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. )

Article 1

Subject matter

Article 2

Definitions

For the purposes of this Regulation, in addition to the definitions set out in Regulation (EC) No 470/2009, the following definitions shall apply:

— ‘major metabolites’ means metabolites comprising ≥ 100 μg/kg or ≥ 10 % of the total residue in a sample collected from the target animal species in the metabolism study,

— ‘marker residue’ means a residue whose concentration is in a known relationship to the concentration of total residue in an edible tissue,

— ‘dairy starter cultures’ means prepared cultures of microorganism employed in the manufacture of a variety of dairy products including butter, cheese, yoghurt and cultured milk.

Article 3

Entry into force

This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union.

This Regulation shall be binding in its entirety and directly applicable in all Member States.

ANNEX I

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

I. GENERAL PRINCIPLES

I.1. Safety and residue tests for the establishment of maximum residue limits (‘MRLs’) shall be carried out in conformity with the provisions related to Good Laboratory Practice (‘GLP’) as laid down in Directive 2004/10/EC of the European Parliament and of the Council. (¹) If data are available that have not been generated under GLP conditions, the potential impact of this shall be addressed.

I.2. Use of experimental animals in safety and residue tests shall comply with Directive 2010/63/EU of the European Parliament and of the Council (²).

I.3. Documentation presented in relation to safety and residue tests shall name the laboratory where the work was performed and shall be signed and dated. Summaries of any studies that are not accompanied by the raw data shall not be accepted as valid documentation. Design, methods and conduct of the studies, name and qualifications of investigator, place and period of time during which the study was undertaken shall be clear from the test reports. The experimental techniques shall be described in such detail as to allow them to be reproduced, and the investigator shall establish their validity. All abbreviations and codes, irrespective of whether they are internationally accepted or not, shall be accompanied by a key.

I.4. Where applicable, all observed results from the studies submitted shall be evaluated by an appropriate statistical method and be discussed in conjunction with the other available studies. The results of all studies shall be presented in a form that facilitates their review.

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

I.6. Biological substances other than those identified in Article 1(2)(a) of Regulation (EC) No 470/2009 of the European Parliament and of the Council (³) shall be:

I.7. For chemical-unlike biological substances, a report describing the scientific basis for the request on whether a full MRL evaluation is required or not shall be required together with the following information: The information provided above shall be evaluated in accordance with the guidance published by the European Medicines Agency (‘Agency’) in order to determine whether a ‘no MRL required’ classification according to the classification provided for under Article 14(2), point (c), of Regulation (EC) No 470/2009 is appropriate.

I.8. Certain aspects of the data to be submitted in support of a MRL application for a substance for use in minor species or for minor uses may be reduced in comparison to the requirements for a substance that does not fall into this category. Evaluation shall be made based on the data requirements laid out in the Agency's ‘ Guideline on safety and residue data requirements for pharmaceutical veterinary medicinal products intended for minor use or minor species (MUMS)/limited market ’ (⁴).

I.9. The general principles for the derivation of MRLs for biocidal substances used in animal husbandry laid down in Article 10 of Regulation (EC) No 470/2009 shall be the same as for veterinary medicinal products.

II.   SAFETY FILE

II.1. A full safety data package as described in this section shall be required for MRL evaluation for substances that have not previously been used in food-producing species.

II.2. Where relevant and high quality literature data where all the details of the study are described are available, it may be possible to rely on these in place of a full study report commissioned by the applicant.

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

III.   RESIDUE FILE

III.1. In general a full residue data package shall be required. If data are not provided for standard endpoints this shall be thoroughly justified.

ANNEX II

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

I. ELABORATION OF MRLs

I.1.1. Where it is considered appropriate in accordance with this Regulation to establish numerical MRL values, MRLs shall routinely be recommended for the edible tissues listed below:

I.1.2. When determining the MRLs, consideration shall be given to the following issues:

I.1.4. Using the residue depletion data, the total residue burden in the standard food basket shall be calculated based on the observed residue levels at each time point on the residue depletion curve, so that the time point at which the total residue burden falls below the ADI is established. If the full ADI is available then these residue levels, rounded up as appropriate (usually to the nearest 50 μg/kg for tissues), shall be considered as potential MRLs. Consideration shall also be given to the factors listed under Section II points 1 to 7 and, if appropriate (e.g. if less than the full ADI is available), a subsequent time point on the residue depletion curve shall be used as the point from which to derive the MRLs.

I.1.5. Once MRL levels have been derived, the Theoretical Maximum Daily Intake (‘TMDI’) of residues shall be calculated using the standard food basket and assuming that residues are present in all food commodities at the level of the proposed MRLs. The TMDI is calculated by adding exposure to residues from all tissues obtained using the following calculation: Amount per edible tissue or product = (proposed MRL for the tissue or product x (times) daily consumption of the tissue or product)/(divided by) Ratio of the marker to total residue in the tissue or product.

I.2.1. A ‘No MRL required’ classification may be recommended in those cases where it is clear that the establishment of numerical MRLs is not necessary for the protection of the consumer. The consumer exposure to residues shall always remain at safe levels (below the ADI or alternative limit) in order for a ‘No MRL required’ classification to be recommended.

I.2.2. Substances may be regarded as candidates for a ‘No MRL required’ status, if they fulfil one or more of the criteria stated below. It shall be noted, however, that fulfilment of one or more of these criteria shall not be regarded as automatically implying that a ‘No MRL required’ status shall be recommended. The following specificities of each individual substance shall be fully evaluated before reaching a conclusion:

I.2.3. In some cases a ‘No MRL required’ recommendation may incorporate a restriction on the way the substance is to be used (for example, a restriction ‘for cutaneous use only’ may be recommended in cases where it is clear that no residues of concern will result following cutaneous use, but the possibility of harmful residues cannot be ruled out following administration of the substance by a different route).

II.   AVAILABILITY OF ALTERNATIVE MEDICINES AND OTHER LEGITIMATE FACTORS

The need for the substance in order to avoid unnecessary suffering for target animals or to ensure the safety of those treating them may be relevant factors to consider in those cases where practical treatment alternatives are lacking. These considerations may justify acceptance of a reduced data package in line with the recommendations provided in the Agency's ‘ Guideline on safety and residue data requirements for pharmaceutical veterinary medicinal products intended for minor use or minor species (MUMS)/limited market ’ (²⁹). These factors may also be considered in relation to the need to set MRLs at levels that will allow development of a product with a practicable withdrawal period, as defined in Directive 2001/82/EC of the European Parliament and of the Council (³⁰).

II.2.1. Where relevant, consideration shall be given to the possibility that microbiologically active residues impact on microorganisms used for industrial food processing, in particular as regards the manufacture of dairy products.

II.2.2. Information on testing that shall be considered in order to address this issue is detailed in Annex I Section III.6.

II.2.3. The recommended MRLs shall be set at levels that ensure that food processing is not adversely affected (e.g. dairy starter cultures).

II.3.1. For some substances, for which setting numerical MRLs is not practicable (e.g. substances that may be naturally present in animal produce), the feasibility of undertaking residue control shall be considered on a case-by-case basis. This shall be determined based on the consideration of the potential risk posed to the consumer.

II.3.2. In cases where the time taken for residues to deplete to the recommended MRL may be longer in one (or more) tissue type than in others, it shall be recommended that, if the entire carcass is available, the tissues selected for monitoring of residues shall be those in which depletion of residues to the level of the MRL is slowest, as compliance with the MRL in this tissue will indicate compliance with the MRLs in other tissues also. This is particularly likely in those cases where residues are seen to be low in one or more tissues at all-time points and consequently the recommended MRL values for this (or these) tissue(s) are based on the limit of quantification of the analytical method.

II.4.1. For substances proposed for use in species that produce milk or eggs, consideration shall be given to the possibility of recommending MRLs in these commodities. Where MRLs cannot be recommended in milk or eggs for safety reasons, it shall be stated that use of the substance shall be restricted to animals not producing milk or eggs for human consumption.

II.4.2. If appropriate, consideration shall be given to recommending a restriction on the use of the substance. For example, if the residue data provided relate only to cutaneous application of the substance and there are concerns that residue levels in food of animal origin would be considerably higher if the substance were applied by another route, then consideration shall be given to recommending that use of the substance be restricted to cutaneous use.

II.4.3. If establishment of MRLs may increase the likelihood of misuse or illegal use of the substance (for example in relation to use as a growth promoter) this shall be clearly stated. Similarly, if the establishment of MRLs may increase good practice and limit misuse or illegal use this may also be stated.

II.4.4. Other factors may be considered on a case-by-case basis where evidence exists to indicate that there is a specific relevant concern regarding the use of the pharmacologically active substance. As a general principle, MRL assessments do not consider the effects of food processing (particularly cooking) on residues. However, if data are available indicating that food processing can be expected to increase levels of residues of concern, consideration shall be given to the potential impact on consumer health.

II.5.1. Since it is not possible to predict, with certainty, the future use of a substance in other species and with a view to increasing availability of veterinary medicinal products, as a general principle, it shall be considered that, unless MRLs are proposed in all food commodities included in the standard food basket, an adequate portion of the ADI shall remain unused.

II.5.2. MRL applications usually focus on tissues, however, potential future uses in milk, eggs and honey shall be considered. In general, a part of the ADI shall be reserved for future uses and MRLs that use the full ADI shall only be accepted in exceptional cases.

II.5.3. When considering the need to maintain an unused portion of the ADI, a number of substance specific factors shall be considered, including:

II.6.1. In order to ensure that all sources of consumer exposure to the substance are considered, all known uses of the substance shall be considered and the consumer exposure that results from these uses shall be estimated. MRLs shall be proposed at levels that ensure that the total amount of residues from all sources likely to be ingested do not exceed the ADI.

II.6.2. In the case of substances also used as plant protection products, a general guidance figure for the portion of the ADI that may be reserved for veterinary use shall be 45 % of the ADI.

II.6.3. Where the existing pesticide product authorisation allows and sufficient data are available on intake from plant protection use, it may be possible to allocate a larger part to veterinary use without exceeding the ADI. In order to identify the proportion of the ADI that is available, the MRL approved for the plant protection product shall be taken into account.

II.6.4. As the methodology used in establishing MRLs for edible tissues for plant protection products differs to that used for veterinary use, care shall be taken when combining the estimated exposure risk from the different methodologies.

II.6.5. For dual-use substances used as biocides in animal husbandry, the CVMP Guideline on risk characterisation and assessment of maximum residue limits (MRL) for biocides (³¹) shall be followed.

II.6.6. With regard to feed additives, consultation with the European Union Register of Feed Additives shall indicate if the substance has been authorised for use in animal feed. When evaluating such substances, EFSA shall be consulted.

II.7.1. The muscle MRL shall be set at a level for monitoring of residues in non-injection site muscle, as consumers routinely ingest non-injection site muscle and rarely ingest injection site muscle.

II.7.2. For those injectable substances for which depletion of injection site residues when compared to the muscle MRL would result in extended (prohibitive) withdrawal periods, an Injection Site Residue Reference Value (‘ISRRV’) shall also be established by the Agency. The ISRRV shall be set at a level that ensures that, at the likely withdrawal period, a standard food basket including 300g of injection site muscle would contain residues below the ADI.

II.7.3. The ISRRV shall not be published in the Annex to Regulation (EU) No 37/2010; the value shall only be available in the European Public MRL Assessment Report (‘EPMAR’) and shall be used when deriving a withdrawal period for the veterinary medicinal product.

III.   CONSIDERATIONS ON POSSIBLE EXTRAPOLATION OF MRLs

III.1. The extrapolation of MRLs shall be considered in line with the requirements as set out in the Commission Regulation (EU) 2017/880 (³²).

III.2. Data that may be useful in relation to the extrapolation considerations shall be submitted as part of the dossier, where available.