Withdrawal period refers to the minimum period of time from administering the last dose of medication and the production of meat or other animal-derived products for food. It ensures that food does not contain residues of pharmacologically active substances in excess of the maximum residue limit (MRL).

If no numerical MRLs are set, the relevant health-based reference value (e.g. ADI) may not be exceeded. This will ensure that there are no residues in food obtained from treated animals, i.e. meat, milk, eggs and honey, which may be harmful for the consumer.

Withdrawal periods are set based on study data provided by the applicant with the authorization application dossier. As withdrawal periods do not only depend on the active ingredient itself, but also on the excipients, the dosage form, treatment duration and route of administration, they refer to a specific veterinary medicinal product. Within residue depletion studies the elimination of pharmacologically active substances contained in a veterinary medicinal product is examined.

Within these residue studies, animals are treated with the veterinary medicinal product at the highest intended dose. Groups of animals are slaughtered at various time intervals after the last treatment and marker residue concentrations in samples from muscle, liver, kidney and fat are analysed. If the veterinary medicinal product is intended for use in animals producing milk, eggs or honey, residue studies for these food commodities are also needed. As absorption, distribution, metabolism and elimination of pharmacologically active substances differ between species, usually residue depletion studies for all requested animal species need to be provided. .

Withdrawal periods are set using statistical approaches such as (log-) linear regression analysis of residue data from edible tissues. Within this concept withdrawal period is defined as the time point when the 95% tolerance interval of residues concentrations is below the MRL with 95% confidence. A similar tolerance limit can be obtained from residue data in milk, based on the time points when residue concentrations per animal deplete below the MRL.

If statistical approaches cannot be applied to the available residue data, the so called “alternative approach” may be used. The period between last treatment and first time point, when residue concentrations in all tissue samples deplete to below the resp. MRL is used as point of departure. To account for biological variability and other factors, a safety span of usually 10 to 30% of that period is added.

For edible tissues one withdrawal period per species is set. Withdrawal periods are given in days or for milk in hours.

In case veterinary medicinal products are intended for subcutaneous use and/or intramuscular use, residue concentrations at injection sites have to be taken into account separately. Degradation or release of pharmacologically active substances from injection sites depends on various factors, such as physico-chemical properties of substances, their formulation (e.g. fast-acting versus long-acting formulations) as well as type and place of injection. In addition to samples from normal muscle, samples from injection sites according to a fixed sampling scheme (see EMA GL on injection sites residues) need to be collected and residue concentrations are measured.
Withdrawal periods for edible tissue have to ensure that residue concentrations at injection sites deplete below the MRL resp., if available, below the injection sites residue reference values (ISRRV).

Further information on conduct of residue depletion studies (e.g. number of animals, study design, sampling) and estimation of withdrawal periods can be taken from the scientific guidelines on safety and residues listed on the EMA webpage (see sections “Residues and Withdrawal Periods”).

Animal owners are responsible for compliance with withdrawal periods. To control for compliance with MRLs and to detect the illegal use of prohibited or unauthorized substances, a Multiannual National Control Plan has been established. The program has been carried out for food of animal origin since 1989 and is coordinated by the BVL.

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