Maximum Residue Limit (MRL) Proposal for Amoxicillin, Neomycin, Ormetoprim, Tetracycline, Chlortetracycline, Oxytetracycline, Tilmicosin, Tricaine Methanesulfonate, Tulathromycin and Zoalene

March 12, 2010

Dear Stakeholder:

The Veterinary Drugs Directorate (VDD) of Health Products and Food Branch, Health Canada, is considering regulatory amendment which may be of interest to you.  More specifically, the VDD is proposing to establish Maximum Residue Limits (MRLs) in Table III Division 15, Part B of the Food and Drug Regulations for amoxicillin, neomycin, ormetoprim, tetracycline, chlortetracycline, oxytetracycline, tilmicosin, tricaine methanesulfonate, tulathromycin and zoalene in edible tissues of food-producing animals as indicated in the following table:

Common Name (or brand name) of drug	Name of Substance for Drug Analysis Purposes	MRL p.p.m.	Foods	Target Tissue
Amoxicillin	Amoxicillin	0.01 0.01	Swine Edible tissues Chickens Edible tissues	Edible tissues
Neomycin	Neomycin	0.5 10.0 1.5 0.5	Cattle, swine, goats, sheep, chickens, turkeys and ducks Muscle, liver and fat Kidney Milk Eggs	Kidney
Ormetoprim	Ormetoprim	0.1	Salmonids Edible tissues	Edible tissues
Tetracycline	Tetracycline	0.2 0.6 1.2 0.1	Cattle, swine, sheep, chickens and turkeys Muscle Liver Kidney Milk	Edible tissues
Chlortetracycline	Chlortetracycline	0.2 0.6 1.2 0.1 0.4	Cattle, swine, sheep, chickens and turkeys Muscle Liver Kidney Milk Eggs	Edible tissues
Oxytetracycline	Oxytetracycline	0.1	Milk
Tilmicosin	Tilmicosin	0.1 1.0 0.1 1.5	Cattle and sheep Muscle Liver Swine Muscle Liver	Liver
Tricaine Methanesulfonate	Tricaine Methanesulfonate	0.01	Salmonids Edible tissues	Edible tissues
Tulathromycin	A common hydrolytic fragment CP-60,300 (expressed as tulathromycin equivalents)	1.0 2.0 4.0 1.5 4.0 5.0	Cattle Muscle Liver Kidney Swine Muscle Liver Kidney	Liver
Zoalene (or Dinitolmide)	Zoalene (3,5-dinitro-o- toluamide) and 3-amino-5-nitro-o- toluamide	6.0	Turkeys Kidney	Kidney

Amoxicillin is a semi-synthetic penicillin antibiotic with a broad spectrum of bactericidal activity against a wide range of common gram-positive and gram-negative pathogens. Amoxicillin also has potential for producing allergic reactions.  It is rapidly absorbed after oral administration.  Amoxicillin has a low capacity for protein binding and is widely distributed in various tissues after absorption.  Like other beta-lactam antibiotics, it prevents the bacterial cell wall from forming by interfering with the final stage of peptidoglycan synthesis.  Amoxicillin is approved in Canada for the treatment of infections in chickens and swine.

Neomycin is an aminoglycoside antibiotic produced by Streptomyces fradiae, and, with a long history of use.  It consists of 3 components, A, B and C and is used in veterinary medicine as the sulphate salt.  Component B (framycin, also known as soframycin) is the major component of commercial preparations of neomycin (>90%), which possesses the highest therapeutic activity.   Neomycin is used to treat bacterial gastrointestinal infections in cattle, sheep, swine, goats, ducks, chickens and turkeys by the oral route.

Ormetoprim is a diaminopyrimidine structurally related to trimethoprim.  It blocks the conversion of dihydrofolic acid to tetrahydrofolic acid by inhibiting dihydrofolate reductase.  Ormetoprim is used in combination with sulfadimethoxine for the treatment of furunculosis in salmonids (trout and salmon).  Sulfadimethoxine/ormetoprim combination shares mechanisms of action and probably the bacterial spectrum of activity with trimethoprim/sulfa drugs combinations.  Alone, sulfonamides are bacteriostatic agents, but in combination with either ormetoprim or trimethoprim, the potentiated sulfas are bactericidal.

Tetracyclines (chlortetracycline, oxytetracycline and tetracycline) are broad spectrum antibiotics that are effective against a wide range of gram positive and gram negative bacteria.  They inhibit growth of bacteria, mycoplasma, chlamydiae, rickettsiae and some protozoae, interfering with protein synthesis in these microorganisms.  Tetracyclines are approved in Canada for the treatment of infections in cattle, sheep, chickens, turkeys and swine.  Chlortetracycline and oxytetracycline are derived from Streptomyces spp.  Tetracycline, however, is semisynthetic, similar to some newer derivatives like doxycycline and minocycline.  In Canada, tetracyclines are extensively used in human and veterinary medicine.  Oxytetracycline is the most commonly used veterinary drug in Canada approved for use in many food producing animals.  In addition to therapeutic uses, tetracyclines are also used in agriculture for disease prevention.  Chlortetracycline and oxytetracycline are also approved for the claim of growth promotion and increased feed efficiency in food-producing animals.

Tilmicosin is a macrolide antibiotic synthesized from tylosin for veterinary use.  It has an antibacterial spectrum similar to tylosin with enhanced activity against Pasteurella multocida and Pasteurella haemolytica.  It is recommended for treatment and prevention of pneumonia in cattle, sheep, and swine, associated with Pasteurella multocida and Pasterurella haemolytica, Actinobacillus pleuropnemoniae, mycoplasma species and, other microorganisms found sensitive to this compound.  Tilmicosin is available as an injectable formulation, administered subcutaneously in cattle and sheep for the treatment of respiratory diseases and as a medicating ingredient for swine feeds for control and treatment of respiratory diseases.

Tricaine Methanesulfonate (ethyl 3-aminobenzoate methanesulfonate; TMS) is used for the temporary immobilization of fish, amphibians, and other aquatic, cold-blooded animals.  It is normally a local anaesthetic, but when fish are immersed in its solution, TMS acts on the central nervous system as a general anaesthetic.  TMS is extensively metabolised, rapidly excreted and is of low oral acute toxicity.  It is approved in Canada for anaesthesia or sedation of salmonids.

Tulathromycin is a semi-synthetic macrolide antibiotic of the sub-class triamilide.  Its mode of action is primarily bacteriostatic but may be bactericidal against some pathogens.  It acts by binding to a bacterial ribosomal sub-unit thereby inhibiting protein synthesis.  Tulathromycin is used for treatment of bacterial respiratory diseases in cattle and swine.  This product is not allowed to be used in lactating dairy cattle.

Zoalene (or Dinitolmide) is a feed additive for poultry used to prevent coccidiosis infections.  It is a broad-spectrum anticoccidial drug, preventing seven main strains of Eimeria coccidium.  It has been approved for use in poultry as an aid in the prevention of caecal and intestinal coccidiosis in broiler chickens, replacement chickens and growing turkeys.

The result of our comprehensive assessment shows residues of the above veterinary drugs, at the above-noted concentrations, will not pose any undue health risk for consumers.  The proposed MRLs will be published in the Canada Gazette, Part I, after consideration of comments from Stakeholders.

VDD invites the public to submit written comments on the proposed MRLs for amoxicillin, neomycin, ormetoprim, tetracyclines, chlortetracycline, oxytetracycline, tilmicosin, tricaine methanesulfonate, tulathromycin and zoalene up to 60 days from the date of publication of this consultation document.  This consultation is available for comment from March 12, 2010 to May 12, 2010.  Interested parties are encouraged to provide comments and suggestions by May 12, 2010.  The VDD will consider all comments received before making a final decision on the proposed MRLs.

Comments should be sent by regular mail, e-mail or fax to:

Consultations - Veterinary Drugs Directorate
Policy, Regulatory and International Affairs Division
Veterinary Drugs Directorate,
Health Products and Food Branch, Health Canada
Holland Cross Complex
11 Holland Ave.
Ground Floor, Suite 14
Ottawa, Ontario
K1A 0K9

ConsultationVDD-DMV@hc-sc.gc.ca

Fax: 613-957-3861

Thank you for your interest in this matter.

Daniel Chaput
Director General
Veterinary Drugs Directorate
Health Products and Food Branch
Health Canada