COMMISSION OF THE EUROPEAN COMMUNITIES 
Brussels, 05.05.1997 
COM(97) 182 final 
1996 COMMISSION REPORT 
ON THE DEVELOPMENT, VALIDATION AND LEGAL 
ACCEPTANCE OF ALTERNATIVE METHODS TO ANIMAL 
EXPERIMENTS IN THE FIELD OF COSMETICS. 

TABLE OF CONTENTS 
SUMMARY 4 
PARTI 8 
1996 COMMISSION REPORT 
A. INTRODUCTION AND BACKGROUND 8 
B. OBJECTIVES AND CONSTRAINTS 9 
1. Consumer safety 9 
2. The reduction and elimination of animal suffering 10 
3. International aspects and the GATT/TBT rules 12 
4. The interests of the SMEs 14 
C. EXISTING AND EXPECTED RESULTS 14 
1. Tests on ingredients and combinations of ingredients 14 
2. Finished cosmetic products 16 
D. CONCLUSIONS DRAWN BY THE COMMISSION FROM THESE 
OBJECTIVES, CONSTRAINTS AND RESULTS IN ITS DRAFT DIRECTIVE 
PARTIALLY POSTPONING THE DEADLINE OF 1 JANUARY 1998 AND IN 
ITS REFLECTIONS ON THE PRESENTATION OF A PROPOSAL FOR A 
EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE AMENDING ARTICLE 
4(1)(l) OF THE BASIC DIRECTIVE 17 
E. CONCLUSIONS AND OUTLOOK 18 
A 
PART 2 21 
SCIENTIFIC ASPECTS 
A. INITIATIVES TAKEN IN 1996 21 
1. ECVAM 21 
2. Scientific Committee on Cosmetology (managed by DG XXIV) 22 
3. DG XII 22 
4. COLIPA 23 
5. OECD... 24 
B. STATISTICS ON ANIMAL EXPERIMENTS 25 
C. STATE OF PROGRESS IN 1996 IN EACH INDIVIDUAL AREA 26 
1. Photoirritation/phototoxicity 26 
2. Percutaneous absorption 27 
3. Eye irritation 30 
4. Skin irritation 30 
5. Skin sensitisation 31 
6. Skin compatibility of the finished product 32 
Summary 
INTRODUCTION AND BACKGROUND 
This 1996 report is the third report to be presented by the Commission. It reviews 
the situation at October 1996, i.e. just before the date by which the Commission 
had to present draft measures postponing the date for the ban on animal testing in 
cases where alternative methods of testing have not been scientifically validated 
as offering an equivalent level of protection for the consumer, taking into account 
OECD guidelines. It belongs in the context of the sixth amendment to the basic 
Cosmetic Products Directive adopted by the Council on 14 June 1993 (Directive 
93/35/EEC), which provides for the banning of cosmetic products which contain 
ingredients or combinations of ingredients tested on animals as of 1 January 1998 
unless alternative methods are not available by this date, in which case the 
Commission must present draft measures to postpone the ban. The sixth 
amendment also provides that the Commission shall present annual progress 
reports to the EP and Council. 
The 1996 report consists of two parts. The first, more general part: 
- describes the objectives and constraints which have to be addressed. 
- summarises the existing and expected results, 
- specifies the conclusions drawn by the Commission from these objectives, 
constraints and results in preparing its draft proposal for a Directive 
postponing the deadline of 1 January 1998. 
The second part of the report is more scientific. It explains: 
- the initiatives taken in 1996 by the various parties involved in the 
research, validation and legal acceptance of alternative methods. 
- the difficulties involved in obtaining statistics, 
- the state of progress in each individual domain. 
OBJECTIVES AND CONSTRAINTS 
There are two key objectives - namely ensuring the safety of cosmetic products 
for human health and the elimination/reduction of animal suffering. 
Cosmetic products, which include personal hygiene products, are used 
throughout a person's life. The Cosmetic Products Directive makes it 
incumbent on manufacturers to ensure that cosmetic products are safe for 
human health and, as of 1 January 1997, to keep a safety information 
dossier which will be accessible to the monitoring authorities. The 
Cosmetic Products Directive has also established a system of lists of 
substances that are banned, subject to restrictions, or authorised 
respectively. These lists are regularly adapted to technical progress, on the 
basis of an opinion delivered by the Scientific Committee on 
Cosmetology, which takes into account the results of tests. 
The banning of all new ingredients would not make tests superfluous 
because the safety of ingredients must be regularly reexamined in the light 
of scientific progress. Neither can one outlaw all innovation - a measure 
which would bankrupt numerous SMEs. 
- The reduction and elimination of animal suffering is an ethical imperative. 
Although animal tests in the field of cosmetic products account for a mere 
0.03% of all animal tests, they have been given priority. 
The report describes the work done in 1996 by the following parties: 
* the Commission and notably ECVAM, the European Centre for the 
Validation of Alternative Methods, a unit of the Joint Research 
Centre; DG XI "Environment, Nuclear Safety and Civil Protection, 
which manages Directive 86/609 on the protection of animals used 
for scientific and experimental purposes; DG XII "Science, 
Research and Development", in funding research programmes; 
DG XXIV "Consumer Policy", which manages the Cosmetic 
Products Directive and the Scientific Committee on Cosmetology. 
* the Scientific Committee on'Cosmetology; 
* COLIPA/the European Cosmetic, Toiletry and Perfumery 
Association; 
* the OECD. 
However, the report emphasises that the development, validation and acceptance 
of alternative methods is a process which has proven more complex and arduous 
than initially foreseen and that, as in all scientific research, it is impossible to 
guarantee a precise result by a given date. The report also stresses that the utmost 
prudence is called for as regards the use of human volunteers, who cannot serve 
as a substitute for animal experiments pure and simple. 
The constraints that have to be borne in mind are mainly: 
* compliance with the rules of international trade, notably those of the WTO 
(World Trade Organisation). The point is that any measure having the 
effect of banning products from third countries on the grounds that these 
products have been tested on animals poses problems of compatibility 
with the rules of international trade. It would appear necessary to 
investigate the subject in greater detail in the context of preparing an EP 
and Council Directive which the Commission intends to propose during 
the coming months, designed to amend the basic Cosmetic Products 
Directive so as to address, in a legally appropriate text, the ban on animal 
testing by regulating in particular the question of finished products. 
the interests of the employment-generating SMEs, which also must be 
taken into account. Measures must be taken to ensure that they are trained 
and informed. 
EXISTING AND EXPECTED RESULTS 
The results are summarised in the first part of the report and described in greater 
detail in the second part. 
A distinction must be made between (a) ingredients and combinations of 
ingredients and (b) finished cosmetic products. 
As regards tests on ingredients/ combinations of ingredients the report makes it 
clear that no alternative method offering an equivalent degree of protection is 
available to date, or likely to be available by 1 January 1998. 
Methods which do not involve animal trials will however become progressively 
available in the fields of percutaneous absorption and local risks to the eye and 
skin: photoirritation, eye irritation and skin irritation. 
However, as regards tests concerning the system risks - i.e. risks involving 
exposure of the organism as a whole as opposed to local risks - there is no hope 
that animal trials can be replaced on schedule. However, the number of animals 
used is being steadily reduced. 
In general it will be possible to evaluate the safety of the finished products after 
1 January 1998 without recourse to animal trials, thanks notably to existing 
knowledge on the safety of the ingredients, and by methods not involving the use 
of animals, even if these methods are not liable to be the subject of an OECD 
guideline, which deals exclusively with ingredients and combinations of 
ingredients. However, in certain cases there may be a risk of toxic effects, due for 
example to the interaction of the ingredients or to the fact that skin penetration of 
the ingredients is facilitated by the vehicle used. In such cases tests on animals 
would remain necessary. 
CONCLUSIONS DRAWN BY THE COMMISSION FROM THESE 
OBJECTIVES, CONSTRAINTS AND RESULTS 
The Commission's draft directive designed to postpone the deadline of 
1 January 1998 takes into account the objectives, constraints and results described 
in the report. 
The Commission notes that, while progress has been made in research into 
alternative test methods, notably in the fields of percutaneous absorption and local 
risks to the eyes and skin, the fact remains that no alternative method has yet been 
scientifically validated and accepted andthat the OECD has not yet adopted 
pertinent guidelines on toxicity tests in the field of alternative testing methods. 
The situation is unlikely to change before 1 January 1998. 
Hence the draft Directive proposes the postponement of the date mentioned in 
Article 4(1 )(i) of Directive 76/768/EEC, in compliance with the second sentence 
of that provision, until 30 June 2000, before which date it can be foreseen that no 
alternative testing method will have been adequately scientifically validated and 
accepted. 
It also provides that before 1 January 2000 the Commission shall present draft 
measures taking into account progress made by that date. 
The Commission also wishes to promote research into and the validation of 
alternative methods. 
As regards finished products, the Commission will take measures to promote the 
dissemination among SMEs of methods not involving the use of animals. 
The Commission has also initiated reflections and intends, in the coming months, 
to present a proposal for a European Parliament and Council Directive on the 
amendment of Article 4 (1) (i) to address, in a legally appropriate text, the ban on 
animal testing in respect of finished cosmetic products - barring exceptional cases 
- as of 1 January 1998, in order to comply with the requirements of Directive 
76/768. 
This proposal for a Directive should also regulate aspects relating to products 
from third countries and clarify certain concepts and references in the text that 
have given rise to questions. 
Since the Directive will be based on Article 100a, this Commission proposal 
requires the approval of the European Parliament and the Council. 
f 
PART! 
1996 Commission Report 
on the development, validation and legal acceptance of alternative methods to animal 
experiments in the field of cosmetics. 
A. INTRODUCTION AND BACKGROUND 
The Commission has already presented two annual reports on 1994 and 1995 data 
concerning progress in the development, validation and legal acceptance of 
alternative methods to animal experiments in the field of cosmetics. 
This 1996 report reviews the scientific situation at October 1996. 
This 1996 report belongs in the context of Directive 76/768/EEC on cosmetic 
products, whose new Article 4 (1) (i), introduced by Council Directive 93/35 of 
14 June 1993, provides that Member States shall ban the placing on the market of 
cosmetic products containing ingredients or combinations of ingredients tested on 
animals after 1 January 1998 in order to meet the requirements of this Directive. 
However, this Article specifies that "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 scientifically 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". 
This 1996 report comprises two parts. The first, more general part, describes the 
objectives and constraints that have to be addressed, the existing and expected 
results as regards ingredients and combinations of ingredients on the one hand 
and finished products on the other, and the conclusions drawn by the Commission 
from these objectives, constraints and results in preparing its draft proposal for a 
Directive to postpone the deadline of 1 January 1998. 
The second part of the report is more scientific. It describes: 
the initiatives taken in 1996 by the different parties involved in the 
development, validation and legal acceptance of alternative methods, 
specifying wherever possible the cost of these initiatives 
- the difficulties in obtaining statistics 
8 
the state of progress in each individual domain. 
B. OBJECTIVES AND CONSTRAINTS 
Two principal objectives must be pursued and wherever possible reconciled in the 
field of cosmetic products: (a) ensuring consumer safety and (b) reducing and, 
ideally, eliminating animal suffering. 
Moreover, various constraints must be borne in mind, the two primary ones being 
(a) the international arena and the need to comply with WTO rules and the rules 
of free competition, and (b) the interests of firms, notably employment-generating 
small and medium-sized enterprises. 
1. Consumer safety 
Consumer safety must remain paramount. Here it should be noted that the 
notion of "cosmetic products" encompasses not only so-called 
"decorative" products, such as lipstick or nail varnish, but also articles 
such as soap, shampoos, toothpaste which are used throughout a person's 
lifetime from early childhood on. It is essential that these products should 
not cause harmful, immediate and visible effects, such as irritation, or 
long-term, latent effects such as risks of carcinogenicity or teratogenicity, 
etc. 
To ensure that cosmetic products are safe for human health in all these 
respects, it is necessary to check not only the safety of the finished product 
but also - and primarily - that of the ingredients used in its manufacture. 
It is for the manufacturer to ensure the safety of the ingredients, in 
compliance with Article 2 of the Cosmetic Products Directive, according 
to which cosmetic products must not be liable to cause damage to human 
health when they are applied under normal conditions of use; 
manufacturers may also be held liable in the event of damages pursuant to 
Council Directive 85/374/EEC on liability for defective products. 
Pursuant to Council Directive 93/35/EEC of 14 June 1993 amending for 
the sixth time the basic Cosmetic Products Directive, the manufacturer 
must, as of 1 January 1995, keep certain information readily accessible to 
the competent authorities, including "assessment of the safety for human 
health of the finished product. To that end the manufacturer shall take into 
consideration the ' general toxicological profile of the ingredient, its 
chemical structure and its level of exposure." 
The Cosmetic Products Directive also includes a series of annexes 
featuring positive and negative lists of substances. The general principle is 
that substances may be used freely, unless they are prohibited (Annex II), 
or subject to certain limitations and conditions (Annex III). There are three 
exceptions to this general principle: the only colouring agents, 
preservatives and UV filters authorised are those featuring in positive lists 
(Annexes IV, VI and VII). 
A substance can only be included in these lists, which are adapted to 
technical progress each year by a Commission Directive, if it has been the 
subject of an opinion delivered by the Scientific Committee on 
Cosmetology concerning its toxicity for human health. This SCC opinion 
is prepared on the basis of all the existing scientific data and notably the 
test results furnished by industry, which may concern sensitisation, 
mutagenicity, eye irritation, skin irritation, photoirritation, 
carcinogenicity, teratogenicity, and acute, subchronic and chronic toxicity, 
etc. 
While some 7 000 substances are already used in cosmetic products and 
while for many cosmetic substances new tests are not generally required. 
it should however be stressed that such tests may sometimes be crucial in 
reevaluating, on the basis of technical progress and new scientific 
knowledge, certain substances which have been in use for a very long 
time. Hence each year the SCC examines a series of banned substances 
(numbering approximately 400) and substances subject to certain 
limitations and requirements (numbering approximately 50). 
It must also be possible to examine the risks associated with the use of 
these products in combination. Thus on safety grounds it is not possible to 
dispense entirely with animal trials, even in respect of substances already 
in use. Moreover, in the cosmetic products sector - as in all other 
industrial sectors - it would be neither wise nor reasonable to bring 
innovation to a standstill. Even if consumers were to foresake their quite 
legitimate hope of obtaining ever better products, a blanket ban on 
innovation by outlawing the use of new substances would certainly spell 
ruin for numerous European cosmetic product manufacturers, mainly 
employment-generating SMEs. 
The reduction and elimination of animal suffering 
Reduction and, where possible, elimination of animal suffering is an 
objective that deserves the closest attention and in respect of which 
resources should be mobilised at all levels. 
This objective reflects ethical imperatives concerning respect for life, 
deep-seated public aspirations, and the wishes of the European Parliament. 
It finds expression in several European instruments, including Directive 
86/609/EEC on the protection of animals used for experimental and other 
scientific purposes and Directive 93/35/EEC (the sixth amendment to the 
initial Cosmetic Products Directive). 
While consumer safety must be assured, we must also do our utmost to 
ensure that animal tests are replaced by alternative tests as soon as 
possible, provided these afford an equivalent level of protection. Although 
animal trials in the cosmetics field account for a mere 0.03% of all animal 
tests and although all chemical substances already have to be tested in 
10 
order to provide the toxicity data required under Directive 92/32/EEC, 
cosmetic products have been prioritised and there has been a major drive 
in recent years, notably since the adoption of Directive 93/35/EEC, to 
promote the development of alternative methods. These endeavours, as 
well as progress to date and the outlook for the future, are described in the 
1994 and 1995 annual reports on the development, validation and legal 
acceptance of alternative methods to animal experiments in the field of 
cosmetic products, already presented by the Commission to the EP and the 
Council. 
Notably, these reports describe the work done by a number of players. Part 
II reviews the activities of these players in 1996. 
In particular, these players are: 
ECVAM (the European Centre for the Validation of Alternative Methods), 
a unit of the Ispra Joint Research Centre, which coordinates the validation 
of alternative methods at Community level, provides a forum for pooling 
information and works on the development, updating and management of 
a database and promotes dialogue between all interested parties. 
In 1996 ECVAM continued to organise workshops of direct relevance to 
evaluating the safety of cosmetic products (based on e.g. data concerning 
alternative methods); it published in ATLA recommendations methods for 
assessing percutaneous absorption and for skin sensitisation testing, and 
recommendations on the application of biostatistical methods to the 
development and validation of alternative toxicological methods; it 
subsidised and coordinated a study for testing UV filters listed in Annex 
VII to the Cosmetic Products Directive (photoirritation); it conducted a 
formal validation study on four tests of skin corrosion, and maintained 
regular contacts with the OECD and began a number of prevalidation 
studies relevant to the cosmetics industry. 
The Commission (DG XI "Environment, Nuclear Safety and Civil 
Protection") which manages Directive 86/609/EEC on the protection of 
animals used for experimental or other scientific purposes, has continued 
to follow the matter. The Commission (DG XII "Science, Research and 
Development") has also subsidised research programmes including the 
development of alternative methods. 
In the context of its consumer policy, the Commission (DG XXIV) has 
funded research and participated in or organised meetings with all the 
partners involved and organised and followed up the meetings of the SCC. 
The Scientific Committee on Cosmetology - whose mandate is to deliver 
scientific opinions to the Commission on ingredients listed in the Annexes 
to the Cosmetic Products Directive and on the applicability of alternative 
methods validated in the process of evaluating the safety of cosmetic 
products, and on the proposal for a Directive which the Commission must 
il 
present concerning the postponement of the deadline for the ban on animal 
tests in cases in which alternative methods will not be available by 
1 January 1998 - met on numerous occasions in 1996 both in plenary and 
in its Alternative Methods Subcommittee, sometimes jointly with the 
European Industry. Besides the activities documented in Part II, the SCC 
adopted in 1996 a document titled "The use of alternatives to animal 
studies in the safety evaluation of cosmetic ingredients or combinations of 
ingredients". 
Finally, at OECD level, work has been done on percutaneous absorption 
(meeting of the national coordinators in Paris in September 1996). 
It is important to note that the development, validation and acceptance of 
alternative methods cannot be achieved overnight, despite all the effort 
that is being invested. 
Hence the validation phases - i.e. the complex process by which the 
pertinence, reliability and reproducibility of a test developed for routine 
application and legal acceptance is evaluated and monitored - have turned 
out to be more numerous and complex than initially foreseen, and new 
phases have had to be incorporated. 
Moreover, as in the case of all scientific research, it is well-nigh 
impossible to guarantee a precise result by a given date, and certain 
studies, which were thought to be on the verge of completion - such as the 
EU/HO study on alternatives to the Draize test - turned out to be 
disappointing as regards the predictability of the risk. 
As regards alternative tests on human volunteers, for example in the field 
of skin irritation, the utmost prudence is called for; such tests should only 
be countenanced in the proven absence of real risks. 
For all that, progress to date has already made it possible to substantially 
reduce the number of animals used and to mitigate their suffering. - for 
example the use of three basic in vitro mutagenicity tests will obviously 
lead to further improvements in the future. 
3. International aspects and the GATT/TBT rules 
It is important to note that any measure that leads to banning the 
importation of cosmetic products into the Community solely because these 
products or their ingredients have been tested on animals might prove 
incompatible, with the rules of international trade. The main restriction that 
public international law imposes on a state is to forbid - except in the 
event of a specific rule to the contrary - any exercise of its power on the 
territory of another state. 
12 
Firstly, the WTO outlaws quantitative restrictions on imports (Art XI§1). 
Moreover, Article III §4 proscribes all discriminatory measures between 
like products, i.e. in accordance with the accepted interpretation, products 
which do not present physical differences. Since the test method clearly 
has no physical effect on the product, a discrimination based on this 
criterion might be held to fall foul of Article III§4. 
Finally, such a measure would not be easy to justify in the context of the 
general exceptions featured in Article XX of the GATT (and more 
specifically subsection b), which authorises - within the terms of Article 
XX - measures "necessary to protect human, animal or plant life or 
health". In the absence of case law in this area, it is not possible to claim 
that protection of animal welfare could be covered by the exception. 
Secondly, as regards measures designed to verify compliance with the 
provisions of the Cosmetic Products Directive - viz. requirements in 
regard to the protection of human health - the provisions of the Agreement 
on Technical Barriers to Trade (TBT) and notably those of Article 6 must 
be borne in mind. Article 6 promotes the mutual recognition of conformity 
evaluation procedures: "Members shall ensure that, whenever possible, 
that results of conformity assessment procedures in other Members are 
accepted, even when these procedures differ from their own, provided they 
are satisfied that those procedures offer an assurance of conformity with 
applicable technical regulations or standards equivalent to their own 
procedures". 
Bearing these provisions in mind, the extraterritorial application of a 
Community measure banning animal'trials could be considered as contrary 
to the Community's international commitments. Moreover, Article 4(1 )(i) 
of this Directive specifies that the ban on animal testings may be 
postponed if there are no scientifically validated alternative methods 
which offer the consumer an equivalent degree of protection. Hence it 
would be difficult to deny the equivalence, from the viewpoint of human 
health protection, of animal tests with alternative test methods which are 
recognised as equivalent. 
It should be noted that the rationale behind the ban is not that animal tests 
do not permit correct assessment of compliance with the provisions of the 
Cosmetic Products Directive, but is based purely on ethical 
considerations. 
Thus any decision on the use of alternative methods could also be 
challenged if it were adopted on a unilateral basis. Moreover the TBT 
Agreement strongly encourages the members of the WTO to adopt the 
pertinent international systems for assessment of the conformity of a 
technical regulation (Article 9). However, Article 9 also specifies that this 
applies only to the extent that these international systems are in 
compliance with the provisions of Articles 5 and 6 of the selfsame TBT 
Agreement (Article 9§3). 
Thus it is very important to remain at least within the framework of the 
Organisation for Economic Cooperation and Development (OECD), to 
which moreover Directive 93/35 refers. 
Part II of this report explains the role played by the OECD in regard to 
alternative methods in the different domains of the safety of cosmetic 
products and highlights the close links which the Commission has also 
developed and maintains with the OECD in this specific field. 
The Commission is reflecting on to all matters relating to the rules of 
international trade in the context of preparing a proposal for a European 
Parliament and Council Directive designed to amend the basic Cosmetic 
Products Directive to address, in a legally appropriate text, the ban on 
animal testing, notably by regulating the question of finished cosmetic 
products. 
4. The interests of the SMEs 
Finally, apart from consumer safety and the ethical imperative to 
reduce/eliminate animal suffering, the reasonable interests of the 
cosmetics industry should also be taken into consideration, notably those 
of the employment-generating SMEs. The alternative methods to be 
developed should be accessible to SMEs, even if they do not have as many 
"in-house" toxicologists or the same amount of experience or field data, or 
the internal laboratories and financial resources available to the large 
firms. 
In this context, COLIPA will be launching a major drive to provide 
information and training, in collaboration with its large member firms. 
Moreover, it seems that specialised laboratories are springing up whose 
services the SMEs will be able to draw on for alternative trials, as and 
when such trials reach maturity. 
ECVAM could also be involved - possibly together with COLIPA (Scaat) 
- in training SMEs in the use of alternative methods for evaluating the 
safety of cosmetic products. 
C. EXISTING AND EXPECTED RESULTS 
1. Tests on ingredients and combinations of ingredients 
It should be noted that, as shown in Part II, no alternative method offering 
consumers an equivalent degree of protection has yet been scientifically 
validated and accepted by the regulatory authorities. The OECD has not 
yet adopted pertinent guidelines for toxicity tests in the field of alternative 
testing methods for ingredients and combinations of ingredients used in 
cosmetic products. 
14 
However progress has been made and it looks as though alternative 
methods will progressively become available in the various safety 
domains pertaining to percutaneous absorption and local risks to the eye 
and skin (photoirritation, eye irritation and skin irritation). 
However, these methods will not be validated and accepted by 1 January 
1998, despite the high expectations that were had, mainly in regard to 
percutaneous absorption and photoirritation. 
In regard to percutaneous absorption and local risks, the situation is as 
follows: 
Photoirritation 
Photoirritation mainly concerns UV filters. A special study to follow the 
EU/COLIPA validation study is scheduled for 1996. This is directed by 
Zebet, and subsidised and coordinated by ECVAM. The study should 
make it possible to test UV filters in Annex VII to the Cosmetic Products 
Directive and to prepare a protocol with a view to submitting a draft 
guideline to the OECD. The first results of this special study should be 
available by September 1997. 
Percutaneous absorption 
In May 1996, after discussions with the Commission, the industry 
presented the OECD with a draft new guideline on in vitro percutaneous 
absorption. "In-house" data were provided to support this dossier. A 
meeting of the OECD national coordinators' group was held in Paris in 
September 1996, but the rate of progress toward acceptance slow. 
The Scientific Committee on Cosmetology has emphasised that the test 
protocols used by industry had not yet been subjected to the formal 
validation study and that the documentation was incomplete. However, the 
SCC has in recent years agreed to use in vitro percutaneous absorption 
data in evaluating the safety of several cosmetic ingredients. 
Eye irritation 
The 1995 Report stressed that the results of the validation studies of 
alternative methods to the Draize eye irritancy test had been disappointing 
(EU/Home Office study and COLIPA study). 
ECVAM and COLIPA held a meeting in December 1996 to discuss the 
outcomes of the EC/HO and COLIPA studies and plan new initiatives. 
15 
Skin irritation 
ECVAM has conducted a formal validation study involving four skin 
corrosion tests, whose results are expected in 1997. 
The OECD is also planning a draft testing strategy to determine the skin 
irritation potential of chemical substances. 
The draft OECD strategy is to use a hierarchical approach by eliminating 
severe skin irritants through consideration of the structure activity 
relations (SAR's) and structure property relations (SPR's) and data 
obtained from in vitro corrosion tests, before considering the use of 
conventional in vivo tests on rabbits or the use of human volunteers. 
A summary of the situation regarding local risks shows that progress 
should proceed apace but that 1 January 1998 is too early for the 
replacement of animal trials. However, as regards reducing the number of 
animals and their suffering, it may be noted that in practice in vitro tests 
are already used as screening or guideline tests and that certain data have 
already been provided to the SCC. 
Skin sensitisation 
Research has led to a better understanding of the scientific bases of 
skin sensitisation. 
ECVAM is to take action in the light of the report of the ECVAM 
workshop on this topic. 
Mutagenicity 
The combination of three basic in vitro tests already makes it 
possible to demonstrate a mutagenic potential and this combination 
is already being applied in evaluating the safety of cosmetic 
ingredients. 
All tests on ingredients relating to systemic effects 
(Acute toxicity, subchronic toxicity, carcinogenicity, 
teratogenicity). Because they are linked to exposure of the 
organism as a whole, there is no hope that alternative 
methods to replace animal trials will be available in the 
foreseeable future. 
However, the refinement of the methods used has already 
made it possible to reduce the number of animals used and 
mitigate their suffering, and this trend is likely to continue. 
2. Finished cosmetic products 
16 
As regards finished cosmetic products, progress to date suggests that it 
will generally be possible to evaluate their safety on the basis of available 
knowledge on the toxicity of their ingredients and their physicochemical 
properties, using methods which do not involve the use of animals, even if 
these methods are not liable to be the subject of an OECD guideline which 
deals dealing only with ingredients and combinations of ingredients. 
Hence it will only be necessary to resort to animal testing in rare, 
exceptional cases, where there are grounds to fear that the toxic effects of 
the ingredients may be potentiated, notably when skin penetration of the 
ingredients is facilitated by the vehicle used or when such effects result 
from the interaction of the ingredients. The SCC has emphasised this fact 
in its Guidelines on the use of alternative methods to animal studies in the 
safety evaluation of cosmetic ingredients or combinations of ingredients of 
24 Mav 1996. 
Certain cosmetics firms already very often use methods which do not 
involve the use of animals to test their finished products. 
COLIPA (the European Cosmetic, Toiletry and Perfumery Association) 
has announced that it could progressively establish a voluntary ban on 
animal testing for finished cosmetic products - except in the exceptional 
cases referred to above - for the entire European cosmetics industry, and 
that it would be willing to organise technology transfer in this respect. 
COLIPA has also said that it could ensure the widest possible 
dissemination of findings in this area and promote training in European 
companies and laboratories; this training could be coordinated by the 
Commission's services. The Commission, in particular, will promote the 
dissemination of methods not involving animals among the SMEs. It 
could also endeavour to promote such measures at international level. 
D. CONCLUSIONS DRAWN BY THE COMMISSION FROM THESE OBJECTIVES, 
CONSTRAINTS AND RESULTS IN ITS DRAFT DIRECTIVE PARTIALLY POSTPONING 
THE DEADLINE OF 1 JANUARY 1998 AND IN ITS REFLECTIONS ON THE 
PRESENTATION OF A PROPOSAL FOR A EUROPEAN PARLIAMENT AND COUNCIL 
DIRECTIVE AMENDING ARTICLE 4(1)(I) OF THE BASIC DIRECTIVE 
1. The draft Directive prepared by the Commission takes account of the fact 
that, while progress has been made in research into alternative test methods, 
notably in the fields of percutaneous absorption and local risks to the eyes and 
skin, the fact remains that no alternative method has yet been scientifically 
validated and accepted. The OECD has not yet adopted pertinent guidelines for 
toxicity tests in the field of alternative testing methods. 
The situation is unlikely to change before 1 January 1998. 
17 
Hence the draft Directive proposes the postponement of the date mentioned in 
Article 4(1 )(i) of Directive 76/768/EEC, in compliance with the second sentence 
of that provision, for not less than two years. 
Currently it is difficult to predict precisely when certain alternative methods for 
testing certain ingredients or combination of ingredients will be scientifically 
validated. However as it is likely that alternative methods will progressively 
become available in the field of percutaneous absorption, photoirritation, eye 
irritation skin irritation and skin sensitivation, and whereas, besides, the 
Commission is mindful of the objective of Article 4(1 )(i), the draft Directive 
postpones the deadline to a date by which it can be foreseen no alternative method 
will have been adequately scientifically validated and accepted, viz. 30 June 2000. 
It also stipulates that before 1 January 2000 the Commission shall present draft 
measures taking into account progress made by that date. 
Finally, in the context described above, and also in compliance with the 
provisions of Article 130f(3) of the Treaty and Fourth Research Framework 
Programme, the Commission will take the necessary measures to promote 
research into and the validation of alternative methods to animal testing in the 
field of ingredients and combinations of ingredients in cosmetic product 
formulations. This could take the form of a recital in the draft proposal for a 
Directive. 
2. Presentation of a proposal for a European Parliament and Council 
Directive amending Article 4(1 )(i) of the basic Directive 
In the context described in point C.2. above relating to the existing and expected 
results for finished cosmetic products, the Commission has initiated reflections 
and intends, in the coming months, to present a proposal for a European 
Parliament and Council Directive amending Article 4 (1) (i) in order to address, in 
a legally appropriate text, the ban on animal testing in regard to finished cosmetic 
products - barring exceptional cases - as of 1.1.1998, in order to respect the 
obligations of Directive 76/768. 
This proposal for a Directive should also regulate, in a legally appropriate text, 
aspects concerning products from third countries, and clarify the concept of 
"finished products". 
Since the Directive will be based on Article 100a, this Commission proposal 
requires the approval of the Council and the European Parliament. 
E. CONCLUSIONS AND OUTLOOK 
1. This report reviews the situation in the immediate run-up to the date by 
which the Commission must present a draft measure postponing the 
deadline of 1 January 1998 in areas in which alternative methods for 
testing ingredients and combinations of ingredients will not be available 
by that date. 
2. Two objectives must be pursued: consumer safety, which the Commission 
insists must not be compromised in any way, and the 
elimination/reduction of animal suffering. 
* Banning all new ingredients would not remove the need for animal 
tests because the safety of ingredients has to be reexamined in the 
light of new scientific knowledge. Moreover, blocking all 
innovation could put firms out of business and in particular the 
employment-generating SMEs. It should be noted also that 
cosmetic products include personal hygiene products, products for 
babies (...) and not only so-called "decorative" products. 
* Priority should be given to eliminating animal suffering in the field 
of cosmetic products, even if tests in this domain account for a 
mere 0.03% of all tests. The Commission (ECVAM, DG XI, XII, 
XXIV), the Scientific Committee on Cosmetology, the OECD and 
Industry continued to work to this end in 1996. 
However the validation process has turned out to be more complex than foreseen. 
In the SCC's opinion the utmost prudence is called for as regards the use of 
human volunteers, who cannot simply serve as a stand-in for animal experiments. 
j. Two constraints must also be borne in mind: 
a) compliance with the rules of international trade, notably those of the 
WTO(World Trade Organisation). The point is that any measure having 
the effect of banning products from third countries on the grounds that 
these products have been tested on animals poses problems of 
compatibility with the rules of international trade. It would appear 
necessary to investigate the subject in greater detail in the context of 
preparing an EP and Council Directive which the Commission intends to 
propose during the coming months, designed to amend the basic Cosmetic 
Products Directive so as to address, in a legally appropriate text, the ban 
on animal testing by regulating in particular the question of finished 
products. 
b) the interests of the SMEs, which must be trained and informed. 
k As regards the existing and expected results, a distinction must be made 
between ingredients/ combinations of ingredients and finished products. 
a) As regards ingredients and combinations of ingredients, no 
alternative method will be ready by 1 January 1998. However, 
methods should progressively become available for percutaneous 
absorption, photoirritation, eye irritation skin irritation and skin 
sensitivation. 
19 
However, in the case of tests concerning system risks, i.e. exposure 
of the entire organism, there is no hope for alternative methods 
maturing in the foreseeable future. 
b) In general, it should be possible to ensure the safety of finished 
products, thanks mainly to our knowledge of the ingredients, 
without resorting to animal testing, after 1 January 1998. However, 
the SCC has emphasised the need for exemptions to this rule in the 
case of toxic effects caused, for example, by interactions of the 
ingredients. 
c) Progress has however already made it possible to reduce the 
number of animals used. 
5. The Commission has drawn conclusions from these objectives, constraints 
and expected results: 
- the Commission has prepared a draft Directive postponing the date 
of 1 January 1998 in regard to ingredients and combinations of 
ingredients. 
The Commission has also decided to pursue its deliberations on presenting 
a proposal for a European Parliament and Council Directive amending 
Article 4 (1) (i) of the basic Directive in order to address the ban on 
animal testing, notably by regulating the question of finished products. 
20 
PART 2 
SCIENTIFIC ASPECTS 
A. INITIATIVES TAKEN IN 1996 
1. ECVAM 
Of the workshops organised and/or published by ECVAM in 1995 and 
1996 on the development and validation of alternative tests, those of direct 
interest to the assessment of consumer safety are as follows: 
Workshop 13. Methods for Assessing Percutaneous 
Absorption 
Angera, Italy; 30 May-3 June 1994 
Howes et al. (1996) ATLA 24, 81-
106 
Workshop 16 Acute toxicity testing in vitro and 
the classification and labelling of 
chemicals 
Angera, Italy; 18-22 April 1994 
Seibert et al. (1996) ATLA 24, 499-
510 
Workshop 19 Alternative methods for skin 
sensitisation testing 
Angera, Italy; 24-28 April 1995 
de Silva et al. (1996) ATLA 24, 683-
705 
Workshop 24 The development and validation of 
expert systems for predicting toxicity 
Angera, Italy; 1-4 October 1996 
Dearden et al. (1997) ATLA 24, in 
press 
Workshop 25 Current Status and Future 
Development of Databases on 
Alternative Methods 
Neublberg, Germany; 12-15 
September 1996. Report in 
preparation. 
21 
ECVAM has also published in ATLA recommendations on the application 
of biostatistical methods in the development and validation of alternative 
toxicological methods (ATLA 24, 511-530, 1996). 
Of the other ECVAM Task Forces, those dealing with Prevalidation, Skin 
Irritation and Integrated Testing are also particularly relevant to the 
cosmetic testing issue. 
In addition to the ECVAM validation studies on skin corrosivitv and 
phototoxicity, prevalidation studies were begun on modified protocols for 
the bovine corneal capacity and permeability (BCOP) test and the 
fluorescein leakage (FL) test. 
2. Scientific Committee on Cosmetology (managed by DG XXIV) 
The Alternative Methods/Guidelines Subcommittee of the SCC organised 
three joint meetings with COLIPA/SCAAT (15 February 1996, 
19 March 1996, 24 April 1996), a meeting with the Director of ECVAM 
(6 March 1996) and a meeting designed to draw conclusions and adopt an 
opinion (6 May 1996), following consultations with DG XXIV. 
During these meetings the following points were addressed: 
a) Preparation of a discussion document on the "use of alternative 
methods to animal studies in the safety evaluation of cosmetic 
ingredients or combinations of ingredients. 
b) Examination of the final report on the EC/HO study on the 
validation of the Draize eye irritancy test. 
c) Examination of the statistical assessment data of phase 1 of the 
COLIPA study - validation of the eye irritancy test in the rabbit. 
d) Discussion with ECVAM's Unit head on the implementation of the 
provisions of Article 4 of Directive 93/35/EEC. involving a 
general review of the validation studies. 
e) Discussions with COLIPA/SCAAT on Industry's approach to the 
implementation of Directive 93/35/EEC, which is based on the 
experience of the cosmetic firms and the outlook for replacing 
animal tests. 
3. DG XII 
Since 1985 the Commission has been supporting research in the field of 
new in vitro alternatives to animal experiments in pharmaco-toxicology 
applicable to the cosmetic industry. 
The BIOTECH II programme launched after the BAP, BRIDGE and 
BIOTECH I programmes is also contributing to the development of these 
in-vitro alternatives applicable to cosmetic products. Following the second 
call for proposals, three projects are being funded with a total budget of 
ECU 3 825 000. 
The projects are: . 
* BIO4-CT96-0086: 
New immuno-pharmaco-toxicological model: human 
reconstructed epidermis containing Langerhans cells 
Coordinator: Dr. Rainer Schmidt 
L'OREAL S.A. 
Centre Charles Zviak 
9a, rue du Général Roguet 
F - 92383 Clichy Cedex 
* BIO4-CT96-0036: 
Development of in vitro systems using human 
immortalized cell lines for testing skin irritancy 
Coordinator: Professor Charles Lapière 
Laboratory of Experimental Dermatology 
Université de Liège 
Tour de Pathologie, B 23 
B - 4000 Liège 
* BIO4-C96-0246: 
Development for in vitro tests for drug allergenicity and B 
cell switching to IgE synthesis 
Coordinator: Dr. I. W. Coleman 
Department of Pharmacology & 
Therapeutics 
New Medical Building 
Ashton Street 
GB - Liverpool L69 3BX 
4. COLIPA 
COLIPA/SCAAT (the European Cosmetic, Toiletry and Perfumery 
Association/ Steering Committee on Alternatives to Animal Testing) 
Following the international two-day scientific symposium organised at the 
end of 1995, Scaat has continued its efforts towards getting validated 
alternative methods accepted and introduced into the regulatory 
framework. 
On EYE IRRITATION, the results of the COLIPA validation study 
became fully available and were submitted for review to ECVAM and to 
the SCC and DG XXIV. The relevant working party has drafted a first 
paper on the outcome of the study, which has been accepted for 
23 
publication in Toxicology In Vitro. Further statistical analysis of the data 
generated by the study is in progress. 
On SKIN IRRITATION, the specific working party is drafting guidelines 
on human testing of cosmetic ingredients, expected to be available early 
1997. This follows the issuing of guidelines on human testing of finished 
products, issued in 1995 and now published in Food and Chemical 
Toxicology. Both guidelines incorporate the need for strict ethical 
standards for such testing. 
On PERCUTANEOUS ABSORPTION, a working party has been 
collecting data generated by the cosmetic industry substantiating the 
validity of in vitro testing, as laid down in the COLIPA guidelines 
prepared in 1995. An extensive data package has been made available to 
ECVAM, to OECD, and to the SCC and DG XXIV. 
On PHOTOIRRITATION, a second phase of the EU/COLIPA validation 
study has been successfully completed and discussed with the SCC. The 
SCC has asked for a special study to verify the applicability of the in vitro 
method for UV-filters listed in Annex VII of the Cosmetics Directive. 
This special study will be sponsored by ECVAM and carried out over the 
next year. 
SCAAT has also created a working party "SKIN SENSITISATION". The 
main objective of this new group is to define and execute a research 
programme on mechanisms, which could pave the way to suitable in vitro 
test methods. 
5. OECD 
OECD Guidelines for the Testing of Chemicals and the Principles of 
Good Laboratory Practice (GLP) are developed in the broader context of 
the concept of mutual acceptance of data. Both of these instruments for 
ensuring harmonized data generation and data quality are an integral part 
of the 1981 OECD Council Decision on the Mutual Acceptance of Data 
(MAD). In accordance with this decision, OECD's 28 Member Countries 
agree that data generated in the testing of chemicals in any OECD 
Member Country, when in accordance with OECD Test Guidelines and 
Principles of GLP, shall be accepted in any other Member Country for the 
purpose of assessment and other uses relating to the protection of man and 
the environment. The practical consequence of this decision is that data 
developed in a Member Country under these conditions and submitted for 
fulfilling regulatory requirements in another Member Country, cannot and 
will not be refused. Consequently, OECD Test Guidelines are globally 
accepted as the standard methods for safety testing and as such enhance 
the validity and international acceptance of test data. Recognising the 
significance of OECD Test Guidelines, the European Commission 
strongly supports work on the development of new test guidelines and the 
updating of existing ones. 
24 
B. STATISTICS ON ANIMAL EXPERIMENTS 
On numerous occasions the Commission has urged the Member States, both 
orally and in writing, to provide the necessary statistics. 
1995: 
1. Eight Member States reported that finished cosmetic products had not 
been tested on animals on their territory (Italy, Greece, Belgium, Ireland, 
Sweden, Finland, Luxembourg, Germany). 
2. Six Member States reported that cosmetic ingredients had not been tested 
on animals on their territory (Greece, the Netherlands, Ireland. Sweden, 
Finland, Luxembourg). 
3. Only three Member States (Austria, France, the United Kingdom) 
communicated figures on the number of animals used, while emphasising 
that these figures were not interprétable and that there was uncertainty as 
to what they really signified. In these circumstances the 1995 Report could 
not present comparative tables comprising numerical data, because such a 
table would have given a false picture of reality. 
4. As regards the declarations on thé absence of tests, it is worth mentioning 
that certain Member States that do not manufacture ingredients will 
certainly be using ingredients tested in other Member States or in third 
countries and that certain ingredients used in cosmetic products may have 
been tested for other purposes. 
Following the final reminder from the Commission in October 1996: 
- Ireland and Finland confirmed that cosmetic products had not been tested 
on animals in their countries in 1996. Sweden did likewise for 1995 but 
reported that in November 1996 it did not have data relating to 1996. 
- Portugal reported that cosmetic products were not tested on animals in its 
country. 
- Germany confirmed that finished products were not tested on animals and 
that it had no data as regards ingredients testing. 
- Finally, in the Netherlands the Experiments on Animals Act, which 
entered into force on 5 February 1997, provides that animal experiments 
may not be carried out with a view to developing new cosmetics or to 
testing existing cosmetics which come within the remit of the 
Commodities Act. 
The Commission regrets that it does not have more statistics and is pursuing its 
efforts to obtain them. 
25 
C. STATE OF PROGRESS IN 1996 IN EACH INDIVIDUAL AREA 
1. Photoirritation/phototoxicity 
ECVAM/COLIPA 
The biométrie analysis (= statistical evaluation) of the data produced 
during the second validation phase has been completed for the 3T3 NRU 
PI1 cell viability test. 
The raw data were imported into an EXCEL file and checked for internal 
consistency. A new mathematical model was developed to analyse the 
complex dose-response relationships. 
The predictive value was evaluated by comparing the in vivo 
photoirritation classification of the materials tested with the classification 
based on the values and biological endpoint of the in vitro test. 
The variability of the in vitro classification was calculated on the basis of 
the rate of classification errors. 
The degree of association between the results of the tests conducted by the 
different laboratories was subjected to statistical analysis. 
The results of the biométrie analysis (dated 29° March 1996) indicate 
that the NRU assay is capable of correctly predicting the irritation 
potential in man in regard to most of the substances tested. It may be 
noted that: 
a. (In many cases) the PIF does not represent the exactly measured 
values but estimates which are below or above the critical value 
(>5<) established in phase I of the validation study. 
b. The prediction model proposed in the SOP (Standard Operation 
Procedure) of the 3T3 NRU test predicts well the in vivo 
phototoxicity of most of the substances tested. 
c. The variability of the PIF values grows with the increase in 
absolute PIF values. 
The number of independent tests in each laboratory was too small 
to authorise a valid estimate of intralaboratory variability data; 
NRU: Neutral red uptake assay", which uses the cells as target and cell toxicity as the outcome. 
26 
d. The effects of data variability on the in vitro classification are 
negligible, as the computer analysis of the classification errors 
demonstrates. 
The technical problems responsible for the incorrect classification of 
certain test materials have been identified and will be taken into account in 
evaluating the performance of the 3T3 NRU PI test in the final report. 
In particular, one should bear in mind: 
- possible in vivo classification errors 
errors in preparing the solution due to the total lack of information 
on the coded test substances 
- the deviations in regard to the SOP. 
SCC 
Following an SCC recommendation, which emphasised the importance 
of verifying the applicability of the NRU test in evaluating the safety of 
Annex VII UV filters and creating a database, a third experimental 
phase, directed by ZEBET, and subsidised and coordinated by ECVAM, is 
planned for 1996. The objectives of this study are to test the Annex VII 
UV filters and to prepare an optimised protocol with a view to submitting 
a draft guideline on in vitro photoirritation to the OECD. The first 
results of the third phase should be in by September 1997. 
OECD 
The OECD group of national coordinators has decided not to develop the 
in vivo method on its schedule before termination of the third in vitro 
validation phase at end 1997. If the in vitro method has not been 
completed by that date, the OECD will try to develop the in vivo method. 
2. Percutaneous absorption 
COLIPA 
In May 1996 a method proposed in the ECVAM workshop report, as 
discussed by the industry, ECVAM and OECD secretary, was presented to 
the OECD. 
This draft, which is currently being studied by the OECD group of 
national coordinators, explicates the general principles governing the 
design of protocols for skin penetration tests using the excised skin of 
different mammalian species post mortem. The skin is excised from the 
dead animals: 
[- "know-how" regarding the substance tested and choice of vehicle; 
27 
choice of the type of cell, receptor fluid, cutaneous membrane and 
control of membrane integrity; 
potential significance of the skin metabolism; 
- (finite or infinite) dose and duration of application; 
- temperature and humidity conditions; 
- sample collection and analysis; 
- presentation of the results and content of the final report.] 
To support this guideline COLIPA submitted to the OECD, ECVAM and 
the SCC a dossier consisting of "in-house" data and articles from the 
literature designed to demonstrate the predictive value, reliability and 
robustness of the in vitro approach. 
It may be summarised as follows: 
* Predictive value 
The in vitro tests are useful predictors of in vivo cutaneous 
absorption. 
[Bearing in mind the variability of in vivo data, there is good 
correlation between 
- in vitro (pig) and in vivo (rat) data for 10+8 hair dyes; 
- in vitro (rat) and in vivo (rat) data for 8 coded substances of 
different solubility; 
- in vivo (pig) and in vitro (man) data for 7 colouring agents; 
- in vitro (pig) and in vivo (man) data for 1 UV filter in 
ethanol solution. 
The skin of the pig's ear is a very good model of the human skin in in vitro 
cutaneous absorption tests of oestradiol.] 
It is possible to design prediction models of skin pharmacokinetics on the 
basis of in vitro tests. 
[The in vitro data in the rat can be used in combination with a skin 
pharmacokinetic mode. 
The model correctly predicts experimental in vivo measurements in man 
for an ester in suspension in a mixture of organic solvents and surfactants.] 
* Reliability 
"In-house" experience in this domain pertained to different 
categories of cosmetic ingredients, including UV filters, hair dyes, 
surfactants, mineral hydrocarbons, etc. 
* Robustness 
28, 
The dossier contains scanty information on the intra- and 
interlaboratory variability of the results and their statistical 
analysis. 
[The skin penetration coefficients (Kp) and their standard 
deviations give an idea of the degree of reproducibility of the 
results obtained in a series of in vitro tests conducted on benzyl 
alcohol. Good interlaboratory reproducibility is observed in one 
study conducted in two laboratories using the same in vitro 
protocol (rat) to measure the skin penetration of two UV filters.] 
* Influence of operating conditions 
There are some articles in the literature that provide patchy and 
unsystematic information on the influence of storage conditions, 
the type of cell used, and the batches of skin used. 
[- The use of the excised skin of fresh or deep-frozen pig does 
not influence the results for two UV filters (lipophiles) and 
lactic acid (a hydrophile); 
- the type of cell used (static or continuous flux) does not 
influence the cutaneous absorption of water-soluble 
substances through various types of membranes taken from 
different species (pig, rat, man) into different destination 
solutions; 
- the choice of the destination solution is crucial for 
substances which have low solubility in water; 
- batches of skin taken from three different animals (rats) do 
not influence the data on cutaneous absorption and 
distribution through the skin in respect of two UV filters 
tested using the same vehicle.] 
OECD 
The USA and the EU are at odds about the in vitro approach within the 
OECD's group of national coordinators. 
At its 7th meeting, held in Paris on 18 and 19 September 1996, the group 
of national coordinators decided: 
1. to devote a forthcoming workshop to the study of existing in 
vitro percutaneous absorption data; 
2. to base the decisions on a guideline document to be prepared in 
the coming year by the OECD Secretariat on the criteria for the 
validation and acceptance of alternative methods (on the basis 
of the Solna workshop report); 
3. to develop a dual guideline on in vivo and in vitro tests, in the 
event of rapid development of the in vitro dossier. 
SCC 
29 
Although the SCC has emphasised that the test protocols used by 
industry were not subjected to a formal validation test and although it 
recommended that the existing documentation be supplemented, notably 
as regards intra- and intra-laboratory reproducibility and the influence of 
the vehicle on the release of the cosmetic ingredients, the SCC is 
convinced of the relevance of the in vitro methods and has in recent 
years agreed to draw on in vitro percutaneous absorption data in the 
evaluation of the safety of several cosmetic ingredients for human use. 
3. Eye irritation 
ECVAM/COLIPA 
The international EC/HO validation study of alternatives to the 
Draize eye irritancy test did not achieve the expected objectives but it 
inspired the organisation of an ECVAM/ERGATT workshop on the 
practical aspects of validation and the preparation of a prevalidation 
schedule by ECVAM, as well as the planning of the COLIPA study. 
Limited results were obtained for a small number of protocols in 
COLIPA's first international validation phase of alternatives to the 
Draize test, where prediction models had been prepared for each test. 
Statistical evaluation of the results of the first validation phase indicate 
that the most promising protocols are FLtest2, TEA3 and RBCtest,4 which 
conform reasonably with their prediction models; however, for the first 
two more reproducibility data is required because in each case they have 
only been used by two large laboratories, while the utility of the FL and 
RBC tests has been challenged because the pertinence of their 
classification models is not universally supported. Moreover, no attempt 
has been made to evaluate the idea of a battery of two or more tests to 
replace in vivo assays. 
Currently there are no validated alternative methods capable of 
replacing the OECD-405 in vivo eye irritancy test. 
4. Skin irritation 
ECVAM 
Fluorescein leakage test, measures the damage caused to a cell barrier. 
Tissue Equivalent Assay, measures the time required to cause a 50% reduction in the viability of 
cells in reconstituted human skill. 
Red blood cell haemalysis test, used to evaluate damage to the cell membranes. 
50. 
Following a prevalidation exercise in 1995 on skin corrosion tests (TER, 
CORROSITEX and SKIN and EPISKIN), ECVAM undertook a formal 
validation study involving four skin corrosion tests and 60 test materials, 
whose results are expected in 1997. 
Considerable progress has been made in developing a database to predict 
irritation potential. However the in vitro tests currently being validated 
concern highly irritant substances and so this research - which is very 
useful for classifying and labelling dangerous substances - is only of 
limited use in evaluating the skin tolerance of cosmetic ingredients, which 
are a priori weakly- or non-irritant substances (at their concentration of 
use). 
There are to date no validated alternative methodologies capable of 
replacing the OECD 404 in vivo skin irritancy test. An ECVAM 
workshop on human skin equivalents and their uses is planned for 
1997. 
OECD 
A draft test strategy for determining the skin irritation potential of 
chemical substances is on the programme of the OECD group of 
national coordinators. 
The strategy proposed by the OECD envisages first eliminating the most 
irritant substances through examination of the structure activity relations 
and structure property relations, as well as by using information derived 
from in vitro corrosion tests, before considering recourse to conventional 
tests on rabbits, in vivo, or the use of human volunteers. 
5. Skin sensitisation 
Identifying skin irritation potential which manifests itself as contact 
allergy is important in evaluating the safety of cosmetic ingredients. 
The impressive research work done up to now has helped clarify our 
understanding of the mechanistic bases of skin sensitisation. It seems that 
predicting sensitisation potential is feasible only by combining 
information derived from several supplementary tests. 
ECVAM 
The report of ECVAM workshop 19 reviews the situation and contains 
recommendations for research aimed at replacing current animal tests, 
viz.: 
* refine the DEREK expert system identifying the 
structural alerts of skin sensitisation and develop 
supplementary systems based on the SARs 
(Structure Activity Relationships) 
31 
* standardise the tests "on cultures" of the most 
promising in vitro cells, and notably study the 
essential role of mediators derived from human 
dendritic cells and standardise the methods of 
isolating and cultivating these cells 
* develop other in vitro models, notably on skin 
expiants 
* develop an in vitro skin metabolism system 
* develop an adequate database on the basis of these 
tests, through a validation exercise using a suitable 
in vivo database. 
ECVAM hopes to support a prevalidation study on an in vitro test, in 
1997. 
Bearing in mind the complexity of the process and the fact that predicting 
sensitising potential is a difficult task because of the variability of 
individual response, definitive results in this domain can be expected 
only in the medium term, if not indeed the long term. 
6. Skin compatibility of the finished product 
The guidelines prepared by COLIPA in November 1995 on evaluating the 
skin compatibility oi finished cosmetic products in the framework of 
strictly controlled clinical studies, which were informed by ethical 
considerations and based on prior knowledge of the composition and 
stability of the tested products and prior evaluation of the toxicity data 
pertaining to the ingredients used in the product, have been published in 
Food and Chemical Toxicology [34 (1996) 651-660]. 


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DOCUMENTS 
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ISBN 92-78-19036-5 
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