Residues in Milk - Parasiticides and Drugs other than Antimicrobials

Residue Guideline No. 22
6 February 2001

Introduction

This guideline applies to milk residue trials for the registration of parasiticides and drugs other than antimicrobial drugs, regardless of the method of application or route of administration.  It is applicable to trials in cattle, sheep and goats, and is to be used in conjunction with the residue guidelines listed at the end of this document. Note that antimicrobial drugs are the subject of a separate guideline (Residue Guideline No 25: Residues in milk -  Antimicrobials).

The use of most chemicals and drugs in dairy animals will result in residues in milk. MRLs for parasiticides and drugs in milk are based on individual animal data, and should cover the biological variability that can occur from animal to animal, from farm to farm and from breed to breed.

Objective

The objective of this guideline is to provide guidance in planning residue trials in dairy animals, including those treated in the non-lactational (dry) period, for the purpose of proposing milk MRLs and withholding periods (WHPs).

In addition to the requirement for milk residue data covered in this Guideline, tissue residues in dams and their offspring must also be addressed. Guidance for tissue residue trials can be found in Guideline No. 23.  Further details on the establishment of MRLs and WHPs can be obtained from Guideline No's. 11 and 23.

General Requirements

Before residue trials can be undertaken with dairy animals, a residue definition must be determined based on the findings of metabolism studies and analytical methodology. The route of administration (oral drench, injection or topical application) must also be considered before proceeding with any metabolism studies.  Oral metabolism studies alone are unlikely to suffice for external treatments.  When the trial(s) are undertaken, the results should be adequate for the purpose of setting an MRL and for determining an appropriate withdrawal period following treatment during lactation, any pre-calving interval required, and any meat withholding period for calves/lambs/kids fed contaminated milk or for their dams.

In the case of treatments applied during the non-lactational period, the applicant should consider metabolism data to determine the likelihood of whether chemical residues  will occur in milk at the next lactation.  If residues are likely to occur, a similar study to that described below should be conducted.

When milk residue trials are necessary, at least one residue trial conducted in accordance with the proposed maximum treatment regimen should be undertaken. If trials are conducted in either the USA or the EU, they should fulfil the requirements for Australian registration.  However, for external treatments (where climate can affect residues) trials should be undertaken in Australia.  For trials conducted in Australia, milk from treated animals must not be used for human consumption or supplied for processing, unless it meets current MRLs as listed in the Food Standards Code.  Furthermore, milk from treated cows should not be fed to bobby calves without consideration of an appropriate meat withholding period for the calves. Additionally, APVMA permits will be required for such trials if use of the chemicals is otherwise illegal under State or Federal law.  Applicants should contact the APVMA/State Coordinator for further information. For those products where application to cows, ewes and nannies may result in exposure of foetuses in utero or the newborn via milk, data and/or argument must address tissue residues in the offspring.

All trials should be conducted under conditions as similar as possible to normal commercial operations, including use of the final commercial formulation.  When establishing MRLs and WHPs, the APVMA must consider the maximum treatment regime.  Accordingly, the residue study should include repeat treatments at the highest dose rate (usually for the lightest animal in the lowest weight range category), shortest interval and maximum number of treatments. Samples from individual animals should be collected and analysed.  For external treatments, the influence of climate will need to be considered when selecting suitable locations for the trial(s).

Trial results should be reported according to Residue Guideline No. 11: Reporting of residue trials.  Other guidelines that may be relevant and assist applicants include Residue Guidelines No. 1: Animal transfer studies, No. 3: External treatment of cattle with ecto-parasiticides and No. 16: Injectable veterinary products.

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Specific Requirements

Three aspects unique to dairy cows that need to be addressed in any submission for registration are:

  1. The possibility of a treated dry cow rejoining the milking herd prematurely, soon after dosing, and her milk entering the farm milk supply.
  2. The occurrence of residues in calves as a result of access to milk from treated cows, either from suckling during the first few days post partum or being fed discarded milk.
  3. The occurrence of in utero drug transfer resulting in tissue residues in bobby calves.

These same principles apply to studies involving goats and sheep and the same issues must be addressed.  Although the following paragraphs refer specifically to calves, the principles also apply to lambs and kids.

In the scenarios described above, the milk may contain residues rendering it unsuitable for human consumption and/or leading to the condemnation of calves that have suckled their dams early post partum.  Without the establishment of a meat WHP for bobby calves, the presence of residues in the milk may also render the milk unsuitable for consumption by calves removed from their mothers. Therefore, the residue trials must establish the minimum recommended treatment-to-calving interval during which application/administration of a parasiticide or drug is appropriate.  In this regard, normal animal husbandry practices must be considered.  Pre-calving intervals that approximate the period between drying off and calving increase the risk of violative milk residues, should cows calve early.  Long pre-calving intervals are therefore unacceptable.  Generally, pre-calving intervals of up to 42 days will be acceptable.  For sheep and goats, pre-lambing/kidding intervals should not exceed 35 days.

When milk is destined for human consumption or for feeding to calves destined for human consumption, the trials must also establish the maximum period post partum when milk could contain residues greater than the MRL.  As most calves destined for human consumption are allowed to suckle their dams or consume milk taken from treated cows, tissue residues in calves must be addressed by data and/or argument.  A simple calculation based on the residue likely to be consumed by the calf and the tissue residues likely to result generally suffices.  In some cases, it may be possible to establish a meat WHP for calves that have consumed milk from treated cows based on available data and/or argument.  In other cases, it may be possible to use a label restraint statement to address the likelihood of tissue residues occurring.

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Animals

Drenches and Injections

For milk residues, one trial with a minimum of twenty (20) animals will be acceptable.  The trial should take into account relevant factors such as the fat content of the milk and the volume of production.  Both low and high volume production cows/ewes/nannies, with a minimum of 5 animals at the production extremes, should be included in the trial. Production levels should be representative of those reported for Australia.

External Applications

Climate can affect the residues resulting from external treatments.  Therefore, it is preferable two trials be conducted at two geographically separated dairy farms in Australia.  At each location, ten healthy animals should be randomly selected. Both low and high volume production cows/ewes/nannies, with a minimum of 3 animals at the production extremes, should be included in the trial. Production levels should be representative of those reported for Australia.  Each animal should be identified individually, and its breed, age and weight recorded.  In situations where trial animals are brought onto the farm from another area, the animals should be acclimatised for a period of two weeks before treatment.

After treatment, all animals should be kept together according to the normal husbandry practices on the farm, except  where the test treatment is externally applied to only part of the herd.  The treated animals should be physically separated from the remainder of the herd.  This is to ensure that licking and other direct contact does not affect absorption and subsequent excretion into the milk, and to prevent contamination of the remainder of the herd.

The report of the trial should include details of the facilities and the feeding practices. Details of the experimental animals to be included are: species, breed, weight, age, pregnancy status, stage of lactation, milk production, fat content of milk, number of animals treated, date and time of treatment(s), dates of calving, animal health during the study.

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Application

The test material should be the commercial formulation.  The accuracy of any applicator should be determined at the beginning and end of application.  Any prepared solution should be sampled and analysed to confirm that the treatment was at the prescribed rate.

Each animal is treated as described on the label (or proposed label) directions. The residue study should address the maximum treatment regime.  That is, data are required on repeat treatments at the highest application rate, shortest interval and maximum number of treatments.  In the case of non-lactating animal treatments, the product should be applied at the point in the dry period expected to result in the highest level of residue when the animal comes into lactation.  There is no requirement to determine residues at lesser applications.  Where daily exposure (eg back rubbers and dust bags) or continuous exposure (eg ear tags, boluses and implants) is involved, sufficient sampling is required to show when residues plateau in milk.  An adequate number of time points at the plateau concentration is required (3 or 4 generally are acceptable).  This allows the maximum concentration in milk to be established prior to the commencement of depletion.

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Sample Collection

When sampling, all udder quarters should be milked out, the whole sample mixed thoroughly, and a sub-sample taken.  Appropriate records must be maintained to verify the validity of the sampling programme.  In addition, the fat content of all milk samples analysed should be determined by gravimetric or Babcock method (eg AS 2300.1.3-1988 or AS 2300.1.4.2-1988) to demonstrate the validity of sampling. It will be necessary to ensure that procedures are adopted to prevent cross-contamination between treated animals during the milking process e.g. flushing out of the milking lines between animals; ensuring that in handling the animals, cross-contamination between skin (hide) and udder does not occur.  Care will need to be taken in rainy weather, or when overhead sprinklers are used to cool cows in hot weather, that pour-ons do not wash from the backline onto the udder.  Normal dairy hygiene practices should be adopted.  Sample containers will, as a minimum, be labeled with the information indicated in Figure 1.

Figure 1 - Suggested label for samples

Figure 1: Suggested label for samples

Duplicate milk samples (200 mL each for residue and fat determinations, respectively) will be taken from individual animals:

  • at the morning OR afternoon milking on the day before treatment, and
  • at the morning AND afternoon milking on sufficient days after treatment to show the peak and the decline of the residues which comprise the residue definition. 

Larger samples could be required if the chemicals partition into the milk fat.

The time points for sample collection can be suggested by metabolism data.  The morning and afternoon samples taken on the same day are to be handled and analysed separately (i.e. NOT combined).  Milk samples from different animals must not be pooled.

The fat solubility of a chemical should be considered before analysing milk samples.  The FAO Manual [1] gives guidance as to fat solubility as follows:

  • the octanol-water partition coefficient should be the prime indicator of fat-solubility, supplemented by inferences which may be drawn from the distribution of residues between fat and muscle tissues, when the residue consists of a single compound.  In cases where the residue is defined as a mixture
  • information on the log POW of the individual compounds should be considered if available.

In general, when log POW exceeds 4 the compound would be designated fat soluble, and when log POW is less than 3 it would not be so designated.  Pesticides with intermediate log POW would be considered on a case-by-case basis.

Residue analysis must be conducted and reported on whole milk, except in the case of fat-soluble chemicals, where analyses should be done on the fat portion of the milk and the residues expressed on a fat basis.  Records of milk volume and butterfat should be submitted with trial data for the individual cows for the period before and during the collection period.

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Storage Conditions after Collection

Milk samples should generally be maintained at 4°C and sent to the analytical laboratory within 24 hours of collection. In situations where longer periods of storage at either 4°C or <0°C are necessary, storage stability studies will need to be conducted (refer to Residue Guideline No. 8: Stability of residues during storage). The storage temperature must be reported.

Please note: For fat soluble compounds, the fat should be separated from the aqueous layer of the milk prior to freezing as some changes can occur in the milk that make the separation task difficult when using milk previously frozen.

The information relating to the storage of samples which needs to be submitted includes the date of sample collection, the date of dispatch to the analytical laboratory, the date of receipt by the laboratory, storage conditions during transport and  while awaiting analysis, and the date of analysis.

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Fate of Residues During Processing

The partitioning of parasiticides and other veterinary drugs between the aqueous phase and milk fat of whole milk must be studied and reported. The degree of partitioning will determine  the importance of the residue concentration in processed milk products such as butter, ice cream and cheese.  A partitioning study, involving a minimum of two samples, needs to be submitted.  This study is best accomplished on samples where residues in milk are at a maximum.

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Residue Analytical Method

Residue Guideline No. 19: Residue analytical method should be consulted. The analytical method for milk residue trials must address the residue definition and be validated.

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Extrapolation of Findings Between Animal Species

A general milks MRL entry will be considered when adequate residue data are provided for cattle plus sheep, or cattle plus goats.

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Relevant Residue Guidelines Cited

Residue Guideline No. 1: Animal transfer studies

Residue Guideline No. 3: External treatment of cattle with ecto-parasiticides

Residue Guideline No. 6: Definition of residues for the purpose of setting an MRL

Residue Guideline No. 8: Stability of residues during storage

Residue Guideline No. 11: Reporting of residue trials

Residue Guideline No. 16: Injectable veterinary products

Residue Guideline No. 19:  Residue analytical method

Residue Guideline No. 23:  Data requirements for animal tissue residue trials

Residue Guideline No. 25:  Residues in milk - antimicrobials

For more information contact: APVMA Residues Section


1. FAO Manual on the submission and evaluation of pesticide residues data.  Rome 1997.

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