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GENERAL RULES FOR ADAPTATION OF THE STANDARD TESTING REGIME SET OUT IN ANNEXES VII TO X Annexes VII to X set out the information requirements for all substances manufactured or imported in quantities of:

— one tonne or more in accordance with Article 12(1)(a),

— 10 tonnes or more in accordance with Article 12(1)(c),

— 100 tonnes or more in accordance with Article 12(1)(d), and — 1 000 tonnes or more in accordance with Article 12(1)(e). In addition to the specific rules set out in column 2 of Annexes VII to X, a registrant may adapt the standard testing regime in accordance with the general rules set out in Section 1 of this Annex. Under dossier evaluation the Agency may assess these adaptations to the standard testing regime. The requirements specific to nanoforms in this Annex are without prejudice to requirements applicable to other forms of a substance.

1. TESTING DOES NOT APPEAR SCIENTIFICALLY NECESSARY 1.1. Use of existing data Any data generated as from 1 June 2008 shall not be considered as existing data and shall not be subject to the general rules for adaptation laid down in this point (1.1).

1.1.1. Data on physical-chemical properties from experiments not carried out according to the test methods referred to in Article 13(3) Data shall be considered to be equivalent to data generated by the corresponding test methods referred to in Article 13(3) if the following conditions are met:

(1) adequacy for the purpose of classification and labelling and/or risk assessment;

(2) sufficient documentation is provided to assess the adequacy of the study; and (3) the data are valid for the endpoint being investigated and the study is performed using an acceptable level of quality assurance.

1.1.2. Data on human health and environmental properties from experiments not carried out according to GLP or the test methods referred to in Article 13(3) Data shall be considered to be equivalent to data generated by the corresponding test methods referred to in Article 13(3) if the following conditions are met:

(1) adequacy for the purpose of classification and labelling and/or risk assessment;

(2) adequate and reliable coverage of the key parameters foreseen to be investigated in the corresponding test methods referred to in Article 13(3);

(3) exposure duration comparable to or longer than the corresponding test methods referred to in Article 13(3) if exposure duration is a relevant parameter; and (4) adequate and reliable documentation of the study is provided.

1.1.3. Historical human data Historical human data, such as epidemiological studies on exposed populations, accidental or occupational exposure data and clinical studies, shall be considered. The strength of the data for a specific human health effect depends, among other things, on the type of analysis and on the parameters covered and on the magnitude and specificity of the response and consequently the predictability of the effect. Criteria for assessing the adequacy of the data include:

(1) the proper selection and characterisation of the exposed and control groups;

(2) adequate characterisation of exposure;

(3) sufficient length of follow-up for disease occurrence;

(4) valid method for observing an effect;

(5) proper consideration of bias and confounding factors; and (6) a reasonable statistical reliability to justify the conclusion. In all cases adequate and reliable documentation shall be provided.

When nanoforms are covered by the registration the above approach shall address the nanoforms separately.

1.2. Weight of evidence There is sufficient weight of evidence when information from several independent sources together enable, through a reasoned justification, a conclusion on the information requirement, while the information from each single source alone is insufficient to fulfil the information requirement. The justification must have regard to the information that would otherwise be obtained from the study that shall normally be performed for this information requirement. There may also be sufficient weight of evidence from the use of newly developed test methods, not yet included in the test methods referred to in Article 13(3), leading to a reasoned justification that they provide the information that would enable a conclusion on the information requirement. Weight of evidence may lead to the conclusion that a substance has or has not a particular property.

If there is sufficient weight of evidence, the information requirement is fulfilled. Consequently, further testing on vertebrate animals shall be omitted and further testing not involving vertebrate animals may be omitted. In all cases, the information provided shall be adequate for the purpose of classification, labelling and/or risk assessment, and adequate and reliable documentation shall be provided, including:

— robust study summaries of the studies used as sources of information;

— a justification explaining why the sources of information together provide a conclusion on the information requirement. When nanoforms are covered by the registration, the above approach shall address the nanoforms separately.

1.3. Qualitative or Quantitative structure-activity relationship ((Q)SAR) Results obtained from valid qualitative or quantitative structure-activity relationship models ((Q)SARs) may indicate the presence or absence of a certain dangerous property. Results of (Q)SARs may be used instead of testing when the following conditions are met:

— results are derived from a (Q)SAR model whose scientific validity has been established,

— the substance falls within the applicability domain of the (Q)SAR model,

— results are adequate for the purpose of classification and labelling and/or risk assessment, and — adequate and reliable documentation of the applied method is provided. The Agency in collaboration with the Commission, Member States and interested parties shall develop and provide guidance in assessing which (Q)SARs will meet these conditions and provide examples. When nanoforms are covered by the registration the above approach shall address the nanoforms separately.

1.4. In vitro methods

Results obtained from suitable in vitro methods may indicate the presence of a certain dangerous property or may be important in relation to a mechanistic understanding, which may be important for the assessment. In this context, ‘suitable’ means sufficiently well developed according to internationally agreed test development criteria (e.g. the European Centre for the Validation of Alternative Methods (ECVAM)) criteria for the entry of a test into the prevalidation process). Depending on the potential risk, immediate confirmation requiring testing beyond the information foreseen in Annexes VII or VIII or proposed confirmation requiring testing beyond the information foreseen in Annexes IX or X for the respective tonnage level may be necessary. If the results obtained from the use of such in vitro methods do not indicate a certain dangerous property, the relevant test shall nevertheless be carried out at the appropriate tonnage level to confirm the negative result, unless testing is not required in accordance with Annexes VII to X or the other rules in this Annex. Such confirmation may be waived if the following conditions are met:

(1) results are derived from an in vitro method whose scientific validity has been established by a validation study, according to internationally agreed validation principles;

(2) results are adequate for the purpose of classification and labelling and/or risk assessment; and (3) adequate and reliable documentation of the applied method is provided. When nanoforms are covered by the registration the above approach in points (1) to (3) shall address the nanoforms separately.

1.5. Grouping of substances and read-across approach Substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity, may be considered as a group, or category, of substances. Application of the group concept requires that physicochemical properties, human health effects and environmental effects or environmental fate may be predicted from data for reference substance(s) within the group by interpolation to other substances in the group (read-across approach). This avoids the need to test every substance for every endpoint.

When nanoforms are covered by the registration, the above approach shall address the nanoforms separately. For grouping different nanoforms of the same substance, the molecular structural similarities alone may not serve as a justification. If nanoforms covered by a registration are grouped or placed in a ‘category’ with other forms, including other nanoforms, of the substance in the same registration the obligations above shall apply in the same manner. The similarities may be based on any of the following:

(1) a common functional group;

(2) the common precursors and/or the likelihood of common breakdown products via physical and biological processes, which result in structurally similar chemicals;

(3) a constant pattern in the changing of the potency of the properties across the category.

Structural similarity for UVCB substances shall be established on the basis of similarities in the structures of the constituents, together with the concentration of these constituents and variability in the concentration of these constituents. If it can be demonstrated that the identification of all individual constituents is not technically possible or impractical, the structural similarity may be demonstrated by other means, to enable a quantitative and qualitative comparison of the actual composition between substances. If the group concept is applied, substances shall be classified and labelled on this basis. In all cases, results shall fulfil all of the following conditions:

— be adequate for the purpose of classification and labelling and/or risk assessment,

— have adequate and reliable coverage of the key parameters addressed in the corresponding study that shall normally be performed for a particular information requirement,

— cover an exposure duration comparable to or longer than the corresponding study that shall normally be performed for a particular information requirement if exposure duration is a relevant parameter.