetic product applied per application

C (%) = concentration of ingredients under C (%) = concentration of ingredients under study in the finished productstudy in the finished product

F (dayF (day-1-1) = frequency of application of the ) = frequency of application of the substancesubstance

I (mg/day) = A (g/application) x 103 (mg/g) x C (%) x 10-2 x F (day-1)

Page 33: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

CALCULATION OF THE CALCULATION OF THE SYSTEMIC EXPOSURE SYSTEMIC EXPOSURE

DOSE (SED)DOSE (SED)

Page 34: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

CALCULATION OF THE SYSTEMIC EXPOSURE CALCULATION OF THE SYSTEMIC EXPOSURE DOSE BASED ON THE PERCENTAGE OF DOSE BASED ON THE PERCENTAGE OF SUBSTANCE PENETRATING THE SKIN SUBSTANCE PENETRATING THE SKIN

I (mg/day) = daily dermal exposure to the I (mg/day) = daily dermal exposure to the substancesubstance

DAp (%) = dermal absorption of the DAp (%) = dermal absorption of the substance expressed in percentagesubstance expressed in percentage

60 kg bw = default human body weight60 kg bw = default human body weight

SED = I (mg/day) x DAp (%) x 10-2

(mg/kg bw/day) 60 kg bw

Page 35: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

CALCULATION OF THE SYSTEMIC EXPOSURE CALCULATION OF THE SYSTEMIC EXPOSURE DOSE BASED ON THE ABSOLUTE AMOUNT DOSE BASED ON THE ABSOLUTE AMOUNT OF SUBSTANCE PENETRATING THE SKINOF SUBSTANCE PENETRATING THE SKIN

DADAaa (µg/cm (µg/cm22) = dermal absorption of the ) = dermal absorption of the substance reported as amount (µg)/cmsubstance reported as amount (µg)/cm22

SSA (cmSSA (cm22) = surface of skin area expected to be in ) = surface of skin area expected to be in contact with the cosmetic productcontact with the cosmetic product

60 kg bw = default human body weight60 kg bw = default human body weight F (dayF (day-1-1) = frequency of application of the ) = frequency of application of the

substancesubstance

SED = DAa (µg/cm2) x 10-3 (mg/µg) x SSA (cm2) x F (day-1)(mg/kg bw/day) 60 kg bw

Page 36: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

CALCULATION OF THE CALCULATION OF THE MARGIN OF SAFETY (MOS)MARGIN OF SAFETY (MOS)

Page 37: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

MoS never below 100MoS never below 100

Margin of Safety = NOAEL (mg/kg bw/day)

SED (mg/kg bw/day)

Page 38: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

xxAnimals Humans

Kinetics

4.0

Dynamics2.5

Kinetics

3.2

Dynamics3.2

Interspeciesdifferences

Intraspeciesdifferences

10

10

x x

Page 39: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

UV filter example : Isopentyl 4 methoxycinnamate UV filter example : Isopentyl 4 methoxycinnamate (S27)(S27)

Based on daily application of 1 mg formulation/cmBased on daily application of 1 mg formulation/cm22 over the over the entire body surface (1.8 mentire body surface (1.8 m22) containing at maximum 10% of ) containing at maximum 10% of the active ingredientthe active ingredient

Maximum amount of ingredients applied I = 1800 mg/dayMaximum amount of ingredients applied I = 1800 mg/day Maximum absorption through the skin DAp = o/w : 0.4% or Maximum absorption through the skin DAp = o/w : 0.4% or

w/o : 2%w/o : 2% Systemic exposure dose :Systemic exposure dose :

SED = SED = I (mg/day) x DAp (%)/100I (mg/day) x DAp (%)/100 o/w : 0.12 mg/kg o/w : 0.12 mg/kg bw/daybw/day

60 kg bw w/o: 0.60 mg/kg 60 kg bw w/o: 0.60 mg/kg bw/daybw/day

No observed adverse effect level NOAL = 200 mg/kg bw/dayNo observed adverse effect level NOAL = 200 mg/kg bw/dayMargins of safety = NOAEL = o/w : 1667 w/o : 333 SED

Page 40: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Preservatives : example Preservatives : example iodopropynyl butylcarbamate iodopropynyl butylcarbamate

(P91)(P91) Industry proposed to reduce the maximum Industry proposed to reduce the maximum concentration in products to 0.05% and to restrict concentration in products to 0.05% and to restrict its use to eye, non rinse off and rinse off productsits use to eye, non rinse off and rinse off products

Maximum exposure in cosmetic products E = Maximum exposure in cosmetic products E = 14.27 g/day resulting from14.27 g/day resulting from Eye products : Eye products : 0.05 g/day0.05 g/day Leave on products : Leave on products : 13.50 g/day13.50 g/day Rinse off products : Rinse off products : 0.72 g/day0.72 g/day

Maximum amount of ingredients daily applied :Maximum amount of ingredients daily applied : I = E x 0.05/100 = 7.14 mg/dayI = E x 0.05/100 = 7.14 mg/day

Page 41: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Preservatives : example iodopropynyl Preservatives : example iodopropynyl butylcarbamate (P91)butylcarbamate (P91)

Maximum amount of ingredients daily applied : I = 7.14 Maximum amount of ingredients daily applied : I = 7.14 mg/day mg/day

Maximum absorption through the skin : Dap = 54%Maximum absorption through the skin : Dap = 54% Systemic exposure dose:Systemic exposure dose:

SED = SED = I (mg/day) x Dap (%)/100 I (mg/day) x Dap (%)/100 = 0.064 mg/kg w/day= 0.064 mg/kg w/day 60 kg bw60 kg bw No observed adverse effect level NOAEL = 10 mg/kg No observed adverse effect level NOAEL = 10 mg/kg

bw/daybw/dayMargin of safety = NOAEL = 10 = 156 SED 0.064

Page 42: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Hair dyes : example : Kardinal rot (B31)Hair dyes : example : Kardinal rot (B31)Oxidation or PermanentOxidation or Permanent

Based on an usage volume of 100 ml containing at Based on an usage volume of 100 ml containing at maximum 1.25%maximum 1.25%

Maximum amount of ingredients applied : I = 1250 Maximum amount of ingredients applied : I = 1250 mgmg

Maximum absorption through the skin : A = 0.05%Maximum absorption through the skin : A = 0.05% Dermal absorption per treatment : I x A = 0.625 Dermal absorption per treatment : I x A = 0.625

mgmg Systemic exposure dose : SED = Systemic exposure dose : SED = I x A I x A = 0.01 = 0.01

mg/kg bwmg/kg bw 6060 No observed adverse effect level NOAEL = 5 mg/kg No observed adverse effect level NOAEL = 5 mg/kg

bwbw

Margin of safety = NOAEL = 5 = 500 SED 0.01

Page 43: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Hair dyes : example : Kardinal rot (B31)Hair dyes : example : Kardinal rot (B31)Semi PermanentSemi Permanent

Based on an usage volume of 35 ml containing at maximum Based on an usage volume of 35 ml containing at maximum 2.5%2.5%

Maximum amount of ingredients applied : I = 875 mgMaximum amount of ingredients applied : I = 875 mg Maximum absorption through the skin : A = 0.05%Maximum absorption through the skin : A = 0.05% Dermal absorption per treatment : I x A = 0.438 mgDermal absorption per treatment : I x A = 0.438 mg Systemic exposure dose : SED = Systemic exposure dose : SED = I x A I x A = 0.0073 mg/kg bw= 0.0073 mg/kg bw 6060 No observed adverse effect level NOAEL = 5 mg/kg bwNo observed adverse effect level NOAEL = 5 mg/kg bw

Margin of safety = NOAEL = 5 = 685 SED 0.0073

Page 44: EXPOSURE TO COSMETICS: CALCULATION OF THE SAFETY MARGIN AND THE ACCEPTABLE LIFETIME RISK FOR COSMETIC INGREDIENTS

Fragrance ingredients : example : musk Fragrance ingredients : example : musk ketoneketone

The concentration in the different fragranced cosmetic The concentration in the different fragranced cosmetic products was considered case by caseproducts was considered case by caseType of Type of

cosmetic cosmetic productsproducts

Application Application quantity in quantity in grams per grams per applicationapplication

Application Application frequency frequency per dayper day

Retention Retention factor (%)factor (%)

Fragrance Fragrance compound in compound in product (%)product (%)

Musk ketone Musk ketone in fragrance in fragrance compound compound

(%)(%)

Musk ketone Musk ketone in product in product

(%)(%)

Exposure to Exposure to Musk ketone Musk ketone

(mg/day)(mg/day)

Body LotionBody Lotion 88 0.710.71 100100 0.40.4 6.96.9 0.0280.028 1.571.57

Face CreamFace Cream 0.80.8 22 100100 0.30.3 6.96.9 0.0210.021 0.330.33Eau de Eau de ToiletteToilette 0.750.75 11 100100 8.08.0 6.96.9 0.5520.552 4.144.14Fragrance Fragrance CreamCream 55 0.290.29 100100 4.04.0 6.96.9 0.2760.276 4.004.00AntiperspiranAntiperspirant/Deodorantt/Deodorant 0.50.5 11 100100 1.01.0 6.96.9 0.0690.069 0.350.35

ShampooShampoo 88 11 1010 0.50.5 6.96.9 0.0350.035 0.280.28Bath Bath ProductsProducts 1717 0.290.29 11 2.02.0 6.96.9 0.1380.138 0.070.07

Shower GelShower Gel 55 1.071.07 1010 1.21.2 6.96.9 0.0830.083 0.440.44

Toilet SoapToilet Soap 0.80.8 66 1010 1.51.5 6.96.9 0.1040.104 0.500.50

Hair SprayHair Spray 55 22 1010 0.50.5 6.96.9 0.0350.035 0.0300.030

                  TotalTotal 12.012.0

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Fragrance ingredients : example : musk Fragrance ingredients : example : musk ketoneketone

Maximum daily exposure to musk ketone: I = 12.85 mg/dayMaximum daily exposure to musk ketone: I = 12.85 mg/day Maximum estimated absorption through the skin : DAp = Maximum estimated absorption through the skin : DAp =

14%14% Systemic exposure dose : Systemic exposure dose : SED = SED = I (mg/day) x DAp (%)/100 I (mg/day) x DAp (%)/100 = 0.030 mg/kg bw/day= 0.030 mg/kg bw/day 60 kg bw60 kg bw No observed adverse effect level NOAEL = 7.5 mg/kg bw/dayNo observed adverse effect level NOAEL = 7.5 mg/kg bw/day

Margin of safety = NOAEL = 7.5 = 250 SED 0.030

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Calculation of the margin of Calculation of the margin of safety : only applies for safety : only applies for

ingredients with threshold dose ingredients with threshold dose of toxicityof toxicity

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Risk characterization when there is Risk characterization when there is no threshold dose of toxicity :no threshold dose of toxicity :

Ex : acceptable lifetime cancer risk Ex : acceptable lifetime cancer risk basing on the dose descriptor T25 basing on the dose descriptor T25 from animal studiesfrom animal studies

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The dose descriptor T25 is defined as The dose descriptor T25 is defined as the chronic dose rate (in mg/kg bw) the chronic dose rate (in mg/kg bw) which gives 25% of the animal tumours which gives 25% of the animal tumours at a specific tissue site, after at a specific tissue site, after corrections for spontaneous incidence, corrections for spontaneous incidence, within the life time of that specieswithin the life time of that species

T25 must be calculated for the most T25 must be calculated for the most relevant data-setrelevant data-set

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The human dose descriptor (HT) is The human dose descriptor (HT) is extrapolated from animal dose descriptor extrapolated from animal dose descriptor (T)(T)

LTCR = Systemic Exposure Dose (mg/kg bw) Human Dose Descriptor (mg/kg bw)

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Calculation of the HT25 dose descriptorCalculation of the HT25 dose descriptor(SCCNFP 25 Sept 2001, Dybing E 1997 and Sanner T 2001)(SCCNFP 25 Sept 2001, Dybing E 1997 and Sanner T 2001)

T25 are converted into the corresponding T25 are converted into the corresponding human dose descriptor HT25 by using the human dose descriptor HT25 by using the following expression in order to take into following expression in order to take into account the basic metabolic differences account the basic metabolic differences between humans and test species :between humans and test species :HT25 = T25/ (bw human/bw animal)HT25 = T25/ (bw human/bw animal)0.250.25

(bw human/bw animal)(bw human/bw animal)0.250.25 = 3.6 in the rat = 3.6 in the rat(bw human/bw animal)(bw human/bw animal)0.250.25 = 7.0 in the mouse = 7.0 in the mouse

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The HT25 value is calculated by linear The HT25 value is calculated by linear extrapolationextrapolation

LTCR = SED(mg/kg bw/day) HT25(mg/kg bw/day)/0.25

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According to numerous According to numerous standards in line with the view of standards in line with the view of the WHO, a lifetime cancer risk the WHO, a lifetime cancer risk level of 10-6 is considered as level of 10-6 is considered as

acceptable at the present time.acceptable at the present time.

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Coloring agent CI 26100; CI Solvent Coloring agent CI 26100; CI Solvent Red 23; CAS 65-66-9; EINECS 201-638-Red 23; CAS 65-66-9; EINECS 201-638-

44 Purity : no data availablePurity : no data available Contaminated by : aniline, 2-naphtol, 4- aminoazobenzeneContaminated by : aniline, 2-naphtol, 4- aminoazobenzene Uses : not allowed to come to vicinity of the eyesUses : not allowed to come to vicinity of the eyes Evaluation:Evaluation:

Ames : negative (standard)Ames : negative (standard) CHO cells : positiveCHO cells : positive Carcinogenic potential orally and painting : negativeCarcinogenic potential orally and painting : negative Protective effect via CYP1A and GST enzymeProtective effect via CYP1A and GST enzymeMay release 4-aminoazobenzene by reductive cleavageMay release 4-aminoazobenzene by reductive cleavage

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CI 26100CI 26100Daily exposure resulting from cosmetic Daily exposure resulting from cosmetic usesuses

Oral hygiene products : not usedOral hygiene products : not used Eye products : not usedEye products : not used Non rinse off products : 3610.0 µg/dayNon rinse off products : 3610.0 µg/day Rinse off products : 30.0 µg/dayRinse off products : 30.0 µg/day

Total amount retained : 3640.0 µg/dayTotal amount retained : 3640.0 µg/day

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CI 26100CI 26100Systemic exposure dose to potential carcinogenic Systemic exposure dose to potential carcinogenic

amines :amines : Rate of cleavage: 3.0%Rate of cleavage: 3.0% Rate of penetration: 0.3%Rate of penetration: 0.3% Molecular weight/correction factor: 197/352Molecular weight/correction factor: 197/352 Body weight: 60 kg bwBody weight: 60 kg bw

SED = SED = 3640 µg/day x 3/100 x 0.3/100 x 197/352 3640 µg/day x 3/100 x 0.3/100 x 197/352 = 3.06 x 10= 3.06 x 10-6-6 mg/kg mg/kg bw/daybw/day

1000 µg/mg x 60 kg bw1000 µg/mg x 60 kg bw

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CI 26100CI 26100 Lifetime of cancer risk on the basis of the HT25 dose Lifetime of cancer risk on the basis of the HT25 dose

descriptordescriptor T25 (rat) of contained amine = 140.0 mg/kg bw/dayT25 (rat) of contained amine = 140.0 mg/kg bw/day For rat : HT25 = T25/3.6 = 38.89 mg/kg bw/dayFor rat : HT25 = T25/3.6 = 38.89 mg/kg bw/day

LTCR = LTCR = SED SED = = 3.06 x 10 3.06 x 10-6-6(mg/kg bw/day) (mg/kg bw/day) = 2.0 x 10= 2.0 x 10-8-8

HT 38.89 mg/kg bw/day/0.25HT 38.89 mg/kg bw/day/0.25

Basing on an acceptable lifetime cancer risk level of 10Basing on an acceptable lifetime cancer risk level of 10-6-6, , this azo dye presents an acceptable level of risk in cosmetic this azo dye presents an acceptable level of risk in cosmetic areaarea

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CONCLUSIONCONCLUSION

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Wide variety of cosmetic productsWide variety of cosmetic products Wide variety in the condition of useWide variety in the condition of use Need of a margin to insure safetyNeed of a margin to insure safety Impossibility to determine a global safety Impossibility to determine a global safety

margin on the finished productmargin on the finished product Obligation to establish this safety margin Obligation to establish this safety margin

through the knowledge of the sensitive through the knowledge of the sensitive ingredientsingredients

Necessity of a case by case approachNecessity of a case by case approach

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THANK YOUTHANK YOU