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REGULATIONS

Alternatives to Animal Experiments in the Cosmetic Sector

A cosmetic product put on the market within the European Union must not cause damage to consumers' health under normal, reasonable, or forseeable conditions of use (Art.2, Directive 76/768/EEC, amended by Directive 93/35/EEC).

Several mechanisms were triggered by this Directive in order to fulfill its main requirements regarding consumers' health protection, namely by banning the use of certain toxic cosmetic ingredients, or by restricting the use of certain ingredients which could be toxic to consumers when applied at a certain level, or by authorizing substances of particular functions.

As for other sectors of toxicity testing (pesticides, drugs, food additives, industrial chemicals, etc.), the relative test procedures are those reported in the Commission Directive 84/449/EEC and in the Annex to Commission Directive 92/69/EEC; OECD Guidelines for testing of chemicals are also suitable information for the safety evaluation of cosmetics (OECD, Vol.1 and 2, 1993).

The majority of these official and international test procedures is based on the use of animal models; thousands of studies have been performed during the last 30 years and their results have been discussed, interpreted, and applied for the identification and management of human risk, as a consequence of human exposure to those chemicals (Commission Regulation 1488/94). The Sixth Amendment to Cosmetic Directive 76/768/EEC has inserted the new recital:

"Assessment of the safety of use of the ingredients employed in cosmetics and of the finished product, should take into account the requirement of Directive 86/609/EEC which concerns protection of animals used for experimental and other scientific purposes."

Within the scope of the European Commission, Directive 86/609/EEC affirms a few general principles which must regulate the use of animals in toxicity experiments on chemicals. These principles, although at variance with those of previous regulations, have stimulated the layout of strategies of research and development of methodologies for the knowledge of the toxic effects of chemical substances, in agreement with alternative, scientifically valid principles.

Directive 86/609/EEC affirms that all experiments on animals are forbidden, unless they are carried out with the object of:

  • research aimed at preserving the species at issue, or
  • essential biomedical purposes, provided that the species employed in experiments represent the only specific ones for attaining the purpose.

This means, in principle, a restriction on animal experimentation in the very scope of toxicity studies and above all, in those cases where the predictive significance of studies of similar effects on humans, is rather scant.

The above mentioned rule firmly maintains (Art. 7.2) that "an experiment shall not be performed if another scientifically satisfactory method obtaining the result sought, not entialing the use of an animal, is reasonably and practically available."

As a consequence of this position, Council Directive 76/768/EEC was amended by Council Directive 93/35/EEC, by imposing a ban of testing on animals of ingredients or combinations of ingredients as from January 1st, 1998 (Council Directive 76/768/EEC amended, Art. 4(1) (i).

The Sixth Amendment states, however, that if there has been insufficient progress in developing satisfactory methods to replace animal testing, and in particular in these cases where alternative methods of testing, despite all reasonable endeavors, have not been scientifically validated as offering an equivalent level of protection for the consumer, taking into account OECD toxicity testing guidelines, the Commission shall 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. Before submitting such measures, the Commission shall consult the Scientific Committee on Cosmetology.

Clearly, the legislator has intended to ban the testing on animals of cosmetic ingredients or finished products, in relation to the problem of the toxicity or safety evaluation of these specific chemicals, or their combinations, only provided that there are some alternative methodologies available.

Alternative Methodologies mean any modification to the present toxicity assay testing protocols which are intentionally and scientifically approved and based on animal model, in such a way as to introduce a different mode of conducting toxicological studies necessary to assess the safety of ingredients employed in the manufacture of finished cosmetic products.

Alternative Methodologies must offer a level of protection to consumers equaling that presently offered by toxicological studies performed on animals: this implies that the alternative methods must be scientifically validated.

The in vitro methodologies for evaluating the toxic potential of cosmetic ingredients which have been reported in the scientific literature, or, those which have been submitted to validation studies during the last 3 years have not yet been demonstrated to be useful in the prediction of toxic risk to humans. The precision of prediction is so low that practical utility of such prediction is questionable (M. Balls et. al., Toxicology In Vitro, 9, 871-929, 1995).

The in vivo studies allow the possibility to investigate the toxicological profile of a cosmetic ingredient when applied to an animal by a route of exposure similar to that of human exposure. They provide for the determination of the non observed adverse effect level (NOAEL) and also the adverse effects of higher exposure.

The following presentation is an indication of the state-of-art of development and validation of alternative methodologies to the use of animals in the safety evaluation of cosmetic ingredients and finished products according to the position of the DGXXIV-EC, under the advice of its consulting Scientific Committee on Cosmetology.

1. FINISHED PRODUCTS

The SCC confirms the view that evaluation of the safety of finished products can in general be based on the knowledge of the ingredients' toxicity, provided that supplementary information is available in certain cases:

  • when the vehicle used in the formulation is different to solvents used in the toxicity tests and when there is a likelihood of an increase on skin penetration or skin irritation;
  • when a new, potentially toxic substance is liable to be created through the combination of ingredients present in the finished product.

The in-house experience acquired by the major cosmetics firms is particularly interesting in the domain of in vitro tests on finished products.

It shows that tests on finished products can generally be restricted to in vitro tests thanks to prior knowledge of the toxicity data on the ingredients: However, no in vitro alternative tests has yet been successful in the validation study.

2. PERCUTANEOUS ABSORPTION

The experience gained by the European cosmetic industry in the critical domain of in vitro percutaneous absorption took concrete shape with the presentation in May 1996 of a draft OECD guideline describing the fundamental principles to be considered and the criteria to be followed in defining the test protocols.

In support of this guideline, Colipa submitted to the OECD, to ECVAM and to the SCC a dossier comprising the "in-house" data and articles published in the literature. The USA and the EU are at odds about the in vitro approach within the OECD's group of national coordinators.

At the 7th meeting, held in Paris on the 18th and 19th of September, 1996, the group of national coordinators decided:

  • to devote a forthcoming workshop to the study of exisiting in vitro percutaneous absorption data;
  • 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);
  • to develop a dual guideline on in vivo and in vitro tests, in the event or rapid development of the in vitro dossier.

Although the SCC has emphasized that the test protocols used by the industry were not subjected to a formal validation test and although it recommended that the existing documentation be supplemented, notably as regards intra- and inter-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. PHOTOTOXICITY/PHOTOIRRITATION

In the first phase (prevalidation) of the EU/COLIPA study of in vitro photoirritation, analysis of the results obtained with a cell viability test (323 NRU) made it possible to determine a photoirritation factor to distinguish a photoirritant from non-photoirritant substances.

The results of the complete statistical analysis dated 15 April 1996 (pertaining to the second experimental (validation) phase) indicate that the NRU test can correctly predict irritant potential in man for most of the substances tested.

Following the SCC recommendation, which emphasized the importance of verifying the applicability of the NRU test in evaluating the safety of UV filters in Annex VII and to prepare an optomized protocol with a view to submitting a draft guideline on in vitro photoirritation to the OECD. The first results of this third phase should be available by September 1997.

The OECD group of national coordinators decided not to develop the in vivo method on its schedule before the end of 1997. If the in vitro method has not been completed by that date, the OECD will try to develop the in vivo method.

4. EYE IRRITATION

The international EC/HO validation study of alternatives to the Draize eye irritancy test did not achieve the expected objectives but it triggered the organization of an ECVAM workshop on the practical aspects of validation and the preparation of a prevalidation schedule, as well as the planning of the Colipa study.

Limited results were obtained for a small number of protocols in Colipa's international validation phase of alternatives to the Draize test, where prediction models had been prepared for each test.

Colipa has organized discussions on the second experimental validation phase. Since the analysis of the results of the first phase revealed the variability of the in vivo data, Colipa envisages using specific test materials, authorizing a more mechanistic approach.

Currently there are no validated alternative methods capable of replacing the OECD 404 in vivo eye irritancy test and Colipa does not expect significant progress to emerge from the second validation phase before 2000.

However, one might consider encouraging a flexible approach by attempting to evaluate the potential of certain categories of ingredients acting via common mechanisms by comparison with the data available for appropriate control substances.

5. SKIN IRRITATION

There are to date no validated alternative methods capable of replacing the OECD 404 in vivo skin irritation test.

A draft test strategy for determining the skin irritation potential of chemical substances is on the programme of the OECD group of national coordinators.

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.

6. ACUTE TOXICITY

In its draft revision of Annex I to the guidelines for evaluating the safety of cosmetic products, the SCC spells out that acute toxicity data only have to be provided when they are already available (for example, as a result of compliance with the provisions of the seventh amendment to Directive 67/5481EEC on the notification, classification, and labelling of dangerous substances).

Two in vivo acute toxicity methods recently adopted by the OECD (fixed dose method, acute toxic class method) contribute to reducing the number of animals tested and the suffering they incur by comparison with the classical Method (OECD 401).

The OECD group of national coordinators proposes including in the text of Guideline 401 a declaration addressed to the animal welfare associations to the effect that this method is not recommended and should not be used except when warranted.

7. SKIN SENSITIZATION

Determining skin sensitization potential, as reflected in contact allergies, is important for evaluating the safety of cosmetic ingredients. Bearing in mind the process's complexity and the fact that predicting sensitizing potential task because of the variability of individual response, definitive results in this domain can only be expected in the medium term, if not indeed the long term.

A proposal for developing an in vitro test for the detection of sensitizing chemical substances was launched in 1991 (DGXII).

Since then, significant research work has been undertaken to define the mechanistic bases of skin sensitization. The report of a workshop organized by ECVAM in April 1995 is currently is the press.

8. SUBCHRONIC TOXICITY

The SCC considers that the use of animal experiments to study one or more potential toxicological effects (for example, subchronic toxicity, remains a scientific necessity).

The SCC stresses that it is aware that toxicity data may be available for new ingredients that are subject to the chemical substances notification procedures.

In the case of the development of ingredients evaluated by the SCC which have specific biological properties, the manufacturer's liability is not confined with compliance with the provisions governing the notification of chemical substances. Evaluation of the systemic risk is a key element in evaluating the safety of new ingredients for human use, even if the fact that they are produced in quantities exempts them from complete notification.

9. MUTAGENICITY/GENOTOXICITY

Among the six revised short-term tests + one new test, which were adopted on 19 September 1996 by the OECD group of national coordinators, the combination of three in vitro tests:

  • reverse mutation assay on bacteria (OECD 471/472)
  • chromosome aberration test on in vitro mammal cells (OECD 473)
  • gene mutation test on in vitro mammal cells (OECD 416)

provides evidence of mutagenic and/or genotoxic potential, is applicable and is already being applied in the evaluation of the safety of cosmetic ingredients.

Use of in vivo tests in limited to confirmation of a mutagenic activity observed in vitro.

10. PHOTOMUTAGENICITY

In 1990 the SCC adopted recommendations to test the photomutagenicity of UV radiation absorbing substances.

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

Moreover, Colipa has organized a round robin of analysts whose results have allowed to develop the criteria to be complied with to define photomutagenicity protocols. The SCC has recommended that the test protocols used by Colipa be the subject of a validation study.

This recommendation has not been taken up until now because of the difficulty of planning a validation study in the absence of in vivo reference data.

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