1 cosmetology

Sri Noegrohati, GMU

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Cosmetology
An Introduction on
The Effectivity and Safety

Sri Noegrohati

Fac of Pharmacy

Gadjah Mada University

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Sri Noegrohati, GMU

Cosmetic product

any substance or preparation intended to be placed in contact with

any part of the external surfaces of the human body (the epidermis, hair system, nails, lips and external genital organs) or

with the teeth and the mucous membranes of the oral cavity

with a view exclusively or mainly to cleaning them, perfuming them, changing their appearance, protecting them, keeping them in good condition or correcting body odours and/or protecting them or keeping them in good condition.

growth in the use of cosmetics

In recent years, everyone uses cosmetic women, men, babies and children

wide range of general and specific cosmetics currently available for purposes such as

(a) facial treatment (lips, eyes and hair) and body care (hands, nails and feet), which is provided by creams, emulsions, lotions, gels, oils, lipsticks, face masks and antiwrinkle products,

(b) personal hygiene products (toilet and deodorant soaps, bath and shower preparations, deodorants and antiperspirants, depilatories, shaving creams and gels, after-bath powders, make-up cleansers, hair cleansers, teeth and mouth care products, external intimate hygiene products)

(c) sunscreens and related products (e.g. sunbathing lotions, products for tanning without sun, skin whiteners).

Responsibility of cosmetic Manufacturer

regulatory compliance,

assure cosmetic product safety under the normal conditions of use.

demonstrate cosmetic efficacy (fulfilling that claimed on the label).

thorough control their quality

able to justify this on authority investigation.

Safety and eficacy

Safety data can be obtained either

specifically on the finished products or be deduced from the properties of their ingredients.

toxicological studies: sensitivity, allergic reactions, etc

surveillance of cosmetics in use to detect possible side effects.

Efficacy data can be obtained through different studies (moisturized state, elasticity, etc.),

Both safety and efficacy have to be considered under the following conditions:

The final product must in accord with the composition designed by the manufacturer and be in a perfect state.

The cosmetic has to be applied by the user under the normal given conditions.

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Sri Noegrohati, GMU

Safety in cosmetic products

A cosmetic product must not cause damage to human health when applied under normal or reasonably foreseeable conditions of use, taking account, in particular, of

the products presentation,

its labelling,

any instructions for its use and disposal as well as any other indication or

information provided by the manufacturer or his authorized agent or by any other person responsible for placing the product on the Community market.

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Sri Noegrohati, GMU

Cosmetics Management

Cosmetics Ingredient

(Cosmeceutical, formulations, perfume, preservatives)

Risk Benefit

consumer consumer

workers esteem

environment social-economy

Risk-Benefit Analysis

Yes Acceptance No Management

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Sri Noegrohati, GMU

Safety control in Cosmetic product

Particular attention is needed for long-term safety aspects, since cosmetic products may be used extensively over a large part of the human lifespan.

The safety of a cosmetic product is based on the safety of its ingredients,

Toxicity testing has been concentrated on ingredients, and particularly on those that are intended to react with biological matrices are of most concern for human health.

the safety-in use of cosmetic products

controlling the ingredients,

their chemical structures,

toxicity profiles,

and exposure patterns

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Sri Noegrohati, GMU

CHEMICAL AND PHYSICAL SPECIFICATIONS OF COSMETIC

1) chemical identity;

2) physical form;

3) molecular weight;

4) purity of the chemical;

5) characterisation of the impurities or accompanying contaminants;

6) solubility;

7) partition coefficient (Log Pow);

8) additional relevant physical and chemical specifications.

Small changes in the nature of impurities can considerably alter the toxicity of substances results of safety studies on a particular substance are only relevant when they refer to that substance used, with its own specific purity and impurity patterns.

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The scientific evaluation of known or potential adverse health effects resulting from human exposure to cosmetic product. The process consists of :

Hazard identification

Hazard assessment

Exposure assessment

Risk characterization

The Risk Assessment

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Sri Noegrohati, GMU

Safety evaluation of cosmetic
based upon the principles and practice of the risk assessment process [WHO 2001]


Dose-response assessment

Exposure assessment

Risk characterisation

risk management

risk communication

Scientifically based

Political will

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Sri Noegrohati, GMU


The identification of known or potential health effect associated with a particular agent

based on the results of in vivo tests, in vitro tests, clinical studies, accidents, human epidemiological studies and, when available, quantitative structure activity relationship (QSAR) studies.

The intrinsic physical, chemical and toxicological properties of the molecule under consideration are studied to identify whether the substance has the potential to damage human health.

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Sri Noegrohati, GMU

RELEVANT TOXICITY STUDIES ON COSMETIC INGREDIENTS

Acute toxicity

fixed dose method [OECD 420]

up-and-down procedure [OECD 425]

Irritation and corrosivity

Skin irritation and skin corrosivity, classical Draize in vivo skin irritation test [OECD 404].

Mucous membrane irritation, classical Draize in vivo eye irritation test [OECD 405].

Skin sensitisation

The Local Lymph Node Assay (LLNA) based on the extent of stimulation of proliferation of lymphocytes in regional lymph nodes [OECD 429]

The Magnusson Kligman Guinea Pig Maximisation Test (GPMT), an adjuvant-type test, which means that the allergic response is potentiated by intradermal injection [OECD 406]

The Buehler test is a topical application non-adjuvant technique [OECD 406]

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Sri Noegrohati, GMU

Repeated dose toxicity

the adverse general toxicological effects occurring as a result of repeated daily dosing with, or exposure to, a substance for a specific part of the expected lifespan of the test species

Repeated dose (28 days) toxicity (oral dermal inhalation)

Sub-chronic oral toxicity test :

Repeated dose 90-day oral toxicity study in rodents and non- rodents; and dermal dose and inhalation dose study using rodent species

Chronic toxicity test

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Sri Noegrohati, GMU

Genotoxicity

providing an indication of induced damage to DNA (but not direct evidence of mutation) via effects such as

unscheduled DNA synthesis (UDS)

sister chromatid exchange (SCE)

DNA strandbreaks,

DNA adduct formation or mitotic recombination (MR),

as well as tests for mutagenicity

Recommended test methods

a bacterial reverse mutation test (the Ames test) [OECD 471] OR an in vitro mammalian cell gene mutation test* [OECD 476]

in vitro mammalian cell chromosome aberration test [OECD 473],

Carcinogenicity test [OECD 452]

Combined chronic toxicity / carcinogenicity test [OECD 453]

Two-generation reproduction toxicity test [OECD 416]

Teratogenicity test - rodent and non-rodent [OECD 414]

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Photo-induced toxicity

Phototoxicity (photoirritation) and photosensitisation

The "3T3 Neutral Red Uptake Phototoxicity Test (3T3 NRU PT)" is an in vitro method based on a comparison of the cytotoxicity of a chemical when tested in the presence and in the absence of exposure to a non-cytotoxic dose of UVA/visible light.

Photomutagenicity / Photoclastogenicity of UV radiation absorbing cosmetic ingredients

the established biological mechanisms (alteration of genes, chromosomes, DNA sequences)

Human data

irritation, allergic contact dermatitis, contact urticaria and sunlight, -especially UV light-, induced reactions.

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Sri Noegrohati, GMU

Dermal / percutaneous absorption

Human exposure occurs mainly via the skin cross a number of cell layers of the skin reach the circulation (blood and lymph vessels)

dermally applied substance which has transpassed the skin and is detected in the receptor fluid, is considered to be systemically available (= dermal bioavailability)

Influenced by

lipophilicity of the compounds,

the thickness and composition of the SC (body site)

the duration of exposure,

the amount of topically applied product,

the concentration of the compounds considered

occlusion, etc.

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Risk Assessment Procedure

Dose-response assessment : relationship between the toxic response and the exposure is studied.

In the case of an effect with a threshold, the dosage at which no adverse effects are observed (NOAEL), is determined.

If the NOAEL is not available, the LO(A)EL is used.

In the case of non-threshold carcinogens, a dose-descriptor is determined.

Exposure assessment : amount and the frequency of human exposure to the compound are determined (including potential specific groups at risk, e.g. children, pregnant women, etc.).

Prinsip Dasar Evaluasi Keamanan

Identifikasi potensi bahaya

(studi toksisitas, epidemiologik, QSAR)

Pengkajian Dosis-respons Pengkajian Paparan

NOAEL

Dosis Aman Terprediksi

Dosis Benchmark Dosis Paparan Sistemik

Karakterisasi Risiko

BATAS AMAN

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Sri Noegrohati, GMU

Elements that affect risk estimates

Epidemiology: epidemiological data, not sufficient for quantitative risk characterization, nevertheless may be used for comparison with the risks derived from animal data.

Site/species/strain/gender activity: carcinogen, mutagen, reproductive toxicity

Chemical class, nanoparticles

Toxicokinetics, differences between humans and animals toxicokinetic data on the relative bioavailability or target-dose of the carcinogen or its active metabolite could indicate that the risk may be higher or lower than calculated from the animal data. A similar reasoning can be followed for toxicodynamic.

DEFINISI
Dosis aman terprediksi (mg/kg berat badan/ hari)
= NOAEL/100

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Sri Noegrohati, GMU

SED
The Systemic Exposure Dosage () of a cosmetic ingredient is the amount expected to enter the blood stream (and therefore be systemically available) per kg body weight and per day. It is expressed in mg/kg body weight/day. For this definition a mean human body weight of 60 kg is commonly accepted.

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Sri Noegrohati, GMU

Dermal absorption of test substance reported in g/cm :
SED (mg/kg bw/day) = Systemic Exposure Dosage DAa (g/cm) = Dermal Absorption reported as amount/cm2 SSA (cm) = Skin Surface Area expected to be treated with the finished cosmetic product F (day-1) = Frequency of application of the finished
product
60 kg = default human body weight Dermal absorption of test substance reported in g/cm : A (g/day) = Amount of the cosmetic product applied daily C (%) = the Concentration of the ingredient under study in
the finished cosmetic product on the application site
DAp (%) = Dermal Absorption expressed as a percentage

In vitro dermal penetration

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Sri Noegrohati, GMU

The Franzs diffusion cell consists of an upper donor and a lower receptor chamber, separated by a skin preparation. The test substances (e.g. sunscreen lotion) that are applied on the stratum corneum faces the donor compartment. The receptor fluid is well mixed (magnetic stirrer) throughout the experiment (adapted from Balaguer et al., 2006).

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Sri Noegrohati, GMU

Mean exposed skin surface area per product type [Bremmer et al. 2003; US EPA 1997]

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Sri Noegrohati, GMU

Calculation of the daily exposure to cosmetics using Colipa data [SCCNFP/0321/02].

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Sri Noegrohati, GMU

Margin of Safety (MoS)
In risk characterisation, the last phase in the safety evaluation of a cosmetic ingredient, an uncertainty factor (100) is used to extrapolate from a group of test animals to an average human being, and subsequently from average humans to sensitive subpopulations applies. For cosmetics, this factor is called the MoS.

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Sri Noegrohati, GMU

Risk Characterization

the probability that the molecule under investigation causes damage to human health and to what extent, are examined.

In the case of a threshold effect, the Margin of Safety (MoS) is calculated according to the formula :

where SED represents the Systemic Exposure Dosage.

In the case of non-threshold carcinogens use "T25 method" chronic dose rate that will give 25% of the animal's tumours at a specific tissue site

HT25= T25/(B.W. human/B.W animal)

MoS

NOAEL

SED

100

=

Lifetime cancer risk

SED

HT25 / 0.25

=

Keamanan Kosmetika
suatu konsep ilmiah berdasarkan kajian toksikologikkosmetika dinyatakan aman apabila tidak berrisiko pada paparan normal sesuai dengan cara penggunaan yang telah ditentukan,
Evaluasi Keamanan Kosmetika adalah proses identifikasi dan kuantifikasi risiko yang mungkin terjadi dengan dasar toksikologi, terdiri atas:
evaluasi keamanan komposisievaluasi keamanan bahan bakuevaluasi keamanan produk jadievaluasi keamanan parfum evaluasi kelayakan wadah, kemasan dan informasi

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Sri Noegrohati, GMU

Risk Management

The process of weighing policy alternatives to accept, minimize or reduce assessed risks and to select ans implement appropriate options

Risk Communications

An interactive process of exchange of information and opinion on risk among tisk assessors, risk managers and other interested parties

National Institution (BPOM)

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Govermental institution

Manufacturer

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Sri Noegrohati, GMU

ANNEXES

Annex II is a list containing substances that must not form part of the composition of cosmetic products.

Annex III is defined as a list of substances that are allowed to be used in cosmetic products, but only subject to the restrictions and conditions laid down.

Annex IV constitutes a list of colouring agents permitted for use in cosmetic products.

Hair dyes included in Annexes III (oxidative (permanent) hair dye components) and IV (semi-permanent hair dyes: some azo-dyes)

Annex VI is a list of preservatives, including maximum allowed concentrations in finished products.

Annex VII is a list of UV absorbing or UV reflecting substances with their maximum authorised concentrations in cosmetic products.

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SUBSTANCES PROHIBITED IN ALL COSMETIC PRODUCTS: Annex II

Part 1: 769 substances considered as

Very Toxic:

CMR of category 1, 2 and 3,

prevention, control and eradication of certain transmissible agents, conventional infectious agents or other hazards such as toxic substances

Part 2: 34 fragrance ingredient contact allergy (International Fragrance Association, IFRA)

type IV immunological reaction caused by low-molecular weight substances that come in close contact with the skin may cause facial, axillary and/or hand eczema

the statement: contains perfume is presently required

SUBSTANCES WHICH COSMETIC PRODUCTS MUST NOT CONTAIN EXCEPT SUBJECT TO RESTRICTIONS: Annex III

The substance may not be used except for the purposes or contained other than specified (column 3)

The concentration of the substance in a product may not exceed the limit specified (column 4)

the information specified in column 6 should be included

Other substances in Annex 3

Part 1: Total 95

Thioglycolic acid esters: Hair waving or straightening products for general use (8%) and for professional use (11%)

m- and p-Phenylenediamines, Oxidizing colouring agents for hair dyeing for general use (6%) and for professional use (10%)

Hydrogen peroxyde, in hair dyeing/bleaching and textile bleaching, of hydrogen peroxide is equal or greater than 5 %, max 12%, Risk of tooth injury if tooth bleaching is performed using concentrated (ca 35%), max. 0.1%.

The new additional data to support the safety of hydrogen peroxide up to 6 % in tooth whitening products does not provide the necessary reassurance in terms of risk assessment to the consumer in various application forms (strips, trays, etc).

Part 2: SUBSTANCES PROVISIONALLY ALLOWED up to 2004, Total 62

COLOURING AGENTS Annex IV

Sub-column 1 = Colouring agents allowed in all cosmetic products;

Sub-column 2 = Colouring agents allowed in all cosmetic products except those intended to be applied in the vicinity of the eyes, in particular eye make-up and eye make-up remover;

Sub-column 3 = Colouring agents allowed exclusively in cosmetic products except cosmetic products intended to come into contact with the mucous membranes;

Sub-column 4 = Colouring agents allowed exclusively in cosmetic products intended to come into contact only briefly with the skin

PRESERVATIVES WHICH COSMETIC PRODUCTS MUST NOT CONTAIN EXCEPT SUBJECT TO RESTRICTIONS Annex VI

Part 1 Total 56

The substance may not be used or contained other than in the types of product specified in column 3.

The concentration of the substance, when it is used as a preservative, in a product may not exceed the limit set out in column 4.

Where a product is intended to be mixed with another product in specified proportions before use, the level of concentration shall not calculated by reference to the mixture.

Other requirements are specified in column 5.

All preservative substances containing formaldehyde or any substances which release formaldehyde must be labelled with the warning "contains formaldehyde" when the concentration of formaldehyde in the final product exceeds 0.05 %

Preservatives that need more attention

Parabens, alkyl esters of p-hydroxybenzoic acid

allowed as antimicrobial preservatives for use in food products, medicinal products and cosmetics.

in the light of the present knowledge, there is no evidence of demonstrable risk for the development of breast cancer caused by the use of paraben-containing underarm cosmetics.

Triclosan, 2,4,4'-Trichloro-2'-hydroxydiphenyl ether

antibacterial properties and also some antifungal and antiviral properties.

It is marketed under diverse registered names, including Microban (when used in plastics and clothing), Biofresh (on acrylic fibres), Irgasan DP-300 (cosmetics), Lexol 300, Ster-Zac, Cloxifenolum and others (1).

Causing resistance development by certain micro-organisms and cross-resistance

toxicological assessment of the safe use of triclosan is a matter of urgency because triclosan has been identified in human milk of some European populations.

UV FILTERS WHICH COSMETIC PRODUCTS MUST NOT CONTAIN EXCEPT SUBJECT TO RESTRICTIONS Annex VII

Part 1: total 27

apply to a particular substance in column 2.

The concentration of the substance in a product may not exceed the limit specified in column 3.

Where a product is intended to be mixed with another product in specified proportions before use, the level of concentration shall be calculated by reference to the mixture.

Other requirements are specified in column 4.

UV filters that need more attention

Zinc oxide safe for use up to 25 %?

It is understood that microfine and ultrafine zinc oxide is widely used in sunscreen products. The safety to the consumer of this use remains to be assessed.

PABA

Using conventional tests: Applications of 5% PABA in sunscreen formulation on human skin have shown that irritation is negligible.

photosensitisation studies: Freunds complete adjuvant (FCA) was positive.

has a potential to cause photoallergy (PA-reactions).

PABA showed chromosomal damage in CHO cells at high concentrations

requires a new dossier in which data to all relevant toxicological endpoints and conform to modern standards

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Sri Noegrohati, GMU

Safety control in Cosmetic product

Particular attention is needed for long-term safety aspects, since cosmetic products may be used extensively over a large part of the human lifespan.

The safety of a cosmetic product is based on the safety of its ingredients,

Toxicity testing has been concentrated on ingredients, and particularly on those that are intended to react with biological matrices are of most concern for human health.

the safety-in use of cosmetic products

controlling the ingredients,

their chemical structures,

toxicity profiles,

and exposure patterns

ANALYTICAL METHODS for COSMETICS
the methods of analysis necessary for checking the composition of cosmetic products and the criteria of microbiological and chemical purity of cosmetic products and methods for checking compliance with those criteria shall be determined.Annex II (banned substances + CMR)Annex III (restricted substances)Annex IV (cosmetic dyes)Annex VI (preservatives)Annex VII (UV filters)

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Sri Noegrohati, GMU

informations readily available for the competent authorities :

The qualitative and quantitative composition of the product;

The physical and chemical and microbiological specifications of the raw materials and the finished product and the purity and microbiological control criteria of the cosmetic product;

The method of manufacture complying with the good manufacturing practice

Assessment of the safety for human health of the finished product.

The name and address of the qualified person or persons responsible for the assessment

Proof of the effect claimed for the cosmetic product,

Data on any animal testing performed by the manufacturer,

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SAFETY EVALUATION OF FINISHED COSMETIC PRODUCTS

soaps are applied in dilute form and, although the area of application may be extensive, the product is rapidly washed off,

products used on the lips and mouth will be ingested to some extent,

cosmetics used around the eyes and genital regions may come into contact with the conjunctiva or mucosa, respectively, potentially resulting in reactions due to the thin epithelial lining of these areas,

body lotions or body creams may be applied over a large surface of the body and the ingredients, often at appreciable concentrations, may remain in contact with the skin for several hours,

sunscreens, due to their extensive skin contact, combined with direct exposure to UV radiation for prolonged periods, require a distinct type of safety evaluation

permanent hair dyes undergo oxidative reactions on the hair and the intermediates and final products formed come into contact with the skin.

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Factors taken into considerations :

class of cosmetic product(s) in which the ingredient may be used,

method of application: rubbed-on, sprayed, applied and washed off, etc.,

concentration of the ingredient in the finished cosmetic product,

quantity of product used at each application,

frequency of application,

total area of skin contact,

site of contact (e.g., mucous membrane, sunburnt skin),

duration of contact (e.g., rinse-off or leave-on products),

consumer target group (e.g., children, people with "sensitive skin"),

quantity likely to enter the body,

projected number of consumers,

application on skin areas exposed to sunlight.

ASEAN COSMETIC DIRECTIVES

General Provisions of
The ASEAN Cosmetic Directive

1. Member States shall undertake all necessary measures to ensure that only cosmetic products which conform to the provisions of this Directive, its Annexes and Appendices may be placed in the market.

2. Notwithstanding to Article 4 and without prejudice to Article 5 and Article 11, a Member State may not, for reasons related to the requirements laid down in this Directive, its Annexes and Appendices, refuse, prohibit or restrict the marketing of any cosmetic products which comply with the requirements of this Directive, its Annexes and Appendices thereto.

3. The company or person responsible for placing the cosmetic products in the market, shall notify the regulatory authority responsible for cosmetics (hereafter referred to as regulatory authority) of each Member State where the product will be marketed of the place of the manufacture or of initial importation before the product is placed in the market.

4. The company or person responsible for placing the cosmetic products in the market shall for control purposes keep the products technical and safety information readily accessible to the regulatory authority of the Member State concerned.

ARTICLE 4: Ingredient Listings

Member States shall adopt the Cosmetic Ingredient listings of the EU Cosmetic Directive 76/768/EEC including the latest amendments.

ARTICLE 5: ASEAN Handbook of Cosmetic Ingredients

1. Notwithstanding the Article 4, a Member State may authorize the use within its territory of other substances, not contained in the lists of substances allowed, for certain cosmetic products specified in its national authorization, subject to the following conditions:

a) the authorization must be limited to a maximum of three years;

b) the Member State must carry out an official check on cosmetic products manufactured from the substance or preparation use of which it has authorized;

c) cosmetic products thus manufactured must bear a distinctive indication which will be defined in the authorization.

Safety Requirements

1. A cosmetic product placed on the market must not cause damage to human health when applied under normal or reasonably foreseeable conditions of use, taking account, in particular, of the products presentation, its labeling, instructions for its use and disposal, warning statements as well as any other indication or information provided by the manufacturer or his authorized agent or by any other person responsible for placing the product on the market.

2. The provision of such warnings shall not, in any event, exempt any person from compliance with the other requirements laid down in this Directive.

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Nanomaterials in cosmetic products

A nanoparticle is a particle with one or more dimensions at the nanoscale and is defined as a particle

Alpha Hydroxy Acids and Beta Hydroxy Acids in Cosmetics

AHA

glycolic acid

lactic acid

malic acid

citric acid

glycolic acid + ammonium glycolate

alpha-hydroxyethanoic acid + ammonium alpha-hydroxyethanoate

alpha-hydroxyoctanoic acid

alpha-hydroxycaprylic acid

hydroxycaprylic acid

mixed fruit acid

tri-alpha hydroxy fruit acids

triple fruit acid

sugar cane extract

alpha hydroxy and botanical complex

L-alpha hydroxy acid

glycomer in crosslinked fatty acids alpha nutrium (three AHAs).

BHA

salicylic acid (or related substances, such as salicylate, sodium salicylate, and willow extract) *

beta hydroxybutanoic acid

tropic acid

trethocanic acid
ingredients in cosmetics intended to reduce the signs of aging in the skin. make users more sensitive to sunlight and especially to the ultraviolet (UV) radiation component of sunlight Use sun protection