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Commission Regulation (EU) 2018/782Show full title

Commission Regulation (EU) 2018/782 of 29 May 2018 establishing the methodological principles for the risk assessment and risk management recommendations referred to in Regulation (EC) No 470/2009 (Text with EEA relevance)

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  1. Introductory Text

  2. Article 1.Subject matter

  3. Article 2.Definitions

  4. Article 3.Entry into force

  5. Signature

    1. ANNEX I

      Methodological principles for the scientific risk assessment referred to in Article 6 of Regulation (EC) No 470/2009

      1. I. GENERAL PRINCIPLES

        1. I.1. Safety and residue tests for the establishment of maximum residue...

        2. I.2. Use of experimental animals in safety and residue tests shall...

        3. I.3. Documentation presented in relation to safety and residue tests shall...

        4. I.4. Where applicable, all observed results from the studies submitted shall...

        5. I.5. Test reports shall include the following information (where applicable):

        6. I.6. Biological substances other than those identified in Article 1(2)(a) of...

        7. I.7. For chemical-unlike biological substances, a report describing the scientific basis...

        8. I.8. Certain aspects of the data to be submitted in support...

        9. I.9. The general principles for the derivation of MRLs for biocidal...

      2. II. SAFETY FILE

        1. II.1. A full safety data package as described in this section...

        2. II.2. Where relevant and high quality literature data where all the...

        3. II.3. If data are not provided for standard endpoints, thorough justification...

        4. II.4. Detailed and critical summary

          1. II.4.1. A detailed and critical summary of the safety file shall...

          2. II.4.2. The detailed and critical summary shall:

          3. II.4.3. Annexes to the detailed and critical summary shall include:

        5. II.5. Precise identification of the substance concerned by the application

          1. II.5.1. The data shall demonstrate that the substance has been precisely...

          2. II.5.2. Batches used in safety studies shall be identified and adequate...

          3. II.5.3. Information on the chemical and physicochemical properties of the substance...

        6. II.6. Pharmacology

          1. II.6.1. Pharmacodynamics

            1. II.6.1.1. Data from the pharmacodynamic studies shall aim to enable the...

            2. II.6.1.2. Particular consideration shall be given in relation to pharmacodynamic effects...

            3. II.6.1.3. Studies relevant to the establishment of a pharmacological ADI shall...

            4. II.6.1.4. Data on the pharmacodynamic effects of a substance shall:

            5. II.6.1.5. If pharmacodynamic data are not provided, their absence shall be...

            6. II.6.1.6. If a pharmacological ADI is not derived, its absence shall...

          2. II.6.2. Pharmacokinetics

            1. II.6.2.1. Pharmacokinetic investigations shall provide information on the absorption of the...

            2. II.6.2.2. Metabolites produced in the laboratory animal species shall be compared...

            3. II.6.2.3. The pharmacokinetic data obtained from studies in laboratory animals shall...

            4. II.6.2.4. Pharmacokinetic data in laboratory animals shall also be used to...

            5. II.6.2.5. Pharmacokinetic data may also help to explain unusual results obtained...

          3. II.6.3. Toxicology

            1. II.6.3.1. General principles

              1. II.6.3.1.1. Animal studies shall be performed by the oral route since...

              2. II.6.3.1.2. Animal studies shall be conducted in established strains of laboratory...

              3. II.6.3.1.3. The substance to be tested shall be the active substance....

              4. II.6.3.1.4. VICH GL33: Studies to evaluate the safety of residues of...

            2. II.6.3.2. Single-dose toxicity, if available

              1. II.6.3.2.1. Acute toxicity studies may have been performed for reasons other...

              2. II.6.3.2.2. If available, acute toxicity data which may contribute to the...

            3. II.6.3.3. Repeat dose toxicity

              1. II.6.3.3.1. Repeat dose (90 day) oral toxicity testing

                1. II.6.3.3.1.1. Data from repeat dose (90 day) oral toxicity studies shall...

                2. II.6.3.3.1.2. Data from repeat dose oral toxicity testing studies shall:

                3. II.6.3.3.1.3. Guidance on the design of repeat dose (90-day) studies is...

                4. II.6.3.3.1.4. The absence of repeat dose (90-day) oral toxicity studies in...

              2. II.6.3.3.2. Repeat-dose (chronic) toxicity testing

                1. II.6.3.3.2.1. Chronic toxicity testing shall be conducted in at least one...

                2. II.6.3.3.2.2. The data from chronic oral toxicity testing studies shall allow:...

                3. II.6.3.3.2.3. Guidance on the design of repeat dose (chronic) studies is...

                4. II.6.3.3.2.4. If a repeat dose (chronic) oral toxicity study is not...

            4. II.6.3.4. Tolerance in target species, if available

              1. II.6.3.4.1. Data on tolerance in target species shall not be required...

              2. II.6.3.4.2. If available, data on tolerance in target species may contribute...

            5. II.6.3.5. Reproductive toxicity, including developmental toxicity

              1. II.6.3.5.1. Study of the effects on reproduction

                1. II.6.3.5.1.1. General reproductive toxicity testing shall be conducted in at least...

                2. II.6.3.5.1.2. Tests for effects on reproduction shall aim to identify and...

                3. II.6.3.5.1.3. Tests shall identify potential effects on male and female reproductive...

                4. II.6.3.5.1.4. If evidence suggests the occurrence of effects on development of...

                5. II.6.3.5.1.5. The data shall allow the establishment of a NO(A)EL or...

                6. II.6.3.5.1.6. Guidance on the design of reproduction toxicity testing studies is...

                7. II.6.3.5.1.7. If a reproduction toxicity study is not provided, its absence...

              2. II.6.3.5.2. Study of developmental toxicity

                1. II.6.3.5.2.1. The aim of developmental toxicity studies shall be to detect...

                2. II.6.3.5.2.2. If clear evidence of teratogenicity is seen in the rat,...

                3. II.6.3.5.2.3. Guidance on the approach towards developmental toxicity testing is described...

                4. II.6.3.5.2.4. Studies shall use the oral route of administration.

                5. II.6.3.5.2.5. The data shall allow the establishment of a NO(A)EL or...

                6. II.6.3.5.2.6. If a developmental toxicity study is not provided, its absence...

            6. II.6.3.6. Genotoxicity

              1. II.6.3.6.1. In most cases the substance to be tested shall be...

              2. II.6.3.6.2. VICH GL23: Studies to evaluate the safety of residues of...

              3. II.6.3.6.3. Results of genotoxicity tests shall be used to evaluate whether...

              4. II.6.3.6.4. Exposure to certain genotoxic substances is known to be associated...

              5. II.6.3.6.5. The deliberate use of genotoxic substances that interact directly with...

              6. II.6.3.6.6. The results from the genotoxicity tests shall contribute to the...

              7. II.6.3.6.7. A substance that directly induces clearly positive findings in genotoxicity...

              8. II.6.3.6.8. In the absence of data to demonstrate that observed genotoxicity...

              9. II.6.3.6.9. Clearly negative results from a standard battery of genotoxicity tests...

              10. II.6.3.6.10. If equivocal results are seen in genotoxicity tests, the need...

              11. II.6.3.6.11. In general the genotoxicity of major metabolites shall be considered...

              12. II.6.3.6.12. In principle, identification of minor metabolites shall not be required....

              13. II.6.3.6.13. Minor metabolites are those present at levels below 100 μg/kg...

              14. II.6.3.6.14. If the structure of a minor metabolite is known or...

              15. II.6.3.6.15. Similarly, if there is a concern that a minor metabolite...

              16. II.6.3.6.16. For any of these substances (potentially genotoxic minor metabolites produced...

              17. II.6.3.6.17. If more than one minor metabolite is DNA reactive, in...

              18. II.6.3.6.18. Substances and metabolites that may cause cancer by mechanisms other...

            7. II.6.3.7. Carcinogenicity

              1. II.6.3.7.1. Criteria for the selection of substances for carcinogenicity testing

                1. II.6.3.7.1.1. VICH GL28: Studies to evaluate the safety of residues of...

                2. II.6.3.7.1.2. In those cases where carcinogenicity testing is deemed appropriate, the...

                3. II.6.3.7.1.3. Genotoxic carcinogens shall not be accepted for use in food-producing...

                4. II.6.3.7.1.4. A substance that induces positive findings in carcinogenicity tests may...

                5. II.6.3.7.1.5. If carcinogenicity testing is not undertaken, the absence of such...

          4. II.6.4. Other requirements

            1. II.6.4.1. General principles

              1. II.6.4.1.1. The need for safety data addressing other potential effects shall...

              2. II.6.4.1.2. Factors to be taken into account when considering the need...

            2. II.6.4.2. Special studies (e.g. immunotoxicity, neurotoxicity)

              1. II.6.4.2.1 Immunotoxicity

                1. II.6.4.2.1.1. If relevant effects are seen in repeated dose or other...

                2. II.6.4.2.1.2. For certain classes of substance (such as beta lactam antibiotics)...

                3. II.6.4.2.1.3. Details shall be provided of all immunological studies performed with...

                4. II.6.4.2.1.4. Data obtained from such studies shall be taken into account...

              2. II.6.4.2.2. Neurotoxicity, developmental neurotoxicity and delayed neurotoxicity

                1. II.6.4.2.2.1. Neurotoxicity testing shall be required where repeated dose studies indicate...

                2. II.6.4.2.2.2. Substances that have been shown in other toxicological assays to...

                3. II.6.4.2.2.3. Neurotoxicity testing shall be performed using the oral route and...

                4. II.6.4.2.2.4. Although OECD Test Guideline 424 does not specifically address effects...

                5. II.6.4.2.2.5. If a substance has been shown to cause neuropathology or...

                6. II.6.4.2.2.6. Organophosphates shall be tested for delayed neurotoxicity in a hen...

                7. II.6.4.2.2.7. The neurotoxicity studies shall allow the establishment of NO(A)ELs or...

            3. II.6.4.3. Microbiological properties of residues

              1. II.6.4.3.1. Potential effects on the human gut flora

                1. II.6.4.3.1.1. For substances with antimicrobial activity, antimicrobial effects on the human...

                2. II.6.4.3.1.2. The data shall be used to derive a microbiological ADI....

                3. II.6.4.3.1.3. The risks that result from residues shall be clearly distinguished...

                4. II.6.4.3.1.4. As described in the VICH GL36, the following two endpoints...

                5. II.6.4.3.1.5. Any departures from the established guidance shall be justified and...

                6. II.6.4.3.1.6. If no testing for effects on the human intestinal flora...

            4. II.6.4.4. Observations in humans

              1. II.6.4.4.1. Any available data on health effects seen in humans following...

              2. II.6.4.4.2. The data related to exposure of humans may provide valuable...

          5. II.6.5. Findings of other EU or international scientific bodies

            1. II.6.5.1. If relevant safety evaluations of the substance have been undertaken...

          6. II.6.6. Determination of an ADI or alternative limit

            1. II.6.6.1. Determination of an ADI

              1. II.6.6.1.1. Derivation of the toxicological ADI

                1. II.6.6.1.1.1. The toxicological ADI shall be derived by dividing the selected...

                2. II.6.6.1.1.2. The formula used to determine the toxicological ADI shall be...

                3. II.6.6.1.1.3. The choice of the NO(A)EL or BMDL and the uncertainty...

                4. II.6.6.1.1.4. Unless otherwise justified, the toxicological ADI shall be derived from...

                5. II.6.6.1.1.5. If using the benchmark dose (‘BMD’) approach, the BMDL shall...

                6. II.6.6.1.1.6. In selecting the default values for the magnitude of the...

                7. II.6.6.1.1.7. In relation to uncertainty factors, the default assumption is that...

                8. II.6.6.1.1.8. Where the results of animal studies indicate teratogenic effects at...

                9. II.6.6.1.1.9. It may occur that the most sensitive endpoint is observed...

                10. II.6.6.1.1.10. The choice of uncertainty factors for use in deriving the...

                11. II.6.6.1.1.11. Where the ADI is to be set on the basis...

                12. II.6.6.1.1.12. The refinement of the standard approach for selecting uncertainty factors...

                13. II.6.6.1.1.13. Further refinement of the intra-species and inter-species tenfold uncertainty factors...

                14. II.6.6.1.1.14. For the multiplication of uncertainty factors the use of probabilistic...

                15. II.6.6.1.1.15. The use of these and other approaches for the refinement...

                16. II.6.6.1.1.16. Having regard to the previous considerations, the uncertainty factor used...

              2. II.6.6.1.2. Derivation of the pharmacological ADI

                1. II.6.6.1.2.1. Pharmacological ADIs shall not be derived for all pharmacologically active...

                2. II.6.6.1.2.2. Guidance on the need for a pharmacological ADI as provided...

                3. II.6.6.1.2.3. Where a pharmacological ADI is needed, the approach for its...

              3. II.6.6.1.3. Derivation of a microbiological ADI

                1. II.6.6.1.3.1. As described in Section II.6.4.3 microbiological ADIs shall be derived...

              4. II.6.6.1.4. The overall ADI

              5. II.6.6.1.5. Substances with non-threshold effects

            2. II.6.6.2. Alternatives to the ADI

              1. II.6.6.2.1. Substances for which recommended dietary intake levels have been established...

                1. II.6.6.2.1.1. For most minerals and trace elements there is a natural...

                2. II.6.6.2.1.2. The ADI approach is not appropriate for use in the...

                3. II.6.6.2.1.3. This approach may be appropriate for minerals, elements, vitamins and...

              2. II.6.6.2.2. Substances to which consumers are exposed via food or other...

                1. II.6.6.2.2.1. When consumer exposure to residues of the active substance in...

                2. II.6.6.2.2.2. The chemical make-up of herbal/vegetable based products (including extracts) is...

                3. II.6.6.2.2.3. When using this approach it is important to exclude any...

              3. II.6.6.2.3. Endogenous pharmacologically active substances

                1. II.6.6.2.3.1. If the pharmacologically active substance is identical to an endogenously...

                2. II.6.6.2.3.2. Human exposure to such substances may be expected to come...

                3. II.6.6.2.3.3. Consumer exposure to residues may be best estimated by comparing...

                4. II.6.6.2.3.4. This approach may be appropriate for hormones and other endogenously...

              4. II.6.6.2.4. Substances that lack bioavailability

                1. II.6.6.2.4.1. For substances that are not absorbed following oral ingestion, systemic...

      3. III. RESIDUE FILE

        1. III.1. In general a full residue data package shall be required....

        2. III.2. Detailed and critical summary

          1. III.2.1. A detailed and critical summary of the residues file shall...

          2. III.2.2. The detailed and critical summary shall:

          3. III.2.3. Annexes to the detailed and critical summary shall include:

        3. III.3. Metabolism and residue kinetics in the target species

          1. III.3.1. Metabolism and residues data shall be required to characterise residues...

          2. III.3.2. The data shall be provided in the form of a...

          3. III.3.3. The test material shall contain the substance of concern in...

          4. III.3.4. Guidance provided in VICH GL46: Studies to evaluate the metabolism...

          5. III.3.5. Guidance provided in VICH GL49: Studies to evaluate the metabolism...

          6. III.3.6. Specific guidance relating to residue studies to be undertaken for...

          7. III.3.7. The total residues study (usually performed with radiolabelled drug) shall...

          8. III.3.8. A suitable marker residue shall be identified. The marker residue...

          9. III.3.9. The ratio of marker to total residues describes the relationship...

          10. III.3.10. By monitoring the depletion of total residues in the edible...

          11. III.3.11. Information from the metabolism study shall also allow comparison of...

          12. III.3.12. Any departures from established guidance shall be justified and the...

        4. III.4. Monitoring and exposure data, if relevant

          1. III.4.1. Monitoring or exposure data of the pharmacologically active substance shall...

        5. III.5. Residue analytical method

          1. III.5.1. A validation report of the analytical method used for quantification...

          2. III.5.2. Analytical methods shall be provided at least for those food...

          3. III.5.3. The availability of standards shall be confirmed and contact details...

          4. III.5.4. Any departures from the requirements above shall be justified and...

          5. III.5.5. The analytical method shall be evaluated for compliance with VICH...

          6. III.5.6. Following the Agency's opinion, the validation data may be shared...

        6. III.6. Potential effects on the microorganisms used for industrial food processing...

          1. III.6.1. The residues evaluation shall include an assessment of the potential...

          2. III.6.2. The data shall be used to establish a residue concentration...

          3. III.6.3. The studies to be performed shall follow Agency's guidance for...

          4. III.6.4. Any departures from the established guidance shall be justified and...

          5. III.6.5. If no testing of microorganisms used for industrial food processing...

        7. III.7. Findings of other EU or international scientific bodies

          1. III.7.1. If relevant residues evaluations of the substance have been undertaken...

    2. ANNEX II

      Methodological principles for the risk management recommendations referred to in Article 7 of Regulation (EC) No 470/2009

      1. I. ELABORATION OF MRLs

        1. I.1. Derivation of numerical MRLs

          1. I.1.1. Where it is considered appropriate in accordance with this Regulation...

          2. I.1.2. When determining the MRLs, consideration shall be given to the...

          3. I.1.3. In deriving MRLs it shall be assumed that the consumer...

          4. I.1.4. Using the residue depletion data, the total residue burden in...

          5. I.1.5. Once MRL levels have been derived, the Theoretical Maximum Daily...

        2. I.2. The ‘No MRL required’ classification

          1. I.2.1. A ‘No MRL required’ classification may be recommended in those...

          2. I.2.2. Substances may be regarded as candidates for a ‘No MRL...

          3. I.2.3. In some cases a ‘No MRL required’ recommendation may incorporate...

      2. II. AVAILABILITY OF ALTERNATIVE MEDICINES AND OTHER LEGITIMATE FACTORS

        1. II.1. Availability of alternative medicines

        2. II.2. Technological aspects of food and feed productions

          1. II.2.1. Where relevant, consideration shall be given to the possibility that...

          2. II.2.2. Information on testing that shall be considered in order to...

          3. II.2.3. The recommended MRLs shall be set at levels that ensure...

        3. II.3. Feasibility of controls

          1. II.3.1. For some substances, for which setting numerical MRLs is not...

          2. II.3.2. In cases where the time taken for residues to deplete...

        4. II.4. Conditions of use and application of the substances in veterinary...

          1. II.4.1. For substances proposed for use in species that produce milk or...

          2. II.4.2. If appropriate, consideration shall be given to recommending a restriction...

          3. II.4.3. If establishment of MRLs may increase the likelihood of misuse...

          4. II.4.4. Other factors may be considered on a case-by-case basis where...

        5. II.5. Need for an unused portion of the ADI

          1. II.5.1. Since it is not possible to predict, with certainty, the...

          2. II.5.2. MRL applications usually focus on tissues, however, potential future uses...

          3. II.5.3. When considering the need to maintain an unused portion of...

        6. II.6. Exposure from other sources (combined exposure to dual-use substances)

          1. II.6.1. In order to ensure that all sources of consumer exposure...

          2. II.6.2. In the case of substances also used as plant protection...

          3. II.6.3. Where the existing pesticide product authorisation allows and sufficient data...

          4. II.6.4. As the methodology used in establishing MRLs for edible tissues...

          5. II.6.5. For dual-use substances used as biocides in animal husbandry, the...

          6. II.6.6. With regard to feed additives, consultation with the European Union...

        7. II.7. Injection site residues

          1. II.7.1. The muscle MRL shall be set at a level for...

          2. II.7.2. For those injectable substances for which depletion of injection site...

          3. II.7.3. The ISRRV shall not be published in the Annex to...

      3. III. CONSIDERATIONS ON POSSIBLE EXTRAPOLATION OF MRLs

        1. III.1. The extrapolation of MRLs shall be considered in line with...

        2. III.2. Data that may be useful in relation to the extrapolation...

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