Maximum residue limits (MRL)

For non-biological veterinary medicinal products for food-producing animals: NO. Article 5(5) of Regulation (EU) 2019/6 states that "a marketing authorisation for a veterinary medicinal product intended for one or more food-producing animal species may only be granted if the pharmacologically active substance is allowed in accordance with Regulation (EC) No 470/2009 and any acts adopted on the basis thereof for the animal species concerned". Therefore, to obtain a marketing authorisation for a non-biological veterinary medicinal product intended for food-producing species in the European Union, MRLs must be established in advance for all pharmacologically active substances for the concerned animal species (e.g., sheep, fin fish) and relevant foodstuffs (e.g. milk, honey). These include the active ingredient(s) and excipients, depending on whether the substance has pharmacological activity at the dose that is intended to be administered to the target species.

For non-immunological biological veterinary medicinal products for food-producing animals, either MRLs are needed or, in certain cases, the CVMP may conclude that a biological substance does not require a full MRL evaluation and can be included in the list of biological substances considered as not requiring an MRL evaluation as per Commission Regulation (EU) 2018/782.

The active principles of biological origin intended to produce active or passive immunity or to diagnose a state of immunity and used in immunological veterinary medicinal products are exempted from MRL requirements as per Regulation (EU) No 470/2009.

YES, if they have pharmacological activity at the dose that is intended to be administered to the target species, they require MRLs.

Specific legislation regarding the establishment of MRLs is applicable in the European Union:

• Regulation (EC) No 470/2009 of the European Parliament and of the Council of 6 May 2009 laying down Community procedures for the establishment of residue limits of pharmacologically active substances in foodstuffs of animal origin, repealing Council Regulation (EEC) No 2377/90 and amending Directive 2001/82/EC of the European Parliament and of the Council and Regulation (EC) 726/2004 of the European Parliament and of the Council, Official Journal L 152 of 16 June 2009, pages 11–22.
• Commission Regulation (EC) No 37/2010 of 22 December 2009 on pharmacologically active substances and their classification regarding maximum residue limits in foodstuffs of animal origin, Official Journal L 15 of 20 January 2010, pages 1–72.
• Commission Implementing Regulation (EU) 2017/12 of 6 January 2017 regarding the form and content of the applications and requests for the establishment of maximum residue limits in accordance with Regulation (EC) No 470/2009 of the European Parliament and of the Council, Official Journal L4 of 7 January 2017, pages 1–7.
• Commission Regulation (EU) 2017/880 of 23 May 2017 laying down rules on the use of a maximum residue limit established for a pharmacologically active substance in a particular foodstuff for another foodstuff derived from the same species and a maximum residue limit established for a pharmacologically active substance in one or more species for another species, in accordance with Regulation (EC) No 470/2009 of the European Parliament and of the Council, Official Journal L135 of 24 May 2017, pages 1–5.
• 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, Official Journal L132 of 30 May 2018, pages 5–30.

Allowed substances for use in veterinary medicinal products intended for food-producing species are listed in Table 1 of the Annex to Commission Regulation (EC) No 37/2010, where the relevant MRL values or a "No MRL required" classification for the concerned target animal species and relevant foodstuffs are identified. The Annex is updated by Commission Regulations published regularly in the L-series of the Official Journal of the European Union (OJ) (see EUR-Lex).

Table 1 of the Annex to Commission Regulation (EU) No 37/2010 includes substances that are allowed in veterinary medicinal products for use in food-producing species and in biocidal products for use in animal husbandry.

For each substance the table includes either:

• definitive MRLs established for the relevant foodstuffs (these were previously in Annex I of Council Regulation 2377/90),
• provisional MRLs established for the relevant foodstuffs (these were previously in Annex III of Council Regulation 2377/90). Provisional MRLs can be established, for a defined period of time, when not all the requirements have been fully addressed. However, the outstanding issues should not relate to any major human safety concerns, so that it is possible to conclude that residues at the proposed levels do not present a hazard to the health of the consumer. Once the outstanding issues have been satisfactorily addressed, provisional MRLs are replaced by definitive MRLs,
• a statement that there is no MRL required (these were previously in Annex II of Council Regulation 2377/90). For these substances it is considered that it is not necessary to establish MRLs for the protection of human health. These substances may be used in veterinary medicinal products for food-producing species for the animal species identified and according to the conditions established, if any (e.g., specific route of administration).

For further details on the assessment of a substance, the reader should consult the European Public MRL Assessment Report (EPMAR, previously called the Summary Report) for the substance concerned.

Table 2 of the Annex includes substances that are prohibited for use in veterinary medicinal products for use in food-producing species and in biocidal products for use in animal husbandry (these were previously in Annex IV of Council Regulation 2377/90). Residues of these substances are considered to represent a risk to the safety of the consumer at any level or the data made available for the establishment of MRLs were insufficient to allow a recommendation.

In order to obtain the establishment of MRLs for a new substance an MRL application has to be submitted to the European Medicines Agency.

The procedure for the submission of an application for the establishment of MRLs is defined in Article 8 of Regulation (EC) No 470/2009 and further explained in Commission Implementing Regulation (EU) 2017/12 of 6 January 2017 regarding the form and content of the applications and requests for the establishment of maximum residue limits in accordance with Regulation (EC) No 470/2009 of the European Parliament and of the Council.

Applicants should notify the Agency of their intention to submit an MRL application. A letter of intent indicating the name of the substance, intended use, target specie(s) and intended submission date should be submitted to the Agency 6 months before the intended submission of the application for the establishment of MRLs. If the applicant has a valid micro, small and medium-sized enterprise (SME) status or a limited markets classification, this information should also be included. Applicants are advised to liaise with the Agency in order to agree on an adequate time delay between submission of the MRL application and submission of any related MA application.

Once the applicant has notified his intention to submit an application, the CVMP appoints a rapporteur and, if appropriate, a co-rapporteur. The applicant is notified of the appointment of the rapporteur (and co-rapporteur if appropriate), as well as of the preferred submission date (closest to the submission date identified by the applicant). For applications for extensions or modifications of MRLs, usually no co-rapporteur is appointed.

For an MRL application for a new substance a full dossier should be submitted respecting the requirements of Commission Implementing Regulation (EU) 2017/12 and following the methodological principles outlined in Commission Regulation (EU) 2018/782.

The practical aspects for submission of such an application are explained in the EMA standard operating procedure (SOP) on the evaluation procedure for applications and requests for the establishment or review of maximum residue limits (MRLs) (SOP/V/4150).

The establishment of MRLs for a new animal species requires the submission of an application for the extension of the existing MRLs to the new animal species. In such a case, normally only a residue file is required, because the acceptable daily intake (ADI) is the same regardless of the indications and target animal species. However, the procedure is essentially similar to that for full applications.

Extension applications may also make reference to the principles and criteria of the CVMP for extrapolating an MRL established for a pharmacologically active substance derived for one species or foodstuff to another foodstuff or species (MRLs in line with Article 5 of Regulation (EC) No 470/2009). These are described in Commission Regulation (EU) 2017/880. The CVMP uses the same criteria when evaluating extension applications.

In order to modify existing MRLs, a new application for their modification is required. The data required depend on the basis of the modification request. If the proposal is to amend the MRLs based on new residue data only, then no safety data would be required. However, if the intended modification of the MRLs is based on a request for the amendment of the acceptable daily intake (ADI) for the substance, the relevant safety data would also be required. An application for the modification should then be submitted to the European Medicines Agency under Article 3 of the Regulation (EC) No 470/2009.

When submitting an MRL application, a fee is payable to the European Medicines Agency as required by the legislation in force. Please refer to fees for MRL applications.

The legislation on fees (Council Regulation (EC) No 297/95) makes no distinction between fees for MRL applications for major species/uses or minor species/uses. However, Article 9 of the above mentioned Regulation provides, in principle, for the possibility of granting total or partial fee exemptions for veterinary medicinal products for the treatment of rare diseases affecting minor animal species or for extensions of existing MRLs to additional animal species. In particular, partial fee exemptions may be applicable for MRL applications for active substances used in products that have been classified as intended for a limited market (Art 4(29) of Regulation (EU) 2019/6) and for which the benefit of its availability on the market to animal or public health is greater than the risk inherent in the fact that less than usual data is provided (Art 23 of Regulation (EU) 2019/6). Further information on the classification of such products is available on the veterinary limited markets webpage of the Agency’s website.

In addition, applicants may request the Executive Director to grant an ad hoc fee reduction. Such requests are expected to be exceptional and require the applicant to justify that the request is made (1) in exceptional circumstances and (2) for imperative reasons of public or animal health. Further information is available in the Explanatory note on general fees payable to the European Medicines Agency, available via the 'fees payable to the European Medicines Agency' webpage of the Agency’s website.

The establishment of MRLs, as a legal provision in the EU, is the responsibility of the European Commission. Established MRLs are published on an ongoing basis in the L-series of the Official Journal of the European Union (OJ) (see EUR-Lex).

All opinions of the CVMP including MRL recommendations are summarised in the CVMP meeting highlights, which is normally published on the Friday following each CVMP meeting. In accordance to its policy on transparency, EMA also publishes summary opinions on MRL recommendations on its website following the CVMP meeting at which the opinion is adopted. The summary opinion includes the name of the substance, the target animal species, the MRL values in the relevant target tissues and any other provision, if relevant. These can be found under the following link

• Summary opinions pending EC decisions on MRLs listed by substance name

For substances included in the Annex to Regulation (EC) No 37/2010, European Public MRL Assessment Reports (EPMARs, previously called Summary Reports), on the scientific evaluations carried out by the Committee for Veterinary Medicinal Products (CVMP), are published on the European Medicines Agency website. These can be found under the following link:

• MRL assessment reports listed by substance name

Some substances included in Table 1 of Annex to Commission Regulation (EC) No 37/2010 with a "No MRL required" status were considered, at the time of the evaluation, as falling into the category of "Substances generally recognised as safe" (for further details please refer to Commission Regulation (EC) 2796/95 and Commission Regulation (EC) 1931/99;, neither of them still in force). The Committee for Veterinary Medicinal Products (CVMP) considered a "No MRL required" status for these substances based on the fulfilment of specific criteria ensuring consumer safety (e.g., rapid metabolism to simple organic metabolites such as carbon dioxide, acetic acid and ethanol, low oral bioavailability etc.). No individual European Public MRL Assessment Reports (EPMARs, previously called Summary Reports) are available for some of these substances.

CVMP Summary Opinions on the establishment of MRLs are normally published on the EMA website on the Friday following the CVMP meeting at which the opinion was adopted. The documents are withdrawn after publication of the relevant MRL regulation in the Official Journal of the European Union (OJ) (see EUR-Lex).

European Public MRL Assessment Reports (EPMARs, previously called Summary Reports) on substances for which MRLs have been established are published on the EMA website as soon as possible (usually within 2 weeks) after publication of the relevant MRL regulation in the Official Journal of the European Union (see EUR-Lex).

The question of whether the MRLs established for a racemic mixture apply to the individual isomers requires case by case consideration. Up to now the CVMP has considered the specific cases of:

• menthol
• ketamine
• ketoprofen

and concluded that for these cases the MRLs established for the racemic mixture also apply to the individual isomers.

Legislation (Regulation (EU) 2019/6) requires that all pharmacologically active substances contained in a veterinary medicinal product for food-producing species need to be allowed in accordance with Regulation (EC) No 470/2009 and any acts adopted on the basis thereof. It follows that the active substances as well as any other pharmacologically active ingredients (excipients including preservatives and adjuvants) need to be included in Table 1 of the Annex to Commission Regulation (EU) No 37/2010 and only substances that are considered not to be pharmacologically active do not.

Many excipients have been included in Table 1 of the Annex to Commission Regulation (EC) No 37/2010 with a "No MRL required" classification, while others, considered not to be pharmacologically active, have been entered into the list of substances considered as not falling within the scope of the Regulation (EC) No 470/2009, often called the "out of scope" list.

An excipient that is neither listed in Table 1 of the Annex to Commission Regulation (EC) No 37/2010 nor in the "out of scope" list, can only be used in a veterinary medicinal product intended for food-producing species if it is concluded that the substance cannot be expected to show pharmacodynamic activity at the dose at which it is/will be administered to the target animal.

In order to have an excipient included in the list of substances considered as not falling within the scope of Regulation (EC) No 470/2009, a request should be submitted to the Agency. Data requirements for such requests are laid out in the CVMP "Guideline on data to be provided in support of a request to include a substance in the list of substances considered as not falling within the scope of Regulation (EC) No 470/2009".

In the case of requests that do not require extensive evaluation, the CVMP may decide to include the substance in the "out of scope" list. In this case, no fee is charged. If a more in-depth scientific assessment is required, the applicant will be advised to make a formal request for scientific advice, in which case a fee for the scientific advice would have to be paid. Detailed guidance to applicants regarding scientific advice can be found on the European Medicines Agency website. The procedure for providing scientific advice to applicants is explained in the SOP on the "Evaluation procedure for CVMP Scientific Advice requests" (SOP/V/4016).

The applicant is advised to consider the MRL status of all product ingredients prior to the submission of the marketing authorisation application.

In some cases, particularly relating to branded excipients, the competent authority may accept inclusion of the relevant data in accordance with the CVMP guideline referred to above within the marketing authorisation application procedure dossier. In this case, the competent authority will conclude on whether the excipient falls within the scope of the Regulation (EC) No 470/2009 as part of the marketing authorisation application evaluation.

During the above considerations, it may be concluded that a maximum residue limit application is required, in which case a MRL application for the excipient should be submitted. See question 5 for further guidance on how such an application can be made.

The requirement to establish MRLs under Regulation (EC) No 470/2009 applies to pharmacologically active substances for use in veterinary medicinal products and to pharmacologically active substances for use in biocidal products for use in animal husbandry where residues may present a hazard to consumer health. Feed additives have a different authorisation procedure in the EU, established by different legislation (Regulation (EC) No 1831/2003) and Regulation (EC) No 470/2009 is not applicable to those substances. The European Medicines Agency is not responsible for the evaluation/authorisation of feed additives. Therefore, questions concerning feed additives and their conditions of use should be addressed to the European Commission in Brussels.

The establishment of withdrawal periods is part of the marketing authorisation procedure for each individual veterinary medicinal product and is not simply substance-related.

Information on the established withdrawal periods is accessible via the public portal of the Union Product Database established according to Article 55 of Regulation (EU) 2019/6.

Questions regarding withdrawal periods for veterinary medicinal products authorised nationally in a specific Member State should be addressed to the Competent Authority of the Member State concerned. Addresses of the Members States' Competent Authorities are available on the Heads of Medicines Agencies website (HMA National contacts).

The European Medicines Agency website contains numerous guidelines on data requirements and on the determination of withdrawal periods. Software applications for the calculation of the withdrawal periods in accordance with these guidelines are also available free of charge from the same section under the following pages: Determination of withdrawal periods for edible tissue - Scientific guideline and Determination of withdrawal periods for milk - Scientific guideline.

Biocidal substances are used in many different situations and residues of biocidal substances may potentially enter the food chain as a result of a number of these uses (including exposure of plants to biocides, exposure of food-producing animals to biocides and contamination of foodstuffs with biocides). Regulation (EC) No 470/2009 gives the Committee for Veterinary Medicinal Products (CVMP) responsibility for performing MRL evaluations for pharmacologically active substances used in biocidal products for use in animal husbandry, where such an evaluation is deemed necessary. All other aspects of the evaluation of biocidal products are outside the responsibility of CVMP but are undertaken by the Competent Authorities for biocides in Member States supported by ECHA and the Commission. The CVMP has published a guideline on the risk characterisation and assessment of MRLs for biocides (Risk characterisation and assessment of maximum residue limits (MRL) for biocides).

Regulation (EC) No 470/2009 elaborates the principles by which the European Commission can establish so-called "Reference Points for Action" (RPAs) for residues of pharmacologically active substances for which MRLs have not been (nor cannot be) established. It is important to stress that RPAs are NOT MRLs. RPAs are residue concentrations whose detection by food control laboratories is technically feasible. In the event that the RPA is exceeded, the Member State is obliged to reject the consignment as it cannot be legally placed on the EU market (see Article 23 of Regulation (EC) No 470/2009). Therefore, RPAs are established by the European Commission in order to set the harmonised standards for the monitoring of unauthorised substances.

MRLs established by third countries do not have any legal force in the EU. Therefore, substances that do not have EU MRLs cannot be used to treat food producing species in the EU.