The withdrawal period; a guideline

For all veterinary medicinal products intended for food producing animals, a withdrawal period has been determined. This is however an advice rather than a period set in stone. In this article we will explain what a withdrawal period is and which factors can be of influence. Additionally, we will provide two examples to demonstrate the importance of a good understanding of this subject in everyday practice.

What is a withdrawal period?

The withdrawal period is the time period required after cessation of treatment to assure that drug residues in animal products are below the Maximum Residue Limit (MRL).

The advised withdrawal period is based on the use of veterinary medicines according to the product registration and was determined in healthy animals. The advised product withdrawal period is the minimal withdrawal period that should be applied. Veterinarians prescribing the treatment can advise to prolong the withdrawal period when they deem this necessary.

Which factors can influence the withdrawal period?

There are several factors that can influence the withdrawal period.

Diseases

Several diseases can result in a slower elimination rate of medicinal products. Primarily liver and kidney disease are known risk factors; they might delay elimination and therefore prolong the withdrawal period.

Drug combinations

The pharmacokinetics of a veterinary medicinal product can be influenced by other medicines which are administered before, together with or after the veterinary medicinal product issued. Prolongation of the elimination period occurs in particular when you combine veterinary medicinal products that are excreted via the same elimination route.

Treatment repetition

When the treatment is repeated immediately or shortly after the first treatment period, this may result in accumulation of the active substance in the body.

Acidification of the drinking water

Acidification of the drinking water is sometimes used to increase the solubility and stability of veterinary medicinal products. It can however also increase the biological bioavailability of the drugs and therefore prolong the withdrawal period. Only when veterinary medicinal products already contain citric acid or another acid as part of their formulation, the marketing authorisation holder has taken this into account when determining the advised withdrawal period.

Contamination of the drinking water system

Medicinal residues can stick to contaminants in the drinking water system and when acids are then used post treatment, these residues can re-dissolve. This means that the animals are exposed to the active substances again after the treatment is supposed to have been ceased already.

Not completely emptying the bulk tanks

When bulk tanks are used it is important to empty the tanks completely before the water tap is opened again. This will prevent dilution of the product with clean drinking water and thus the exposure of animals for prolonged periods of time.

Cascade and off label use

When veterinary medicinal products applied via the cascade are used to treat other species than those mentioned in the registration, it is mandatory to maintain a withdrawal period of at least 7 days for milk and eggs and 28 days for meat. When veterinary medicinal products are applied for a different indication, but for a species mentioned in the registration, it is officially not needed to adjust the withdrawal period. A different off label indication can however influence the withdrawal period by altering/influencing the rate of elimination. In such cases it is advised to prolong the advised withdrawal period after all.

Veterinary medicinal products should be administered according to the product characteristics. When it is however needed to administer a veterinary medicinal product in a different dosage or via a different method in the context of Good Veterinary Practice, it can be needed to derogate from the registration. In these cases it can be needed to adjust the withdrawal period too. This is preferably done based upon trials in which the pharmacokinetics of the medicinal product in that dosage and for that route of administration are determined in the animal species treated.

Two examples

Below you can find two examples to demonstrate the importance of withdrawal periods in everyday life.

Acidification of the drinking water

Acids are often used to improve the solubility and stability of veterinary medicinal products, such as doxycycline containing products. Dopharma’s Doxylin® 50% WSP already contains citric acid and under normal circumstances it is not needed to add extra citric acid. However, when other doxycycline products are used, it is often necessary to use an acid as water conditioner. Some acids are also used on their own, such as Vitamin C.

The addition of acids to the pre-solution as well as the separate use of acids can influence the withdrawal period. When acids are used together with antibiotics, the biological bioavailability of the antibiotics administered can be increased. When acids are used after completion of the antibiotic treatment, they can re-dissolve residues of veterinary medicinal products that are present in the drinking water system. Animals will then be exposed again. Depending on the concentration of the residues in the drinking water and the period until slaughter this can result in residues.

Benzylpenicillins and the Delvotest

When the Delvotest is used to determine the presence of benzylpenicillin in milk, residues are sometimes found whilst the withdrawal period has been respected. False positive testing results can be the explanation for this. Please find below three factors that can cause false positive results when using the Delvotest.

The detection level

The MRL of benzylpenicillin in milk is 4 μg/kg (4 ppb). The detection level of the Delvotest is however much lower than this. The Delvotest detection level for benzylpenicillin appears to be roughly 1 ppb, which is only one fourth of the MRL.

Contamination
Research at Dopharma’s laboratory showed that the Delvotest showed positive results on some samples which did not contain any antimicrobials. These false positives were the result of contamination. Despite all precautions (use of new materials, clean working environment, etc.) contamination resulted in false positive results. This even occurred under laboratory conditions. It can therefore be concluded that the Delvotest is very sensitive to contamination.

Natural inhibitors

The product description of the Delvotest mentions that milk can contain some natural inhibitors such as lactoferrin or lysozymes. These molecules can also result in false positive test results.

The Delvotest does not seem to be sensitive to the presence of disinfectants in the milk. One disinfectant that can be used to disinfect the udder after milking has been studied in our laboratory: 4XLA.

The Delvotest is a non-specific, qualitative test and a correct and reproducible quantification of benzylpenicillin in milk to determine if this exceeds the MRL is therefore not possible. The Delvotest appeared to be extremely sensitive to contamination and all precautions should be taken to avoid contamination when using this test.

When the result of the Delvotest is positive it is advised to do a confirmatory re-test. The milk can be heated (a few minutes at 80˚C) to neutralise some contaminants. The milk that has to be tested can also be diluted with milk from the tank (in a ratio of 1:3) to decrease the sensitivity of the test to the level of the MRL.

The Delvotest appears to be the most commonly used test, but there are several other similar tests on the market. Dopharma has not performed any laboratory tests with those tests. However, looking at the specifications of several other tests, the same problems are to be expected. The sensitivity of most tests is at or below the MRL which means that you can expect positive test results whilst the level of the antibiotic(s) examined is still below the MRL.

References

  • Huyghebaert, A. (2006), Advies 42-2006 (Wetenschappelijk Comité van het Federaal Agentschap voor de Veiligheid van de Voedselketen, Brussel).
  • Dutch legislation: Wet dieren, Besluit diergeneesmiddelen en Regeling diergeneesmiddelen.
  • European legislation: Directive 2001/82 and Regulation EEG nr 37/2010.
  • Reference picture: Different kinds of meat, eggs and two bottles of milk – Image by © Imagemore Co., Ltd./Corbis