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What we heard report – Consultation on the proposal for registration requirements for Mycotoxin Detoxification Agents (MDAs)

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Introduction

The Canadian Food Inspection Agency (CFIA) is continuing to move forward on providing more flexible alternatives to the marketing of feed products while still maintaining strict standards for the safety of feed, food, animals and the environment to enhance the health and well-being of Canada's people, environment and economy. The classification of livestock feed and veterinary drug products is an important component of these alternatives. An outcome of the classification work undertaken with Health Canada’s Veterinary Drugs Directorate was that a new Appendix, E-1, on Mycotoxin Detoxification Agents (MDAs), was published in the guidance document on classification of veterinary drugs and livestock feeds.

Appendix E-1 specifically provides guidance and criteria to clarify the regulatory differences between drugs and feeds, and assists in defining the appropriate regulatory oversight for a product destined for use in livestock species as an MDA.

Consultation overview

Once feed purposes for MDAs were classified, the CFIA developed guidance on the data requirements needed to complete a pre-market application of a new feed ingredient or product for use as an MDA. This draft guidance document was available for general consultation until May 10, 2019 on the CFIA website.

10 sets of written comments were received as part of that consultation. This report consolidates and summarizes the comments received on the proposal and the CFIA's response to those comments.

The CFIA would like to thank everyone that participated in the consultation for contributing their time to the process and sharing their views.

What we heard

Respondent profile

Table 1: Respondent profile
Category of respondent Distribution
Feed Industry – Individual 3
Feed Industry – Association 2
Livestock Producer – Association 3
Other Feed Inputs 1 (academic institution)
Government (Canadian Federal/Provincial) 1
Total 10

Key respondent messages

While stakeholders provided suggestions for modifying some requirements, there was a general agreement that having this pathway for MDAs as feeds was needed and beneficial to the industry. It was agreed that products should be proven to be effective while balancing the need for a process that allowed for products to be accessible.

There were 3 main common themes which could be defined.

  1. Need to meet regulatory maximum limits:

    Many respondents felt that the ability to conduct research trials that included mycotoxins at concentrations greater than the current maximum levels as set out in regulatory guidance is important to demonstrate efficacy. The limitations placed on research in the original proposal would not allow product efficacy to be clearly evident.

    • The CFIA agreed and has modified the research restrictions to allow for higher concentrations of mycotoxins to be used in research trials. The data set will also need to include a mycotoxin concentration below the maximum concentration listed in the regulatory guidance.

    Respondents also requested the CFIA to recognize the importance of having tools for adding MDAs to feeds that include mycotoxin concentrations above the regulatory maximums. It was felt that there should be more flexibility to use MDAs in feeds in situations where the feed contains mycotoxin concentrations greater than the allowable regulatory maximum limits.

    • Feeds having concentrations of mycotoxins above regulatory maximum limits are considered to be contaminated. As the fungi and mycotoxins are unlikely to be evenly distributed in feed and could form pockets of high toxin concentrations, it is very difficult to monitor how treatment with a MDA has affected the feed as a whole. This uneven treatment could result in feeds containing pockets of mycotoxins at concentrations exceeding safety standards and the feeding of unsafe feed. In addition, some mycotoxins are storage mycotoxins (for example, aflatoxins) meaning that the fungi can continue to grow and produce mycotoxins even after harvest and during storage when conditions favour fungal growth. If the feed was stored for a prolonged period of time after treatment with the MDA, some toxins may reappear. As such, the CFIA will not be allowing MDAs to be used to treat feeds containing mycotoxins at concentrations exceeding regulatory maximums. As such, use of MDAs as a preventative step remains a proactive measure to limit the occurrence of mycotoxin contamination in feed. Extensive references in support of mycotoxin distribution and sampling techniques exist; a small reference list is provided below.

    Neither the European Union (EU) or the United States, Food and Drug Administration (US-FDA) allow MDAs to be used in feeds that exceed set maximums for mycotoxins.

  2. Efficacy trial requirements:

    Respondents commented on the type and number of efficacy studies required to support the efficacy of MDAs. Some respondents did not agree with the need for in vivo trials to validate an MDA claim. Others suggested that traditional production and performance trials could be used to support the efficacy of MDAs, especially for those MDAs acting in the feed rather than in the animal. The original guidance stated that a minimum of 3 efficacy trials per species would be required. Many respondents commented that this requirement should be more in line with what is required by the EU and the US-FDA and that species could be batched to avoid the need for excessive studies.

    • The CFIA has reconsidered the need to require in vivo testing for all modes of action of MDAs and has updated the guidance to provide clarification. Any MDA acting in the feed by degrading the mycotoxin into non-toxic compounds and where it can be demonstrated that this action is not reversible could suffice with an in vitro study demonstrating this mode of action. That said, the safety of the degradation products must be demonstrated. Conditions would need to meet expected Canadian feed production and environmental conditions.
    • Other modes of action, including those that act by the binding of the mycotoxin, will continue to require in vivo studies to demonstrate that the mycotoxin is not released in the animal, for example, in vivo.
    • The use of toxicosis or the prevention of toxicosis as endpoints in scientific studies, or animal production or performance endpoints are not considered acceptable as indicators of MDA efficacy; relevant biomarkers in urine, feces or systemic circulation need to be monitored.
    • The CFIA does not agree that performance studies alone can support an MDA claim. An indication of improved production and performance cannot be attributed to the detoxification of the mycotoxin. A demonstrated mode of action is required. Some of the constituents of the MDAs by themselves can influence other areas of the animal to result in enhanced performance; this may not solely reflect the MDA effect. Furthermore, a large number of animals is required to measure small differences in production and performance studies. As the use of relevant biomarkers in urine, feces, or systemic circulation to demonstrate the mode of action is much more sensitive, it should require fewer animals.
    • With regards to the minimum number of studies required, the CFIA has modified the requirement to align with the EU and the US-FDA. The guidance will now reflect that a minimum of 3 in vivo studies per the target livestock species must be presented in support of product efficacy for each target mycotoxin
      • For products intended to be used as feed in all livestock species, excluding fish, studies representing each of the three major digestive systems in livestock production (for example, a poultry, a non-ruminant mammal (swine) and a ruminant species) may be provided
      • For products intended for use in feeds for fish, 3 studies should be performed in salmonids or relevant species
    • These considerations are in line with how MDAs are regulated in both the EU and the US-FDA
  3. Requirements for Safety Studies:

    Clarification was requested for the requirement regarding testing for binding of key nutrients and medications, specifically what testing the CFIA expects.

    • The CFIA believes that it would be too prescriptive to define which nutrients and medications should be targeted for consideration as the endpoints could change based on the feed matrix and the MDA product in question. Certainly the modes of actions of some clays, bentonites, and aluminosilicates, for example, have indicated the capacity to bind medications. An applicant should consider the nature of their product and its properties. Reference to current ingredient descriptions in Schedule IV and the Compendium of medicating ingredient brochures, insofar as existing ingredient compatibility with medicated feeds and existing medication specific incompatibilities must be considered.

    Clarity was requested as to the need to provide efficacy data for ingredients rather than mixed feed.

    • The CFIA considers that single ingredients could be the active agent or action could be due to a mixed product dependent on the product itself and its mode of action. The efficacy requirements would be the same and the guidance would be applicable for either situation.

Next steps

CFIA has updated the proposed guidance on registration requirements for Mycotoxin Detoxification Agents, and will incorporate this guidance into RG 1, Chapter 3.

References

  1. Occurrence, prevention and remediation of toxigenic fungi and mycotoxins in silage: a review
    Eva Wambacq Ilse Vanhoutte Kris Audenaert Leen De Gelder Geert Haesaert
    First published:17 December 2015
  2. A Contribution to Reduce Sampling Variability in the Evaluation of Deoxynivalenol Contamination of Organic Wheat Grain, Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2013;30(12):2159-64. doi: 10.1080/19440049.2013.853227. Epub 2013 Dec 7.
  3. Getting the Measure of Mycotoxins: Testing controls grain quality along every step of the supply chain
  4. Mycotoxins in the grain market C. R. Hurburgh, Jr.
  5. Grain Fungal Diseases and Mycotoxin Reference, September 2006 - PDF (610 kb)
  6. The 6 biggest challenges in mycotoxin and how to overcome them, September 2017
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