Guidelines for Evaluation of Safety and Efficacy of Teat Dip Formulations

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1. Introduction

For the purpose of these guidelines a "teat dip" is defined as a liquid formulation designed for dipping cows' teats at each milking in order to reduce the incidence of new intra mammary infections (IMI).

Teat dips are considered to be drugs as defined in Section 2 of the Food and Drugs Act. Drugs that have not previously been sold in Canada are considered to be 'New Drugs' as per Section C.08.001 of the Food and Drug Regulations. In order to sell a new drug in Canada, a manufacturer must comply with Section C.08.002 of the Regulations to receive a Notice of Compliance and a Drug Identification Number prior to its sale.

Teat dips that function only as a physical barrier may be subject to Medical Devices Regulations, whereas those functioning both as a drug and a physical barrier may be subject to both sets of regulations.

These guidelines are of a general nature and are subject to revision from time to time depending upon advances in the state of the art.

2. Evaluation of Safety

2.1. General Safety

Teat dips should be non-irritating and non-sensitizing to the skin of the user and the treated cows.

Where appropriate, separate studies may be required to assess skin irritation and skin sensitization. Irritation studies should be conducted on intact and abraded skin of albino rabbits. Skin sensitization is best studied in albino guinea-pigs. In addition to the above studies, eye irritation studies may be required.

2.2. Human Safety

2.2.1. Drug Toxicity

For basic laboratory animal toxicity data required for a new drug submission a reference may be made to section 3.3 of the Drugs Directorate Guidelines for the Preparation of Veterinary New Drug Submissions.

Ideally teat dips should have minimal absorption through the skin and their use should not result in excretion of the active ingredients in milk. Any absorption which might occur under actual conditions of use must be considered undesirable as it might result in toxic effects. The extent to which toxicity might result is usually evaluated by tests conducted in an animal model of a different species. The test material is applied to about 10% of the body surface of albino rabbits. If there is evidence that the teat dip is absorbed to a substantial extent by the skin, then additional toxicity studies in laboratory animals may be required.

2.2.2. Drug Residues

Residues in milk of the active ingredient(s) of a teat dip may result from its absorption via the skin or may result from direct contamination following the use of the dipping solution. Hazards to human health can result from the presence of such residues in milk or in edible tissues consumed as food.

Studies will be required to determine residues in milk, of the active ingredient(s), and in certain cases those of excipients, of a teat dip. Bucket milk samples from six cows should be collected for analysis before starting the use of the teat dip and following 2, 4 and 6 weeks of its recommended use on cows.

In addition, if there is evidence that a teat dip which is absorbed through the skin is likely to accumulate in tissues of cows, then studies may be required to determine residues of its active ingredients in edible tissues of treated cows.

2.2.3. Analytical Methods

A description of analytical methods must include details of assay procedures used to measure residues of the active ingredient(s), and excipients when required, in milk or tissues.

All raw data obtained on control, spiked and treated milk samples including data on detectability and recovery of the drug should be submitted. Results indicating the levels of drug residues in the milk or in the edible tissues during a set period of time, such as 6 weeks, should be given in tabulated form.

2.3. Safety in the Intended Species

The safety of teat dips when used according to label recommendations in cows should be studied in complete herds in several geographic locations in Canada or under conditions of climate and management resembling those in Canada. At least one study should cover the complete fall season and may extend into the winter months to identify any adverse effects of the interaction between the test teat dip and adverse environmental conditions. The remainder of the studies should last for a minimum of four weeks. Additional studies may be required to reflect special conditions of use.

Observations on the condition of the teats and teat ends should be made by a veterinarian one week before starting a study and at regular intervals during the study. Teat condition should be recorded whenever clinical mastitis occurs during the study. During the first month of the study the observations should be made at weekly intervals and thereafter the observations should be made at monthly intervals. The observations should include examinations for dryness, scaling, chapping, sores, pox lesions, teat erosions and proliferative growths around the teat orifice.

These studies may be combined with studies conducted to assess the "Efficacy Under Natural Exposure (Field) Conditions" outlined under 3.2.2.

2.4. Safety in Intended Species for a Preclinical Submission

Data showing lack of irritation of rabbit skin will be considered adequate for pre-or post-milking use of a proposed teat dip formulation. However, when a teat dip is recommended for both pre- and post-milking use, data obtained from at least one study conducted in dairy cattle will be required to show lack of irritation following the recommended use of the proposed teat dip for a minimum of four weeks. This safety study in dairy cattle may be combined with the drug residue studies described in section 2.2.2., above.

3. Evaluation of Efficacy

3.1. In-vitro Antimicrobial Activity

3.1.1. Antimicrobial or Germicidal Activity in the Absence of Organic Load

Antimicrobial activity of teat dips should be determined by using a suitable standard method, such as:

3.1.1.1. Phenol coefficient method for phenolic compounds,

3.1.1.2. Use dilution method for disinfectants that are miscible with water (to determine the maximum dilution effective for intended use),

3.1.1.3. Available chlorine germicidal equivalent concentration method for water-miscible chlorine disinfectants,

3.1.1.4. Test for determining activity of germicidal and detergent sanitisers as modified by the U.S. National Mastitis Council Inc.

3.1.2. Antimicrobial or Germicidal Activity in the Presence of Organic Load

Tests should be conducted to ascertain that a proposed teat dip maintains adequate biocidal activity under varying conditions of organic load, such as with 2, 5 or 10% whole milk added to the teat dip being tested.

3.2. In-vivo Efficacy

Studies are required to demonstrate that the teat dip is efficacious in reducing the incidence of new IMI significantly (P<0.05) or by at least 50%. A manufacturer may use a judicious combination of studies conducted under experimental and natural exposure conditions. The in-vivo efficacy studies conducted according to the label recommendations may be combined with the studies conducted to demonstrate "Safety in the Intended Species" outlined under section 2.3., above.

3.2.1. Efficacy Under Experimental Exposure Conditions

3.2.1.1. Post-milking Teat Dips

Efficacy studies conducted under experimental exposure conditions may consist of:

3.2.1.1.1. repeatedly exposing all teats of test cows to a known mastitis pathogen or a mixture of pathogens, suspended in milk at a known concentration, immediately after removing the milking machine for five to seven days a week;

3.2.1.1.2. applying teat dip to one front and one rear teat of the udder in the test teat dip, immediately following the exposure to bacterial suspension, while keeping the remaining two teats as undipped controls;

3.2.1.1.3. Appropriate negative and positive control; and

3.2.1.1.4. la comparaison du nombre d'infections intramammaires nouvelles qui pourraient survenir dans les quadrants de pis dont les trayons sont traités ou non traités, à l'aide de méthodes statistiques appropriées.

3.2.1.2. Pre-milking Teat Dips

In most situations pre-milking use of a teat dip will be additional to the use of a post-milking teat dip. In such cases combined use of pre- and post-milking dipping may be compared with the post-milking use of the teat dip. However, it is possible that a manufacturer may want to market a teat dip for pre-milking use only. Efficacy studies for teat dips recommended for pre-milking use may consist of:

3.2.1.2.1. repeatedly exposing all teats of test cows to a known mastitis pathogen or a mixture of pathogens, suspended in milk at a known concentration, immediatelybeforemilking and immediately after removing the milking machine;

3.2.1.2.2. applying teat dip to one front and one rear teat of the udder in the test teat dip, immediately following the pre-milking exposure to bacterial suspension, while keeping the remaining two teats as undipped controls; and

3.2.1.2.3. the guidelines 3.2.1.1.3. and 3.2.1.1.4., above, apply.

3.2.2. Efficacy Under Natural Exposure (Field) Conditions

Studies to assess the efficacy of a teat dip in preventing new infections under field conditions should be conducted in a minimum of two complete herds in each of the controlled clinical or field trials using adequate numbers of cows (3,4,7,). For testing under field conditions, a positive control group, treated with an acceptable teat dip, may be included.

Efficacy trials under natural exposure conditions may consist of:

3.2.2.1. dipping the teats of half of the cows in a herd in the test teat dip according to label recommendations while keeping the teats of the remaining cows as undipped controls;

3.2.2.2. monitoring treated animals for general condition, udder health, adverse reactions and side effects; and

3.2.2.3.comparing the number of new IMI's which may occur in udder quarters with dipped and undipped teats, by using appropriate statistical procedures.

3.2.3. Generic Teat Dips

A teat dip having the same active ingredient(s) as a currently marketed teat dip may be compared with the marketed teat dip to demonstrate bioequivalence to it. The marketed product should preferably be the innovator's product that has received a Notice of Compliance pursuant to Section C.08.004 of the Regulations.

3.2.4. Preclinical/Investigational Submission

3.2.4.1. In vitro Antimicrobial Activity tests as outlined under 3.1., above.

3.2.4.2.Antimicrobial or Germicidal Activity in the Presence of Organic Load as outlined under section 3.1.2., above.

4. Interaction Between Teat Dips and Other Drugs

If the label for a teat dip recommends its concomitant use with other drugs, studies may be required to show that no drug interactions or adverse effects result from such a use.

5. Teat Sprays

Guidelines for teat dips appearing under sections 2 to 4, above, also apply to liquids intended for applying to teats by spraying. The sprayable form of a currently marketed teat dip is considered as its generic form. For comparing the two forms, a reference may be made to Pankey and Watts.

6. References

  • Department of National Health and Welfare, Office Consolidation of the Food and Drugs Act and Regulations, Supply and Services Canada Publishing Centre, Ottawa, Canada, 1991.
  • Department of National Health and Welfare, Drugs Directorate Guidelines for the Preparation of Veterinary New Drug Submissions. Canada Communications Group-Publishing, Ottawa, Canada K1A 0S9, 1991.
  • Hogan, J.S., Eberhart, R.J., Galton, D.M., Harmon, R.J., Nickerson,S.C., Oliver, S.P. and Pankey, J.W. Protocols for Determining Efficacy of Premilking Teat Dips. Research Committee, National Mastitis Council, Inc., 1840 Wilson Blvd., Arlington, Virginia 1989.
  • Hogan, J.S., Eberhart, R.J., Galton, D.M., Harmon, R.J., Nickerson,S.C., Oliver, S.P. and Pankey, J.W. Protocols for Evaluating Efficacy of Postmilking Teat Dips. J. Dairy Sci. 73:2580-2585, 1990.
  • Horwitz, W. (Ed.) Official Methods of Analysis of the Association of Official Analytical Chemists. Association of Official Analytical Chemists. Washington, D.C., 14th Edition, 1984.
  • Teat Dip Committee,Proposed Guideline to Determine Biocidal Activity Within a Teat Dip Solution. Guideline E, Proposed Protocols and Guidelines for Determining Efficacy and Safety of a Teat Dip. National Mastitis Council Inc., 1840 Wilson Road, Arlington, Virginia, 1977.
  • Pankey, J.W., Cuming, A.L., Daggett, R.D., Ebberhart, R.J., Farnsworth, R.J. and McDuff, C.R. Update on Postmilking Teat Antisepsis. J. Dairy Sci. 67: 1336-1353, 1984.
  • Pankey, J.W. and Watts, J.L.Evaluation of Spray Application of Postmilking Teat Sanitizer. J. Dairy Sci., 66: 355-358, 1983.
  • Roessler, W.G.Safety Evaluations on Antimicrobial Chemicals. In "Disinfection, Sterilization, and Preservation", by S.S. Block, Lea and Febiger, Philadelphia, 1977, pp. 152-166.
  • Sieber, R.L. and Farnsworth, R.J.Prevalence of Chronic Teat-End Lesions and Their Relationship to Intramammary Infection in 22 Herds of Dairy Cattle. J.A.V.M.A., 178(12): 1267, 1981.
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