RG-1 Regulatory Guidance:
Chapter 3 – Guidance on data requirements for feed approval and registration
3.28 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 animal exposure to known mycotoxins. These substances may exert their effects on mycotoxins by reducing gastrointestinal absorption, decreasing bioavailability, promoting excretion or by modifying the structure of the mycotoxin.

MDAs may be regulated as a drug or a feed depending on a number of factors as defined in 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 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 exert their effects either prior to ingestion or within the gastrointestinal tract, and function to:

1. directly bind to the mycotoxin
2. degrade the mycotoxin
3. inactivate the mycotoxin itself (for example, enzymes)

MDAs that aid in reversing or mitigating adverse effects or toxicosis due to mycotoxins by causing changes in physiological functions in the animal may be considered drugs.

Regulatory status

MDAs that are regulated as feed are considered specialty products and must be approved and registered by the Canadian Food Inspection Agency (CFIA) prior to their importation, manufacture or sale in Canada.

MDAs can only be used in feeds that are considered safe for livestock consumption in accordance with the Canadian standards for mycotoxins and are not for use to remediate livestock feeds that do not comply with the Canadian standards for mycotoxins. (RG-8, Section 1: mycotoxins in livestock feed). MDAs may mitigate against additional mycotoxin production by storage mycotoxins (for example, aflatoxin) and may work as a preventative aid against additive or synergistic effects of multiple mycotoxins.

Fit for purpose and efficacy as an MDA

To be classified as an MDA, the active ingredient must have demonstrated an effect corresponding to its purpose, that is, a mode of action consistent with an MDA effect, as stated above, when used or fed as directed. Supporting data must be provided from in-house studies or peer reviewed literature that are reflective of the ingredient fed at similar rates and duration of feeding as per the label. In addition, the market formulation (mixed or a single ingredient product) must have a claim which is supported by efficacy studies.

This document is divided into the following 3 parts:

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

The data requirements outlined below, including the checklist, must be carefully reviewed and followed prior to submitting an application to the CFIA for feed registration.

After reviewing all documents, if specific questions on requirements remain, please contact the CFIA 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 mycotoxin targeted by the MDA
• Target livestock species and feed type
• Directions for use and applicable use rates for 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 full activity until the expiration date
• Caution and warning statements, if applicable
• Statement on interactions with veterinary drugs, if applicable

1.3 Product identification and description

The application package must include the following information:

1.3.1 General information

• Cover letter explaining the purpose of the product for registration
• Summary of documentation/information included with the application
• 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 other registered feeds in the formulation
• Complete characterization of the product and active ingredients if a mixed product
  • If the product contains ingredients that are not listed in Schedule IV or V, additional information as per RG-1, Chapter 2 - 2.3 single ingredient feed evaluation requirements and Chapter 2.7 guidelines for the assessment of novel feeds: microbial sources.
  • For products whose active ingredients are clay minerals, elemental and mineralogical characterization and identity of each constituent clay mineral as well as information on the structure is to be provided with verification of physical properties obtained from analysis such as X-Ray Diffraction, Differential Thermal analysis, Infrared Spectroscopy, and atomic absorption spectrophotometry.
• Background supportive information pertaining to approvals in other jurisdictions (if applicable)
• Detailed manufacturing process
• Name(s) of the targeted mycotoxin(s)
• Intended livestock species
• Directions for use
• Target livestock feeds (for example, for use in complete feeds, for use in grains prior to mixing)
• Proposed product claim(s)
• Proposed shelf-life

1.3.2 Analytical information

• Certificates of analysis (CoAs) for the active agent from 3 different and recent lots of product.
• The analytical methodology used to substantiate the proposed label guarantee(s).
• Analytical methodology for the detection of the specific targeted mycotoxin in each target feed matrix (for example, in the premix, complete feed, and ingredients).
  • This must include evidence that the action of the MDA does not interfere with the capability to determine the mycotoxin levels in feed. This is especially important for clays and other substances that act by binding, or otherwise reducing the levels of mycotoxins.
• The method of sample preparation (for example, grinding, etc.) used in the analytical method must reflect the form of feed in the proposed use of the MDA (for example, whole versus ground corn).
• Product samples may be required to verify any analytical methodology provided 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

A battery of in vitro studies should be submitted to provide evidence of the intended effect of the additive.

While in vitro studies may aid in elaborating the mode of action, they do not sufficiently mimic the conditions in the digestive tract and the differences between target animals and their metabolism under practical conditions. Demonstration of the efficacy of most MDAs can only be fully established by in vivo studies that show:

• reduction of the absorption of mycotoxins
• increased excretion of mycotoxins
• degradation/transformation of mycotoxins
• reduced concentration of mycotoxins in food of animal origin

The following specific criteria should be considered in designing appropriate studies in support of MDA claims:

• The mode of action should be declared and demonstrated with a minimum of one study for each identified target mycotoxin as per the directions for use specified on the label.
  • May be provided as an in vitro study.
• The target animal species is specified.
• Treatments with mycotoxin concentrations below listed maximum limits are used in the studies. There are described in RG-8, Section 1: mycotoxins in livestock feed.
  • If justified, an additional treatment which includes mycotoxin(s) concentrations in feeds exceeding the maximum limits can be added, however, a rational must be provided^Footnote 7.
  • Positive controls cannot exceed the maximum limits.
• An analysis and method that is reflective of the mode of action with appropriate endpoints in feed and target tissues is provided.
• For MDAs that act by binding (for example, clays), the mycotoxin binding capacity should be provided.
• For MDAs that act in the feed by degrading the mycotoxin into non-toxic compounds, and can demonstrate that this action is not reversible, an in vitro study may be used. The safety of the degradation products must be demonstrated. Studies need to be undertaken in farm-scale commercial feed manufacturing and should meet expected Canadian environmental conditions.
• To fully demonstrate the efficacy of the MDA for modes of action, other than via degradation as described in the previous bullet, in vivo studies most accurately allow for the validation of the intended effect in the animal. For these studies:
  • A minimum of 3 complete in vivo studies per target livestock species must be presented in support of product efficacy for each target mycotoxin.
  • For products intended to be used in feeds for all livestock species, excluding fish, at least one study per each of the 3 representative major digestive systems in livestock production (that is, poultry, non-ruminant mammal (swine) and ruminant species) must be provided.
  • For products intended for use in fish feeds, 3 studies performed in salmonids or relevant species are required.
• If the product is intended for use at various inclusion rates, the in vivo studies showing significant effects at the lowest recommended rate are included.
• All studies are performed with the final product(s) for which registration is sought with consideration of the feed matrix.
• Studies should measure relevant bio-markers as endpoints such as mycotoxin or mycotoxin metabolite excretion in feces or urine, or concentration in peripheral circulation (plasma, blood, and serum), animal products or tissues.
  • While animal performance end-points are not considered acceptable as indicators of MDA efficacy impacts on performance should be measured and reported in the study.
• A significant difference (p≤0.05) in the relevant biomarkers between the control and treatment groups is demonstrated.

Where the results of these studies have not been published in the peer-reviewed literature, complete copies of the raw data and complete printouts of the statistical analysis are required for review.

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/stability of the MDA activity over the specified shelf life of the product.
  • If an active ingredient/substance has been identified, verify the stability of the specific MDA mode of action. For example:
    • for MDAs that act by binding, the stability of the binding capacity.
    • for enzyme based MDAs, the stability of the enzyme activity.
    • for chemical based MDAs, the stability of the chemical.
  • If no specific active ingredient can be measured then the default would be the demonstration of maintained efficacy (that is, another efficacy study after the MDA has been stored).
• If the MDA treated feeds are meant to be stored prior to their use, the applicant must demonstrate that the MDA treated feed remains stable (that is, the bound, degraded, or modified form is stable) throughout the proposed storage time and conditions of the MDA treated feed.
• Submit certificates of analysis 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/activity of the active ingredient(s) or substance(s) or binding capacity 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 MDA is not reduced during feed processing, for example, it is heat stable following pelleting. If the MDA is mixed into feed which is then pelleted 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 must demonstrate that pelleting does not reduce 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 during the approval process and may not require the submission of new safety studies. If the MDA product is a new single ingredient, or is used at rates exceeding that for the previously approved purpose, 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.

• The presence of any metabolites and breakdown products must be determined, and an assessment of their inherent toxicity to animals, humans and the environment must be evaluated.
  • Combined effects of both the MDA and any metabolites must be considered in this analysis.
• The transfer to resulting foods of animal origin must be considered and discussed; 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 their safety.

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. A consideration of the MDAs ability to reduce the availability of key nutrients and medications must be included in the submission and scientific data may be required.

Which nutrients and veterinary drugs to consider should be based on the feed matrix and the MDA product. Applicants should be aware of how components of the target feed could interact with their particular product.

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 CFIA (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.

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 or efficacy questions emerge after the original registration.

Changes made to the formulation 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. An application for renewal with a significant change would be required.

Submission checklist for Mycotoxin Detoxification Agents (MDAs) feed application:

• Printable checklist - PDF (339 kb)

The completed checklist, for Mycotoxin Detoxification Agents (MDAs) submissions, must be included with each application for feed registration. Submissions received without a completed checklist will not be accepted.

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.

1.1 Administrative requirements for each product

Required information: 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 (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

• Proposed Labels including all required information as per Section 1.2.

1.3 Product identification and description

For products with deficiencies previously identified by the CFIA, 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 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 CFIA prior to being used in the mixed feed.
• For new ingredients, provide a detailed written description of the manufacturing process. A production flow diagram is also recommended.
• Certifications of analysis (original and signed) from 3 different and recent lots of product to support the proposed label guarantees for each active ingredient.
• Analytical methodology used to support the proposed label guarantees for each active ingredient, as above.
• Product 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.

1.4 Requirements in support of product claims and other information

• Acceptable studies in support of claims. Address all design considerations as listed in section 1.4.1.
• Certificates of analysis and 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 3 certificates of analysis at the beginning of the shelf life period and 3 certificates of analysis from the same 3 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 (original and signed) for a minimum of 3 different lots of product.
• If certificates of analysis are not provided, required statements added to label as per section 1.4.3.

1.5 Data requirements in support of safety

• 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 4: Renewals of feed registration

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

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