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220User Guide for Thresholds and ClassificationsR68 Possible risk of irreversible effectsA substance is included in category 3, if there is evidence from appropriate mutagenicity studiesthat human exposure can result in the development of heritable genetic damage, but thisevidence is insufficient to place the substance in category 2.Source: EC (1967).ReferencesEC 1967. General classification and labelling requirements for dangerous substances and preparations.Council Directive 67/548/EEC of 27 June 1967 on the Approximation of Laws, Regulations andAdministrative Provisions Relating to the Classification, Packaging and Labelling of Dangerous Substances.European Commission, Annex VI. http://ec.europa.eu/environment/dansub/consolidated_en.htm.January 2012 EPA0109
221User Guide for Thresholds and Classifications15. Carcinogenic Effects – Subclass 6.715.1. General considerations15.1.1. Carcinogenicity overviewSee section 9.6 in chapter 9 above for definitions of the key terms used in this chapter.The purpose of carcinogenicity studies is to observe test animals for the development of neoplastic lesionsduring or after prolonged and repeated exposure to various doses of a test substance. Exposure shouldoccur by an appropriate route and encompass a major portion of the animal‘s life span. Carcinogenesis isconsidered a multi-stage phenomenon with direct and indirect effect on the genome leading to thedevelopment of cancerous cells. The predominant theory is that ‗initiating‘ events, which directly mutateDNA, are needed to cause cells to become cancerous. This process can be accelerated by promotionalfactors that increase cell division or decrease the effectiveness of repair mechanisms. The entirephenomenon usually takes considerable time for all the necessary events to occur and the effects tomanifest. Chemical carcinogens can have initiating and/or promoting properties.Chronic studies also observe test animals after prolonged and repeated exposure for a major portion of theirlife span, but determine effects that require a long latent period or are cumulative to become manifested.These studies generate data to identify the majority of chronic effects and to determine dose–responserelationships for general toxicity, including neurological, physiological, and biochemical effects and exposurerelated,morphological effects. The endpoints identified in chronic studies are considered as specific targetorgan effects (see chapter 17).Some studies are designed to detect both carcinogenic and chronic effect endpoints.15.1.2. Weight of evidenceThe best quality data should be used as the fundamental basis for classification. Preferably, classificationshould be based on primary data sources. It is essential that test conditions be clearly and completelyarticulated.Data from internationally harmonised test methods are preferred for classification under this subclass. Datashould preferably be derived using Organisation for Economic Co-operation and Development TestGuidelines or equivalent, according to the principles of Good Laboratory Practice. When such data are notavailable, classification should be based on the best available data using a weight-of-evidence approach.See section 1.3 in chapter 1 for information about assessing data quality. See Appendix 15A for a detailedlist of acceptable test methods for carcinogenicity.January 2012 EPA0109
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