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(BQ) Part 2 book Safety assessment of cosmetics in Europe presents the following contents: Safety assessment of cosmetic ingredients present in technical information files of finished products, the cosmetic technical information file in practice, the use of alternativemethods in the safety assessment of cosmetic ingredients, appendices,...
4 Safety Assessment of Cosmetic Ingredients Present in Technical Information Files of Finished Products Safety Assessment of Cosmetic Ingredients Present in Technical Information Files of Finished Products Rogiers V, Pauwels M (eds): Safety Assessment of Cosmetics in Europe Curr Probl Dermatol Basel, Karger, 2008, vol 36, pp 94–114 4.1 Introduction As explained in detail in section 1.2.7, two distinct channels are operative for the safety evaluation of cosmetic ingredients, namely the safety evaluation of cosmetic ingredients of direct relevance to Council Directive 76/768/EEC [EU, 1976a], currently taken care of by the SCCP, and the safety evaluation of all ingredients present in finished cosmetic products, carried out by a qualified safety assessor The most extensive list of data requirements imposed by the SCCP consists of: (1) acute toxicity (if available), (2) irritation and corrosivity, (3) skin sensitisation, (4) dermal/percutaneous absorption, (5) repeated dose toxicity, (6) mutagenicity/genotoxicity, (7) carcinogenicity, (8) reproductive toxicity, (9) toxicokinetics, (10) photo-induced toxicity, (11) human data Points 1–6 are generally considered the minimal base set requirements, whereas points 7–9 may become necessary when considerable oral intake is expected or when the data on dermal/percutaneous absorption indicate a considerable DA Photoinduced toxicity data (point 10) are specifically required when the cosmetic product is expected or intended to being used on sunlight-exposed skin [SCCP, 2006b] In the previous chapter, we have seen that the majority of SCC(NF)P submissions indeed contained points 1–6, but equally point (see 3.2.5.a) As opposed to cosmetic ingredients taken up in the Annexes of the Cosmetic Products Directive, there is no official framework providing clear guidelines for the safety assessment of ingredients used in finished cosmetic products The cosmetic legislation only states that the safety of a cosmetic product needs to be assessed ‘by taking into consideration the general toxicological profile of the ingredients, their chemical structure and their level of exposure’ [EU, 1993] Experience has learnt that the retrieval of sound and sufficient toxicological data on individual ingredients of cosmetic products often constitutes a major obstacle for safety assessors In many cases, they will turn to the respective raw material suppliers to obtain physicochemical specifications and minimal toxicological data packages on their ingredients Although the SCCP is not responsible for the safety assessment of ingredients not taken up in the Annexes to Dir 76/768/EEC [EU, 1976a], some general considerations are provided in the SCCP Notes of Guidance Inter alia, the Committee alleges that acute toxicity, skin and eye irritation, skin sensitisation and a basic set of mutagenicity data, form the minimal data package to enable a scientifically sound safety evaluation of a cosmetic ingredient The SCCP advises that suppliers should be encouraged to deliver at least these data to all their customers in the cosmetic industry, especially since some substances are socalled ‘actives’ and are not necessarily safe at all concentrations used [SCCP, 2006b] In a real-life situation, the aforementioned minimal toxicological data package can not always be obtained, e.g when a cosmetic company wants to develop a ‘new’ cosmetic product and needs certain ingredients from a raw material supplier The latter may be reluctant to disclose all information on these substances, in particular since in this early phase no commercial links yet exist Another example is the typical situation of SMEs, which may be put at a disadvantage because of reduced spending power towards suppliers Sometimes, only important clients receive all available toxicological information In cases where the requested data are difficult to obtain or are incomplete, it may be necessary to consult external sources of physicochemical and toxicological data that can be accessed independently from raw material suppliers Before such an extensive search is initiated, it is useful to know which data can be found on specific types of compounds Since Dir 76/768/EEC [EU, 1976a] does not impose specific data requirements for the majority of cosmetic ingredients that are no candidates for inclusion in one of the Annexes of the Cosmetic Products Directive, we have to refer to the complex web of EU regulations mentioned in chapter of this book Besides safety tests carried out (on a voluntary basis) for certain cosmetic ingredients, the availability of data will depend upon the requirements and data accessibility measures laid down in the other legislation(s) governing these substances A useful evaluation of expected data availability is given in section 1.3 Finally, it must be emphasised that the accessible parts of available toxicological data not necessarily consist of full study reports In general, summaries and study results are described, while the details and raw data of the studies remain property of the company involved The list of available sources is long and includes websites of official organisations, freely accessible databases and their commercial counterparts Out of our own experience, an overview of useful data sources is compiled in order to assist the cosmetic safety assessor in her/his comprehensive task 4.2 Database Search for Safety Information on Cosmetic Ingredients 4.2.1 General Considerations From a practical point of view, potentially relevant safety data for cosmetic ingredients usually are a combination of: 96 Rogiers и Pauwels – the standard toxicological data package available for chemical substances, typically consisting of LD50 values, irritation and sensitisation data, NOAEL values out of repeated dose toxicity studies, results of mutagenicity, carcinogenicity and/or reproductive toxicity studies, etc., – additional relevant data including official classifications and industrial threshold limit values, data on analogous substances, relevant data in the public literature, etc Besides official documents and websites at the EU and non EU level, free and commercial databases and websites all over the world have proven to be storehouses of information As the number of data sources containing safety data is very diverse, they need to be compiled in a structured overview in order to obtain, within a limited time frame, the key information that exists on a particular cosmetic ingredient In addition, a general and realistic overview of the usefulness of the available data sources and points of strength and weaknesses forms the basis of a good search, followed by a scientific evaluation of the quality of the obtained information Our own experience in safety assessment of cosmetics will be the guide through the quest for safety data in practice and the judgment of their quality and relevance Although the focus of this section clearly resides on the search for human toxicity data, the same channels as those mentioned hereunder may equally be explored to search for physicochemical and/or ecotoxicological data 4.2.2 Useful Data Sources a) Types of Data Sources Relevant information can be extracted from worldwide official instances’ websites, industry-governed websites and freely available and commercial databases As far as the latter are concerned, it is important to distinguish between bibliographical databases containing citations from extended lists of periodicals, journals, books, etc., and factual databases containing the actual data on a specific subject Most interesting for our purpose are factual databases comprising fields with physicochemical, toxicological and/or ecotoxicological data, by preference accompanied by plain references Companies such as the Scientific and Technical Network (STN®)1 and Thomson Dialog Datastar2 commercialise sets of bibliographical and factual databases by selling CD-ROMs and/or allowing registered users to consult the databases through the Internet http://www.stn-international.de/ (consulted July 2007) http://www.dialog.com/products/datastar/ (consulted July 2007) Safety Assessment of Cosmetic Ingredients Present in TIFs of Finished Products 97 b) Free Information Sources on the Internet GoogleTM3, Yahoo!®4 and MSN Search5 Coverage: the World Wide Web, generating lists of Internet links that match the entered keyword(s) Comment: • the number of hits gives a general idea on the amount of available data; • reliability of data cannot be guaranteed EUR-Lex6 Coverage: European treaties, legislation, case-law and legislative proposals7, including consolidated versions8 of EU Directives Comment: without the correct search items (literal wording in the legislative texts), it may be unexpectedly hard to retrieve existing information Directorate-General (DG) Enterprise, Cosmetic Section9 Coverage: existing and upcoming cosmetic-related legislation10, discussions on legislative aspects and many useful links Comment: the website has significantly improved over the past years and has become a key tool to follow up the EU cosmetic legislation Directorate-General Health and Consumer Protection (DG SANCO)11 Coverage: overview of EU laws on safety of food and other products, on consumers’ rights and on the protection of people’s health, including links to individual opinions of scientific committees such as the SCCP, previously called SCCNFP12, 13 Comment: an information source of major importance due to the presence of the SCC(NF)P opinions, the website’s practical search value is impaired by the fact that cosmetic ingredients are not necessarily designated by their INCI names European Chemicals Bureau (ECB)14 Coverage: wide range of information related to the EU risk assessment procedures of dangerous substances and preparations, with direct links to consolidated pieces of 10 11 12 13 14 98 http://www.google.be/ (consulted July 2007) http://www.yahoo.com/ (consulted July 2007) http://www.msn.com/ (consulted July 2007) http://europa.eu.int/eur-lex/ (consulted July 2007) http://europa.eu.int/eur-lex/lex/RECH_menu.do?ihmlang ϭ en (consulted July 2007) http://europa.eu.int/eur-lex/accessible/en/consleg/index1.html (consulted July 2007) http://ec.europa.eu/enterprise/cosmetics/index_en.htm (consulted July 2007) http://ec.europa.eu/enterprise/cosmetics/html/cosm_ongoing_init.htm (consulted July 2007) http://ec.europa.eu/dgs/health_consumer/index_en.htm (consulted July 2007) http://ec.europa.eu/health/ph_risk/committees/04_sccp/sccp_opinions_en.htm (consulted July 2007) http://ec.europa.eu/health/ph_risk/committees/sccp/sccp_opinions_en.htm (consulted July 2007) http://ecb.jrc.it/ (consulted July 2007) Rogiers и Pauwels legislation in the chemical field and to the most recent versions of the physicochemical, toxicological and ecotoxicological test protocols15 Comment: user-friendly website with broad coverage of existing and future developments in EU chemical legislation CIR (Cosmetic Ingredient Review) Conclusions – US CTFA16 Coverage: conclusions of safety reviews and assessments of cosmetic ingredients Comment: the relevance of the conclusions is high due to the cosmetic focus; however, they usually not provide the level of detail required for a full risk assessment US National Library of Medicine17 Coverage: medical library covering a large number of freely available databases18, such as: • PubMed19: a widely used bibliographic database including over 16 million citations from Medline and other life science journals for biomedical articles, • TOXNET20: collection of databases on human environmental health, covering: – ChemIDplus21: names, synonyms and structures of more than 370,000 chemicals, – HSDB22: comprehensive, peer-reviewed factual toxicological data for about 5,000 chemicals, together with their human exposure, industrial hygiene, environmental fate and regulatory requirements, – TOXLINE23: broad bibliographic database in the field of toxicology, – CCRIS24: compilation of carcinogenicity and mutagenicity test results for over 8,000 chemicals, – DART25: bibliographic database in the field of developmental and reproductive toxicology, – Multi-Database Search26: search engine allowing to explore the available NLM chemical databases Comment: due to its convenient mix of identification, factual and bibliographical databases, TOXNET shows to be an appropriate starting point for an extended toxicological data search 15 16 17 18 19 20 21 22 23 24 25 26 Annex V to Directive 67/548/EEC through http://ecb.jrc.it/testing-methods/ (consulted July 2007) http://www.cir-safety.org/ (consulted July 2007) http://www.nlm.nih.gov/ (consulted July 2007) http://www.nlm.nih.gov/databases/ (consulted July 2007) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db ϭ PubMed (consulted July 2007) http://toxnet.nlm.nih.gov/ (consulted July 2007) http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?CHEM (consulted July 2007) http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB (consulted July 2007) http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?TOXLINE (consulted July 2007) http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?CCRIS (consulted July 2007) http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?DARTETIC (consulted July 2007) http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?Multi (consulted July 2007) Safety Assessment of Cosmetic Ingredients Present in TIFs of Finished Products 99 US Environmental Protection Agency (US EPA)27 Coverage: • links to existing laws, regulations and dockets in the US28; • IRIS29, a database of human health effects resulting from exposure to various substances found in the environment; • HPVIS30, providing access to (eco)toxicological data on chemicals manufactured in exceptionally large amounts in the US; • documentation on individual aspects of the risk assessment procedure, such as exposure data31, information on human toxicity in general32, test methods and guidelines33 and much more Comment: • a reliable source for information related to chemicals on the US market; • some care is required while extrapolating classifications and regulations to the European situation, which often is quite different US National Toxicology Program (NTP)34 Coverage: reports on the evaluation of agents of public health concern, including development and application of modern toxicology and molecular biology Comment: • a reliable source of information, since the NTP has built up its own testing program and houses large experience in the overall field of risk assessment; • includes the possibility to follow up the actual testing status of substances International Programme on Chemical Safety (IPCS)35 Coverage: information on the scientific basis for the safe use of chemicals, offering access to reviews on the human health and environmental effects caused by chemicals36 Comment: especially the so-called Concise International Chemical Assessment Documents37 are worth to consult 27 28 29 30 31 32 33 34 35 36 37 http://www.epa.gov/ (consulted July 2007) http://www.epa.gov/epahome/lawregs.htm (consulted July 2007) http://www.epa.gov/iris/ (consulted July 2007) http://www.epa.gov/hpvis/index.html (consulted July 2007) http://www.epa.gov/ebtpages/humaexposure.html (consulted July 2007) http://www.epa.gov/ebtpages/humatoxicity.html (consulted July 2007) http://www.epa.gov/epahome/Standards.html (consulted July 2007) http://ntp-server.niehs.nih.gov/ (consulted July 2007) http://www.who.int/ipcs/en/ (consulted July 2007) http://www.who.int/ipcs/publications/cicad/en/index.html (consulted July 2007) http://www.who.int/ipcs/publications/cicad/en/index.html (consulted July 2007) 100 Rogiers и Pauwels Australian National Industrial Chemicals Notification and Assessment Scheme (NICNAS) – Chemical Assessment Reports38 Coverage: reports containing physicochemical, (eco)toxicological and exposure data, followed by recommendations for safe use Comment: the full reports can be downloaded and contain useful descriptions of and full references to useful (eco)toxicological studies European Centre for Ecotoxicology and Toxicology of Chemicals39 (ECETOC) Coverage: fundamental research, manufacturing, risk assessment, toxicological and ecotoxicological testing of chemicals, including reports on individual chemical substances Comment: ECETOC reports incorporate the know-how of a large number of leading chemical companies and represents reliable and useful information The International Fragrance Association (IFRA) Code and Standards40 Coverage: IFRA recommendations on more than 130 fragrance components, in some cases accompanied by toxicological information Comment: this data source has proven impact in the cosmetic world, but improvement is possible as some entries only consist of a short mention of the results of an unpublished study Human and Environmental Risk Assessment41 (HERA) Coverage: risk assessments of ingredients used in household cleaning products Comment: this source provides insight in a number of industry-governed data which are not available through other data sources, but the number of compounds studied is rather restricted International Agency for Research on Cancer (IARC)42 Coverage: monographs on the carcinogenicity of the compounds studied, with detailed information on research on causes of human cancer, mechanisms of carcinogenesis and development of scientific strategies for cancer control Comment: important information source but of limited impact for cosmetics as only few of the studied substances are present in cosmetic products 38 39 40 41 42 http://www.nicnas.gov.au/publications/car/New.asp (consulted July 2007) http://www.ecetoc.org/Content/Default.asp?PageID ϭ 32 (consulted July 2007) http://www.ifraorg.org/GuideLines.asp (consulted July 2007) http://www.heraproject.com/RiskAssessment.cfm (consulted July 2007) http://www.iarc.fr/ (consulted July 2007) Safety Assessment of Cosmetic Ingredients Present in TIFs of Finished Products 101 Occupational Safety and Health Administration (OSHA)43 Coverage: reports on occupational safety, with emphasis on the continuous improvement of safety and health in the workplace Comment: this database only offers secondary information as its emphasis resides on occupational safety c) Commercial Data Sources A Selection of Factual Databases SciFinder44 – Chemical Abstracts Service, USA Coverage: biochemistry, biotechnology, organic and inorganic chemistry, macromolecular and applied chemistry, physical and analytical chemistry, toxicology and environmental science Comment: useful database to locate information on a wide variety of chemistryrelated topics, offering a software package that makes searches easy to perform CIR (Cosmetic Ingredient Review) Full Reports – US CTFA45 Coverage: detailed safety reviews and assessments of cosmetic ingredients Comment: • full CIR reports have the significant advantage of containing company-sensitive information that can not be retrieved through any other public information channel; • CIR is supported by industry, but it consists of an independent expert panel CTFA International Cosmetic Legal and Regulatory Database – CTFA Coverage: • US health laws, including cosmetic-related regulations; • industry guidelines and other documents related to the personal care products industry; • CIR evaluations; • European INCI list Comment: useful database when investigating the global status of a cosmetic ingredient, though restricted to subscribing CTFA members only Note: CTFA has recently changed its name into Personal Care Products Council 43 http://www.osha.gov/ (consulted July 2007) 44 http://www.cas.org/SCIFINDER/ (consulted July 2007) 45 http://www.ctfa-international.org/ (consulted July 2007) 102 Rogiers и Pauwels RTECS (Registry of Toxic Effects of Chemical Substances) – US NIOSH Coverage: toxicological information such as irritation data, mutagenicity, carcinogenicity, reproduction toxicity, long-term toxicity, officially recommended human exposure limits, legislative restrictions, Comment: submitted data are included without peer review and should therefore be looked at critically Beilstein – Beilstein Chemical Data and Software, Germany Coverage: • organic chemistry, including chemical name, molecular and structural formula, preparation methods, physicochemical and biological properties, occurrence in nature, • the information provided is extracted out of critically reviewed documents from the Beilstein Handbook of Organic Chemistry and 176 journals Comment: good data source for organic molecules, large coverage Gmelin – Gmelin Institute of Inorganic Chemistry, Germany Coverage: similar to Beilstein, but for the inorganic and organometallic chemistry, including critically reviewed documents from the Gmelin Handbook of Inorganic and Organometallic Chemistry and 110 journals Comment: a negative point is that no update exists since 1997 MSDS-OHS (Material Safety Data Sheet – Occupational Health and Safety) – MDL Information Systems, USA Coverage: full texts of MSDSs, summary sheets and label data for more than 59,000 substances and/or mixtures Comment: MSDSs are no major data sources for toxicological information Chemlist – Chemical Abstracts Service, USA Coverage: national listings such as TSCA, DSL, NDSL, ECL, ENCS, EINECS, ELINCS and AICS Comment: the mentioned lists are useful for regulatory purposes, but not represent (eco)toxicological data sources A Selection of Bibliographical Databases Kosmet (Cosmetic and Perfume Science and Technology) – IFSCC, UK Coverage: cosmetic product development, knowledge on healthy skin, trading of cosmetics, raw materials research and development, manufacture, analysis, safety aspects, physicochemical and biological properties, stability and packaging Comment: very useful due to the cosmetic focus, though slightly impaired by the frequent occurrence of conference proceedings, which are hard to retrieve Safety Assessment of Cosmetic Ingredients Present in TIFs of Finished Products 103 4.8 Additional relevant toxicological data Type of test: Date of test: Performing laboratory: Short description: Result(s): Reference(s): 4.9 Available ecotoxicological data Type of test: Date of test: Performing laboratory: Short description: Result(s): Reference(s): First aid measures After ingestion: After skin contact: After eye contact: After inhalation: Reference(s): Risk and safety instructions 6.1 EU labelling according to Dir 67/548/EEC and amendments (Dangerous Substances) A EU-labelling of the raw material B Symbols and R-phrases C S-phrases 6.2 Specific labelling and/or restrictions according to Dir 76/768/EEC and amendments (Cosmetic Products) or national legislation(s) A Preconditions for use B Warnings C 200 Appendix Finished Product Dossier Fabrication of the product 1.1 Place(s) of manufacturing Name: Address: Telephone: Fax: 1.2 Manufacturing method 1.3 Person responsible for manufacture Name: Post held: Qualifications: Address: Telephone: Fax: E-Mail: Stability of the product 2.1 Physical stability 2.2 Microbiological stability Physicochemical properties and microbiological data on the product 3.1 Physicochemical properties Parameter Method A Frequency of inspection Expected result (or range) Archiving No./code … Storage of samples of the different batches: … Appendix 201 3.2 Microbiological examinations Parameter Method Frequency of inspection Expected result (or range) Archiving No./code … Storage of samples of the different batches: … Safety data concerning the finished product 4.1 Overview of the toxicological data of the ingredients INCI name Concentration (w/w) Function(s) Toxicological data Ingredient Ingredient Ingredient 4.2 Communication of the necessary data to the National competent authorities and/or poison control centres (according to National legislations) Member State Official Instance A Transmission date Reception date B … A B … … 202 … Appendix 4.3 Toxicological animal testing performed on the finished product Test Type of test Date of test Performing laboratory Contact address Results Reference(s) Test Type of test Date of test Performing laboratory Contact address Results Reference(s) … 4.4 … Toxicological tests using alternative methods Test Type of test Date of test Performing laboratory Contact address Results A Reference(s) Test Type of test Date of test Performing laboratory Contact address Results Reference(s) … Appendix … 203 4.5 Human tests performed on the finished product (patch tests, in-use tests, …) 4.6 Undesirable effects on human health reported during use of the product A Short description of the complaint system in place B Reported undesirable effects on human health Date Complaints (normal use) Follow-up … Date Complaints (improper use) Follow-up … 4.7 Safety assessor Name: Post held: Qualifications: Address: Telephone: E-Mail: Fax: The safety assessor writes a detailed report, taking into account all the relevant data concerning the ingredients (chemical, physicochemical and toxicological properties in Ingredients Dossier), the data or argumentation concerning the finished product (Finished Product Dossier, section 4.1–4.6), the envisaged exposure of the user to the product and the preconditions for use and warnings which must mandatorily be transferred to the labelling 204 Appendix Different types of conclusions are possible, such as: 1) The safety assessor can estimate that, given the present level of knowledge, the product does not show any foreseeable risk to human health under conditions of normal use 2) The safety assessor can define certain conditions and/or restrictions before granting his/her final consent (e.g modification of labelling, modification of conditions of use, restrictions on certain concentration levels, …) 3) The safety assessor can conclude that the use of the product could lead to incontestable negative consequences for the user (based on ingredient/finished product data, reports of side effects, …) Therefore the safety of the product cannot be ensured Signature Date Efficiency of the finished product 5.1 Claims made Claim 1: Claim 2: … 5.2 Executed efficacy tests Tests performed to substantiate claim 1: Test Type of test Results A Reference(s) Test Type of test Results Reference(s) … Appendix … 205 Tests performed to substantiate claim 2: Test Type of test Results Reference(s) Test Type of test Results Reference(s) … … … 5.3 Additional information or argumentation Packaging and labelling 6.1 Overview of data on ingredients concerning packaging and labelling 6.2 Labelling of the finished product A Mandatory obligations B Additional labelling 6.3 Packaging materials and weight/volume 6.4 Packaging procedure 6.5 Identification of the batch number 6.6 Check on the end product A Weight check Archiving No Aspect Weighing Frequency 1) 2) 3) … 206 Appendix B Other checks 6.7 Person responsible for packaging Name: Post held: Qualifications: Address: Telephone: E-Mail: A Appendix 207 Rogiers V, Pauwels M (eds): Safety Assessment of Cosmetics in Europe Curr Probl Dermatol Basel, Karger, 2008, vol 36, pp 208–209 Appendix 4: Data Input Forms: General Information A Appendix 209 Subject Index A-Cute Tox project 133 Acute toxicity, animal testing alternatives 131–134 Aerosol dispenser’s label directive, relevance for cosmetics 25 AGRICOLA, databases 105 Animal testing alternative analysis in SCCP dossiers acute toxicity background 131–133 oral toxicity 133, 134 eye irritation background 136, 137 data in opinions 137, 138 mutagenicity/genotoxicity background 146 data in opinions 146, 147 photo-induced toxicity background 147–149 data in opinions 149 repeated dose toxicity testing background 142, 143 data in opinions 143 reproductive toxicity background 144, 145 data in opinions 145, 146 skin irritation background 134, 135 data in opinions 135, 136 skin sensitization background 138–140 data in opinions 140–142 study design 131 summary 173–177 toxicokinetics 144 ban challenges 44, 45 210 Cosmetic Products Directive 6, numbers and time frame historical perspective 149–153 projection under REACH 153, 154 prospects 154–157 technical information file 123 Beilstein, chemical data and software 103 Benchmark dose (BMD), hazard identification 35 Biocidal Products Directive general provisions 17 relevance for cosmetics 17 Biosis, databases 105 Bovine corneal opacity and permeability test (BCOP) 137, 138 Buehler test 139 Chembank, databases 105 Chemical Abstracts, databases 104 Chemical Safety NewsBase (CSNB), databases 105 CMR substances, provisions 10 Cosmetic Ingredient Review (CIR) commercial data 102 Internet resources 99 Cosmetic Products Directive animal testing ban 6, Annexes cosmetic product definition milestones 1, public information prerequisite recasting proposals 9–11 safety assessment pathways 7–9 safety prerequisite and responsibilities 3, summary 167 technical information file prerequisite transposition into Belgian law 183–187 Cosmetic, Toiletry, and Fragrance Association (CTFA), commercial data 102, 103 Dangerous Preparations Directive general provisions 15 relevance for cosmetics 15–17 Dangerous Substances Directive general provisions 11–13 relevance for cosmetics 13–15 Data availability, combined impact of vertical legislations 19–21 Database search, safety information on cosmetic ingredients data quality evaluation 109, 110 data sources bibliographical databases 103–105 CD-ROMs 105 commercial data 102, 103 Internet resources 98–102 manufacturer data 105, 106 types 97 general considerations 96, 97 risk assessment of cosmetic ingredients in finished products 110–112 steps commercial database search 109 free Internet search 107 identification 107 legal restriction check 108 toxicological data search 108 summary 171, 172 Dermal absorption studies alternatives 81, 82 controversies 79–81 margin of safety calculations 78, 79 principles 74–76 Scientific Committee on Consumer Products requirements 74 shortcomings in reports 76, 77 Detergents, legislation 18, 19 Directorate General Enterprise, Internet resources 98 Dose-response, assessment 35, 36 Draize test eye irritation 136 skin irritation 134 EMBASE, databases 104 Embryotoxic stem cell test 145 Subject Index Episkin test 134, 135 EUR-Lex, Internet resources 98 European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), Internet resources 101 European Chemicals Bureau (ECB), Internet resources 98, 99 European Food Safety Authority (EFSA) general provisions 16 relevance for cosmetics 16, 17 European Inventory of Existing Commercial Chemical Substances (EINCS), components 13, 14 European List of Notified Chemical Substances (ELINCS), components 13, 14 Exposure assessment data needs 45 exposure levels per cosmetic product type 36–38 principles 36 systemic dose calculation 38, 39 Eye irritation, animal testing alternatives 136–138 Food additives, legislation 16, 17 Fragrances, risk assessment challenges 46 General Product Safety Directive (GPSD), relevance for cosmetics 23, 24 Gmelin, commercial data 103 Hair dye industry-Scientific Committee on Consumer Products interactions 70, 71 risk assessment challenges 46 Hazard identification benchmark dose 35 no adverse effects are observed 31, 34, 35 physiochemical and toxicological property determination 31–33 protocols 31–34 HEALSAFE, databases 104 Hen’s egg test-chorio allantoic membrane assay (HET-CAM) 137, 138 Human and Environmental Risk Assessment (HERA), Internet resources 101 Human testing, ethical constraints 48 Industry, Scientific Committee on Consumer Products interaction analysis 69–71 211 International Agency for Research on Cancer (IARC), Internet resources 101 International Fragrance Association (IFRA), Internet resources 101 International Nomenclature for Cosmetic Ingredients (INCI) recasting 11 technical information file 118 International Pharmaceutical Abstracts (IPA), databases 104 International Programme on Chemical Safety (IPCS), Internet resources 100, 101 Isolated chicken eye assay (ICE) 137 Isolated rabbit eye assay (IRE) 137 IUCLID, databases 105 Kosmet, database 103, 104 LED10, dose descriptor 35 Lethal dosage LD50 tests 131, 132 LIFESCI, databases 105 LINTOP project 144 Local lymph node assay (LLNA) 139–142, 148 Low volume eye test (LVET) 136 Magnusson-Kligman test 138, 139 Margin of safety (MoS) calculation 39, 40 dermal absorption studies 78, 79 Material Safety Data Sheet (MSDS), commercial data 103, 105, 106 Medical devices general provisions 19 relevance for cosmetics 19 Medicinal Products Directive general provisions 17, 18 relevance for cosmetics 18 Medline, databases 104 MicroMass test 145 Mutagenicity/genotoxicity studies animal testing alternatives 146, 147 Scientific Committee on Consumer Products reports presence of studies 84, 85 shortcomings 85 requirements 82, 83 Nanoparticles, risk assessment challenges 47 National Library of Medicine (NLM), Internet resources 99, 100 212 National Toxicology Program (NTP), Internet resources 100 No adverse effects are observed (NOAEL) hazard identification 31, 34, 35 repeated dose toxicity testing 142, 143 Nominal Capacities Directive, relevance for cosmetics 24, 25 Occupational Safety and Health Administration (OSHA), Internet resources 102 Organisation for Economic Co-operation and Development (OECD), risk assessment protocols 31–34 Perfumes, see Fragrances Photo-induced toxicity, animal testing alternatives 147–149 Plant Protection Products Directive general provisions 19 relevance for cosmetics 19 Prepackaged products, legislation 24 Protection of Experimental Animals Directive, relevance for cosmetics 22, 23 Public information, Cosmetic Products Directive prerequisite Raw material suppliers, responsibilities and challenges 46, 47 Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH) animal testing numbers and time frame 153, 154 general provisions 11–13 relevance for cosmetics 13–15, 112 Regulation, versus directive 9, 10 Repeated dose toxicity, animal testing alternatives 142, 143 Reproductive toxicity, animal testing alternatives 144–146 ReProTect project 145 Risk assessment challenges 44–49 cosmetic ingredients in finished products 110–112 dose-response assessment 35, 36 exposure assessment exposure levels per cosmetic product type 36–38 principles 36 systemic dose calculation 38, 39 Subject Index hazard identification benchmark dose 35 no adverse effects are observed 31, 34, 35 physiochemical and toxicological property determination 31–33 protocols 31–34 overview 29, 30 risk characterization lifetime cancer risk 40 margin of safety calculation 39, 40 threshold of toxicological concern 40, 41 risk communication 42, 43 risk management 41, 42 Scientific Committee on Consumer Products (SCCP) animal testing alternatives, see Animal testing data requirements 94 dermal absorption study alternatives 81, 82 controversies 79–81 margin of safety calculations 78, 79 principles 74–76 requirements 74 shortcomings in reports 76, 77 functions 5–7, 9, 29 identity and physiochemistry requirements 72, 73 shortcomings in reports 73, 74 mutagenicity/genotoxicity studies reports presence of studies 84, 85 shortcomings 85 requirements 82, 83 opinions classification 58, 59 critical analysis content comparison of submissions discussed in 2003 and 2006 64–69 industry interplay analysis 69–71 ingredient types 62, 63 methodology 60, 61 number of opinions in new millennium 61, 62 success rate 63, 64 summary 167, 168 Subject Index tables 188–190 SciSearch, databases 104 Skin irritation, animal testing alternatives 134–136 Skin sensitization, animal testing alternatives 138–142 Small businesses, risk assessment challenges 48, 49 Standards, harmonization 10 Systemic exposure dosage (SED), calculation 38, 39 T25, dose descriptor 35 TD50, dose descriptor 35 Technical information file (TIF) components 115, 116 Cosmetic Products Directive prerequisite database search, see Database search, safety information on cosmetic ingredients practical aspects 123–125 proposal for legal requirements administration part 125, 193, 194 animal testing data 123 existing data of undesirable effects 121, 122 finished product part 125, 126, 201–209 ingredients part 125, 195–200 manufacturing method 120 microbiological checks 119 physiochemical data 118, 119 proof of effects claimed 122 prospects for change 126, 127 purity 119, 120 qualitative and quantitative composition 117, 118 safety assessment of finished product 120, 121 safety assessor name and address 121 stability 119 summary 172, 173 3T3 Neutral Red Uptake Phototoxicity Test 148, 149 Threshold of toxicological concern (TTC), risk characterization 40, 41 TOXCENTER, databases 104 Toxicokinetics, animal testing alternatives 144 Training, risk assessment challenges 47, 48 Whole embryo culture test 145 213 ... reliability of the source of information in the overall reliability score 4.3 Risk Assessment of Cosmetic Ingredients in Finished Cosmetic Products in the EU The risk assessment of the ingredients included...4 Safety Assessment of Cosmetic Ingredients Present in Technical Information Files of Finished Products Rogiers V, Pauwels M (eds): Safety Assessment of Cosmetics in Europe Curr... made 5 .2. 4 Safety Assessment of the Finished Cosmetic Product The major part of the process of safety assessment of finished cosmetic products has already been discussed under section 4.4 Indeed,