Maximum residue limits (MRL)

The maximum residue limit (MRL) is the maximum allowed concentration of a residue in a food product obtained from an animal that has received a veterinary medicine or that has been exposed to a biocidal product for use in animal husbandry.

The European Medicines Agency's (EMA) Committee for Veterinary Medicinal Products (CVMP) is responsible for recommending MRLs, which, when adopted by the European Commission, become legally binding food safety standards. EMA provides guidance on establishing MRLs and submitting an application.

The European Union (EU) requires by law that foodstuffs such as meat, milk or eggs must not contain residue levels of veterinary medicines or biocidal products that might represent a hazard to the health of the consumer. Regulation (EC) No 470/2009 lays down the rules and procedures for the establishment of MRLs.

Before a veterinary medicine intended for food-producing animals is authorised in the EU, the Committee for Veterinary Medicinal Products (CVMP) evaluates the safety of its pharmacologically active substances and their residues and recommends MRLs. The Agency has published scientific guidance relevant to the establishment of MRLs for veterinary medicines.

Similarly, the CVMP is responsible for establishing MRLs for pharmacologically active substances in biocidal products for use in animal husbandry. Whilst the same principles and guidelines apply to the establishment of MRLs for pharmacologically active substances in medicines and in biocides, the Agency has published additional guidance on the risk characterisation and assessment of MRLs for biocides.

Active principles of biological origin used in immunological veterinary medicines fall outside the scope of the Regulation (EC) No 470/2009 and are therefore exempt from an MRL evaluation.

Certain other biological substances may not require a full MRL assessment.

Substances considered not to exert pharmacological effects (non-active substances) may also be considered to fall outside the scope of Regulation (EC) No 470/2009 and thus are also exempt from an MRL evaluation.

Human dietary exposure to residues: public consultation (new)

EMA and the European Food Safety Authority (EFSA) sought comments on a harmonised approach to the assessment of dietary exposure to residues of veterinary medicines, feed additives and pesticides in food of animal origin.

EMA together with EFSA released the report for public consultation in June 2022.

All interested parties, including pharmaceutical companies, were invited to comment until 13 September 2022.

    The assessment of dietary exposure is used by EMA in the establishment of maximum residue limits for pharmacologically active substances of veterinary medicines.

    It is also used by EFSA in its work on feed additives and pesticides

    The report compares available models of consumer exposure, making recommendations that EMA and EFSA will use to develop their harmonised approaches. This is necessary to address inconsistencies in dietary exposure assessment in the EU that stem from different regulatory frameworks and scientific approaches.

    The draft report was developed by a working group including CVMP experts. This followed a mandate issued by the European Commission in 2020.

    Assessment criteria and extrapolation

    As of 19 June 2018, Commission Regulation (EU) 2018/782 describes the methodology to be used in the scientific risk assessment and establishment of risk management recommendations relevant to MRL applications. These rules replace previous guidance on MRLs as outlined in Volume 8 of 'The rules governing medicinal products in the European Union' .

    As of June 2017, Commission Regulation (EU) 2017/880 sets out the principles and minimum criteria for the extrapolation of an MRL to either another foodstuff from the same species or to the same foodstuff from another species.

    When finalising an MRL evaluation, the CVMP routinely considers if its conclusions can be extrapolated to additional species and foodstuffs, regardless of whether the applicant has specifically requested this. This aims to increase the availability of veterinary medicines.

    The CVMP uses the same criteria when evaluating extension applications.

    Post assessment

    The Agency sends the CVMP opinion on the MRL application to the European Commission, which confirms the classification of the substance by including it in the annex to Commission Regulation (EU) No 37/2010

    Substances that may be used in veterinary medicines for food-producing species or biocidal products for use in animal husbandry are listed in table 1 (allowed substances) of the annex with the following information:

    • the definitive MRL to be applied to each food commodity; or
    • provisional MRL to be applied to each food commodity. This classification is established for a defined period and only in those cases where there are no grounds for supposing that residues of the substance at the level proposed will present a hazard to the health of the consumer but where further information is still required in order to finalise the evaluation of the substance; or
    • a statement that no MRL is required - for substances where residues at the predicted levels do not pose a hazard to the health of the consumer.

    Substances considered to represent a hazard to the health of the consumer at any level are included in table 2 (prohibited substances) of the annex. These substances must not be used in veterinary medicines for food-producing animals or in biocidal products for use in animal husbandry.

    Publication of information on MRLs

    The Agency publishes the following information on MRL assessments:

    • A brief statement on the adoption of an opinion recommending the establishment of an MRL in the corresponding CVMP meeting highlights.
    • A summary opinion of the CVMP on the MRL for those substances for which a recommendation is made to the European Commission.
    • The CVMP MRL opinion for substances evaluated after the entry into force of Regulation (EC) No 470/2009 on 6 July 2009.
    • A European public MRL assessment report (EPMAR) containing more detailed information on the CVMP's evaluation following the publication of the Commission Regulation.

    Biological substances not requiring an MRL evaluation

    Biological substances other than active principles of biological origin used in immunological veterinary medicines can be either 'chemical-like' or chemical-unlike'.

    'Chemical-like’ substances present similar concerns to chemical substances and are subject to a full MRL assessment.

    ‘Chemical-unlike’ substances are more complex substances that may contain multiple chemical types whose residues can be cells, amino acids, lipids, carbohydrates, nucleic acids and their breakdown products. The CVMP decides on a case-by-case basis whether 'chemical-unlike' substances require a full MRL assessment.

    For full details, see Annex I.6 of Commission Regulation (EU) 2018/782.

    Applicants who consider that a biological substance is ‘chemical-unlike’ can submit an application to vet.applications@ema.europa.eu for the CVMP to evaluate the need for an MRL assessment.

    The application should include a report and supporting information explaining the scientific basis for the request. It should also address the points in Annex I.7 of Commission Regulation (EU) 2018/782.

    Applicants should notify EMA that they intend to apply at least two months before submitting their application, by emailing the following information to  vet.applications@ema.europa.eu:

    The evaluation has a:

    • 60-day timetable if the CVMP does not require further information from the applicant;
    • 90-day timetable if the CVMP requires further information from the applicant and adopts a list of questions

    EMA charges a fee for evaluating the application. It invoices the fee to the applicant's address after it has validated the application.

    When the outcome of the assessment is that the biological substance does not require a full MRL evaluation, EMA publishes a summary of the CVMP's assessment and includes the substance in the following list:

    Summaries of CVMP assessments to determine whether a substance may be included in the list of biological substances considered as not requiring an MRL evaluation

    Substances considered not to exert pharmacological effects

    Non-active ingredients considered not to exert pharmacological effects, including many excipients, are considered to fall outside the scope of the MRL Regulation.

    The CVMP determines on a case-by-case basis whether a non-active ingredient exhibits pharmacological effects and poses a risk to the consumer. If the CVMP concludes that no MRL evaluation is required, EMA includes the substance in the following list:

    Applicants who consider that a component of their product is not pharmacologically active can submit a request to the CVMP to have the substance included in the above list. For more information, see:

    Submitting an MRL application

    Applicants need to submit an application to EMA to have an MRL established for a new pharmacologically active substance or to extend an existing MRL to a new animal species.

    EMA charges a fee for MRL applications. It may grant a total or partial fee exemption for veterinary medicinal products classified as eligible for authorisation according to Article 23 of Regulation (EU) 2019/6, i.e. applications for limited markets.

    Pre-submission guidance

      Applicants should:

      • submit the MRL application at least 6 months before the marketing authorisation application;
      • notify EMA in writing of the name of the substance, the intended use (indication), target species and intended target submission date, at least 6 months before the intended submission of the MRL application. If the company has a valid micro, small and medium-sized enterprise (SME) status or a classification as eligible for authorisation according to Article 23 of Regulation (EU) 2019/6, they should include this information in the notification.

      The data requirements and dossier structure are laid down in Commission Implementing Regulation (EU) 2017/12.

      Applicants can request the clarification on specific issues and/or a pre-submission meeting by writing to vet.applications@ema.europa.eu. Requests for pre-submission meetings should include details of the intended application, including:

      • substance and species
      • nature of the application i.e. full application / extension / modification
      • preferred dates for pre-submission meeting
      • names and affiliation of participants
      • specific questions for discussion.

      EMA provides more pre-submission guidance in the form of questions and answers.

      Submission of the application

      For submitting an application applicants should use the MRL application form and consult the recommended submission dates:

      Applicants need to submit their application through the eSubmission Gateway / Web Client portal. For more information and guidance on registration with the system, see the Veterinary eSubmission website.

      The submission procedure is defined in Article 8 of Regulation (EC) 470/2009 and further described in Commission Implementing Regulation (EU) 2017/12.

      For information on the practical aspects of the submission of the application and its evaluation, see:

      Questions and answers

      How useful was this page?

      Add your rating
      Average
      6 ratings
      2 ratings
      3 ratings
      2 ratings