45.2.1 Skin Irritation . . . . 871

Contents

45.1. Introduction . . . . 869

45.2 Cosmetics Directive . . . . 869

45.2.1 Skin Irritation . . . . 871

45.2.2 Skin Corrosivity . . . . 871

45.2.3 Eye Irritation . . . . 871

45.2.4 Skin Sensitization . . . . 871

45.2.5 Dermal Absorption, Percutaneous Penetration . . . . 871

45.2.6 Photoirritation . . . . 871

45.3 Detergent Regulations . . . . 871

45.4 Dangerous Substances Directive (DSD) . . . . 872

45.5 Dangerous Preparations Directive (DPD) . . . 872

45.6 Nickel . . . . 872

45.7 Chromate . . . . 872

References . . . . 872

45.1 Introduction

Europe has the most highly developed set of legisla- tion regarding contact dermatitis. Rather than cata- logue the varying aspects of legislation globally, we have limited the material to a relatively brief consid- eration of this European perspective, since we believe that it provides a good model. Legislation and regula- tions regarding chemical substances, preparations, detergents and cosmetics are mentioned, together with information on legislation relating to two very important allergens, nickel and chromate.

45.2 Cosmetics Directive

In Europe, cosmetic safety legislation is governed by the Cosmetics Directive (76/768/EEC) which is then incorporated into the national legislation of the EU member states. DG Enterprise (Unit F3) of the Euro- pean Commission is responsible for this Directive.

The full text is published in English on the website:

http://pharmacos.eudra.org/F3/cosmetic/pdf/vol_1en.

pdf.

Regular updates are published in all of the official EU languages: http://pharmacos.eudra.org/F3/cos metic/Consolidated_dir.htm.

Annex 1 of the Cosmetics Directive provides an il- lustrative list of cosmetic products.Annex 2 is a list of substances that are prohibited from use in cosmetic products available in Europe. Annex 3 tabulates sub- stances that may be used, but only under certain re- strictions (such as for application to hair only, not for oral hygiene). Annexes 6 and 7 are positive lists of preservatives and UV filters.

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Annex 2 – prohibited

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Annex 3

– restricted/conditions of use

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Annex 4

– coloring agents

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Annex 6 – preservatives

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Annex 7 – UV filters

In due course it is probable that there will be a posi- tive list of hair dyes (only those substances on the list may be used).

Relatively few ingredients are included in the var- ious annexes. However, the cosmetic industry uses several thousand substances for which there is no specific regulation. The so-called inventory of cos- metic ingredients is an indicative but not exhaustive listing of these substances. Again, the inventory is the responsibility of DG Enterprise, which publishes it (see http://pharmacos.eudra.org/F3/cosmetic/cosm_

inci_index.htm). Part 1 of the inventory lists general cosmetic ingredients; Part 2 lists fragrance ingre- dients. The inventory contains the INCI name (Inter- national Nomenclature for Cosmetic Ingredients) that must be used for ingredient labeling purposes in the European Union. The INCI system is based on the CTFA nomenclature used in the USA. The important

Legislation

Ian R. White, David Basketter 45

differences between the American (voluntary) sys- tem and that used in Europe (legal) are the use of Lat- in scientific names for biological extracts (rather than common names in the USA), color index num- bers (FD&C in the USA) and aqua (water in USA).

The prime reason for the differences was to ensure that language was “scientific” and acceptable to all nations, rather than being obviously English.

Ingredient listing was introduced in the sixth amendment of the cosmetic Directive, although a compromise was reached where fragrance composi- tions in cosmetics would be indicated simply by the word parfum. This “fragrance exception” was includ- ed because of the lobbying activities of the industry, but identification of 26 “established” fragrance aller- gens was introduced with the seventh amendment of the Directive. Since March 2005, identification has been required if one of the fragrance substances is present at levels >10 ppm for leave-on products and

>100 ppm for rinse off. This should ensure that the great majority of individuals with identified fra- grance allergies can adequately avoid exposure.

These levels were suggested by the European Parlia- ment as a pragmatic solution, as the “safe” levels for most of the fragrance substances are largely un- known.

Before a cosmetic ingredient is added to one of the annexes in the Cosmetics Directive, there is a re- quirement that a scientific evaluation of the sub- stance is provided by the independent advisory com- mittee of the European Commission. Until 1997 this was the Scientific Committee for Cosmetology (SCC). From 1997 until 2004 it was the Scientific Committee for Cosmetics and Non-Food Products (SCC NFP), and since 2004 the Scientific Committee for Consumer Products (SCCP). All of the opinions of the SCC NFP are available on the website of DG Sanco (Directorate General for Consumer Safety and Health Protection) http://europa.eu.int/comm/

health/ph_risk/committees/sccp/sccp_opinions_en.

htm, as are those of the SCCP http://europa.eu.int/

comm/health/ph_risk/committees/04_sccp/sccp_

opinions_en.htm.

A request for assessment is presented to the advi- sory committee via DG Enterprise. Requests are made because evaluation is required by the Directive, there is concern raised by a Member State or scientif- ic/clinical data suggests a problem that needs to be evaluated. The information evaluated by the SCCP is normally supplied in a complete dossier (containing the toxicological, chemical, epidemiological data:

published, “on file” and “gray” material) of a sub- stance provided by industry, but information may be submitted by others (which happened with methyldi- bromo glutaronitrile and hydroxyisohexyl 3-cyclo-

hexene carboxaldehyde, where the dermatological community provided the data).

DG Sanco is responsible for assessments of risk, whilst DG Enterprise is concerned with the manage- ment of risk (Fig. 1).

The above scientific advisory committees have produced Guidelines for the Safety Evaluation of Cosmetic Ingredients. These guidelines are regularly updated as science and technology progresses and are available from the website.

Although a cosmetic product must comply with all regulatory requirements, it is also a requirement that the safety of each cosmetic product (including that of the ingredients that have not been regulated) be independently assessed by an individual with ap- propriate expertise – the assessor. Every cosmetic product has an associated dossier containing techni- cal details of the ingredients and a safety (toxicologi- cal) assessment (Fig. 2).

45 assessment versus management ^Safety

Assessment Management

• DG SANCO – consumer • DG ENTERPRISE safety and health responsible for legal

protection regulation of

• Provides scientific advice cosmetics

• Scientific committees • Member states – SCCP

Fig. 1. Safety assessment versus management

Safety evaluation of cosmetic ingredients

Ingredients in annexes Ingredients in dossier

SCCP Safety assessor

DG Sanco

Manufacturer, importer,

DG Enterprise marketer

Risk management Risk management For Commission: Industrial measures for adaptations to consumer protection technical prograess

Fig. 2.Safety evaluation of cosmetic ingredients

The seventh amendment also introduced a time- line for the prohibition of animal experiments used to evaluate the safety of cosmetic ingredients that must comply with the requirements of the Directive.

There has been prohibition of testing of finished cos- metic products on animals since September 2004.

Additionally, with exceptions, there is to be a gradual prohibition of testing of ingredients on animals as al- ternative validated methods are adopted. There will also be a parallel prohibition of the sale of cosmetics when an ingredient has been tested on animals, with- in or outside of the EU, to meet the requirements of the Cosmetics Directive after March 2009. The ex- ceptions consist of repeat dose toxicity, toxicokinet- ics and reprotoxicity, which will be permitted until 2013. The timeline was introduced into the seventh amendment by a process of conciliation, and was po- litically driven.

There are several steps associated with the process of risk assessment:

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Hazard identification

– In vivo, in vitro tests, QSAR, epidemiology

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Dose-response assessment

– NOAEL (no observed adverse effect level)

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Exposure assessment

– Amount, frequency, specific groups

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Risk characterization – Margin of safety

As far as dermatological assessments are concerned, the following represents the status (2005) of the vali- dation of and the movement towards the reduction or replacement of animal (in vivo) testing methodol- ogies:

45.2.1 Skin Irritation

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Draize in vivo skin irritation test – OECD 404, EC B.4

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Several in vitro skin irritation tests under vali- dation

45.2.2 Skin Corrosivity

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Three validated alternatives:

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TER – Rat Skin Transcutaneous Electrical Re- sistance Test (draft OECD 430, EC B.40)

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EPISKIN and EpiDerm – reconstructed hu- man epidermal equivalent (draft OECD 431, EC B.40)

45.2.3 Eye Irritation

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No validated alternative to Draize in vivo test (OECD 405, EC B.5)

ECVAM – the European Centre for Validation of Alternative Methods (http://ecvam.jrc.it/

index.htm) – is currently evaluating

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Bovine Cornea Opacity-Permeability test

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Neutral organic chemicals

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Red Blood Cell; Neutral Red Uptake

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Surfactants

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Hen’s Egg Test – Chorioallantoic membrane

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Screening finished products

45.2.4 Skin Sensitization

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Magnusson Kligman Guinea Pig Maximiza- tion Test (OECD 406, EC B.6)

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Local Lymph Node Assay (OECD draft 429) – allows reduction of animal use and refine-

ment of data obtained

45.2.5 Dermal Absorption, Percutaneous Penetration

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In vivo (draft OECD Guideline 427)

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In vitro (draft OECD Guideline 428) – isolated human/pig skin

45.2.6 Photoirritation

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3T3 Neutral Red Uptake Phototoxicity Test (draft OECD 432, EC B.41)

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Expected that chemicals showing photoaller- gic properties may be positive

45.3 Detergent Regulations

The Detergents Regulations of the European Union came into force in October 2005: http://europa.

eu.int/eur-lex/pri/en/oj/dat/2004/l_104/l_104200404 08en00010035.pdf.

This regulation requires the listing of preserva-

tives in detergents, household and similar products

when present at any concentration in a finished

product, and the identification of the presence of any

of the fragrance allergens itemized in the Cosmetics Directive and present at >100 ppm (such products are treated as rinse-off cosmetics). The Regulations also require that formulation details are released if needed to investigate an adverse reaction.

45.4 Dangerous Substances Directive (DSD)

The legislation embodied in the DSD deals with all new chemical substances that are being produced in the European Union [1]. Sections consider skin sensi- tization and skin irritation. Test methods for the identification of skin sensitizers are clearly set out [2, 3], but the legislation also admits a wide range of chemical structure and human evidence in addition.

Where a substance is identified as a skin sensitiz- er, then it is classified and labeled as R43: May cause sensitization by skin contact. Similar strategies apply to the identification of skin irritants, where the clas- sification may be R38: Irritant, R34: Causes burns, or R35: Causes severe burns, depending on the severity of the observed effects. It is unfortunate that, to date, no such categorization of skin sensitizers has been adopted, despite clear proposals from a recent EU ex- pert group [4].

The outcome of classification under the DPD is re- flected in the manufacturer’s safety data sheet (MSDS) when that substance is supplied, for example to a consumer product manufacturer.

45.5 Dangerous Preparations Directive (DPD)

The legislation contained in the DPD represents, in effect, the consequences for a preparation if a sub- stance in that preparation is classified as irritating or sensitizing [5]. The key consequence is the labeling of the preparation with an appropriate warning, such as: May cause sensitisation by skin contact. However, all labeling is subject to largely administrative (not scientifically-based) threshold limits. Thus, for most sensitizing substances, labeling a preparation as car- rying a skin sensitization risk is only required when the concentration of the sensitizing substance in the preparation is 1%. The aim here is to protect health by limiting the induction of skin sensitization. To take account of the potential failure of this legisla- tion, such that individuals do become sensitized, ad- ditional labeling is shortly to come into force such that, for a concentration between the above labeling threshold and up to a factor of ten lower, the prepar-

ation must be labeled with the name of the sensitiz- ing substance and the words added: May cause an al- lergic reaction.

It might be considered unfortunate that even in the EU, where regulations regarding skin sensitizers and irritants are at their most developed, there is no harmonization between the legislation (for example, to protect those already sensitized, the name of the sensitizer, written in simple language, is clearly suffi- cient, without any additional wording). It is also most unfortunate that the relative potency of the allergen is not taken into account during labeling (except in rare cases, usually after a considerable clinical prob- lem has arisen).

45.6 Nickel

Nickel is still the most common contact allergen in the EU (and elsewhere). However, in the EU, this is set to change as a result of a relatively recent Directive [6], which arose from action originating in Denmark.

The directive limits the allowed release of nickel from metal objects in prolonged contact with the skin to 0.5 µg/cm

per week. The impact of this limit has already paid dividends in Denmark, where a sharp reduction in nickel allergy is now evident [7]. It seems likely that the same will happen elsewhere in Europe.

45.7 Chromate

The European Union has also regulated exposure to chromate in cement. Cement and cement-containing preparations may not be used or placed on the mar- ket if they contain, when hydrated, more than 0.0002% (2 ppm) of soluble chromium VI out of the total dry weight of the cement. The Member States of the European Union have been required to meet this limit since January 2005.

References

1. EU (1996) EU dangerous substances directive. 22nd adap- tation to technical progress (96/54/EC). Official J Eur Com- mun L248 : 199

2. EU (1996) EC Test Method B6. Commission Directive 96/54/EC of 30 July 1996, adapting to technical progress for the twenty-second time Council Directive 67/548/EEC on the approximation of the laws, regulations and administra- tive provisions relating to the classification, packaging and labelling of dangerous substances. Methods for the deter- mination of toxicity, B6. Acute toxicity skin sensitisation.

Official J Eur Commun L248 : 206–212

45

3. OECD (2002) Guidelines for testing of chemicals. Guideline no. 429. Skin sensitisation: the local lymph node assay. Or- ganisation for Economic Cooperation and Development, Paris

4. Basketter DA, Andersen KE, Lidén C, van Loveren H, Bo- man A, Kimber I, Alanko K, Berggren E (2005) Evaluation of the skin sensitising potency of chemicals using existing methods and considerations of relevance for elicitation.

Contact Dermatitis 50 : 39–43

5. EU (1998) EU Council Directive 88/379/EEC of 7 June 1988 on the approximation of the laws, regulations and admin- istrative provisions of the Member States relating to the classification, packaging and labelling of dangerous prep- arations. Official J Eur Commun L18 : 14

6. EU (1994) Nickel Directive: European Parliament and Council Directive 94/27/EC of 30 June 1994: amending for the 12th time Directive 76/769/EEC on the approximation

of the laws, regulations and administrative provisions of the Member States relating to restrictions on the marketing and use of certain dangerous substances and preparations.

Official J Eur Commun L188 : 1–2

7. Nielsen NH, Linneberg A, Menné T, Madsen F, Frolund L, Dirksen A, Jorgensen T (2002) Incidence of allergic contact sensitization in Danish adults between 1990 and 1998; the Copenhagen Allergy Study, Denmark. Br J Dermatol 147 : 487–492

8. EU (2003) Cement Directive: Directive 2003/53/EC of the

European Parliament and of the Council of 18 June 2003

amending for the 26th time Council Directive 76/769/EEC

relating to restrictions on the marketing and use of certain

dangerous substances and preparations (nonylphenol,

nonylphenol ethoxylate and cement). Official J Eur Com-

mun L 178 : 24–27