Source: EURLEX
Language: en
Format: md

**I** *** * ***

**COMMISSION OF THE EUROPEAN COMMUNITIES**

Brussels, 24.07.1996

**COM(96)** **365 final**

**REPORT FROM THE COMMISSION**

**DEVELOPMENT, VALIDATION AND LEGAL ACCEPTANCE OF**
**ALTERNATIVE METHODS TO ANIMAL EXPERIMENTS IN THE FIELD OF**

**COSMETIC PRODUCTS**

**1995**

**DEVELOPMENT, VALIDATION** AND LEGAL ACCEPTANCE **OF**
**ALTERNATIVE METHODS TO ANIMAL EXPERIMENTS IN THE FIELD OF**

**COSMETIC PRODUCTS**

**1995**

**SUMMARY**

**I** **INTRODUCTION**

**The Commission's obligations**

Article 4(ij of Directive 76/768/EEC, as amended by Directive 93/35/EEC, specifies that
_**"Member States**_ _shall prohibit the marketing of cosmetic products containing ..._
_**ingredients or**_ _combinations of ingredients tested on animals after 1 January 1998..."._

The ambiguity of the expression "combinations of ingredients" has been resolved as far
as the Commission is concerned, which considers that the ban also covers finished
cosmetic products.

The implementation of this ban is linked to the development of _"satisfactory_ _methods to_
_**replace animal**_ _testing ... scientifically validated as offering an equivalent level of_
_**protection for the**_ _consumer"._

With a view to providing regular information on how the situation is developing it is
**specified that** _"ftjhe_ _Commission shall present an annual report to the European_
_**Parliament and the**_ _Council on progress in the development, validation and legal_
_**acceptance of**_ _**alternative methods**_ _to those involving experiments on_ _animals._ _That report_
_**shall contain precise data on the number**_ _and type of_ _experiments_ _related to cosmetic_
_**products carried**_ _out on animals"._

**1994 Report**

A first report was presented in 1994. It described interesting but limited results,
concluding that "animal models cannot be replaced, though they can contribute to
reducing the number of animals used...". However, the outlook was reasonably optimistic
as regards the validation of alternative methods for eye irritation, percutaneous absorption,
phototoxicity/photoirritancy and basic mutagenicity tests. It was also underlined that given
the current stage of the art it was unlikely that animal tests could be totally replaced in
toxicity studies for evaluating the systemic risk, i.e. action via the circulatory system on
the organism in its entirety after percutaneous absorption.

**H** **1995 REPORT**

The objectives of the report and the notion of the potential risk for human health are the
same as in the 1994 report.

The players involved in implementing this instrument are:

the European Commission: DG XI, DG-JRC, DG XXIV, DG XII

the European industry, represented by COLIPA (the European Cosmetic, Toiletry
and Perfume Association)

the American administration and the American Cosmetology Federation, CFTA

- the Japanese administration and the Japanese Cosmetology Federation, JCIA
the OECD.

**1** **Clarification of the validation stages**

Validation is the procedure via which the reliability and relevance of a procedure are
established to a specific end. This process turned out to be more complex than envisaged
and will take more time than foreseen. It has been necessary to define more precisely the
validation stages of the new tests (development of a test and production of a protocol;
prevalidation; validation proper; objective and independent evaluation of the study,
progress towards legal acceptance).

2 **The initiatives**

The various players have taken numerous initiatives with a view to achieving the
prescribed objectives.

PGXI

DG XI manages Directive 86/609/EEC on the protection of animals used for
experimental and other scientific purposes and, to this end, is responsible for
collecting statistics on the animals used. It also manages Directive 67/548/EEC
on the classification and labelling of dangerous chemical substances, whose
annexes define the test methods recognised by the EU.

DG-JRC:

ECVAM (European Centre for the Validation of Alternative Methods) has
already organised 14 seminars on the development and validation of
alternative methods. Seven, of these seminars concerned the safety of
cosmetic products and the reports have been published. Two other reports
on the prevalidation and validation procedures are also available.

      - ECB (European Chemicals Bureau) provides the technical and scientific
support needed by DG XI.

DG XXTV/CSC (Scientific Committee on Cosmetology):

      - DG XXIV plays a motor role in implementation, being responsible for the
Cosmetic Products Directive, and must prepare for the Commission the
draft measures postponing the deadline for the ban on animal tests, should
this be necessary.

      - The CSC and its subcommittee more specifically responsible for
alternative methods have evaluated various documents and dossiers
presented by COLIPA. They have also adopted a document titled "The
information required for the scientific evaluation of validation studies of

###### **11**

alternative tests with a view to their utilisation in evaluating the safety of
cosmetic products"

D3XII

DG XII has funded various research programmes on the development and
validation of alternative methods.

COLIPA/SCAAT (Steering Committee on Alternatives to Animal Testing)
Besides preparing dossiers and participating in numerous studies COLIPA
organised an international scientific symposium on alternatives to animal tests in
Brussels on 29 and 30 November 1995.

_**r**_

USA

     - The American government is actively seeking international cooperation
with a view to issuing recommendations.

     - The FDA (Food and Drug Administration), which is the agency
responsible for the safety of cosmetic products, has expressed its
misgivings as regards the ban on animal experiments in the
implementation of Directive 93/35/EEC.

OECD

The OECD publishes guidelines on toxicity tests, approved by the Member States.
A guideline on the in vitro control of percutaneous absorption is currently under
discussion.

**3** **Statistics on animal experiments**

The compilation of data specifically relating to cosmetic ingredients and products is
difficult because the collection of data on the number of animals used for experimental
**and** other scientific purposes in application of Directive 86/609/EEC is not foreseen on
an annual basis.

Eight Member States have declared that animal tests for finished cosmetic
products have not been conducted on their territory (Italy, Greece, Belgium,
Ireland, Sweden, Finland, Luxembourg, Germany).

- Six Member States have declared that animal tests for cosmetic ingredients have
not **been** conducted on their territory (Greece, Netherlands, Ireland, Sweden,
Finland, Luxembourg).

- Three Member States (Austria, France, United Kingdom) have communicated
figures while specifying in some cases that these figures are unreliable and not
interprétable.

It should also be noted that certain Member States that do not produce ingredients may
use ingredients tested in other Member States or in third countries and that certain
ingredients may have been tested for other purposes.

**cc/ag**

**Conclusions and perspectives** relating to the development of alternative methods
for the various toxicity tests used in the evaluation of the safety of cosmetic
ingredients and cosmetic products.

**4-1** _**Ingredients**_

Phototoxicitv/photoirritancv (skin reaction after epicutaneous application of a
chemical substance in the presence of UV radiation). This concerns in particular
UV filters.

The results of Phase II of the EU/COLIPA international validation study on in
vitro photoirritancy tests have already allowed considerable progress to be made.
A Phase HI is envisaged. A supplementary study on UV filters will be necessary.
Validation should be possible in the near future.

Percutaneous absorption
A new guideline on in vitro tests for percutaneous absorption could be approved
by the Member States and the OECD in the near future.

Skin irritation
It is proposed to evaluate skin irritation of cosmetic ingredients on-human
volunteers. This could be done provided prior studies concerning the toxic risk
furnish adequate guarantees.

Skin sensitisation
In vitro evaluation of skin sensitisation requires more in-depth research into the
mechanistic basis of sensitisation before a validation study can be considered.

Eve irritation
The results of the validation studies of alternative methods to the Draize eye
irritation tests have been disappointing (EU/Home Office study and COLIPA) and
none of the tests used met the studies' objective. A more flexible approach to
experimentation could be encouraged by accepting a combination of scientificallyvalidated methods and evaluating the toxicity of the substances under
consideration by comparison with appropriate benchmark substances.

Photomutagenicitv (all modifications of the information content of the genetic
material arising in the presence of UV radiation)
Recommendations have been proposed on the criteria to be adopted with a view
to defining the in vitro test protocols.

Skin corrosivity
Corrosive ingredients are not used in cosmetic products. However, the ECVAM
validation study of in vitro tests on skin corrosivity could be used at the screening
phase and provide essential information, before considering studies on human
volunteers.

IV

**Mutagenicity**
**In vitro tests to evaluate the mutagenic potential of cosmetic ingredients are in**

**current use. In vivo tests are carried out only when the in vitro tests results are**
**unsatisfactory.**

**It will probably be impossible to totally replace in vivo tests to evaluate the**
**systemic risk, such as tests of acute toxicity, subchronic toxicity, carcinogenicity,**
**toxicity of reproduction and development, in the foreseeable future. However by**
**refining the methods used it has already been possible to reduce substantially the**
**number of animals used.**

**4-2** _**Finished**_ _**cosmetic**_ _**products**_

**Eye tolerance and skin tolerance of finished cosmetic products can normally be**
**evaluated in vitro provided the data relating to the** **ingredients'** **toxicity and their**
**physico-chemical properties are known and provide the necessary guarantees.**

**Skin compatibility (absence of skin irritation) of finished cosmetic products can**
**be evaluated in man provided this is done in the context of strictly controlled**
**clinical studies.**

**It is important to emphasise that the use of** **human** **volunteers as a way to replace**
**animal tests must be considered with the greatest prudence. Such studies, whose**
**ethical dimension is obvious, should only be authorised after in vitro and in vivo**
**tests have demonstrated mat there is no risk of serious consequences.**

**In summary: -** **The validation of alternative methods for evaluating**
**percutaneous absorption and photoirritancy in the case of**
**ingredients, and for evaluating eye tolerance and skin**
**tolerance in the case of finished products, can be envisaged**
**in the near future.**
**Progress in alternative methods for evaluating eye irritation,**
**skin irritation and skin sensitisation in relation to**
**ingredients requires that additional studies first be carried**
**out;**
**The development of in vitro methods in the domains**
**involving a systemic risk is not likely in the foreseeable**
**future, even if it may be possible to reduce the number of**
**animals used.**

**GLOSSARY**

**CAPT:** **Committee of Adaptation to Technical Progress**
**CAAT:** **Centre for Alternatives** **to** **Animal Testing** **(John** **Hopkins University. USA)**
**CFTA:** **Cosmetic, Toiletry and Fragrance Association (USA)**
**COLIPA:** **European Cosmetic, Toiletry and Perfumery Association**
**DEREK:** **Deductive Estimation of Risk from Existing Knowledge**
**ECB:** **European Chemicals Bureau**
**ECVAM:** **European Centre for the Validation of Alternative Methods**
**ERGATT:** **European Research Group for Alternatives in Toxicity Testing**
**ES** **AC:** **ECVAM Scientific Advisory Committee**
**EU:** **European Union**
**EU/HO** **international validation study:**

**European Union/Home Office international validation study**
**FDA:** **Food and Drug Administration (USA)**
**FDCA:** **Food, Drug and Cosmetics Act (USA)**
**FLT:** **Fluorescein Leakage Test** *****
**FRAME:** **Fund for the Replacement of Animals in Medical Experiments**
**GLP:** **Good Laboratory Practice**
**ICC V** **AM:** **US** **Inter-Agency** **Coordinating Committee for** **the** **Validation of Alternative**
**Methods**

**IF** **AW:** **International Fund for Animal Welfare**
**IRAG:** **Interagency Regulatory Alternatives Group**
**IVTIP:** **In Vitro Testing Industrial Platform**
**JCIA:** **Japanese Cosmetics Industry Association**
**JRC:** **Joint Research Centre**
**MMAS:** **Modified Maximum Average Score**
**MHW:** **Ministry for Health and Welfare (Japan)**
**NIEHS:** **National Institute of Environmental Health Sciences (USA)**
**NRU:** **Neutral Red Uptake Assay**
**NTP:** **National Toxicology Program (USA)**
**PM:** **Prediction Model**
**OECD:** **Organisation for Economic Cooperation and Development**
**QSAR:** **Quantitative Structure-Activity Relationships**
**RBC:** **Red Blood Cell Haemolysis Test**
**SCAAT:** **Steering Committee on Alternatives to Animal Testing**
**SCC:** **Scientific Committee on Cosmetology**
**SLAT:** **Scweizerisches Institut fur Alternativen zu** **Tierversuchen**

**TEA:** **Tissue Equivalent Assay**
**UV:** **Ultra Violet**
**ZEBET:** **Zentralstelle** **zur** **Erfassung** **und** **Bewertung** **von** **Ersatz** **und**
**Erganzungsmethoden zum** **Tierversuch** **im** **Bundesgesundheitsamt**

#### **vi**

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**17-18**

**18-19**

**19-20**

**A.**

**B.**

**D.**

**E**

**F.**

**G.**

**CONTENTS**

**Introduction**

**Clarification of the stages in validation**

**- Validation of alternative methods used for different purposes**

**- Stages in the evaluation of new tests**

**Initiatives in 1995**
**The Players**
**The initiatives**

**1.** **European Union**
**DGXI**
**DG-JRC (ECVAM-ECB)**
**DG** **XXIV/SCC**

**DG XII**

**COLIPA/SCAAT**

**2.**

**3.**

**4**

**USA**

**Japan**
**OECD**

**The state of play**

**Statistics on animal experiments**

**Conclusions**

**The outlook**

A. **INTRODUCTION**

This is the second of the reports which the Commission must present annually to the
European Parliament and Council on progress in the development, validation and legal
acceptance of methods which could replace animal experiments for cosmetics testing.

_**'The**_ _**Commission**_ _**shall present an annual report to the**_ _**European**_ _**Parliament and**_
_**the Council on progress in the**_ _**development,**_ _**validation and legal acceptance of**_
_**alternative methods to those involving experiments on animals. That report shall**_
_**contain precise data on the number and type of**_ _**experiments**_ _**relating to cosmetic**_
_**products carried out on**_ _**animals.**_ _**The Member**_ _**States shall be obliged to collect that**_
_**information in addition to collecting statistics as laid down by Directive**_
_**86/609/EEC**_ _**on the**_ _**protection of animals used for**_ _**experimental**_ _**and other**_ _**scientific**_
_**purposes. The**_ _**Commission**_ _**shall in particular ensure the**_ _**development,**_ _**validation**_
_**and legal acceptance of**_ _**experimental**_ _**methods which do not use live**_ _**animals.**_ _**'**_
_**(Article 4(i) of Directive 76/768/EEC, as**_ _**modiûeé**_ _**by Directive 93/35/EEC).**_

With the exception of the objectives, players and notion of potential risk for human health,
which remain unchanged, the points developed in the first annual report (COM(94) 606)
are reviewed:

Clarification of the stages in validation (B)

Initiatives in 1995 (C)
The state of play (D)
Statistics on animal experiments (E)
Conclusions (F)
The outlook (G)

**B.** **CLARIFICATION OF THE STAGES IN**

**VALIDATION**

**The Commission's main objective remains that of encouraging the development,**
**validation and legal adoption of alternative methods which can offer the consumer a**
**level of protection at least equivalent to that achieved by using animal studies.**

**Validation is the process by which the reliability and relevance of a procedure are**
**established for a specific purpose.**

The stages involved in achieving this objective are more numerous, and the process a
more complex one, than initially foreseen.

The first Amden workshop (held in Switzerland in 1990) laid down the theoretical basis
which is essential for the validation process, viz. intra-laboratory validation, interlaboratory evaluation, the development of databases, and evaluation of the results.

Experience with validation studies conducted since 1990 has shown that it is necessary to

better define the various objectives of the validation studies and to integrate new stages
into the process of evaluating new tests.

**ECVAM (European** Centre **for** the Validation of Alternative Methods), a unit of the
Environment Institute of the Joint Research Centre (ISPRA), is at the hub of the
discussions on validation, and major contributions have been made in the following fields:

- practical aspects of validation
- prevalidation scheme

- international discussions with ICCVAM (US Inter-Agency Coordinating Committee
for the Validation of Alternative Methods) and the OECD (Organisation for
Economic Cooperation and Development) on the harmonisation of validation and
acceptance criteria.

Recommendations concerning the practical and logistical aspects of validating alternative
tests were made at the second Amden Workshop (24-28 January 1994), organised jointly
by ECVAM and ERGATT (the European Research Group for Alternatives in Toxicity
Testing), and are set out in ECVAM workshop report No 5.

_**Validation**_ _**of alternative**_ _**methods**_ _**used for**_ _**diffèrent**_ _**purposes**_

Validation of alternative tests can be conducted with four main types of objectives in
mind. A distinction is made between:

1. Validation of alternative procedures for the use in non-regulatory studies.

2. Validation of alternative tests for inclusion as part of regulatory guidelines.

3. Validation of alternative tests to replace existing guidelines.

4. Validation of alternative tests which are designed to provide part of the information
required by a regulatory guideline.

_**Stages in the**_ _**evaluation**_ _**of new tests**_

**1.** **Development of a test and production of a protocol**

The criteria taken into consideration in developing a test mainly comprise a
description of the basis of the method, the definition of its scientific objective, the
specification of its biological endpoint, and the expression and interpretation of the
results, via a prediction model (PM).

The **prediction model** must enable the result obtained with an alternative method
to be converted into a correct prediction of in vivo toxicity.

The prediction model is critical for the success of a validation programme. It
enables a clearly defined hypothesis to be tested and an objective evaluation of test
performance, and it serves as a guide for planning the validation study.

**2.** **Prevalidation**

Experience has shown that the outcome of large and expensive validation studies
can be compromised if their managers do not insist that optimised test protocols
and proof of their performance are submitted before the start of the formal
validation study. The objectives of prevalidation, and a scheme of the prevalidation
process, are described in the first report of the ECVAM Prevalidation Task Force.

The aims of prevalidation are:

to optimise and standardise the protocol
to evaluate the method's transferability.

The prevalidation exercise comprises three phases:

refinement of the protocol, involving collaboration between the laboratory
which has developed the method and the laboratory designated to optimise
the method
transfer of the protocol, involving collaboration between the first two
laboratories and the laboratory designated for the transfer
a blind study, involving, as a minimum, participation of the three
laboratories responsible for studying the protocol's performance.

**3.** **Validation**

The validation stage comprises a formal inter-laboratory study.

The main stages are:
study design
selection of the tests

selection of the laboratories

selection and distribution of the test materials
collection and analysis of the results
evaluation of the study.

**4.** **Independent** assessment **of the conduct and outcome of the study.**

This should include an objective evaluation of the value of the scientifically
validated tests by comparison with other tests, taking into account the validation
objectives.

**5.** **Progression towards legal acceptance**

It is essential that any new method that is considered to be adequately validated as
a replacement for an existing method receives as widespread international
recognition as possible. For example, the OECD test guidelines are particularly
important in this respect, since they are used for tests conducted in member
countries in Europe and North America, and in Japan, Australia and New Zealand.
Furthermore, under the OECD Mutual Acceptance of Data Agreement, member
countries have agreed to accept data from tests performed according to OECD test
guidelines, provided that the principles of Good Laboratory Practice (GLP) are

observed. The OECD has established a procedure for updating test guidelines and
for the introduction of new test methods.

**C.** **INITIATIVES IN 1995**

THE PLAYERS

For the record, the players involved in encouraging the research, development and
validation of alternative methods are:

**1.** **EUROPEAN UNION**

**The European** Commission

Several Commission services are involved in issues relating to animal
experimentation and the development and evaluation of alternative methods.

_DG XI, Environment, Nuclear Safety and Civil Protection_ manages and is
responsible for Directive 86/609/EEC, on the protection of animals used for
experimental or other scientific purposes, and for Directive 67/548/EEC, on the
classification, packaging and labelling of dangerous substances.

DG- _JRC, Joint Research Centre_

_ECVAM,_ European Centre for the Validation of Alternative Methods
_ESAQ_ ECVAM Scientific Advisory Committee
_ECB,_ European Chemicals Bureau

_DG_ _XXIV:_ _Consumer_ _Policy_

_Unit A3_       - Products, manages Directive 76/768/EEC (the Cosmetics
Directive)
_SCO._ the Scientific Committee on Cosmetology, a Commission advisory
committee

_DG XII, Science, Research and Development_ funds research programmes:

**European industry**

_COLIPA_    - Comité de Liaison Européen des Industrie Cosmétiques, des Produits de
Toilette et de la Parfumerie, has set up SCAAT.

SCAAT - Steering Committee on Alternatives to Animal Testing; supervises
COLIPA's validation studies and coordinates the validation efforts of the

cosmetics industry on a worldwide basis.

2. **USA**

_CTFA_   - Cosmetic, Toiletry and Fragrance Association

**3.** **JAPAN**

_J CIA_    - Japanese Cosmetics Industry Association

**4.** **ORGANISATION** **FOR** **ECONOMIC** **COOPERATION** **AND**
**DEVELOPMENT (OECD)**

The OECD publishes test guidelines, as approved by consensus among its member
countries. These guidelines are almost identical to the Annex V test methods of the
EU, and, in association with the principle of Mutual Acceptance of Data, provide
an opportunity for international harmonisation and for a rational approach to the
application of the Three Rs.

THE INITIATIVES

**1.** **EUROPEAN UNION**

**DGXI**

**DG XI, Environment, Nuclear Safety and Civil Protection** has reached agreement with
the Member States on the best approach to be adopted in gathering, on a bi-annual basis,
the statistical data required under Articles 13 and 26 of Directive 86/609/EEC on the
protection of animals used for experimental and other scientific purposes. The table which
the Member States must complete includes a figure for the total number of animals used
for cosmetic testing. DG XI is also responsible for Directive 67/548/EEC and for the EU
test methods, as detailed in Commission Directive 87/302/EEC and in the Annex to
Commission Directive 92/69/EEC (Part B - Methods for the Determination of Toxicity).

DG XI supported the EU/HO international validation study on alternatives to the Draize
eye irritation test, and also the EU/COLIPA international validation study on in vitro
phototoxicity.

**DGJRC**

**ECVAM (the European Centre for the Validation of Alternative Methods)** is at the

service of all the DGs concerned with the issues associated with alternative methods.

ECVAM was established by the European Commission in accordance with a
Communication from the Commission to the Council and the European Parliament in
October 1991, and in response to Article 23 of Directive 86/609/EEC, which stated that:

"The Commission and Member States should encourage research into the development and
validation of alternative techniques which could provide the same level of information as
**that** obtained in experiments using animals, but which involve fewer animals or which
entail less painful procedures, and shall take such other steps as they consider appropriate
**to encourage** research in this field".

ECVAM has been set up to:

1. Coordinate the validation of alternative test methods at the European Union level.
2. **Act** as a focal point for the exchange of information on the development of
alternative test methods.
3. Establish, maintain and manage a database on alternative procedures.
4. Promote dialogue among legislators, industries, biomedical scientists, consumer
organisations and animal welfare groups, with a view to the development,
validation and international recognition of alternative test methods.

The ECVAM opening symposium organised at ISPRA on 18 October 1994 was devoted to
discussion of the validation of replacement alternative methods. At this symposium,
ECVAM's role in the development, validation and acceptance of alternative tests and test
**strategies,** including those for cosmetics testing, was considered, and may be summarised
**as** follows:

contribute to the development of guidelines via the validation process itself, since
this is linked to the development and acceptance of pertinent and reliable tests for
specific objectives;
identify priorities, taking into account the state of the art in specific fields;
ensure that the alternative tests relate to simple, distinct and well-defined biological
outcomes whose mechanistic basis is sufficiently well known;
promote a multi-disciplinary approach with a view to developing integrated test

strategies, incorporating quantitative structure-activity relationships (QSAR),
biokinetics and cell and tissue culture methods;
address the difficulties resulting from the lack of test materials with associated

high-quality in vivo data;
encourage the réévaluation of the existing guidelines and regulatory procedures;
achieve consensus by working with the appropriate government, industrial,
academic and other bodies;
draw up criteria for validation, for independent evaluation of the results of

validation studies, and for the legal acceptance of alternative tests and tests
strategies, through active cooperation with such bodies as the OECD and ICCVAM
**(Inter-Agency** Coordinating Committee for the Validation of Alternative Methods,
USA).

To **date,** ECVAM has organised several workshops on the development and validation of
**alternative** tests and has published the reports of 14 of these workshops. ECVAM **has**
**given priority to alternatives for cosmetics testing.** The reports of direct relevance to
evaluating the safety of cosmetics are:

report 2 In vitro phototoxicity testing (1994)
report 5 Practical aspects of the validation of toxicity test procedures (1995)
report 6 A prevalidation study on in vitro skin corrosivity testing (1995)

report 7 Development and validation of non-animal tests and testing strategies:
the identification of a coordinated response to the challenge and the
opportunity presented by the Sixth Amendment to the Cosmetic
Directive (1995)
report 8 The integrated use of alternative approaches for predicting toxic hazard

(1995)
report 11 The Three Rs: the way forward (1995)
report 13 Methods for assessing percutaneous absorption (published in 1996)

Two other reports were published in 1995 on:

the validation of alternative test methods (a joint statement by ECVAM and the
ECB)
the first ECVAM Prevalidation Task Force Report.

ECVAM's priorities in the field of cosmetics testing for 1995-1998 include:

developmental toxicity
metabolism
corrosivity
phototoxicity
dermal penetration
ocular and dermal irritation

sensitisation

**ECB (the European Chemicals Bureau)** provides technical and scientific support for
DGXI on the classification and labelling of dangerous substances, on notification of new
substances, on existing chemicals, on export/import control of dangerous substances, and
on testing methods (according to Annex V of Directive 67/548/EEC). An effective liaison
is being developed between the ECB and ECVAM with respect to replacement alternative
test methods, and modifications to animal procedures which reduce the numbers of
animals required or lessen the suffering of any animals necessarily used in complying with
regulations and guidelines.

**DG XXIV / SCC**

**DG XXIV** **Consumer** **Policy,** which manages the Cosmetic Directive (Directive
76/768/EEC), remains the driving force and has expanded its activities with a view to the
fullest possible compliance with the provisions of Directive 93/35/EEC within the agreed
time limits.

**If alternative methods have not been scientifically validated and legally accepted,**
**DG XXIV has been instructed to prepare for the Commission draft measures**
**designed to extend the time limit for the ban on animal tests in accordance with the**
**Committee** **for** **Adaptation** **to** **Technical** **Progress** **Procedure** **(Article** **10,**
**Directive 76/768/EEC).**

**8**

This Committee (CATP) is made up of representatives of the Member States and is
chaired by a Commission representative. The Chairman submits to the Committee the
draft measures to be adopted.

The opinion is delivered by qualified majority.

In compliance with the new co-decision procedure, the European Parliament will be
informed at the same time and under the same conditions of all draft measures submitted

to the CATP.

_**If there has been**_ _**insufficient**_ _**progress in developing**_ _**satisfactory methods**_ _**to replace**_
_**animal testing, and in particular in those cases where alternative methods of**_
_**testing, despite all reasonable**_ _**endeavours,**_ _**have not been scientiûcally validated as**_
_**offering an equivalent level of**_ _**protection**_ _**for the consumer, taking into account**_
_**OECD toxicity test guidelines, the**_ _**Commission**_ _**shall, by 1 January 1997, submit**_
_**draft measures to postpone the date of**_ _**implementation**_ _**of this provision, for a**_
_**sufficient period, and in any case for no less than two years, in accordance with**_
_**the procedure laid down in Article 10. Before submitting such measures, the**_
_**Commission will consult the Scientific Committee on Cosmetology. (Article 4(i) of**_
_**Directive 76/768/EEC, as**_ _**modified**_ _**by Directive 93/35/EEC).**_

On several occasions DG XXIV has urged the Member States to meet their obligations
regarding the collection of precise data on animal experiments concerning ingredients and
finished cosmetic products. The statistical data to be collected under Directive 93/35/EEC
with regard to cosmetic products go beyond the data which Member States must supply to
comply with the requirements of Directive 86/609/EEC. The Member States have been
requested to submit these more detailed data on an annual basis.

DG XXIV has liaised regularly with DG XI and with ECVAM, and has facilitated
communication between all players.

**SCC:** **the Scientific Committee on Cosmetology,** a Commission advisory committee, has
been requested to deliver a scientific opinion to DG XXIV on the applicability of validated
alternative methods for ^evaluating the safety of cosmetic products for human use.

**The** **SCC** **[1]** **s subcommittee on alternative methods and guidelines** organised two
working meetings (2 February, 11 May) and two joint meetings with SCAAT/COLIPA
(19 September, 1 December) during which the following actions were developed.

**1.** **Evaluation of documents and dossiers submitted by COLIPA**

_**In**_ _**vitro photoirritation**_ _**(EU/COUPA)**_

An analysis of the data communicated by COLIPA - viz. the partial results
published in the literature, in regard to the prevalidation phase, and partial
information on phase 2 has not allowed the SCC to deliver a scientific opinion on
**the draft** _**as a whole.**_

However, the SCC emphasises that the animal models are inadequate for predicting
the phototoxic effects in man and **considers that a study of** **[ M]** **in** **vitro"** **phototoxic**

**potential is an important step in the process of evaluating the safety of**
**cosmetic products containing UV filters.**

_In_ _vitro_ _percutaneous absorption (COLIPA)_

After analysis of the documents presented by COLIPA, viz. guidelines for in vitro
percutaneous absorption tests, standard protocols and a general overview of in
vitro/in vivo correlations, the SCC recommends presenting the "in vitro"
percutaneous absorption methodology in a standard manner and supplementing the
methodology with intra- and inter-laboratory results obtained on suitably chosen
test materials and vehicles.

_Photomutagenicity_ _(COLIPA)_

The COLIPA recommendations in the final report transmitted to the SCC indicate
the criteria to be used in defining the test protocols.

The SCC regrets that it cannot yet base the evaluation of the photomutagenic
potential of UV filters on validated tests, despite the fact that it developed general
criteria for realising photomutagenicity tests in 1990 (SPC/803/90).

**2.** **Information required for the scientific evaluation of the validation studies of**
**the alternative tests with a view to using them in evaluating the safety of**
**cosmetic products**

Taking into consideration the problems arising in connection with validation of the
alternative methodologies, the SCC considered there was a need to prepare a
document that would be of direct use for future validation studies.

The qualitative and quantitative aspects of the validation process are taken into
account in this report. The criteria selected:

concern the _scientific_ _validation_ of the tests

make it possible to measure a degree of toxicity
are applicable to cosmetic ingredients

involve definition of the statistical analysis procedures

The need to provide evidence of protocol optimisation and to formalise the link
between in vitro and in vivo data in the form of a mathematical relationship are
highlighted.

**DGXII**

**DG XII, Science, Research and Development** funds research programmes, notably
including the development and validation of alternative methods according to Decision N°
1110/94/EC of the European Parliament and the Council of 26 April 1994 concerning the
Fourth Framework Programme for Research and Technology Development, which clearly
set out instructions as follows: "Whenever possible, experimentation and testing on

**10**

animals should be replaced by in vitro or other methods...

Several programmes on the development and validation of in vitro tests have been
supported by DG XII or are in progress. Some of the projects could be of use for the
cosmetic sector:

BRIDGE - Final report (EUR 15777, published in 1995)

Development of a predictive in vitro test for the detection of sensitising
compounds.

BIOTECH (1992-1994)

Some projects concern in vitro developmental toxicology.

BIOTECH (1994-1998)

The work programme foresees prenormative research on in vitro alternatives to
animal experiments in pharmacotoxicology.

rVTIP (In Vitro Testing Industrial Platform): forum organised to improve contacts
between technology producers and users. Two meetings were organised in 1995, on
progress with the Fourth Framework Programme and on an overview of progress made
with validation.

**COLEPA/SCAAT**

For each field of investigation SCAAT has established specific working parties made up of
various experts to implement the validation work.

An international scientific symposium on alternatives to animal experiments was organised
by COLIPA in Brussels on 29 and 30 November 1995, with representatives of industry,
the scientific community, the Commission and the European Parliament, and animal
protection societies.

The first session, devoted to VALIDATION, emphasised the critical role of prediction
models and surveyed ongoing validation studies on photoirritation and eye irritation. The
session ended with a round table on the perspectives of a regulatory approach.

The second session, devoted to DEVELOPMENT, included presentations on percutaneous
absorption, skin compatibility and skin sensitisation.

The third session, devoted to SAFETY EVALUATION, addressed the initiatives taken by
the SCC as well as the approaches of the British and German regulatory authorities.
Emphasis was placed on the importance of providing scientific data in support of the
cosmetics industry's "in-house" studies and test strategies for evaluating the safety of
finished products.

The presentations were supplemented by a poster exhibition. In the context of this
exhibition, a brochure setting out the approach of IFAW (the International Fund for
Animal Welfare) was provided to the participants. As there is clearly no question of

**11**

replacing animal tests by a simple in vitro test, IFAW presents a phase-based strategy
based essentially on alternatives which focus on the use of cells and tissues of human
origin, excluding all in vivo animal experiments and recommending in vivo tests on
volunteers.

The symposium highlighted the important role of COLIPA (European cosmetics industry)
in undertaking research into the development and validation of alternative methods. The
work being done by the major European cosmetic companies is very substantial when one
considers the number of animals used in cosmetic experiments and the knowledge acquired
greatly benefits other industries.

Moreover, the symposium provided the different players involved with precise scientific
information and gave rise to an interesting exchange of views. A joint approach of
industry and the Commission was called for, so that animal tests in the fields of skin
compatibility, photoirritation and percutaneous absorption can rapidly be replaced.

2. **USA**

The US government is keen on **international cooperation** to recommend an approach and
to define the criteria for the regulatory adoption of new alternative methods, clearly
establishing the conditions under which these methods are used (biological outcomes,
relevance for classes of substances, etc.). ICCVAM organised a workshop on the
validation and regulatory acceptance of alternative toxicological testing methods, sponsored
by the National Institute of Environmental Health Sciences (NIEHS) and the National
Toxicology Program (NTP), in December 1995 in Arlington, Virginia. The purpose of the
workshop was to discuss the draft ICCVAM report containing recommendations about
criteria and processes for the validation and regulatory acceptance of new and revised
toxicological testing methods.

The Food and Drug Administration (FDA) is the US agency responsible for cosmetics
safety. The FDA has interactive relations with the public and private agencies involved in
the development and validation of alternative tests, and focuses on methods which generate
reliable scientific data.

**The FDA has misgivings about the prohibition of animal experiments in the**
**implementation of Directive 93/35/EEC.** Certain cosmetics manufactured in the EU
might not satisfy the safety requirements (for health) laid down by the US FDCA (Food,
Drug and Cosmetics Act).

**3.** **JAPAN**

The Japanese Ministry for Health and Welfare (MHW) is responsible for testing and test
guidelines in Japan. Japanese research groups are particularly involved in the validation of
alternatives to the Draize eye test. The acceptance of the alternatives depends on their
specific role in the evaluation of eye irritation (screening or replacement; individual test or
batteries of tests). JCIA considers that it would be difficult to recommend for regulatory
testing purposes for evaluating the safety of cosmetic products, a test or test battery
whose predictivity was less than that of in vivo methods.

12

**4.** **OECD**

In October 1994, the 5th meeting of the National Coordinators of the OECD Test
Guidelines Programme agreed that an attempt should be made to internationally harmonise
the various published and advocated concepts for the validation of alternative test methods.
In view of the international debate on the issue, it was considered timely for the OECD to
step in and provide a platform for all parties involved, through which it might be possible
to reach international consensus on validation and acceptance criteria. The National
Coordinators emphasised that existing proposals should be used as the basis for an
internationally acceptable approach, rather than the development of yet another concept. In
this respect, the work of centres such as CAAT (Johns Hopkins University Center for
Alternatives to Animal Testing) in the US, ECVAM in the EU, ERGATT, and various
national centres and committees (e.g. FRAME in the UK, IRAG and ICCVAM in the US,
NCA in the Netherlands, SIAT in Switzerland, and ZEBET in Germany) was wellrecognised.

The National Coordinators agreed that an OECD Workshop would be the best approach,
since such a meeting would offer ample opportunity for all parties having an interest in the
subject to discuss the issue and to seek consensus. Furthermore, it was considered of
crucial importance that member countries would include in their nominations individuals
having responsibilities in the regulatory area. Sweden offered to host the workshop.

A Steering Committee was established in January 1995 to advise the OECD Secretariat on
the scope and structure of the Workshop, and to assist in the development of the
programme for the Workshop, which was scheduled for 22-24 January 1996, in Solna,
Sweden. ECVAM and ZEBET were represented on this Steering Committee.

**D.** **THE STATE OF PLAY**

**METHODS UNDER DEVELOPMENT AND VALIDATION**

_**Skin sensitisation**_

Sensitisation is an area of considerable research and is extremely relevant to cosmetics
safety. An interesting approach to the in vitro evaluation of skin sensitisation was
presented at the symposium organised by COLIPA (29-30 November 1995). An ECVAM
workshop on skin sensitisation was helcl during 1995, the report of which will be
published in 1996.

The chemical structures and sensitising potentials of various compounds have been
extensively examined and expert computer systems, such as DEREK (Deductive
Estimation of Risk from Existing Knowledge), are being developed to identify structural
alerts associated with skin sensitisation potential. A possible predictive approach could be
based on measurement of the molecular signals induced in cell cultures by sensitising
substances.

13

**Notably in this domain it should be emphasised that prediction of sensitisation potential in**
**humans remains a major problem because of the inter-individual variability in response.**

_**Photomutagenicity Validation**_ _**(COLIPA)**_

**Since 1990, COLIPA has submitted dossiers on UV filters containing photomutagenicity**
**data obtained from different types of tests.**

**COLIPA organised a ring test to define a suitable protocol by using two substances whose**
**photomutagenic** **potentials were known, and which were activated by UV-A radiation and**
**different bacterial strains. The results of this ring test have made it possible to draft**
**recommendations on the criteria for selecting bacterial strains or cell cultures, the solar**
**simulator, the technique of sample irradiation, UV radiation doses, doses of substances to**
**be tested, and the use of positive** **controls.** **It is difficult to plan a validation study in the**
**absence of** _**in vivo**_ **reference data.**

_**Percutaneous**_ _**absorption**_

**ECVAM, COLIPA and the OECD have collaborated to facilitate the international adoption**
**of a testing guideline on in vitro percutaneous absorption.**

_**Pbotoinitation/phototoxicity:**_ _**Validation**_ _**- phase U**_ _**(EU/COUPA)**_

**ECVAM and DG XI are represented on the Management Team for the study, which is**
**being coordinated by ZEBET, and is examining the possibility of a supplementary**
**validation study designed to predict the photoirritant potential of UV filters.**

**In the first (prevalidation) phase of the study, analysis of the results obtained in a cell**
**viability test made it possible to determine a photoirritancy factor for distinguishing**
**photoirritant substances from non-photoirritant substances. The objective of the second**
**(validation) phase, planned as a blind trial, was to determine whether a cell toxicity test**
**and a test measuring cell damage (the NRU** **[1]** **and the combined test RBC** **[2]** **[photohaemolysis**
**+ haemoglobin oxidation]) could correctly predict the photoirritant potential of 32**
**chemical substances, which have been administered systemically or topically in man.**

**The** **pretiminary** **results of phase II, which ended in 1995, are confined to the NRU test**
**used in all the laboratories. The RBC protocol was used only in three laboratories.**
**Supplementary statistical evaluations were carried out by an independent biostatistician and**
**will be available during the first half of** **1996.**

**'NRU:** **neutral red uptake** **assay|§|**

**2** **RBC:** **red blood cell haemolysis test; used to evaluate damage to the cell membranes**

**14**

_Eye_ _**irritation:**_ _**final report on the**_ _**EC/HO**_ _**study on alternatives to the Draize eye**_
_**irritation test**_

The objective of this study was to determine whether nine alternative tests, alone or in
combination, could replace the Draize test for severely irritant test materials or evaluate
the irritant potential of chemical substances, with or without regard to the chemical class
and over the entire range of measurable potentials.

A total of 60 chemical substances were analysed independently in 37 laboratories. The
results were compared with the MMAS (modified maximum average score) obtained in the
Draize test and submitted for statistical evaluation.

With the exception of predicting the irritant potential of surfactants, none of the nine tests
achieved any of the envisaged objectives.

Many valuable lessons were learned during this study, which were taken into account in
the planning of the COLIPA study. They also led to the ECVAM workshop on practical
aspects of validation, and to the development of the ECVAM prevalidation scheme. The
variablility of the in vivo data was identified as a major obstacle for the establishment of
the relevance and reliability of the in vivo tests.

_Eye_ _**irritation: Validation**_ _**(COIJPA)**_

The validation exercise was conducted on 23 cosmetic ingredients (surfactants, alcohols,
preservatives), of which 20 were the same as those tested in the EC/HO study, and on 32
cosmetic formulations (with a large range of physico-chemical forms). The test materials
were tested in vivo in compliance with OECD guideline 405.

The specific objectives of this study were to determine whether the data obtained on the
basis of 10 in vitro protocols currently used in the cosmetic industry (of which five had
also been evaluated in the EC/HO study):

correlate acceptably with the MMAS (modified maximum average score);
correlate acceptably with the individual scores and recovery times, such as those
described in OECD guideline 405;
correctly predict the eye irritation potential in the rabbit on the basis of algorithms
for the alternative method.

**For the first time in a validation study, prediction models (PMs) were laid down**
**before the start of the study.** They define precisely the biological outcomes obtained for
each in vitro model and how to convert each in vitro biological outcome into a prediction
of eye irritation potential. The PMs used in this study are based on historical data
available for the ingredients and formulations of interest to the cosmetics industry, notably
for substances with a low to moderate irritation potential.

**The programme did not permit complete validation because of the small number of**
**laboratories that participated in assays specific to the** **programme.** **None of the**
**methods tested can yet validly replace the Draize eye irritation** **test.**

**15**

The reliability of the PMs was evaluated by determining whether the inter-laboratory
results were reproducible and whether the data were distributed within the prediction
intervals of the predefined PMs.

The RBC test showed good inter-laboratory reproducibility and also satisfied the reliability
criteria.

Three of the protocols tested conformed reasonably with their prediction models (FLT [3],
RBC, TEA [4] ), but supplementary studies are necessary to resolve several technical
problems associated with the PMs before final conclusions about their performances can
be drawn.

**This validation study highlights the importance of the availability of good-quality in**
**vivo data.**

The in vivo data available are adequate for evaluating the risk. However, in order to
compare the in vivo and in vitro data, the two sets of data should theoretically have as
small a variability as possible, to permit precise statistical evaluation. Experience has
shown that this is not always the case.

Examination of the results indicate that certain PMs could be refined and tested in a future

study.

_**Skin corrosivity: Prevalidation (ECVAM)**_

Four skin corrosivity tests are being evaluated and optimised (TER - rat skin
transcutaneous electrical resistance assay, CORROSITEX, Skin [2] and EPISKIN) with a
view to planning a formal validation study for 1996.

_**Skin compatibility (COUPA)**_

Skin compatibility is defined **as the absence of skin irritation in normal conditions** of
use and in reasonably foreseeable conditions of improper use.

Seven COLIPA member companies evaluate the skin compatibility of their finished
products in man under controlled conditions, because the irritation potentials of most
cosmetic products are very low.

COLIPA has developed guidelines for evaluating the compatibility of finished cosmetic
products on human skin:

**3** **FLT:** **fluorescein leakage test: measures the damage caused to a cell barrier.**

***TEA:** **tissue equivalent assay; measures the time required to cause a 50% reduction in the** **viability of**

**cells in reconstituted human skin**

**16**

taking ethical requirements into account, studies on man must be conducted in
accordance with the Helsinki Declaration (1964, 1989);
a prudent approach to tests, stage by stage, is essential;
prior knowledge of the composition and stability of the products tested, as well as
prior evaluation of toxicity data on the product ingredients, is necessary.

Guidelines on the skin compatibility of cosmetic ingredients are currently being developed.

_**Human volunteer studies (ECVAM)**_

Human volunteer studies are often listed along with other replacement alternatives for
animal tests. The ethical, legal, safety, logistic and scientific problems associated with
such studies are being investigated by ECVAM, in collaboration with the University of
Pavia, the University of Nottingham, and a number of cosmetic companies.

**E.** **STATISTICS ON ANIMAL EXPERIMENTS**

The collection of data on the number of animals used for experimental or other scientific
purposes pursuant to Articles 13 and 26 of Directive 86/609/EEC is not planned on an
annual basis.

This partly explains the difficulties encountered in collecting annual data specifically
concerning cosmetic ingredients and products.

However, the Commission has on numerous occasions urged the Member States to obtain
the statistics required, as is recalled in relation to the activities of DG XXIV and DG XI.

(1) Eight Member States have declared that animal tests for finished cosmetic products
have not been carried out on their territory (Italy, Greece, Belgium, Ireland,
Sweden, Finland, Luxembourg, Germany).

(2) Six Member States have declared that animal tests for cosmetic ingredients have
not been carried out on their territory (Greece, Netherlands, Ireland, Sweden,
Finland, Luxembourg).

(3) Only three Member States (Austria, France, United Kingdom) have communicated
figures relating to the number of animals used, while pointing out however that
these figures cannot be interpreted and that uncertainties remain as to their
correspondence to reality. Under these circumstances this report cannot present
comparative tables consisting of numerical data because such a table would give a
false view of reality.

(4) As regards the declarations that tests have not been carried out, it should also be
noted that certain Member States that do not produce ingredients may of course use
ingredients tested in other Member States or in third countries and that certain
ingredients used for cosmetic products may have been tested for other purposes.

17

The Commission strongly regrets that it does not have more precise data at this moment,
but it depends on the Member States for the collection of these data.

###### **F. CONCLUSIONS**

Progress during 1995 with regard to alternative test methods and their validation can be
summarised as follows:

1. The report on Phase II of the EU/COLIPA international validation study on in vitro
tests for **phototoxicity** (photoirritancy) will be made available in 1996, but it is
already clear that the validation of the NRU cell culture test has been very
successful. Those involved in the study are confident that an acceptable OECD
guideline can be drafted within the next two years, i.e. after the final report on the
study has been published and minor refinements to protocols have been made.

2. Experience in European industry on the critical issue of **percutaneous absorption**
has led to a concrete proposal for an OECD guideline for an in vitro test. ECVAM
and COLIPA are working with the OECD and others, to facilitate the adoption of
an in vitro test guideline by the OECD Member Countries.

3. The results of the EC/HO international validation study on alternatives for the
**Draize eye irritancy test** were disappointing, in that none of the tests met the
goals of the study. However, much of value was learned during this study, as a
result of which the quality of future validation studies will be markedly improved.

4. The first phase of the COLIPA evaluation **of alternatives to the Draize** eye test,
conducted on a more-limited range of materials than the EC/HO study, produced
more-promising results, and showed the value of incorporating prediction models
into test protocols.

5. As a result of a COLIPA study, recommendations have been drafted on criteria to
be adopted in defining in vitro test protocols for **photomutagenicity.**

6. As a result of another COLIPA initiative, guidelines on the **skin compatibility**
testing of cosmetic products and their ingredients in man have been developed.

7. The use of human volunteers as a replacement alternative deserves further scrutiny,
but it must be emphasised that such studies should only be conducted after results
from previous in vivo and/or in vitro studies permit avoidance of the risk of any
serious consequences.

8. Validation has turned out to be even more difficult, more time-consuming and
more costly than had been expected. Indeed, discussions are still going on about

18

what validation actually means and how the relevance and reliability of alternative
methods can best be established. ECVAM is at the heart of these discussions, and
particularly important contributions have been made in a number of ways.

9. The ECVAM prevalidation scheme, which is currently under international
evaluation, is likely to improve the success rate of validation studies, and to reduce
the time needed to conduct them, as well as their cost.

10. International discussions have taken place within Europe, and also with the USA
and Japan, on the harmonisation of criteria for the validation and acceptance of
replacement alternative test methods.

G. THE OUTLOOK

_**i**_
1. The emergence of more-realistic expectations of the validation process, and the
success of international discussions on criteria for the validation and acceptance of
replacement alternative methods can be expected to result in substantial progress in
the future.

2. After the conclusion of a further small study on chemicals of particular concern to
the SCC, it can be expected that a draft regulatory guideline for **in vitro**
**phototoxicity** testing will be produced and proposed for acceptance by the
regulatory authorities.

3. It is hoped that a new guideline on in vitro tests for **percutaneous absorption** will
shortly be accepted by the EU Member States and the OECD Member Countries.

4. An acceleration of progress toward the development of standardised and
appropriate in vitro methods for detecting **sensitisation potential** can be expected.

5. A reconsideration of what is expected of **eye irritancy tests** (in vivo and in vitro)
will be essential. Meanwhile, a more flexible approach to testing could be
encouraged, for example, by accepting the evaluation of the toxicities of new
products and ingredients by comparison with knowledge of appropriate benchmark
substances.

6. Greater use could be made of the fact that the **eye tolerance and skin tolerance of**
**finished cosmetic products** can be evaluated in vitro, provided one crucial
condition is met, viz. prior knowledge of the toxicity data pertaining to the
ingredients and their physico-chemical properties. In addition, the skin
**compatibility** of finished cospietic products can be evaluated in the context of
strictly controlled clinical studies.

19

7. A successful outcome can be expected for the ECVAM validation study on tests for
**skin corrosivity,** which could then be used, for example, to provide part of the
information considered essential before human volunteer studies can be considered
permissible.

8. There will be greater emphasis on the integrated use of various different
approaches (e.g. computer-based predictions, in vitro tests), and on hierarchical
testing strategies, to reduce, refine and replace the use of animals for testing

purposes.

The Sixth Amendment to Directive 76/768/EEC provides a unique opportunity for sensible
progress toward the replacement of animal testing in the field of cosmetics. Such progress
is being made, but its continuation will depend upon the maintenance of good relationships
and effective collaborations between all the parties involved, i.e. the Commission and its
advisory committees, the Member States, the cosmetics industry, and the regulatory
authorities.

**20**

###### **ISSN 0254-1475**

### **COM(96) 365 final**

# **DOCUMENTS**

##### **EN 10 15 05 03** **Catalogue number : CB-CO-96-366-EN-C** **ISBN 92-78-07193-5**

**Office for** **Officiai** **Publications of the European** **Communities**

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