Registration requirements for mycotoxin detoxification agents (MDAs)

Background

Mycotoxin Detoxification Agents (MDAs) are substances or mixtures of substances incorporated into a feed matrix to mitigate the toxicity of known mycotoxins by reducing the animal's exposure to the mycotoxins. These substances may exert their effects by reducing gastro-intestinal absorption, decreasing bioavailability, promoting excretion or by modifying the mode of action of the mycotoxins.

MDAs may be regulated as a drug or a feed depending on a number of factors as per the Guidance Document on Classification of Veterinary Drugs and Livestock Feeds. That document provides guidance and criteria to help clarify the regulatory differences between drugs and feeds, and assists in determining the appropriate regulatory oversight for a product destined for use in livestock species. Appendix E-1 of the document specifically addresses the classification of MDAs.

MDAs that may be classified for a feed purpose include those that:

1. directly bind to the mycotoxin either prior to ingestion or within the gastrointestinal tract
2. degrade the mycotoxin (For example, microbial strains)
3. inactivate the mycotoxin itself (For example, enzymes)

MDAs that aid in mitigating adverse or toxic effects of mycotoxins by inducing changes in physiological functions in the animal may be considered drugs.

Regulatory status

MDAs that are regulated as feed do not meet the exemption from registration criteria, as outlined in Section 5(2) of the Feeds Regulation. These products are considered specialty products and must be approved and registered by the Animal Feed Division (AFD) prior to importation, manufacture or sale in Canada.

MDAs should be considered as a preventative aid in feeds that comply with the Canadian standards for mycotoxins (RG-8, Section 1: Mycotoxins in Livestock Feed).

This document is divided into the following three parts:

Part 1 – Registration requirements for new MDAs
Part 2 – Amendments to registrations of MDAs
Part 3 – Renewal of registrations of MDAs

It is recommended that the data requirements outlined below be carefully reviewed and followed prior to submitting an application for feed registration to the AFD.

After reviewing all documents, if specific questions on requirements remain, please contact the AFD at: cfia.afp-paa.acia@inspection.gc.ca.

Part 1: Registration requirements for new MDAs

1.1 Administrative requirements

General administrative information regarding the procedures for application for feed registration can be found in Regulatory Guidance: RG-1, Chapter 1 - Administrative Requirements for Pre-market Assessment and Product Registration of Livestock Feed.

Specific information is found in the attached checklist.

1.2 Labelling

Proposed labels for MDAs must include the following, in addition to standard labelling requirements listed in RG-1, Chapter 4.1 – Labelling and Guarantees - Labelling of Livestock Feed:

• product name
• complete list of ingredients
• a minimum guarantee for each of the active ingredients in the product
• each specific target mycotoxin(s)
• target livestock species and feed type
• directions for use and applicable use rates of the MDA
• date of manufacture
• shelf life (For example, 12 months from the date of manufacture when stored under appropriate conditions)
• recommended storage conditions in order to maintain activity until the expiration date
• cautionary and/or warning statements, if applicable
• statement on interactions with veterinary drugs, if applicable

1.3 Product identification and description

1.3.1 General Information

• cover letter explaining the purpose of the product for registration
• summary of documentation/information included with the application
• background supportive information pertaining to approvals in other jurisdictions
• specification of the target mycotoxin(s), and livestock species
• directions for use
• target livestock feeds.
• proposed product claim(s)
• proposed shelf-life
• detailed product formulation and complete list of ingredients identified by generic name as listed in Schedule IV or V of the Feeds Regulations, and registration number for ingredients listed in Schedule IV, Part II, or mixed feeds.
• if the product is an unapproved single ingredient, additional information as per RG-1, Chapter 2 - 2.3 Single Ingredient Feed Evaluation Requirements

1.3.2 Analytical information

• certificates of analysis from 3 different and recent lots of product
• description of analytical methodology used to substantiate the label guarantee(s)
• product sample or samples may be required to verify analytical methodologies and/or label guarantees. Samples will be requested on a case–by-case basis

1.4 Requirements in support of product claims and other information

The criteria for acceptable scientific studies are outlined in RG-1, Chapter 2.2 - Registration Requirements for Specialty Products

1.4.1 Studies in support of claims

While in vitro studies may aid in elaborating the mode(s) of action, efficacy of MDAs can only be fully demonstrated by in vivo studies.

In addition, the following specific criteria should aid in the design of appropriate studies in support of MDA product claims.

• the targeted mycotoxin(s) against which the additive will exert its function and the target species must be specified
• the concentration of mycotoxin(s) in feeds used in the supporting efficacy studies should not exceed the maximum levels described in RG-8, Section 1: Mycotoxins in Livestock Feed
• the mode of action should be declared and demonstrated with a minimum of one study per each target mycotoxin. This may be provided as an in vitro study
• a minimum of 3 complete in vivo studies per target livestock species must be presented in support of product efficacy for each target mycotoxin
  • if the product is intended for use for all livestock feeds except fish feeds, a minimum of 3 studies performed in each of the three major species (poultry, swine and a ruminant (cattle, sheep or goat)) are required
  • if the product is intended for use in fish feeds, the 3 studies should be performed in salmonids
• if the product is intended for use at various inclusion rates, the in vivo studies showing significant effects should be provided to demonstrate efficacy at the lowest recommended rate
• studies should be based on the final product(s) for which registration is sought
• studies to demonstrate efficacy of the MDAs should measure relevant bio-markers as end-points such as mycotoxin or mycotoxin metabolite excretion in faeces or urine, or concentration in peripheral circulation (plasma, blood, and serum), animal products or tissues
  • note that animal performance end-points are not considered acceptable as indicators of MDA efficacy
• the studies should demonstrate a significant difference (P<0.05) in the relevant end-point biomarkers between the control and treatment groups
• where the results of these studies have not been published in a peer-reviewed journal, complete copies of the raw data and complete printouts of the statistical analysis are required for review
• analytical methodology for studies used to support the proposed label claims.
• analytical methodology for determining the concentration of the target mycotoxin in the target feed (For example, premix, complete feed and/or ingredients)

1.4.2 Product Stability and Shelf Life

To support product stability and the shelf life as stated on a product label, it will be necessary to:

• demonstrate maintenance of mycotoxin detoxification effects over the specified shelf life
• submit certificates of analysis (CoAs) for the active ingredient(s) or substance(s) to substantiate the guaranteed shelf life (In other words, at the date of manufacture and the expiry date)
  • a minimum of 3 different lots of the product.
  • CoAs for the level/concentration of the active ingredient(s) or substance at the date of manufacture and at the expiry date must be for the same lot of product
  • storage conditions used in the shelf life study must reflect the recommended storage conditions as stated on the product label

1.4.3 Product stability in pelleted feeds

Provide evidence to demonstrate that the activity of the MDAs is not negatively impacted during feed processing, e.g. heat stable following pelleting. If the product is to be applied before the pelleting of feed, original, signed CoAs for the active (s) for 3 pre- and post-pelleting samples of the feed are required in support of the product stability. The data needs to demonstrate that pelleting does not negatively affect the detoxifying capacity of the MDA. The pelleting conditions used in the pelleting study must reflect the conditions recommended on the label.

If CoAs are not provided, one or more of the following statements will be required on the label:

"Do not pellet." or
"Apply post-pelleting." or
"Pelleting may negatively affect the effectiveness of this product."

1.5 Requirements in support of product safety

In cases where approved ingredients (as listed in Schedule IV and V) are used as MDAs, safety may have already been substantiated for the ingredient itself during the approval process and may not require the submission of new safety studies. If the MDA product is a new single ingredient, a safety assessment will require the submission of data as outlined in RG-1, Chapter 2 - Data Requirements for Single Ingredient Approval and Feed Registration:

• 2.4 Generic Data Requirements for Safety Evaluations of Single Ingredients
• 2.5 Data Requirements for Product Safety Evaluations: Explanatory Notes.

The following specific information must be provided for all MDA products.

1.5.1 Production of new metabolites and breakdown products

If the mode of action of the MDA involves the modification of the mycotoxin through its degradation or metabolism, the production of new metabolites or breakdown products may result in chemicals which are more toxic than the parent compound.

• any metabolites and breakdown products must be demonstrated, and for each, an assessment of its inherent toxicity to animals, humans and the environment must be evaluated
• the transfer to resulting foods of animal origin must be discussed and metabolic fate and residue studies may be required
• if the toxicity of the new metabolite or breakdown product is unknown, toxicity assays may be required to evaluate the safety impact

1.5.2 Potential for interactions

As the mode of action of many MDAs involves the direct binding of the mycotoxin, there exists the potential for the product to affect other constituents in the feed, such as nutrients and veterinary drugs. The assessment may partially have occurred during the original ingredient approval, but if the MDA is a mixed product, the effect may be different.

• it is therefore required that scientific evidence demonstrating that the MDA does not reduce the availability of key nutrients and medications is included in the submission package

Part 2: Amendments to registrations of MDAs

Registrants wishing to make a change to the formula or label of a registered product must submit an application for a Registration Amendment (significant change/re-registration) to the AFD (Category 2 submission). General administrative information regarding application procedures for amendments to feed registrations can be found in RG-1 - Chapter 1 - Administrative Requirements for Pre-market Assessment and Product Registration of Livestock Feed.

Proposed significant changes may include, but are not limited to, changes to:

• label guarantees
• product formulation
• manufacturing process
• label claims
• directions for use and/or application rates
• shelf life of the product
• ingredient stability (heat or pelleting stability)

Data requirements for significant changes to MDAs will be dependent on the changes being requested and would be evaluated on a case-by-case basis. For more information on data requirements for amendments to registrations, refer to RG-1, Chapter 2.2 Registration Requirements for Specialty Products.

Part 3: Renewal of registrations of MDAs

General administrative information regarding the application procedures for renewals of feed registrations can be found in RG-1, Chapter 1 "Administrative Requirements for Pre-market Assessment and Product Registration of Livestock Feed".

Specific information is found in the attached checklist.

Please note that additional information may be requested at the time of renewal if safety and/or efficacy questions emerge after the original registration date.

Changes made to the formulation and/or to the product label (For example, claims, purpose, directions for use, target livestock species feeds, etc.) are considered to be significant changes to existing registrations. These changes cannot be submitted for review and approval at the time of registration renewal unless substantiating information and scientific data (if applicable) has been submitted with the application for registration renewal. This would no longer be considered a Renewal, but an Amendment, and would be subject to appropriate fees as per Part 2, above.

Change in regulatory oversight at time of renewal:
If new factors pertaining to the drug - feed classification become apparent after registration of the product, the renewal application may be returned, and be redirected to Health Canada for consideration as a drug.

Printable checklist - PDF (332 kb)

Submission checklist for mycotoxin detoxification agents (MDAs) feed application

The completed checklist, for mycotoxin detoxification agents (MDAs) submissions, must be included with each application for feed registration.

Indicate the submission page number corresponding to each item in the checklist; if the item does not apply, a written justification must still be provided.

Submissions received without a completed checklist will be returned.

With your submission package, you must include with the following information (mandatory)

1.1 Administrative requirements for each product

Required information	Page number in application or Not Applicable (N/A)
RG-1 Chapter 1: Administrative requirements for registration and approval of livestock feeds
Application for Feed Registration and Renewal. Form Available: 1.3.1 Application for feed Registration and Renewal (CFIA/ACIA 0009)
Total application fees (cheque, money order, Visa, MasterCard, or American Express payable in Canadian Funds) RG-1 Chapter 1: Appendix A for application fees
For a new company or an existing company requiring changes to the signing authority list, include supporting documentation on Establishing a Company File and Signing Authority
For a new applicant residing outside of Canada or an existing company requiring changes to the Resident Canadian Agent, include supporting documentation and a Declaration of Resident Canadian Agent, Form II (CFIA/ACIA 1194)
Cover letter and summary of the documentation included with the application, with the email address of the contact person clearly identified

1.2 Labelling

Required information	Page number in application or Not Applicable (N/A)
Proposed Labels including all required information as per section 1.2

1.3 Product identification and description

Required information	Page number in application or Not Applicable (N/A)
For products with deficiencies previously identified by the AFD, attach the reference number of the return letter or letter of rejection of the application and explain how you have addressed the rejection points in the new submission.
Complete product identification and description as detailed as per Section 1.3.1
Specify target mycotoxins and intended livestock species
For an unapproved ingredient, information as per RG-1, Chapter 2.3
Detailed Product Formulation: (either on a weight for weight basis or as a percentage composition) list the amount of each ingredient by generic name as per Schedule IV or V of the Feeds Regulations, include registration numbers for Part II ingredients or mixed feeds. Note: The source of all single ingredients listed in Schedule IV Part II must be approved and registered by AFD prior to being used in the mixed feed.
For new ingredients, provide a detailed description of the manufacturing process
Certificates of analysis from 3 different and recent lots of product to support the proposed label guarantees for each active ingredient proposed on the label.
Analytical methodology used to support the proposed label guarantees for each active ingredient, as above
Product sample or samples, if required. The sample will be used to validate the analytical method by the CFIA laboratory. Keep a 500 g sample of the final product in stock. When the application is accepted, you will be contacted to send the sample directly to the CFIA laboratory. The following form will need to be completed and attached.

1.4 Requirements in support of product claims and other information

Required information	Page number in application or Not Applicable (N/A)
Acceptable studies in support of claims. Address all design considerations as listed in section 1.4.1
Certificates of Analysis Analytical methodology for studies used to support the proposed label claim
Demonstration in support of product stability and shelf life for the maintenance of the mycotoxin detoxification effects as defined in section 1.4.2
Certificates of analysis (original and signed) for 3 recent and different lots of production of the final product to support the stability and shelf life as above. These must include three (3) CofAs at the beginning of the shelf life period and three (3) CofAs from the same three lots of the product at the end of the desired storage period. The 3 lot samples must be kept in similar storage conditions up to the proposed expiry date.
The analytical methodology/instrumentation used for the above analyses must be included on the certificates
Evidence to demonstrate the activity of the MDAs is not impacted during feed processing as defined in section 1.4.3. This should include Certificates of Analysis for a minimum of three (3) different lots of product.
If CoAs are not provided, required statements added to label as per section 1.4.3

1.5 Data requirements in support of safety

Required information	Page number in application or Not Applicable (N/A)
Description and data demonstrating the safety of the feed as noted in section 1.5. This is required for new ingredients or for a new purpose of an existing ingredient.
If the mode of action results in any new metabolites or breakdown products, the safety of these must be demonstrated. Evidence provided as per section 1.5.1
Scientific evidence demonstrating that the MDA does not reduce the availability of key nutrients and medications in the feed. See section 1.5.2

Part 3: Renewals of feed registration

Required information	Page number in application or Not Applicable (N/A)
If there is a change to the product at renewal, use this checklist to describe the changes as applicable. If there is no change to the product, use the checklist for renewals available in the RG1- Chapter 1 at: Appendix B – Checklist for renewals