Safety assessment of cosmetics

products
(Safety Assessment of Cosmetics-Advanced, Juli 2020)

Purwantyastuti
Dept Pharmacology & Therapeutics
Fac. of Medicine, Univ. of Indonesia

Presented in kursus Safety Assessment of Cosmetics (Advance), July 2020

 References

— ASEAN Guidelines on Cosmetics Safety

— Scientific Committee on Consumer Safety : THE

SCCS'S NOTES OF GUIDANCE
FOR THE TESTING OF COSMETIC SUBSTANCES
AND THEIR SAFETY EVALUATION 8TH REVISION,
11 December 2012
— The "Notes of Guidance" à regularly revised and
updated (incorporate progress of scientific
knowledge/ experience)
A cosmetic ingredient may be:
— 1- a chemically well-defined single substance with
a molecular and structural formula,
— 2- a complex mixture: requiring a clear definition
and often corresponding to a mixture of substances
of unknown or variable composition and biological
nature,
— 3- a mixture of 1 and 2, used in the formulation of
a finished cosmetic product.
Any substance or mixture intended to
A Cosmetic product :
be placed in contact with the external parts of the
human body (epidermis, hair system, nails, lips and
external genital organs) or with the teeth and the
mucous membranes of the oral cavity ……
— The actual safety evaluation process will vary from product
to product, according to the novelty of the product
composition and to the relevance and adequacy of
information available

— As a general rule, the major basis for safety evaluation is

provided by considering the toxicological profile of its
ingredients.

— In almost all cases finished product testing does not require

the use of toxicological tests in animals.
— The rationale behind the safety of the cosmetic product
being based on the safety of its ingredients: à
thousands of different cosmetic products in the market
are derived from a limited number of substances

— This is also the basis for the lists of authorised

colouring agents, preservatives, UV filters, and
banned & restricted substances,
— Article 3 of the ASEAN Cosmetic Directive à
A cosmetic product put on the market must
not cause damage to the human health when
applied under normal or reasonably
foreseeable condition of use……...
— Cosmetic products have to be safe both for
consumers and for involved professionals
(e.g. hairdressers, beauticians, etc.).
Safety assessment of cosmetic product in line with Article 8
d of the ASEAN Cosmetics Directive 1 à requires an
“assessment of the safety for human health of

— the finished product,

— its ingredients, its chemical structure and
— its level of exposure”.
— This safety assessment is to be performed by a qualified
professional defined as the “Safety Assessor”.
 Safety evaluation of cosmetic ingredients
in the EU.
— It is the substances in Annexes II, III, IV, V and VI that fall
under the responsibility of the SCCS. All cosmetics
containing all ingredients other than the substances present
on the Annexes, is the responsibility of the “responsible
person”, as defined by 2009/1223/EC, through the safety
assessor.

— Safety evaluation of cosmetic substances by the SCCS

(SCCP) is based upon the principles and practice of the risk
assessment process usually applied for ingredients in
medicinal products, plant protection products, food
additives [WHO2001; European Commission 2000]
 This risk assessment procedure

1. Hazard identification à identify the potential damage to

human health.

2. Dose-response assessment
3. Exposure assessment
4. Risk characterization à probability that the substance
causes damage to human health and the level of risk, are
examined.

àIn the case of a threshold effect, the Margin of Safety (MoS)

is calculated.

àFor non-threshold effects (e.g. non-threshold carcinogenic

effect) the lifetime risk usually is determined
Physical and chemical properties of substances are
important information à to predict certain
toxicological properties.

— For example, a small molecular weight (MW)

hydrophobic compound is more likely to penetrate
through the skin than a high MW hydrophilic
compound;

— A highly volatile compound could cause significant

inhalation exposure when present in a product
applied to the skin.
The basic requirements for toxicological dossiers of new
substances
1. Chemical identity; physical form; molecular weight;
2. Characterisation and purity of the chemical;
3. Solubility; partition coefficient;
4. Additional relevant physical and chemical specifications;
5. Homogeneity and stability;
6. UV-absorption spectrum;
7. Isomer composition;
8. Function and uses.
About chemical identity
— The precise chemical nature of the substance under
consideration and its structural formula must be given. The
Chemical Abstracts Service (CAS) No. of the chemical, the
International Nomenclature of Cosmetic Ingredients (INCI) name
or Common Ingredient Nomenclature (CIN)
— substances that cannot be identified their structural formulaà
sufficient information should be provided on the method of
preparation (including all physical, chemical, enzymatic,
biotechnological and microbiological steps) and the material
used in their preparation à to assess the probable structure and
activity of the compound.

— safety evaluation of a natural substance (extract)à complete

information on the origin of the raw material (e.g. part of plant),
extraction method and any additional processes and/or
purification steps used
— In the case of a mixture used as “raw material”, all
substances must be given in the qualitative and the
quantitative formula.

— When a salt or ester of a substance is used as cosmetic

ingredientà clearly specified in the dossier.
About Characterisation and purity of the chemical

— The experimental conditions of the techniques used for the

chemical characterisation (UV, IR, NMR, MS, elemental
analysis, etc) ,the resulting spectrum, chromatogram etc. à
should be provided.

— The degree of purity must be clearly defined. The validity of

the analytical methodology used, must be shown.

— The substance(s) used in physical and chemical tests,

toxicity studies, etc., mentioned in the dossier, must be
representative of the substances present in commercial
products.
 RELEVANT TOXICITY STUDIES ON COSMETIC
SUBSTANCES
— The determination of the toxic potential of a cosmetic substance
is based on a series of toxicity studies
— Single dose animal studies, usually carried out with high
concentrations of the test compoundàdetermination / estimation
of “LD50-values”.

— Repeated dose toxicity studies, usually performed with lower

concentrations in daily administration/exposure for a long period
of time (e.g. 28 days/90 days/24 months), à determination of
no-observed adverse effect level (NOAEL) àused in the
calculation of the MoS. These studies also give an indication on
target organs, mechanisms of action, etc.

— Carcinogenicity studies are usually performed with mice and rats

for a period of 18 months to 24 months.
— EU : development and validation of alternative methods that
can provide an equivalent level of information as current
animal tests à use fewer animals, cause less suffering or
avoid the use of animals completely (3R-strategy of
Refinement, Reduction and Replacement).
— Some refinement/reduction have been made to existing in
vivo guidelines.
— A number of replacement guidelines àin vitro methods
have been developed.
— However, there are presently no validated in vitro
replacement methods for repeated dose animal toxicity
studies (including reproductive and developmental
toxicity)
— [Worth et al. 2002, Rogiers and Pauwels 2005, JRC 2010,
Adler et al. 2011].
— As far as skin is concerned, the two main
untoward reactions to be avoided are skin
irritation and skin sensitisation .
— Cosmetic products are often applied on
areas exposed to environmental factors.
Thus, care has also to be taken to avoid
photo-induced reactions such as
photoirritation and photosensitisation .
— Products applied on the scalp or the face
may come in contact with the eyeà eye
tolerance has to be addressed with optimal
attention
§ Systemic toxicity that may result from
percutaneous absorption or from accidental
(children) or reasonably foreseeable (e.g. oral
hygiene products, lipsticks) oral intake
should also be considered.
Ensuring the safety of a cosmetic product : from the choice of raw
materials à to the marketing follow-up.
A number of issues have to be taken into account:
— Cosmetic GMP Guidelines (ASEAN Cosmetic Directive - Technical
Documents) or approved equivalent;
— cosmetic ingredients, safe at a given concentration in a given finished
product;
— Checking local tolerance of the finished product;
— packaging to maintain the quality of the product and to avoid, as far as
possible, risks of misuse or accident;
— Quality control (microbiological and chemical);
— Stability studies (shelf life, preservative effectiveness (challenge test),
compatibility of the product and the packaging, etc);
— labeling - use and disposal, warnings and appropriate action to take in
case of accident;
— follow-up of the product on the market and consumer comments,
— INGREDIENTS : The careful selection of ingredients is the
key issue for ensuring the safety of the finished product.
— Influence on skin penetration may also be of importance,
especially for sensitisation and systemic risks .
— Determination of allergic potential may also require testing
of ingredients formulated with suitable vehicles.
— The safety-in-use of an ingredient largely depends on the
exposure conditions (type of formulation, concentration,
frequency and duration of contact, body area involved,
effect of the sun, etc.) taking into account normal conditions
of use and foreseeable misuse.
— INGREDIENTS TO BE AVOIDED
— SOURCES OF TOXICOLOGICAL DATA
— The composition of fragrances and flavours
— CONDITIONS OF USE AND EXPOSURE Evaluation
of the safety of ingredients has to include
considerations of exposure (magnitude, route,
duration, frequency, etc.)
 Systemic Toxicity
— Quantity likely to enter the body à systemic
toxicity.
— Toxicity studies just like other substances taken as
food, drugs , additional toxicity testing if relevant
— This last point, which relates to systemic
availability, is a critical issue in safety evaluation à
the information is mainly provided by
percutaneous absorption data.
— Find or Calculate NOAEL, LOAEL, LD50, MOS, CR
etc
SAFETY EVALUATION OF FINISHED PRODUCTS

— Local tolerance largely depends on the whole formulation..

— When exhaustive analysis of toxicological data on
ingredients appears insufficient to define with certainty the
local tolerance of the finished product à additional in vitro
and/or in human volunteers.

— Safety assessment may require human testing to check skin

compatibility of both cosmetic
ingredients and finished products.

— Any such trials have to be carried out following the

appropriate ethical requirements
 SAFETY CLAIMS
— A safety claim e.g., “dermatologically tested” has to be
supported by adequate evidence.

— In most cases, appropriate human testing on the finished

product will be necessary rather than animal testing.

— One important prerogative is the safety assessment by a

suitably qualified and experienced person before the trial
starts.
— Ideally, the development of the formulation should take into
account safety aspects from the start by a close
collaboration between safety assessor and formulator.

— A proper choice of ingredient at an adequate concentration

level is sufficient to avoid the major risks (e.g. genotoxicity,
carcinogenicity, systemic toxicity) and also to avoid
sensitisation.

— Testing on finished products is unnecessary in most cases

to assess these risks, provided potential interactions
between ingredients and role of vehicle are considered.
— In most cases, the knowledge of all information available is
sufficient to assess the safety of finished products.
— In the case of totally new ingredients, new
combinations of ingredients or new formulation
processes without safety-in-use experience à
additional testing may be needed.

— However, in all cases, all information on ingredients and

formulations should be made accessible by the
suppliers and formulator to the safety assessor to
ensure an adequate safety assessment.
 RESPONSIBILITIES OF THE SAFETY
ASSESSOR
The person in charge of assessing the safety of the product is
called the safety assessor. The safety assessor is responsible for
determining:
— Whether or not the ingredients present in the formula meet the
requirements of the legislation in respect of the concentration for
authorised substances, absence of substances prohibited by the
law and,
— Whether or not particular endpoint(s) have to be considered for a
given ingredient; Whether the data available are relevant and
sufficient;
— Whether or not interactions of toxicological relevance and/or
modifications to penetration are likely to occur;
— Whether or not complementary data are needed either on
ingredients or on the finished product.
— The Safety Assessor should possess qualification
in relevant fields for example a diploma in the field
of pharmacy, toxicology, dermatology, medicine or
a similar discipline and be suitably trained in the
safety assessment of cosmetics.
— It is in the interest of the company to select a
person knowledgeable in the field of safety
evaluation applied to cosmetics and who is
responsible and ethical.
— The Safety Assessor does not need to be an
employee of the company and can belong to an
external organization or institution, as long as he
has the required qualification.
The safety assessor must:
— Have recognized competence and ethics in the
field;
— Have access both to the toxicological and to the
analytical information needed for a safety view
point.
— Assesses the purity of raw materials, impurity
profile, and control procedures applied, detailed
information on a test mentioned or referred to by
the supplier, quantitative analysis of an impurity
with a potential toxicological relevance, etc;
— Not be involved with the commercial aspects
related to the product;
The judgment of the safety assessor relies on:
— The knowledge and experience of toxicological
properties and safety-in-use of the known
ingredients;
— The history of safety-in-use of products
containing the same or similar ingredients;
The expert judgment of the set of data available
on an unknown, new or novel ingredient;
— If necessary, the results of additional data
obtained either on one or more ingredients or
on the finished product
 The safety assessor may conclude
— The product is safe as such without special warnings or
precautions;
— The product is safe provided a given type of packaging is
used or provided a warning is added or the mode of use
and usage instructions are defined more precisely or
provided a complementary test with favorable results is
performed;
— The product is not safe for the proposed use;
— That available data are not sufficient to determine whether
or not the product will be safe and that further studies
need to be carried out to obtain the required information;
— Specific safety claim(s) may or may not be used.
— A product cannot be marketed if the conclusion of the
safety assessor is à “ the product may not be marketed
safely under the normal or reasonably foreseeable
conditions of use”.
— Recommendations by the safety assessor which are relevant
for the safety-in-use of the product have to be followed.
— They are part of the safety statement the assessor signs
which should be presented, together with the qualifications
of the safety assessor, to the relevant regulatory authorities
(inspectors) when required.
— Selecting the safety assessor thus appears to be a key issue
for the manufacturer of cosmetic products. It is not only a
legal issue: it may also have importance for other aspects
such as, for example, the image of the company as well as
product liability implications.
 Manufacturer Responsibilities
— Careful selection of cosmetic ingredients, making sure they will
be safe at a given concentration in a given finished product
— Checking local tolerance of the finished product
— Selection of adequate packaging to maintain the quality of the
product and to avoid, as far as possible, risks of misuse or
accident
— Applying ASEAN Cosmetic GMP, Quality control
— Appropriate labelling: presentation of the product, instruction for
use and disposal, warnings (if relevant) and appropriate actions
to take in case of accident
— Adequate procedures in case of side effects, visible product
change or adulteration with the marketed product

— Proper selection of the Safety Assessor

 Regulator Responsibilities
— Ensure public health and safety
— Audits samples from the market
— Audit PIF
— Inspection of company premises
— In case of Serious Adverse Event collaborate with the
Industry to take proper actions

— In case of product testing showing potential risk for human

health or adulterated product, take appropriate measures to
remove the product from the market, communicate with the
public and take appropriate action on the responsible
company/person
 REFERENCES
— ASEAN Guidelines for safety evaluation of cosmetic products -
Final
— ASEAN Cosmetic Directive
— Dooms-Goossens, Cosmetics as causes of allergic contact
dermatitis, Cutis, 52, pp. 316-320
— Loprieno, N., Guidelines for safety evaluation of cosmetic
products in the EC countries, Fd. Chem. Toxic., 30, pp. 809-
815
— Human testing for skin compatibility of products or skin
tolerance of potentially irritant cosmetic ingredients, SCAAT
statement (ref 96/304), Colipa, 1996, Brussels
— Barratt M.D., Quantitative Structure Activity Relationships for
skin corrosivity of organic acids, bases and phenols, Toxicology
Letters,1995, 75, pp. 169-176
— Howes, D., Guy R., Hadgraft J. et al, Methods for assessing
percutaneous absorption, ATLA, 24, pp. 81 - 106

— Colipa/EFFA, Guidelines on the exchange of information

between fragrance suppliers and cosmetic manufacturers,
Colipa, 1995
— SCCNFP Notes of Guidance for the Testing of Cosmetic
Ingredients and their Safety Evaluation, 5th revision

— World Medical Association, Declaration of Helsinki, 1964 &

1989(revised), Fernay Voltaire, France

— CIOMS/WHO, International ethical guidelines for biomedical

research involving human subjects, 1993, CIOMS, Geneva
—Thank you