Guidance document: Pre-market submission process for supplemented foods

February 2024

Table of Contents

• 1.0 Introduction
  • 1.1 Scope
• 2.0 Pre-market requests
  • 2.1 When is a submission required?
    • 2.1.1 Substances eligible for addition to the List of Permitted Supplemental Ingredients
    • 2.1.2 Substances ineligible for addition to the List of Permitted Supplemental Ingredients
    • 2.1.3 Food categories ineligible for addition to the List of Permitted Supplemented Food Categories
  • 2.2 Information that should be included for each type of submission
• 3.0 Submission management process
  • 3.1 Pre-submission consultation
  • 3.2 Instructions for sending submissions and additional requested information
  • 3.3 Administrative verification
  • 3.4 Scientific Screening
    • 3.4.1 Screening Letter of Deficiency
  • 3.5 Scientific review
    • 3.5.1 Scientific review Letter of Deficiency
  • 3.6 Decision
    • 3.6.1 Unfavourable decisions
    • 3.6.2 Favourable decisions
  • 3.7 Administrative process to modify one or both of the Lists
• 4.0 Withdrawal of a submission
• 5.0 Filing a new submission
• 6.0 Confidentiality
• 7.0 Single window into the Food Directorate submission management process
• Appendix 1: Data requirements
  • 1.0 To request a modification to the List of Permitted Supplemental Ingredients
  • 2.0 To request a modification to the List of Permitted Supplemented Food Categories

1.0 Introduction

The Food and Drugs Act (FDA) provides the authority to set out requirements and conditions for foods sold in Canada. The Regulations Amending the Food and Drug Regulations and the Cannabis Regulations (Supplemented Foods), hereinafter referred to as the "Supplemented Foods Regulations", came into force on July 21, 2022, and set out the regulatory requirements specific to supplemented foods. These regulations are housed in the Food and Drug Regulations (FDR) (Part B, Division 29 and other applicable provisions), four documents that are incorporated by reference into the FDR, and Subsection 102(2) of the Cannabis Regulations.

The purpose of this guidance document is to describe the pre-market submission process for stakeholders who wish to request changes to the List of Permitted Supplemented Food Categories and/or the List of Permitted Supplemental Ingredients (the Lists), which are two of the documents incorporated by reference into the FDR, as amended from time to time. This guidance also describes the supporting information required by the Food Directorate to be included in the submission in order to demonstrate that such changes would be safe for Canadians. Submissions that receive a favourable decision will result in a new general rule of application for all applicable supplemented foods, following a successful public consultation.

It is the responsibility of the food manufacturer or distributor to ensure that a food offered for sale in Canada complies with all applicable legislation and regulations including the FDA and the Safe Food for Canadians Act, and their regulations. This includes, for example, ensuring compliance with food labelling requirements, provisions for the use of food additives and food flavourings, and the prohibitions in Sections 4 and 5 of the FDA. For more information on interpreting the Supplemented Foods Regulations, and other legislation as it applies to supplemented foods, refer to the Guidance Document: Supplemented Foods Regulations.

1.1 Scope

This document provides general guidance on how to prepare and file a submission to request a change to the List of Permitted Supplemented Food Categories or the List of Permitted Supplemental Ingredients (the requestor is referred to as the "petitioner"). It should be read in conjunction with the Lists.

This document is not applicable to Natural Health Products (NHPs). Petitioners who are unsure about whether their product is a food or an NHP should refer to the Guidance Document: Classification of products at the food-natural health product interface: products in food formats.

Separate guidance documents are available to describe the submission process for food additives, infant formulas and novel foods. More information about determining whether a food is eligible for a submission related to supplemented foods can be found in Section 2.1.

Stakeholders wishing to make health claims, including for permitted supplemental ingredients or substances requested for addition to the List of Permitted Supplemental Ingredients, should refer to the Guidance Documents for Preparing Health Claim Submissions. Questions may be directed to healthclaims-allegationssante@hc-sc.gc.ca.

2.0 Pre-market requests

2.1 When is a submission required?

The List of Permitted Supplemented Food Categories sets out the specific categories of food to which supplemental ingredients may be added. This List should be read in conjunction with the descriptions of each category that are included in Section 4.1.1 of the Guidance Document: Supplemented Foods Regulations.

The List of Permitted Supplemental Ingredients sets out all of the substances (column 1) that may be used as a supplemental ingredient, and the conditions of use for each supplemental ingredient, including:

• The food category or categories, as per the List of Permitted Supplemented Food Categories, to which the supplemental ingredient specified in column 1 may be added (column 2)
• The maximum amount for a supplemental ingredient (including contributions from added and naturally occurring sources), and the units in which the quantity must be declared in the Supplemented Food Facts table (column 3)
• Cautionary statements that are required on the label, and the threshold levels above which these statements are required (column 4)
• Other conditions of use specific to a supplemental ingredient, if applicable; for example, conditions related to the permitted form of the substance, specifications, and/or additional requirements related to labelling, packaging, or representations (column 5)

In addition to other applicable provisions of the FDR and the Safe Foods for Canadians Regulations, supplemented foods must comply with all aspects of the Supplemented Foods Regulations, including the List of Permitted Supplemented Food Categories and the List of Permitted Supplemental Ingredients, before they can be legally sold in Canada. A change to one or both of these Lists is required before a manufacturer or distributor can sell a product in a new food category as a supplemented food, use a new substance as a supplemental ingredient, or use an existing supplemental ingredient under different conditions of use. Stakeholders who wish to request a change to either of the Lists are required by the Food Directorate to file a submission, including a description of the requested change and scientific evidence that supports the safety of the change.

Different types of submissions related to supplemented foods

Supplemented food submissions can generally be categorized into three types of requests:

1. New Supplemental Ingredient: This is an addition of a new substance to the List of Permitted Supplemental Ingredients
2. Modification to Supplemental Ingredient: This is any modification to the conditions of use in column 2 to 5 of the List of Permitted Supplemental Ingredients in respect of a corresponding supplemental ingredient listed in column 1
3. Food Category: This is a modification of the List of Permitted Supplemented Food Categories, including the addition of a new category or modification of a food category that is already listed

When a request affects multiple items in a List or items in both Lists, the petitioner, in discussion with the Food Directorate as needed, should determine whether a single submission or separate cross-referenced submissions should be filed. For example, if a request is made to permit the use of a new substance (i.e., one that is not currently included in the List of Permitted Supplemental Ingredients) as a supplemental ingredient in a new food category (i.e., one that is not currently included in the List of Permitted Supplemented Food Categories), a single submission may be appropriate. However, separate submissions may be more appropriate to support broader conditions of use when, for example, it is requested that the new food category be permitted to contain one or more additional supplemental ingredients.

In the case where separate submissions are filed, cross-referencing the submissions (e.g., describing the relationship of each submission in the cover letter of each linked submission) will ensure that they are administratively linked and evaluated concurrently (to the extent possible) by the Food Directorate.

Petitioners are encouraged to send questions to the Submission Management and Information Unit (SMIU) at smiu-ugdi@hc-sc.gc.ca (see Section 7.0), or to send a request for a pre-submission consultation (See Section 3.1) to the same email address, if they are unsure about whether their requested modification(s) requires one or more submissions.

2.1.1 Substances eligible for addition to the List of Permitted Supplemental Ingredients

Apart from certain exceptions described in Sections 2.1.2, any substance is eligible to be considered for addition to the List of Permitted Supplemental Ingredients as long as the intent is to use and market the substance in supplemented foods, respecting all requirements associated with the labelling and sale of a supplemented food. This would include labelling of the substance under the "supplemented with" heading of the Supplemented Food Facts table (SFFt) and using the substance as a supplemental ingredient in accordance with any conditions of use that may be set out in the List of Permitted Supplemental Ingredients.

A supplemental ingredient submission may be appropriate if the answer to any of the following questions is "yes".

1. Is the substance intended to be represented as a supplemental ingredient (i.e., listed under the "supplemented with" heading of the SFFt)?
2. Do safety data for the substance indicate that conditions of use, including maximum levels of use, are required in order for the substance to be safe for consumption (e.g., similar to substances that are also regulated as medicinal ingredients in NHPs)?
3. Do safety data for the substance indicate that the food containing the substance should have directions of use guiding the daily consumption for the consumer (e.g., Do not [eat/drink] more than x serving(s) per day)?
4. Are there sensitive sub-populations for whom consumption of the substance is not recommended (e.g., children, or pregnant or breastfeeding individuals)?

Petitioners are encouraged to give due consideration as to the reasons for representing a substance as a supplemental ingredient prior to making a submission. If the Food Directorate considers that a substance is inappropriate for addition to the List of Permitted Supplemental Ingredients, the petitioner's request will be refused and the rationale for this decision will be shared with the petitioner (see Section 3.6.1). While there is no regulation that defines the purpose or value of a supplemental ingredient, Section 5 of the FDA generally prohibits labelling a food in a way that is likely to create an erroneous impression regarding its value^{Footnote 1}.

2.1.2 Substances ineligible for addition to the List of Permitted Supplemental Ingredients

The following substances are generally considered ineligible for addition to the List of Permitted Supplemental Ingredients:

• Substances in the List of contaminants and other adulterating substances in foods
• Substances in the List of maximum levels for various chemical contaminants in foods
• Vitamins, mineral nutrients, and amino acids listed in Section 4.2.10.1 and 4.2.11.1 of the Guidance Document: Supplemented Foods Regulations (e.g., folic acid)
• Substances that require more extensive cautionary labelling (e.g., contraindications) under the proposed conditions of use
• Substances included in Schedule I to V of the Controlled Drugs and Substances Act
• Drugs with prescription status (e.g., atorvastatin; penicillin; Vitamin D in oral dosage form containing more than 62.5 µg or 2,500 International Units of Vitamin D per dosage form)
• Substances referred to in item 1 or 3 of Schedule 1 to the Cannabis Act (i.e., phytocannabinoids, or an identical substance)

2.1.3 Food categories ineligible for addition to the List of Permitted Supplemented Food Categories

As per the Supplemented Foods Regulations, certain food categories are ineligible for addition to the List of Permitted Supplemented Food Categories. Submissions to propose addition of ineligible categories to the List will not be accepted for review.

Food categories may be ineligible for addition to the List of Permitted Supplemented Food Categories because they are either subject to other regulatory provisions in the FDR, or due to their higher level of risk for consumers if they were supplemented:

• Foods requiring or permitted addition of vitamins, minerals or amino acids as per the table to Section D.03.002 of the FDR (e.g., milk), other than the exceptions appearing in the List of Permitted Supplemented Food Categories
• Foods for special dietary use regulated under Part B, Division 24 of the FDR (except gluten-free foods)
• Foods regulated under Part B, Division 25 of the FDR
• Foods targeted towards children under 4 years of age, or pregnant or breastfeeding individuals
• Prepackaged unprocessed foods or minimally processed foods
• Beverages containing more than 0.5% alcohol

Further details about ineligible food categories can be found in Section 3.2 of the Guidance Document: Supplemented Foods Regulations.

2.2 Information that should be included for each type of submission

Health Canada's Food Directorate manages the List of Permitted Supplemental Ingredients and the List of Permitted Supplemented Food Categories and requires sufficient information from the petitioner to demonstrate that the proposed change would not pose a safety concern. Guidance on the Food Directorate's data requirements is in Appendix 1 of this document.

Two submission checklists have been also been developed. One is related to requests to modify the List of Permitted Supplemental Ingredients, and one is related to requests to modify the List of Permitted Supplemented Food Categories. These do not replace the cover letter or any other documents pertaining to the submission. They are additional documents summarizing both administrative and scientific or technical information, and are meant to assist the petitioner in the preparation of a submission and the Food Directorate in verifying that the information it requires has been submitted. Petitioners should provide one submission checklist for each request (i.e., for each separate submission).

3.0 Submission management process

The process may begin with an optional pre-submission consultation (see Section 3.1). Once the petitioner decides to proceed with a submission, the steps in the submission management process are as follows:

• Administrative verification upon receipt of a submission
• Scientific Screening
• Scientific Review
• Decision and communication of the Food Directorate's decision to the petitioner
• Administrative process to modify one or both of the Lists

The Food Directorate will aim to provide a decision to the petitioner within 410 days from the date of submission. This includes the time allocated for petitioners to respond to Health Canada's questions of clarification and requests for missing information. Only submissions that result in a favourable decision will proceed to an administrative process to modify the appropriate List or Lists.

3.1 Pre-submission consultation

If petitioners require further assistance after reading the relevant guidance documents, they are encouraged to request a pre-submission consultation with the Food Directorate, as per the Pre-submission consultation guidance: Mandatory Pre-market submissions for the Food Directorate. These consultations could be in the form of emails, phone calls or meetings. They are an opportunity to seek further guidance on submission requirements and eligibility so that a complete submission can be filed at the outset, potentially reducing the number of requests to the petitioner for clarification or additional information, or preventing the submission from being rejected as incomplete. Pre-submission consultation requests may be sent to the SMIU at smiu-ugdi@hc-sc.gc.ca.

3.2 Instructions for sending submissions and additional requested information

Petitioners should use the Application Form for Pre-Market Submissions to the Food Directorate (Online Application Form) and corresponding guidance document How to Complete the Online Application and Transport Form for Pre-Market Submissions to the Food Directorate. Additional information requested at any point during the process (for example, responses to letters of deficiency) should be submitted using the Transport Form for Submitting Additional Documents to Health Canada, with a reference to the submission number assigned to the submission.

3.3 Administrative verification

This step validates that the submission package contains the necessary administrative information.

The Food Directorate will assign a submission number upon receipt of the submission, and the SMIU will verify that the essential components of the submission package are included, such as the contact information, a designated third-party authorization form (if required), a submission checklist, and a cover letter describing the submission and clearly stating the request to the Food Directorate. Petitioners will be asked to provide any missing information in order to continue the submission process.

A Letter of Acknowledgment will be sent electronically to the petitioner if the submission is complete and accepted for the next stage of the submission management process.

3.4 Scientific screening

Submissions containing the necessary administrative information will proceed to a scientific screening step. If the submission includes sufficient scientific and technical information to conduct a scientific review, the Food Directorate will send a Screening Acceptance Letter to indicate that the scientific screening has been completed. Once a submission passes the scientific screening step, additional information may still be required from the petitioner to complete the scientific review. The scientific screening does not fully assess the quality of the data and rationales provided.

3.4.1 Screening letter of deficiency

The Food Directorate will provide an opportunity for the petitioner to address minor deficiencies identified in the scientific screening step through a request for information. Minor deficiencies are usually limited to matters for clarification, whether they be related to the submission or to the evidence provided.

The Food Directorate will also provide an opportunity for the petitioner to respond to major deficiencies, including missing information that is necessary for review but which is not included in Appendix 1.

Petitioners should include a cover letter with their response, describing how each deficiency has been addressed. If sufficient information to address one or more deficiencies is not readily available to the petitioner (i.e., within the timeline identified in the Letter of Deficiency), the petitioner will be notified that the Directorate has closed the submission. Petitioners will have the option to file a new submission, without prejudice, once they are able to address all of the deficiencies identified by the Food Directorate (See Section 5.0).

While the Food Directorate will provide an opportunity to address some deficiencies, if the submission has numerous deficiencies (e.g., missing data or scientific rationales) it would be considered incomplete and may be closed, without prejudice, as a safety assessment cannot be conducted by the Food Directorate.

3.5 Scientific review

This step encompasses the in-depth safety review, by relevant Bureaus across the Food Directorate, to determine whether the requested change is expected to pose a risk to human health. The submission will be evaluated against the principal data requirements described in Appendix 1, and the quality of the data will be considered.

3.5.1 Scientific review letter of deficiency

The Food Directorate will provide an opportunity for the petitioner to address deficiencies identified during the scientific review, through a request for information in the form of a Letter of Deficiency. Petitioners should include a cover letter with their response, describing how each deficiency has been addressed. If an adequate response is not provided within the timeline specified in the Letter, the petitioner will be notified that the Directorate has closed the submission. At any time during the review process, a petitioner may request that a submission be withdrawn (see Section 4.0).

Deficiencies identified at this stage could include matters that require further discussions with the petitioner prior to finalizing the review. For example, in the case of a food category, this could include discussions to ensure that the proposed food category name and description adequately describe the scope of foods to be included; or it could include a revision to the scope of supplemental ingredients to be permitted in that category.

Petitioners may request a consultation with the Food Directorate to discuss the information requested in more detail. The Food Directorate will consider requests on a case-by-case basis.

3.6 Decision

3.6.1 Unfavourable decisions

A submission may be closed during scientific screening if, for example, the requested supplemented food category or supplemental ingredient is ineligible (as described in Section 2.1.2 or 2.1.3) or if the substance is inappropriate for addition to the List of Permitted Supplemental Ingredients as described in Section 2.1.1. A submission may also be closed during scientific screening or scientific review if, for example, a response to a deficiency letter is insufficient (See Sections 3.4.1 and 3.5.1), or if significant safety concerns are identified. In these cases, the decision and its rationale will be communicated to the petitioner as early in the process as possible and the submission will be closed.

In most situations, a submission that has been closed by the Food Directorate may be filed as a new submission at a later date, without prejudice, provided the new submission addresses outstanding deficiencies from the closed submission (See Section 5.0 for details). A petitioner who is concerned about a decision to close a submission, or any other interaction with Health Canada during this process, may also contact the Food and Drugs Act Liaison Office (FDALO) at fdalo-bllad@hc-sc.gc.ca. FDALO is a confidential resource for businesses and stakeholders which receives complaints, concerns or enquiries on matters pertaining to the Food and Drugs Act.

3.6.2 Favourable decisions

If the decision is favourable, the petitioner is notified in writing that the Food Directorate intends to follow its established administrative procedure for modifying the List of Permitted Supplemented Food Categories and/or the List of Permitted Supplemental Ingredients as necessary. The applicable List or Lists must be modified before the supplemented food can be legally sold in Canada.

3.7 Administrative process to modify one or both of the Lists

Following a favourable decision, the Food Directorate notifies the public, including domestic and international stakeholders, of its intent to modify one or both of the Lists via a Notice of Proposal (NOP) published on Health Canada's website. Interested stakeholders are provided a 75-day period from the day on which the NOP is posted to provide comments to the Food Directorate.

At the close of the comment period, the Food Directorate will consider all feedback. If no new scientific information is provided that would require revisions to the proposal, then the Food Directorate will proceed with formally modifying one or both of the Lists. The public will be notified of the change by means of a Notice of Modification (NOM) posted on Health Canada's website. The NOM will specify the changes made and the date on which they come into effect (usually the day on which the notice is published). Once the modification or modifications to the appropriate List or Lists have come into effect, the petitioner will be notified in writing.

More information about the process to modify Health Canada's documents that are incorporated by reference can be found at the incorporation by reference webpage.

4.0 Withdrawal of a submission

Petitioners may withdraw their submission at any time during the submission management process by emailing the SMIU (smiu-ugdi@hc-sc.gc.ca) with the subject line "Submission Number-Withdrawal".

5.0 Filing a new submission

Any submission that has been withdrawn by the petitioner or closed by the Food Directorate may be filed as a new submission at a later date, without prejudice, provided the new submission addresses reasons for closing the submission (e.g., outstanding deficiencies). The Food Directorate will not accept a new submission if it is not possible to address the reason(s) for which the initial submission was closed (e.g., if a food category is ineligible).

When filing a new submission, the petitioner should make reference in the cover letter to the previous submission number and indicate how previously identified deficiencies have been addressed. The submission will be assigned a new submission number, and will re-start the submission management process as a new submission. It is also highly recommended that petitioners request a pre-submission consultation (see Section 3.1) prior to filing a new submission, during which time staff within the Food Directorate will be available to discuss any questions or concerns relating to the closure of the previous submission.

6.0 Confidentiality

The Food Directorate is committed to upholding its obligations with respect to confidentiality in accordance with the Access to Information Act and will keep submitted information confidential to the extent permitted by law. For more information on Access to Information, please visit the website on Access to Information and Privacy published by the Treasury Board of Canada Secretariat.

The disclosure processes to notify stakeholders of proposed and final modifications to the List or Lists do not contain information about the petitioner or confidential business information.

7.0 Single window into the Food Directorate submission management process

Petitioners should submit pre-market requests and associated documents using the Online Application Form for Pre-Market Submissions to the Food Directorate (Online Application Form) and the Transport Form for Submitting Additional Documents to Health Canada, as described in Section 3.2. Questions regarding submissions and requests for pre-submission consultation meetings can be sent to the SMIU at smiu-ugdi@hc-sc.gc.ca.

Appendix 1: Data requirements

The following guidance is intended to provide details about the type of information that can be submitted to meet the Food Directorate's data requirements to support requests to modify the Lists; however, it is not intended to define explicitly all the data that might be required during a safety assessment. During the review, the Food Directorate may request additional information to conduct the pre-market assessment related to the requested modifications to the Lists. Within this appendix, and the associated submission checklists, the word "must" indicates requirements for successful submission and does not indicate a regulatory requirement.

1.0 To request a modification to the List of Permitted Supplemental Ingredients

Substances may be ineligible for addition to the List of Permitted Supplemental Ingredients (see Section 2.1.2) if they are subject to existing provisions in the Food and Drug Regulations (FDR) (e.g., the List of contaminants and other adulterating substances in foods, incorporated by reference into Division 15 of the FDR) or other Canadian legislation (e.g., Cannabis Regulations), or if they have associated safety concerns. Other substances may also be considered inappropriate for addition to the List (see Section 2.1.1). A submission for a substance that is ineligible or inappropriate for addition to the List of Permitted Supplemental Ingredients will not be accepted for Scientific Review. The information in this Section is required for substances eligible for consideration for addition to the List of Permitted Supplemental Ingredients or any modifications to the current listings.

A submission to support a request to add a new substance to the List of Permitted Supplemental Ingredients (i.e., new supplemental ingredient) would require most or all of the information described in this Section. A submission to support a request to modify a supplemental ingredient's conditions of use (i.e., modification to supplemental ingredient), would require only the information relevant to the request, and rationales for why the other information is not considered relevant. For example, a request to increase the maximum amount of a supplemental ingredient should be accompanied by all of the information specified below; however, a request to remove the cautionary statement "Not recommended for those under 14 years old" would require data or a science-based rationale to support the safety of the substance in this sub-population specifically, with rationales provided to indicate why the other information is not provided. Requests to modify Column 2 of the List of Permitted Supplemental Ingredients (i.e., to permit a supplemental ingredient in an additional food category that is already listed in the List of Permitted Supplemented Food Categories) may also require some information described in the Section below, "To request a modification to the List of Permitted Supplemented Food Categories".

1.1 Administrative information

Administrative information must be included for every submission. This includes contact information, the name of the proposed substance or supplemental ingredient, a cover letter describing the submission and clearly stating the request to the Food Directorate, and a designated third-party authorization form (if required). A Supplemented Food Submission Checklist – Supplemental Ingredient must also be submitted. Petitioners that are missing any of this information will be asked to provide the requested information in order to continue the submission process.

1.2 Description of the substance and requested change

1.2.1 Identity of the substance

• Proper name:
  • For organisms or ingredients derived thereof, this includes species and subspecies, variety or strain, as appropriate
  • For discrete substances, this includes any applicable stereochemistry
• Descriptive name:
  • This is a name by which the ingredient is commonly known
  • A descriptive name may be used in place of a proper name, where a standard proper name does not exist (such as for a specific type of crude plant extract), or in addition to a complex proper name that may not be suitable for labelling purposes
  • An appropriate descriptive name may be acceptable for inclusion in the List of Permitted Supplemental Ingredients provided it accurately represents the substance in question
  • An example of an acceptable descriptive name is "green tea extract (EGCG/catechins)", which refers to a green tea extract that is standardized according to the content of EGCG (also known as epigallocatechin-3-gallate) and other catechins

The Food Directorate will consider scientific literature that refers to the proper name or a descriptive name of a substance, provided it is, in fact, about the substance that is the subject of the request.

1.2.2 Source of the requested substance and its method of manufacture

• Source (raw material – e.g., part of plant used)
• If applicable, information pertaining to any natural presence of the substance in foods; or as a normal constituent in the body
• Detailed description of manufacturing process (e.g., detailed description of extraction method, identification of all raw materials used, and description of the technological purpose of each raw material used), including any chemical or non-chemical post-extraction processing that could modify the toxicological properties of the substance (e.g., chemical conjugation; suspension in a carrier matrix or solvent; enteric coating; microsomal or nanosomal preparation)

1.2.3 Composition and specifications of the substance

• Identity (including chemical name(s) and Chemical Abstract Service (CAS) Registry Number(s), if applicable) and composition of the substance (e.g., name and quantitative declaration of components; information on the function of components)
• Specifications for the substance (notably regarding active components or key constituents, impurities, stability)
• Information on validated analytical methods used to establish specifications
• Information about specifications and standards of quality developed by other organizations (e.g., Food Chemicals Codex, European Union Herbal Monographs, United States Pharmacopeia (USP)-National Formulary) that apply to the substance, if available

1.2.4 Proposed maximum amount, and other conditions of use

• Proposed maximum daily amount and maximum amount per serving, if different
• Intended supplemented food categories for addition (e.g., specific supplemented food categories, foods within one or more supplemented food categories, or general application to all supplemented food categories)
• Intended cautionary statements and associated threshold level(s) (e.g., Do not [eat/drink] more than X serving(s) per day; Not recommended for pregnant or breastfeeding women; Not recommended for those under 14 years old; For Adults only (18 years old and older); Do not [eat/drink] on the same day as any other supplemented foods or supplements with [the same supplemental ingredients/(name specific ingredients)])
• Other conditions, as applicable (e.g., packaging conditions to enable adherence to maximum daily amounts and maximum amounts per serving, based on reference amounts for food servings^{Footnote 2})

Only certain types of cautionary labelling are considered appropriate for supplemented foods. Cautionary labelling that is considered appropriate as a risk mitigation tool under the Supplemented Foods Regulations includes statements to help consumers limit their intake of a substance to safe levels, and those that would prevent consumption by certain sensitive sub-populations (e.g., children and pregnant or breastfeeding individuals). In preparing the risk information below, the petitioner should be mindful that ingredients requiring more extensive cautionary labelling (e.g., contraindications) to protect the consumer are not appropriate for foods, including supplemented foods.

1.3 General information on health risk (including non-food formats)

1.3.1 Safety narrative

It is important to include a safety narrative to summarize the information provided and describe how the information substantiates the safety under the proposed conditions of use. If information is not submitted to address the data requirements outlined below, a science-based rationale is needed to describe why the information is not required.

1.3.2 Information on health risk

The petitioner should submit all information on the potential health risks of the requested supplemental ingredient, including but not limited to:

• Known adverse effects associated with its use (e.g., unintended response to the substance)
• Evidence of interactions (e.g., with NHPs, other foods, drugs, alteration of clinical diagnostic tests)
• Known sensitive sub-populations for whom the ingredient is not appropriate (e.g., children, pregnant or breastfeeding individuals, diabetics, those on specific medications)
• Other requirements or instructions for use (e.g., consult a healthcare practitioner for use longer than X duration)

The petitioner should include information about how the risk management measures proposed in the submission would be effective at mitigating the potential health risks. Please note that unless conditions of use, including limited cautionary labelling, result in avoidance of contraindications, the substance may not be appropriate for use in foods, including supplemented foods. If this type of information is not submitted, but is identified as being necessary by the Food Directorate during the scientific review, the submission may be closed. The petitioner will need to provide the additional information that addresses these concerns by filing a new submission.

1.3.3 Information on scientific evaluations, regulatory approvals and authorizations of other national and international programs

In the event that the ingredient has undergone a safety assessment by other national or international scientific programs, the submission should comment on outcomes of the evaluations. In particular, summaries and pertinent details of evaluations conducted by other domestic programs such as the Natural and Non-prescription Health Products Directorate^{Footnote 3}, or by other national or international jurisdictions such as the U.S. Food and Drug Administration^{Footnote 4}, the European Union food safety authorities (e.g., European Commission, European Food Safety Authority, and/or competent authorities of individual Member States)^{Footnote 5}, and Food Standards Australia and New Zealand should be provided.

Such evaluations do not replace the assessment that is to be conducted by the Food Directorate for use of the substance as a supplemental ingredient under the proposed conditions of use; however, such information will be considered by the Directorate in the course of evaluating the substance for its safety when added to foods.

1.4 Toxicology considerations

The safety of a food ingredient can be assessed through pharmacokinetic studies (absorption, distribution, metabolism and excretion studies), toxicological testing, and clinical studies in humans. The intent of submitting these types of data to the Food Directorate is to substantiate the safety of a substance under certain conditions of use as proposed by the petitioner.

Although the safety of most food ingredients can be determined through the standard gamut of toxicological studies (as described in detail below), certain types of ingredients may require additional information and consideration. For example, if the requested substance has a history of therapeutic use, studies regarding the mode of action of the therapeutic effect (i.e., how the substance exerts its therapeutic effect on the human body), as well as possible safety considerations resulting from the therapeutic mode of action, will also be required by the Food Directorate.

Any studies that are submitted to support the safety of a substance should be conducted according to high testing standards (e.g., Organization for Economic Co-operation and Development (OECD) Guidelines for Testing of Chemicals; Good Laboratory Practices) to produce valid results, which must be reported in sufficient detail and clarity so that the Food Directorate has confidence in the findings. For example, such studies would include a detailed description, including specifications, of the test substance used in the study, a complete description of the study design (including the methods used, the type and number of animals treated, the doses used, and the toxicological endpoints measured), as well as a detailed results section. Full study reports should be submitted to the Food Directorate, if available.

It is important that the submission clearly demonstrate that the toxicological information provided applies to the substance that is the subject of the petitioner's request. This is particularly important for substances, such as plant extracts, that may have substantive variability depending on source material, manufacturing process, etc.

Like all food ingredients, those permitted for use as supplemental ingredients could be consumed on a daily basis over an individual's lifetime. Therefore, it is critical to demonstrate that when the substance is used as proposed in supplemented food, it will be safe for long-term consumption by the intended consumer group(s). The petitioner should demonstrate that potential health risks for any particular population group(s) are appropriately mitigated by the proposed conditions of use (which can include appropriate cautionary labelling, as described in Section 1.2.4 of this Appendix). Supplemental ingredients are ingested; therefore, any studies submitted should be conducted using the oral route of exposure (as opposed to the inhalation, dermal, or injection routes).

A summary of the types of toxicological studies used to establish safety for a requested substance is presented below. However, depending on the knowledge available on the substance's chemical structure, properties, distribution in the body, toxicity, and/or on exposure to the substance, all or only some of the studies listed may be required by the Food Directorate.

Pharmacokinetic/toxicokinetic studies

The purpose of these studies is to characterize the absorption, distribution, metabolism and excretion of the requested supplemental ingredient in the body following ingestion. These studies can help determine the most appropriate doses to be used in toxicity tests (linear vs. non-linear kinetics); assist in relating concentration or dose to the observed toxicity associated with the substance; aid in understanding a substance's mechanism of toxicity; facilitate the selection of the most appropriate species for toxicity testing; and help identify potential species differences if data from multiple species are available.

Acute toxicity studies

The purpose of these studies is to determine the adverse effects that may occur in the test species (the rat is most commonly used) within a short time of oral administration of a single dose of a substance (or multiple doses given within 24 hours), and estimate the dose at which half of the test animals experience mortality (lethal dose 50; LD50).

Short-term (sub-chronic) toxicity studies

The purpose of these studies is to determine the adverse effects that may occur in animals (typically rodents) after repeated (daily) oral administration of a substance for 28 or 90 days. These tests can be used to provide an indication of toxicological effects following ingestion, define potential target organs, assess the potential for accumulation of the test material, and estimate a no-observed-adverse-effect level (NOAEL) of exposure which can be used in selecting doses for long-term studies and for establishing safety criteria for human exposure. The more extended of these short-term studies (i.e., the 90-day study) can also be used for more detailed evaluation of toxicity (e.g., measurements of hematology and clinical chemistry parameters).

Long-term (chronic) toxicity and carcinogenicity studies

The purpose of long-term toxicity studies is to determine the adverse effects that may occur after prolonged repeated (daily) oral administration of a substance for a period of time that represents a significant portion of the lifespan of the laboratory animal (e.g., one year in rats). The results of these tests are used to assess the potential of the substance to cause toxicity, and include detailed evaluations of clinical toxicity, behavioral effects, hematology, clinical chemistry, urinalysis, and gross and microscopic pathology.

In addition, long-term carcinogenicity studies of up to two years duration (in rodents) may be performed to assess the potential development of neoplastic lesions during or after oral exposure to various doses of the substance.

Genotoxicity tests

The purpose of these studies is to determine the potential to directly affect the DNA (e.g., mutations) in germ and somatic cells, or the chromosomal structure and/or number (e.g., clastogenicity). Tests are conducted in microbes and mammalian cell lines in in vitro systems, as well as in mammalian in vivo systems.

Developmental toxicity studies

The purpose of these studies is to determine the potential to cause effects on the pregnant test animal and on the developing young, after daily oral administration to the pregnant mother during the part of the gestation period when major organ development is ongoing (which varies, depending on the species used). The tests are conducted in at least one rodent and one non-rodent species (often rabbit).

Reproductive toxicity studies

The purpose of these studies is to determine the potential to adversely affect the reproductive capacity of parental animals, and to cause adverse developmental effects in their offspring after daily oral administration to the animals during premating, mating, gestation and lactation periods. The tests are conducted in rodent species.

Other specialized toxicology studies

The purpose of these studies is to determine the potential to cause specialized adverse effects (e.g., neurotoxicity, immunotoxicity), which are often not fully characterized in other standardized toxicity study protocols (i.e., acute, short-term and long-term studies).

Human clinical studies

The purpose of these studies is to confirm safety in humans, and to assess tolerance in the general population (these studies may also be conducted in a sub-population with a medical condition, for example).

If included, these studies must be reported in sufficient detail and clarity so that the Food Directorate has confidence in the findings. For example, studies should include details on the study design, study population, doses, frequency and duration of use of test material, key findings, and any adverse effects observed in comparison to the control group or group that received a comparator (e.g., group that received a conventional marketed product) if available.^{Footnote 6} Full study reports should be provided to the Food Directorate, if available.

The Food Directorate encourages that submissions be based on all relevant evidence to date, including unpublished human clinical trials. In the case of unpublished studies, full study reports should be submitted, including raw data and information on methodological validation, to allow evaluators in the Food Directorate to gauge their reliability.

Please note that clinical studies where the primary focus is on therapeutic and/or beneficial effects, or relief of specific medical conditions, are not sufficient on their own for use in a safety evaluation of substances requested for use as supplemented ingredients; however, they may be considered in the totality of the evidence.

Alternative methods

Health Canada applies the principles to replace, reduce or refine (3Rs) animal toxicity testing. The Food Directorate will accept the submission of toxicological results from alternative, non-animal methods, rather than those referred to above, on a case-by-case basis. Petitioners who are considering alternative methods are strongly encouraged to request a pre-submission consultation with the Food Directorate.

1.5 Allergenicity considerations

The primary consideration in the allergenicity assessment of a requested supplemental ingredient is the prevention of unexpected and/or unavoidable exposure of susceptible individuals to food allergens. The potential exists that one or more component proteins in an ingredient would have the capacity to cross-react with known food allergens or lead to the development of de novo hypersensitivity. It should be noted that most allergic reactions are generally associated with proteins; however, the vast majority of proteins consumed are not allergenic.

At present, there is no definitive test that can be relied on to directly measure the allergenic potential of an individual protein or of a whole food. Because existing strategies for the assessment of the allergenic potential of proteins were developed for the evaluation of individual, well-defined proteins, they are not easily applied to the entire protein component of a whole ingredient. A preliminary strategy for assessing the allergenic potential of a substance would be to investigate whether plants and/or animals from the same taxonomic family as the substance of interest, that are commonly part of the food supply, are implicated in eliciting an allergic response. The association of a particular family of plants and/or animals with allergic response does not necessarily preclude a substance from a related species being added to the List of Permitted Supplemental Ingredients, but risk management for allergenicity will need to be considered.

1.6 Chemical considerations

The identification and levels of chemical contaminants should be reported. Potential levels and types of contaminants would be specific to the ingredient. It would therefore be necessary to determine the levels and/or ranges of contaminants that may be present in the requested supplemental ingredient. Examples of potential chemical contaminants are inorganic contaminants including metals such as arsenic, cadmium, mercury and lead; organic contaminants including persistent organic pollutants or "POPs" such as DDT, aldrin and dieldrin; and natural contaminants including mycotoxins such as aflatoxins, vomitoxin, ochratoxin, and zearalenone.

It is the petitioner's responsibility to understand the potential chemical contaminants that may be associated with the ingredient, and to include the relevant information in the submission.

All materials (e.g., carrier or extraction solvents, diluents, colours, preservatives, enzymes, flocculating agents, antifoaming agents, pH adjusters, precipitation aids, filtering agents) used in the manufacturing process for the substance should be identified (including chemical name(s) and CAS Registry Number(s), if applicable) and their purpose and level of use indicated. Information should also be provided on potential residues of each material in the substance. If residues are not expected, a detailed scientific rationale (chemistry-based) explaining the absence of residues should be provided.

1.7 Nutritional considerations

There is also a need to submit data supporting the nutritional safety of a requested supplemental ingredient. The petitioner should provide information on direct and indirect effects of the substance on nutritional quality and safety of the food. The nutritional safety assessment determines that the substance or its metabolic products would not have an intended or unintended adverse effect on nutritional quality and safety of the food under the proposed conditions of use, and should consider the level of exposure from other foods. The implications of the substance on nutritional quality and safety of the food should be determined for the population as a whole and/or for specific groups within the general population. The petitioner should demonstrate that potential nutritional health risks for consumers in the general population and/or specific sub-populations are appropriately mitigated by the proposed conditions of use.

Especially, consideration should be given to:

• Presence and composition of antinutrients (e.g., saponins, tannins, isoflavones)
• Potential or observed interactions with nutrients
• Use of the substance by sensitive sub-populations (e.g., pregnant or breastfeeding individuals, children, and persons with medical conditions)
• Nutrient composition, and standardization or concentration of nutrient content
• Bioavailability and metabolic fate of the substance
• Impacts on the functions of key metabolic organs (e.g., liver and adipose tissue) and potential clinical outcomes (e.g., obesity, diabetes)

1.8 Microbiological and molecular biological considerations

There may also be a need to submit data pertaining to the microbiological safety of a requested supplemental ingredient. In this case, the identification and levels of microbial contaminants should be provided, with comparison against appropriate microbial specifications, and data demonstrating compliance with these specifications. For a microbial derived product, a food grade fermentation is expected to yield a pure culture without microbiological contamination prior to downstream processing. Certificates of analysis for appropriate indicator organisms should be provided to demonstrate microbial safety. Documentation on the quality control of the manufacturing process should also be provided, including a description of the manufacturing process and control measures that are applied to ensure quality and prevent microbial contamination.

A requested supplemental ingredient could be produced by a genetically-modified^{Footnote 7} microorganism, or could itself be a genetically-modified microorganism. Where a microorganism has been genetically modified, whether by selection and mutagenesis techniques, recombinant DNA (rDNA), or by gene editing technologies, the submission should contain data that establish the molecular safety. The approach of the safety assessment is based on the principle that the safety of the microorganism is evaluated relative to a wild-type, previously approved, or closely related and well-studied strain having a history of safe use, taking into account both intended and unintended effects. Any significant differences between the assessed microorganism and the relevant comparator strain are then evaluated for potential to cause adverse health effects in humans. Of particular interest to the safety assessment is whether the modification could inadvertently develop or increase the pathogenicity, toxicity, or allergenicity potential of the microorganism or the toxicity or allergenicity potential of products obtained from the microorganism.

1.9 Additional considerations

1.9.1 Environmental assessment of new ingredients

Currently, the New Substances Notification Regulations (Chemicals and Polymers) and the New Substances Notification Regulations (Organisms) (collectively referred to here as the NSNR) of the Canadian Environmental Protection Act, 1999 (CEPA) apply to all substances regulated under the Food and Drugs Act (FDA).

It is the responsibility of the petitioner to ensure that a requested supplemental ingredient meets all applicable regulatory requirements, including those required under CEPA. For example, substances that are not on the Domestic Substances List (DSL) are considered to be new to Canada and are subject to notification under the NSNR. Substances on the DSL do not require notification unless they are subject to significant new activity (SNAc) requirements. Guidance documents on current New Substances Notification requirements for all new substances (including those regulated under the FDA) are available on Environment and Climate Change Canada's New Substances program website.

Questions concerning the NSNR for substances in products regulated under the FDA should be directed to the Environmental Assessment Unit of Health Canada (eau-uee@hc-sc.gc.ca).

2.0 To request a modification to the List of Permitted Supplemented Food Categories

The Supplemented Foods Regulations set out foods and food categories that are ineligible for supplementation. Food categories may be ineligible because of the potential health risk they would pose if they are supplemented (e.g., food categories intended for young children who are more vulnerable to risks related to nutrient imbalances), and/or if they are subject to other provisions in the FDR (see also Section 2.1.3). A submission for a food category that is ineligible for supplementation will not be accepted for Scientific Review. For food categories containing foods at the Food-NHP interface, the submission process may include a step to confirm whether a particular product of interest is a food or an NHP, as per the principles of classification that are detailed in the Guidance Document: Classification of products at the food-natural health product interface: products in food formats. Additional information may be requested during this step.

For food categories eligible for consideration for addition to the List of Permitted Supplemented Food Categories, or any modifications to the current listings, the following information is required.

2.1 Administrative Information

Administrative information must be included for every submission. This includes contact information, the name of the food category, a cover letter describing the submission and clearly stating the request to the Food Directorate, and a designated third-party authorization form (if required). A Supplemented Food Submission Checklist – Food Category must also be submitted. Petitioners that are missing any of this information will be asked to provide the requested information in order to continue the submission process.

2.2 Description of the food category or requested change to a food category

• Proposed name:
  • An appropriate food category name should be submitted, ensuring that there is no overlap with other food categories. If the request results in a favourable decision, this name will be set out in the List of Permitted Supplemented Food Categories.
• Description of the food category:
  • The description of the food category should be included with the submission. Petitioners should ensure that the request is for a specific food category. It should not refer to a broad food category that encompasses a large number of foods or formats of products. For example, "beverages" is a broad food category, whereas "carbonated water-based beverages" refers to a more specific food category. The Food Directorate may engage the petitioner during the assessment process to define the scope of the requested category.
• Food commodities included and excluded under the requested food category:
  • A comprehensive list of all foods that fall within the scope of the requested food category as described should be provided.
  • The submission should include information on any exclusions applicable to the requested food category, such as bulk form products within a food category. This should also include a list of specific foods or food commodities that are excluded, if applicable.
  • The list of commodities along with applicable exclusions are important factors in defining the scope of a food category, which will be outlined in guidance and helps ensure stakeholders have clarity on the foods that fall within a permitted supplemented food category.
• Supplemental ingredient(s) requested to be permitted in the food category:
  • The submission should also include information about the supplemental ingredient(s) that are requested to be permitted in the requested food category. While at the time of their coming into force, the Supplemented Foods Regulations permitted the addition of most supplemental ingredients in all food categories set out in the List of Permitted Supplemented Food Categories, the regulations provide the flexibility to define more specific conditions of use for supplemental ingredients, including defining to which supplemented food categories they can be added. As such, it is the responsibility of the petitioner to indicate the supplemental ingredient(s) requested for addition to the requested food category. For example, a new fat-based food category may be requested for the sole purpose of containing added fat-soluble vitamins. In such a case, the petitioner should list out all the fat-soluble vitamins they wish Food Directorate to permit in the requested food category. The Food Directorate will consider the proposed food category in the context of supplemental ingredient(s) that are requested for addition to the food category.
• Proposed use of the requested food category:
  • The submission should include information on the proposed or intended use of the requested food category (or specific food commodities within the requested food category). The petitioner should also comment on the typical uses of that food category or food commodity. For example, food categories may include foods that are typically used or intended to be used by consumers as ingredients in the preparation of other foods (e.g., spices). These foods and their typical use may make it challenging for consumers to determine the amount of supplemental ingredient(s) consumed and therefore, may not be appropriate as supplemented foods.

2.3 Food consumption information

Petitioners must provide data regarding the estimated consumption of foods within the food category across life-stage and gender groups. This should be based on recent Canadian food consumption data where possible (e.g., data from the most recent Canadian Community Health Survey-Nutrition and associated Food Consumption Tables); however, in cases where this information is not available, the Food Directorate may also consider other data, such as U.S. data (e.g., from the most recent National Health and Nutrition Examination Survey). Food consumption information may be used to confirm that the food is not commonly consumed by a large segment of the population. Supplementation of some commonly consumed foods may not be appropriate as it may lead to excessive or imbalanced intakes of supplemental ingredients in the population due to widespread and frequent use of the food. This is of particular concern for sensitive sub-populations such as children. Disproportionate consumption of foods in a food category by children would factor against the appropriateness of supplementing the food category.

Supplementation of commonly consumed foods may also invalidate methods that were used to establish generally applicable maximum levels for existing supplemental ingredients, which assumed that up to five servings of supplemented foods could be consumed daily. Where a potential exposure risk is identified, the Food Directorate may request additional information and/or conduct its own exposure modelling exercise to determine whether the requested food category could contribute to excessive intake of supplemental ingredient(s). Clear identification by the petitioner of the relevant food commodities (as noted above) within the requested food category is critical to this exercise.

The submission should be accompanied by a sound scientific rationale from the petitioner that supports that the supplementation of the requested food category with the proposed supplemental ingredient(s) does not present an increased health or safety risk relative to the existing list of food categories that may be supplemented.

2.4 Special conditions proposed for the food category

The Supplemented Foods Regulations provide flexibility to define more specific conditions for supplemental ingredients and supplemented food categories, if appropriate. This could include, for example, special packaging conditions, such as packaging a pre-mixed food in single serving sachets, as bulk containers may not allow for consistent preparation of the finished food.

2.5 General safety information

It is important to include a safety narrative to summarize the information provided and describe how the information substantiates the safety of the requested supplemented food category containing the proposed supplemental ingredient(s). The safety narrative should address the overall safety of the requested addition or modification to the List of Permitted Supplemented Food Categories, as applicable to the food category, food commodities, and/or exclusions, based on the conclusions of the information requested above. If the information requested above is not included in a submission, a science-based rationale is needed to describe why the information is not necessary.