Cosmetology

An Introduction on
The Effectivity and
Safety

Sri Noegrohati
Fac of Pharmacy
Gadjah Mada University
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.

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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, afterbath 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.

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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Cosmetics Management
Cosmetics Ingredient
(Cosmeceutical, formulations, perfume, preservatives)

Risk

Benefit

consumer
workers
environment

consumer
esteem
social-economy

Risk-Benefit Analysis
Yes
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Acceptance

No

Management
7

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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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.
9

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The Risk Assessment

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

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Safety evaluation of cosmetic

based upon the principles and practice of the risk
assessment process [WHO 2001]
Scientifically
based

Hazard identification

Dose-response
assessment

Exposure
assessment

Risk characterisation
Political will

risk management
risk communication

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Hazard identification

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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RELEVANT TOXICITY STUDIES

ON COSMETIC INGREDIENTS

Acute toxicity

Irritation and corrosivity

fixed dose method [OECD 420]

up-and-down procedure [OECD 425]
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
13
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GMU
technique
[OECD 406]

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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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 noncytotoxic 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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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.).

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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

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 targetdose 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.

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

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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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
23

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In vitro dermal penetration

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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Mean exposed skin surface area per product

type [Bremmer et al. 2003; US EPA 1997]

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Calculation of the daily exposure to cosmetics

using Colipa data [SCCNFP/0321/02].

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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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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 :

NOAEL
SED

100
MoS =
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)

Lifetime cancer risk =

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SED
HT25 / 0.25
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Keamanan Kosmetika
suatu konsep ilmiah berdasarkan kajian toksikologik
kosmetika 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 komposisi

evaluasi keamanan bahan baku
evaluasi keamanan produk jadi
evaluasi keamanan parfum
evaluasi kelayakan wadah, kemasan dan informasi

National Institution

(BPOM)

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

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Govermental institution

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Manufacturer

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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

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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

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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46

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)

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.
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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

1.

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,
substances not
contained in the lists of substances allowed, for certain cosmetic
products specified in its national authorization,
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,
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.

Nanomaterials in cosmetic
products
A nanoparticle
is a particle with one or more dimensions at the

nanoscale and is defined as a particle <100nm.

divided into two groups:
i) labile nanoparticles which disintegrate upon application to skin into
their molecular components (e.g. liposomes, microemulsions,
nanoemulsions), and
ii) insoluble particles (e.g. TiO2, fullerenes, quantum dots).
Two principal factors cause the properties of nanomaterials to differ
significantly from bulk materials:
increased relative surface area, and
increased quantum effects
When assessing possible risks associated with nanoparticles to
consider their uptake.
For topical applications, the route of exposure is essential
transdermal including follicular and other transadnexal pathways;
exposure via inhalation, ingestion, conjunctival and mucosal surfaces
may be relevant sometimes.
For the nanomaterials presently used in sunscreen products, a safety
dossier on micronized and nanosized ZnO, and nanosized TiO2 in the
light of the recent information and to consider the influence of
physiologically abnormal skin and the possible impact of mechanical
action on skin penetration.

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