Multi-Vitamin/Mineral Supplements

MULTI-VITAMIN/MINERAL SUPPLEMENTS reference

this reference is intended to serve as a guide to industry for the preparation of product documentation forms and labels for supplement market authorization.

• Text in parentheses is additional optional information which can be included on the label at the applicant's discretion except in cases where a plural form of the statement does not apply (e.g., Source of electrolyte(s), when only one electrolyte is included in the product).

• this reference includes specific information for each vitamin and mineral as well as combination rules and may be used to support single ingredient or multi-ingredient products containing any active ingredient from Tables 1, 2 and/or 3.

• Sodium and ingredients where sodium is a substantial component are not included as active ingredients on this reference, due to health concerns associated with chronic supplemental use of sodium, namely hypertension, which remains the most common and most important risk factor for cardiovascular disease. However, the use of sodium as a counter-ion in medicinal or Other ingredients (e.g., sodium salts of minerals) is acceptable where warranted.

• The web-based product documentation form and label must declare all active components (i.e., vitamin and mineral) of a source ingredient as active ingredients and provide their quantity per dosage unit if the total daily dose of that vitamin or mineral exceeds the reference's minimum dosage value. For example, if calcium ascorbate is listed as a source ingredient for calcium and also provides vitamin C (ascorbic acid) at medicinal levels (i.e., ≥ 6 mg/day for adults), then the web-based product documentation form and label must include vitamin C as a active ingredient and its quantity per dosage unit. See Appendix I for additional information.

Proper names, Common names and Source information

• The terms chromic, cupric, ferrous, ferric and manganous are not available on the web-based product documentation form and will not be added; however, these synonyms may be used on the marketed label for chromium (III), copper (II), iron (II), iron (III) and manganese (II) respectively.

• Any hydrated form of a source ingredient listed in Tables 1, 2 and 3 would be acceptable on the marketed label as long as it is included in the source ingredient database.

• For active ingredients from Tables 1.1 to 1.4, both the synthetic and non-synthetic forms are supported by this reference. However, if non-synthetic, the active ingredient must be isolated and purified from a source material listed in its source ingredient database entry. If the source material is not available on the product documentation form, this information may be added to the product label.

• All active ingredients isolated from source materials must be of an acceptable purity. this reference does not support extracts. Consult the source authority source’s product quality guidance for more information on purity standards.

Vitamin proper names, common names and source information

¹,² At least one of the following references was consulted per name: FCC 2026; NIH 2026; Brayfield and Cadart 2025; RSC 2025; USP-NF 2024; IOM 2006. 3 At least one of the following references was consulted per source information: FCC 2026; NIH 2026; Brayfield and Cadart 2025; RSC 2025; USP-NF 2024; FAO 2012; EFSA 2009a; FSANZ 2008; IOM 2006; Van Der Kuy et al. 2002; Chalmers et al. 2000; EC 2000; Zeitlin et al. 1985.

Mineral proper names, common names and source information

¹, ² At least one of the following references was consulted per name: FCC 2026; NIH 2026; Brayfield and Cadart 2025; RSC 2025; USP-NF 2024. ³ At least one of the following references was consulted per source information: FCC 2026; Guiry and Guiry 2026; source ingredient database 2026; NIH 2026; Brayfield and Cadart 2025; RSC 2025; USP-NF 2024; NIH 2015; Jain et al. 2012; EFSA 2010a,b; Summers et al. 2010; EC 2009; EFSA 2009b,c,d,e,f,g,h,i,j; EFSA 2008a,b,c,d,e,f; Nowak et al. 2008; Richards 2008; EFSA 2007; TGA 2007; EFSA 2006; Walsdorf and Alexandrides 2005; Gruenwald et al. 2004; Allen 2002; Ball et al. 2002; EC 2002; Van Der Kuy et al. 2002; Anderson et al. 2001; Hendler and Rorvik 2001; Chalmers et al. 2000; EC 2000; Tsuboi et al. 2000; Ishitani et al. 1999; Patrick 1999; IPCS 1998; Grant et al. 1997; Fujita et al. 1996; Murray 1996; Henderson 1994; Evans and Pouchnik 1993; Zeitlin et al. 1985. ⁴ Bone meal: When bone meal is used as a source material for calcium or phosphorus, it must be sourced from a non-human animal that is not susceptible to transmissible spongiform encephalopathy diseases, including bovine spongiform encephalopathy [Source note 1]. ⁵ Chromium picolinate: If chromium picolinate is indicated as a source ingredient of chromium, additional restrictions apply (refer to Tables 12, 13 and 14). ⁶ If iodine is sourced from Fucus vesiculosus, Fucus serratus, Ascophyllum nodosum, Laminaria digitata or Laminaria japonica, it should be isolated and purified. this reference does not support algal extracts. ⁷ Potassium: At least 100 mg of potassium per day is required to support the uses or purposes listed in Section 4.2.3. Only general uses or purposes are permitted at daily doses below 100 mg of potassium. ⁸ Silicon from Equisetum arvense: Data (or certification) must be submitted to the source authority upon request to show that thiaminase has been inactivated. If silicon is sourced from Equisetum arvense herb top, it should be isolated and purified. this reference does not support Equisetum arvense extracts. ⁹ Zinc picolinate: If zinc picolinate is indicated as a source ingredient of zinc, the product must be for Adults only and the maximum daily dose is restricted to 25 mg (refer to Table 9). In addition, additional restrictions apply (refer to Tables 12 and 14).

Other active ingredient proper names, common names and source information

¹,² At least one of the following references was consulted per name: FCC 2026; NIH 2026; Brayfield and Cadart 2025; RCS 2025; USP-NF 2024. ³ At least one of the following references was consulted per source information: FCC 2026; NIH 2026; Brayfield and Cadart 2025; RSC 2025; USP-NF 2024; FAO 2018; EFSA 2009e; EFSA 2008d; EFSA 2007. ⁴ If lutein is sourced from Tagetes erecta herb flowering oleoresin, it should be isolated and purified. this reference does not support Tagetes erecta extracts. ⁵ If lycopene is sourced from Solanum lycopersicum fruit flesh, it should be isolated and purified. this reference does not support Solanum lycopersicum extracts.

Complementary active ingredients proper names, common names and source information

Note: The active ingredients boron, inositol, nickel, PABA, tin and vanadium are complementary ingredients that must be combined with at least one active ingredient listed in Tables 1, 2 and/or 3. No claim can be supported based on these active ingredients. The product claim(s) must be supported by at least a active ingredient from Tables 1, 2 and/or 3.

¹,² At least one of the following references was consulted per name: FCC 2026; NIH 2026; Brayfield and Cadart 2025; RSC 2025; USP-NF 2024. ³ At least one of the following references was consulted per source information: FCC 2026; NIH 2026; Brayfield and Cadart 2025; RSC 2025; USP-NF 2024; EFSA 2009a,e; EFSA 2008d,g; EFSA 2007; EFSA 2004. ⁴ If PABA is sourced from Saccharomyces cerevisiae whole, it should be isolated and purified. this reference does not support Saccharomyces cerevisiae extracts.

How is it taken?

Oral

Dosage forms

this reference excludes foods or food-like dosage forms as indicated in the Compendium of references Guidance Document.

Acceptable dosage forms by age group:

Infants 0-12 months, Children 1-2 years: The acceptable dosage forms are limited to emulsion/suspension and solution/liquid preparations (Giacoia et al. 2008; EMA/CHMP 2006).

Children 3-5 years: The acceptable dosage forms are limited to chewables, emulsion/suspension, powders and solution/liquid preparations (Giacoia et al. 2008; EMA/CHMP 2006).

Children 6-11 years, Adolescents 12-17 years, and Adults 18 years and older:

What is it used for?

• The use or purpose statements can be combined on the product label as appropriate (e.g. Helps to form red blood cells; Helps in energy metabolism/(and) tissue formation = Helps to form red blood cells and in energy metabolism and tissue formation).

• In addition, claims such as ‘Helps in energy metabolism/(and) tissue formation’ could be listed on the label as ‘Helps in energy metabolism’ or ‘Helps in tissue formation’ or ‘Helps in energy metabolism and tissue formation’.

• Refer to Appendix IX, for multi-vitamin/mineral supplements claims acceptable at Class II and III for products recommended for occasional use only.

General use or purpose statements

Products containing any vitamin from Table 1 and/or beta-carotene from Table 3 at a therapeutic dose

• Source of (a) vitamin(s), a factor/factors in the maintenance of good health.

• Source of (a) vitamin(s), a factor/factors in normal growth and development.

• Source of (a) vitamin(s), to support biological functions which play a key role in the maintenance of good health.

Products containing any mineral from Table 2 at a therapeutic dose

• Source of (a) mineral(s), a factor/factors in the maintenance of good health.

• Source of (a) mineral(s), a factor/factors in normal growth and development.

• Source of (a) mineral(s), to support biological functions which play a key role in the maintenance of good health.

Products containing any vitamin and mineral from Tables 1 and 2 and/or beta-carotene from Table 3 at a therapeutic dose

• Source of (a) vitamin(s) and (a) mineral(s), factors in the maintenance of good health.

• Source of (a) vitamin(s) and (a) mineral(s), factors in normal growth and development.

• Source of (a) vitamin(s) and (a) mineral(s), to support biological functions which play a key role in the maintenance of good health.

Products containing any vitamin and/or mineral from Tables 1 and/or 2 and/or beta-carotene from Table 3 at a therapeutic dose

• Maintains/supports good health.

• Contributes to maintaining general health.

• For maintaining general health.

• A factor in the maintenance of good health.

• A factor in normal growth and development.

Products containing at least one vitamin or mineral from Tables 1 and/or 2 (all vitamins and minerals in the product must be at minimum therapeutic dose as listed in Tables 8 and 9)

• Vitamin supplement.

• Mineral supplement.

• Vitamin and mineral supplement.

Products containing at least two vitamins and/or minerals from Tables 1 and/or 2 (all vitamins and minerals in the product must be at minimum therapeutic dose as listed in Tables 8 and 9)

• Multi-vitamin supplement.

• Multi-mineral supplement.

• Multi-vitamin and multi-mineral supplement.

Specific use or purpose statements

• Refer to Appendix II for guidelines on using the specific uses or purposes outlined in this section.

• Since several active ingredients are associated with a source of antioxidant or electrolyte claim, there is an option to use these statements in plural. The singular should be used when the product only contains one active ingredient associated with these claims; the plural form should be used when more than one active ingredient with such properties are included in the product formulation at therapeutic dose.

• Uses or purposes associated with pregnancy are not acceptable for products containing active ingredients associated with a caution or contraindication regarding this subpopulation (i.e., chromium sourced from chromium picolinate, zinc sourced from zinc picolinate, nicotinamide mononucleotide, PABA and/or vanadium).

Specific use or purpose statements for vitamins

¹ At least two of the following references were consulted per use or purpose statement: CFIA 2025; EC 2015; IOM 2011; NIH 2011; HC 2009a,b; de Benoist 2008; IOM 2006; Shils et al. 2006; Bjørke Monsen and Ueland 2003; MacKay and Miller 2003; IOM 2001; NIH 2001; Groff and Gropper 2000; IOM 2000; IOM 1998; IOM 1997; Colombo et al. 1990. ² For deficiency claims: This use or purpose statement is only acceptable if the vitamin is present at dosages at or above the recommended dietary allowance (RDA) or adequate intake (AI). See Appendix III for RDA and AI definitions and Appendix IV for detailed values according to the subpopulations. Note that most vitamin deficiencies are rare in North America. ³ These vitamins are cofactors in specific biochemical reactions (e.g. inter-conversion of amino acids). This claim is not intended to convey that taking these vitamins helps to boost metabolism, upregulate a bodily system and/or directly convert food to energy. Inferring such claims would be misleading and is not permitted. In order to avoid any misinterpretation of this claim, the terms ‘carbohydrates, fats, proteins, etc.’ must not be used to further specify the term ‘nutrients’. ⁴ Folate: If a product is marketed specifically as a prenatal supplement (for pregnant women), it must have at least 400 μg of folate per day. source authority (HC 2009a,b) recommends that all women who could become pregnant take a daily multivitamin/mineral supplement containing 400 μg of folic acid per day. At a minimum, women who are planning to become pregnant should start taking this supplement 3 months before the pregnancy. ⁵ Folic acid versus L-5-methyltetrahydrofolate: Sources of folate for the neural tube defect claim have not yet been restricted; however, it is important to note that as per HC's guide for healthy pregnancy, only folic acid has been proven to reduce the risk of neural tube defects in clinical trials. Also, individuals who are deficient in vitamin B₁₂ may be less responsive to 5-methyltetrahydrofolate, but do respond to folic acid. ⁶ Niacin/niacinamide: A specific use or purpose statement must be made for products providing > 35 mg niacin, niacinamide or a combination of the two, per day.

Specific use or purpose statements for minerals

¹ At least two of the following references were consulted per use or purpose statement: CFIA 2025; EC 2015; IOM 2011; FDA 2008; Tang et al 2007; IOM 2006; Jackson et al 2006; NAMS 2006; Shils et al. 2006; Meisel et al. 2005; Schwartz et al. 2005; Brown and Josse 2002; IOM 2001; NIH 2001; Groff and Gropper 2000; IOM 2000; IOM 1997; Klimis-Tavantis 1994. ² For deficiency claims: This use or purpose statement is only acceptable if the mineral is present at dosages at or above the RDA or AI. See Appendix III for RDA and AI definitions and Appendix IV for detailed values according to subpopulations. Note that most mineral deficiencies are rare in North America. ³These minerals are involved as cofactors in specific biochemical reactions (e.g. inter-conversion of amino acids). This claim is not intended to convey that taking these minerals helps to boost metabolism, upregulate a bodily system and/or directly convert food to energy. Inferring such claims would be misleading and is not permitted. In order to avoid any misinterpretation of this claim, the terms ‘carbohydrates, fats, proteins, etc.’ must not be used to further specify ‘nutrients’. ⁴Iron: A specific use or purpose statement must be made for products providing > 35 mg iron per day. ⁵Magnesium: A specific use or purpose statement must be made for products providing > 350 mg magnesium per day. ⁶Magnesium deficiency claim: As the RDA for magnesium for children 1-3 years, children 4-8 years and adolescents 14-18 years exceeds the maximum dose, this claim is not permitted for these subpopulations. ⁷Zinc: A specific use or purpose statement must be made for products providing > 40 mg zinc per day.

Specific use or purpose statements for other active ingredients

¹ At least two of the following references were consulted per use or purpose statement: CNF 2024; Abdellatif et al. 2021; Blanco-Vaca et al. 2021; Covarrubias et al. 2021; Picciotto et al. 2016; EC 2015; Erdman et al. 2009; Christen et al. 2008; Fletcher et al. 2008; Johnson et al. 2008; Kristal et al. 2008; Moeller et al. 2008; Schwarz et al. 2008; Silaste et al. 2007; Wickett et al. 2007; IOM 2006; Miranda et al. 2006; Shao and Hathcock 2006; Shils et al. 2006; Zeisel 2006; Barel et al. 2005; IOM 2005a,b; Mohanty et al. 2005; Porrini et al. 2005; Alves-Rodrigues and Shao 2004; Richer et al. 2004; Blakely et al. 2003; Olmedilla et al. 2003; Giovannucci et al. 2002; IOM 2002; Kucuk et al. 2002; Dwyer et al. 2001; IOM 2001; Kucuk et al. 2001; Matos et al. 2001; Groff and Gropper 2000; Brown et al 1999; Gann et al. 1999; IOM 1998; Seyoum and Persaud 1991; Benevenga 1984. ²beta-Carotene: Vitamin A deficiency claim: See Appendix V for guidance on the appropriate use of this claim. ³The term "lipotropic factor" is not permitted to describe choline, methionine or inositol. This term may mislead consumers to perceive that the product is intended for the purpose of weight loss. ⁴ NMN is a vitamin B₃ derivative and therefore uses associated with vitamin B₃ are acceptable. ⁵ This claim is not intended to convey that taking these vitamins helps to boost metabolism, upregulate a bodily system and/or directly convert food to energy. Inferring such claims would be misleading and is not permitted. In order to avoid any misinterpretation of this claim, the terms ‘carbohydrates, fats, proteins, etc.’ must not be used to further specify the term ‘nutrients’.

Subpopulations

Adults 19 years and older is the only acceptable subpopulation for the source ingredients HAP or HVP as well as for the following active ingredients:

• Boron

• Chromium

• Manganese

• Molybdenum

• Nickel

• PABA

• Selenium

• Silicon

• Tin

• Vanadium

• Zinc sourced from zinc picolinate

Adults 18 years and older is the only acceptable subpopulation for the following active ingredients:

• Lutein

• Lycopene

• Nicotinamide mononucleotide

• Potassium

Background on dose

• The daily dose of each vitamin and/or mineral, listed in Tables 8, 9 and 10, must meet the minimum dosage value if a general or specific claim is being attributed to them. In addition, the minimum daily dose must be met for all vitamins and minerals in a product making a (multi-) vitamin and/or mineral supplement claim in the brand name or as part of the recommended uses or purposes.

• For deficiency claims, the active ingredient must be present at dosages at or above the RDA or AI. See Appendix III for RDA and AI definitions and Appendix IV for detailed values according to subpopulations.

• The dose information for vitamins and minerals outlined in this reference is the quantity of the active ingredient as opposed to the source material and/or source ingredient, i.e., the amount of the vitamin itself and elemental mineral, respectively. For products containing calcium, iron, magnesium and/or zinc as active ingredient(s), please refer to Appendix VIII for additional guidance on labelling in order to avoid misinterpretation which may lead to serious health consequences.

• The daily dose of each active ingredient must not exceed the maximum dosage value. Refer to Appendix III for definitions and derivations of dosage values.

• Refer to Appendix VI for conversion factors for pantothenic acid, vitamin A, beta-carotene, vitamin B₁₂, vitamin D, vitamin E and folate.

• Dose information for adults includes pregnant and breastfeeding women, except for products containing chromium sourced from chromium picolinate, zinc sourced from zinc picolinate, nicotinamide mononucleotide, PABA and/or vanadium which require a mandatory risk statement for these subpopulations. See Section 7.0 for additional details.

Dose information for vitamins

¹ Folate:

• The units for folate are in micrograms of folic acid, not in micrograms dietary folate equivalents (DFE). Refer to Appendix VI, 7, for the conversion factors.

• If a product is marketed specifically as a prenatal supplement (for pregnant women), it must have at least 400 μg of folate per day. source authority (HC 2009a,b) recommends that all women who could become pregnant take a daily multivitamin/mineral supplement containing 400 μg of folic acid per day. At a minimum, women who are planning to become pregnant should start taking this supplement 3 months before the pregnancy.

² Niacin/niacinamide: A specific use or purpose statement must be made for products providing > 35 mg niacin, niacinamide, or a combination of the two per day. ³ Vitamin A: There is a potential risk of hypervitaminosis A resulting from the use of products which combine high doses of vitamin A and beta-carotene. See Appendix V ("Mitigating the Risk of Hypervitaminosis A") for information on how to determine acceptable daily doses of each of these active ingredients when used in combination. ⁴ Vitamin B₁₂ + Cobalt: As vitamin B₁₂ is the source ingredient for cobalt, the maximum dose for vitamin B₁₂ and cobalt combined must not exceed 1000 μg vitamin B₁₂ per day. Apply the conversion from vitamin B₁₂ to cobalt as per Appendix VI when applicable. ⁵ Vitamin E: A combination of dl-alpha-tocopherol (synthetic form) and d-alpha-tocopherol (natural form) must not exceed the maximum daily dose of 1000 mg of alpha-tocopherol from all sources [Source note 2] with a maximum of 1500 IU/day of d-alpha-tocopherol and 1100 IU/day of dl-alpha-tocopherol.

1 IU = 0.67 mg for d-alpha-tocopherol; 1 IU = 0.90 mg for dl-alpha-tocopherol which is equivalent to 0.45 mg of the biologically active alpha-tocopherol equivalent.

The total amount of vitamin E should be used to determine if additional risk statements are required (refer to Table 13).

Dose information for minerals

¹ Refer to Appendix VIII for additional wording on the label to clarify that the quantity of the active ingredient is the amount of elemental mineral in order to avoid misinterpretation that may lead to serious health consequences. ² Cobalt + Vitamin B₁₂: As vitamin B₁₂ is the source ingredient for cobalt, the maximum dose for cobalt and vitamin B₁₂ combined must not exceed 1000 μg of vitamin B₁₂ per day. Refer to Appendix VI for conversion from cobalt to vitamin B₁₂. ³ Iron: A specific use or purpose statement must be made for products providing > 35 mg iron per day. ⁴ Magnesium: A specific use or purpose statement must be made for products providing > 350 mg magnesium per day. ⁵ Potassium: At least 100 mg of potassium per day is required to support the uses or purposes listed in Section 4.2.3. Only general uses or purposes are permitted at daily doses below 100 mg of potassium. ⁶ Zinc: A specific use or purpose statement must be made for products providing > 40 mg zinc per day. ⁷ Zinc: As zinc supplementation can cause a copper deficiency, manufacturers of products providing high doses of zinc are encouraged to supplement with sufficient quantities of copper. Refer to Appendix VII to determine how much copper is sufficient to mitigate this risk and for information on how to determine if a risk statement is necessary.

Dose information for other active ingredients

¹beta-Carotene: There is a potential risk of hypervitaminosis A resulting from the use of products which combine high doses of vitamin A and beta-carotene. See Appendix V for information on how to determine acceptable daily doses of each of these active ingredients when used in combination. ²At least two of the following references were consulted: Huang 2022; Okabe et al. 2022; Liao et al. 2021; Christen et al. 2008; Fletcher et al. 2008; Johnson et al. 2008; Kristal et al. 2008; Moeller et al. 2008; Silaste et al. 2007; IOM 2006; Shao and Hathcock 2006; Shils et al. 2006; Porrini et al. 2005; WHO 2005; Alves-Rodrigues and Shao 2004; Richer et al. 2004; Olmedilla et al. 2003; Giovannucci et al. 2002; IOM 2002; Kucuk et al. 2002; Brown et al. 1999; Gann et al. 1999; IOM 1998; Giovannucci et al. 1995.

Dose information for complementary active ingredients

¹The following references were consulted: Weidner et al. 2005; Bardhan et al. 2000; Tisdale et al. 1995; Clegg et al. 1994.

How is it used?

Products providing 500 mg of niacin sourced from nicotinic acid, per day

• Do not exceed the recommended dose except on the advice of a physician.

Products providing 10 mg or more of niacin sourced from nicotinic acid, per day

• Take with food [Source note 3].

Products providing calcium, iron or zinc

• Take with food [Source note 4].

• Take a few hours before or after taking other medications or health products [Source note 5].

In all other cases, optional statement(s), as appropriate

• Take with food or

• Take on an empty stomach.

Products providing 400 mcg or more of folate, per day (e.g. as a prenatal supplement) (optional)*

• 400 mcg of folate per day is adequate for most women (to reduce the risk of neural tube defects). Ask a healthcare professional to determine if you would benefit from additional folate before taking this product.

*Note: It is recommended that products provide 400 micrograms (mcg) of folate per dosage unit. This allows consumers to meet the recommended daily dose of 400 mcg of folate without exceeding it, if a higher dose is unnecessary.

Conditions for combined preparations

When the active ingredients Niacin and/or Niacinamide and/or Nicotinamide mononucleotide are combined, the total quantity per day must not exceed the maximum quantity listed in Table 8 for Niacin/Niacinamide (i.e., 500 mg/day).

Durations of use

Cautions and warnings

¹ Zinc: Statement required if the product does not meet the minimum copper requirements outlined in Appendix VII, Table 24.

Contraindications

Known adverse reactions

Other ingredients

Must be chosen from the current source ingredient database and must meet the limitations outlined in the database.

Storage

Must be established in accordance with the requirements described in the applicable product regulations.

Preparation and quality requirements

• The finished product specifications must be established in accordance with the requirements described in the source authority source’s product quality guidance.

• The active ingredient(s) must comply with the requirements outlined in the source ingredient database.

Appendix I

Source ingredients with two active components

A source ingredient may provide more than one active component in this reference. For example, calcium ascorbate provides both calcium and ascorbic acid (vitamin C). The product documentation form and label must declare all active components of a source ingredient as active ingredients and provide their quantity per dosage unit if the total daily dose of that active component (i.e. vitamin or mineral) exceeds the reference's minimum dosage value.

For certain source ingredients that provide more than one active component, when one of the components is used within its acceptable dosage range it could result in the other component exceeding its acceptable dosage range.

For example, a product formulated to provide the maximum dosage value of calcium for adults (i.e. 1500 mg) from the source ingredient, calcium ascorbate, would provide 13.2 g of vitamin C. This exceeds vitamin C's adult maximum dosage value of 2000 mg; and therefore, such a product would not be supported for safety. Based on the calculation described below, the maximum dosage value of calcium from calcium ascorbate would be 228 mg as this dose provides 2000 mg of vitamin C.

The following table outlines dose restriction information for calcium ascorbate. It provides the maximum dosage values for calcium and its corresponding source ingredient. Below this table is a sample calculation which demonstrates how these values were derived.

Sample Calculation

Question: What is the maximum quantity of calcium (maximum dosage value for adults ≥19 y) from the source ingredient calcium ascorbate that can be used in a formulation?

Solution: In order to make this determination, the quantity of calcium from calcium ascorbate that provides the maximum dosage value for adults ≥19 y of ascorbic acid (vitamin C) must be calculated.

Source ingredient: calcium ascorbate (calcium di-ascorbate): Ca (C₆H₇O₆)₂ There are 2 molecules of ascorbate (C₆H₇O₆) for every one of calcium (Ca)

Molecular weight = MW Maximum dosage value (for adults, ≥19 y) = M Number of molecules = N

Calcium = Ca PMCₐ = 40,1 g/mol MCₐ= ?

Ascorbic acid = Aa PMAₐ = 176,1 g/mol MAₐ = 2 g

[MCₐ]/[PMCₐ x n] = [MAₐ]/[PMAₐ x n] [MCₐ]/[40,1 g/mol x 1] = [2 g]/[176,1 g/mol x 2] MCₐ = [g x 40.1 g/mol x 1]/[176,1 g/mol x 2] MCₐ = [80,2 g²/mol]/[352,2 g/mol] MCₐ = 0,228 g ou 228 mg

Appendix II

Guidelines for use or purpose statements

Under the source’s product-labeling rules, products must indicate at least one use or purpose statement.

Specific use or purpose statements:

Ingredient specific use or purpose statements can be used for any or all of the active ingredients contained in a multi-ingredient product, as applicable (see Section 4.2 - Specific use or purpose statements).

A specific use or purpose statement must be made for products providing magnesium (> 350 mg per day), niacin (> 35 mg per day), iron (> 35 mg per day), or zinc (> 40 mg per day).

Inclusion of active ingredient names in a specific use or purpose statement is optional; for example, the specific use or purpose statement can be applied to the whole product. However, if active ingredient names are specified in a use or purpose statement, the statement must be valid for all active ingredients specified.

Appendix III

Definitions and dosage value derivations

1) Definitions:

Adequate intake (AI): The recommended average daily intake level based on observed or experimentally determined approximations or estimates of nutrient intake by a group (or groups) of apparently healthy people that are assumed to be adequate. An AI is used when a RDA cannot be determined [Source note 37].

Maximum dosage value: The highest active ingredient quantity which a product can supply in a daily dose to support its safe use.

Minimum dosage value: The lowest active ingredient quantity which a product can supply in a daily dose to support recommended claims.

Recommended dietary allowance (RDA): The average daily dietary nutrient intake level sufficient to meet the nutrient requirements of nearly all (97-98%) healthy individuals in a particular life stage and gender group [Source note 38].

Tolerable upper intake level (UL): The highest average daily nutrient intake level that is likely to pose no risk of adverse health effects to almost all individuals in the general population. As intake increases above the UL, the potential risk of adverse effects may increase [Source note 39].

2) Derivations:

AI, RDA and UL values:

These values were established by the Food and Nutrition Board of the Institute of Medicine in collaboration with source authority [Source note 40].

Maximum dosage value:

The method used to set maximum dosage values varied for each active ingredient depending on numerous factors. The method used to derive maximum dosage levels for vitamins and minerals with established physiological functions was different from the method used for those with unestablished physiological functions.

1. Maximum dosage values for vitamins and minerals with established physiological functions were developed based on the following criteria:

   1. Is there an established UL?

      • If there is an established UL, does it apply to supplements only or to food and supplements?

      • If there is an established UL, how was it derived (i.e. what was the critical adverse reaction on which it was based? was it serious or non-serious? if non-serious, could it be mitigated?)?

   2. What is the average dietary intake?

   3. What doses have previously been marketed in Canada?

   4. What do other regulatory agencies and expert groups recommend as their maximum daily dose?

   5. What doses have been used in clinical trials and have demonstrated evidence for safety and efficacy?

   The only vitamins which were excluded from the method outlined above were:

   • Vitamin D (due to its previous listing on the Prescription Drug List at 1,000 IU or 25 µg/day and the separate single ingredient reference for high dose vitamin D);

   • Vitamin K₁ and K₂ [adult dose was set as per the listing on the Prescription Drug List at 120 µg/day [Source note 41] and children's doses were set at the AI level [Source note 42]].

2. Maximum dosage values for minerals with unestablished physiological functions (i.e. boron, nickel, silicon, tin and vanadium) were calculated from the No Observed Adverse Effect Level (NOAEL) divided by an uncertainty factor (UF). The UF chosen was based on the following: 10 for extrapolation of animal data to humans, 10 for intra-species variation, and 10 for chronic use in humans. If applicable, (i.e. NOAEL was based on animal data) the final value was multiplied by an average adult body weight of 70 kg.

With the exception of beta-carotene and potassium, the maximum dosage value for non-vitamin and non-mineral ingredients was set based on doses demonstrated to be safe in clinical trials. For beta-carotene the maximum dosage value was set as per the vitamin A UL (applying the following conversion factor: 6 µg beta-carotene = 1 µg RAE) (HC 1990; FAO/WHO 1967). For potassium, the maximum dosage value was set as per Schedule II of the Regulation respecting the terms and conditions for the sale of medications in Quebec and as previously also applied by the National Association of Pharmacy Regulatory Authorities.

Minimum dosage value:

For active ingredients which did not have an RDA or AI, the minimum dose was set at >0. For the remaining active ingredients (with the exception of potassium), the minimum was set using the following method:

• 5% of the RDA and/or AI was calculated for each subpopulation [This method was modelled after the vitamin and mineral minimum dose requirements of the Food and Drug Regulations, Sections D.01.004 and D.02.002 [Source note 43]].

  1. The highest value derived for children (1-13 years) was applied to all children within this age category;

  2. the highest value derived for adolescents (≥ 14 years) and adults (including pregnant and breastfeeding women) was applied;

  3. The highest value derived for infants (0-12 months) was applied (if applicable).

For potassium, the AI was inappropriate for setting a minimum dosage value; therefore, the minimum was set at >0.

Appendix IV

Recommended dietary allowance (RDA) and adequate intake (AI)

The AI (as indicated by an asterisk) and RDA values are provided below. For the purpose of this reference, these values are intended to:

• provide targets for setting appropriate supplement dosage levels;

• provide the minimum dose for the use or purpose statement: "Helps to prevent (appropriate vitamin or mineral) deficiency"; and

• facilitate the optional labelling of % RDA and AI values.

• RDA and AI values have not been provided for those subpopulations where the vitamin or mineral dosage is outside the scope of this reference.

• For certain minerals, a RDA or AI value has not been established.

• For the prevention of deficiency claims, the daily dose of the active ingredient must meet the highest AI or RDA amount for the given subpopulation.

For example, for vitamin A, if the subpopulation is "Adults 19 years and older" and if the product is not contraindicated for pregnant or breastfeeding women, the RDA value to be met would be 1,300 μg RAE/day.

¹The AI for vitamin K is based on median dietary intakes. Vitamin K₁is the predominant form of vitamin K in the diet [Source note 44]; however this AI applies to vitamin K₁, vitamin K₂ and total vitamin K₁ + K₂.

¹Calculated from the vitamin B₁₂ RDA [Source note 45].

Appendix V

Guidance for products containing beta-carotene

Background:

Although all of the claims for beta-carotene are associated with its vitamin A activity, it is not acceptable to list beta-carotene as a source ingredient for vitamin A. This is because the rate of conversion of beta-carotene to vitamin A in the human body depends on numerous factors (e.g. vitamin A status, dietary factors such as vegetable consumption and fat intake, genetic factors, etc.). In other words, the consumption of supplemental beta-carotene does not always result in a consistent rate of conversion to vitamin A. Nevertheless, products providing beta-carotene do contribute to vitamin A requirements; therefore, all of the health claims associated with beta-carotene are linked to its vitamin A activity. Furthermore, there is a potential risk of hypervitaminosis A associated with the consumption of combinations including both beta-carotene and vitamin A.

Determining dosage requirements for the claim "Helps to prevent vitamin A deficiency":

In order to make any prevention of deficiency health claims, a nutrient must be included in a product at a dose at or above its recommended dietary allowance (RDA) or adequate intake (AI). There are three potential scenarios in which a product would qualify for the claim: "Helps to prevent vitamin A deficiency":

1. The product could provide vitamin A on its own: See Appendix IV to determine vitamin A minimum dosage requirements;

2. The product could provide beta-carotene on its own: See Table 19 below for minimum dosage requirements; or

3. The product could provide both beta-carotene and vitamin A: See Appendix IV to determine vitamin A minimum dosage requirements and apply the conversion factor of 6 µg of beta-carotene = 1 µg all-trans-retinol (HC 1990; FAO/WHO 1967).

¹ These values are based on the RDA and AI values for vitamin A based on the subpopulation [Source note 46] and were derived from the conversion factor of 6 µg of beta-carotene = 1 µg all-trans-retinol; hence, a ratio of 6:1 beta-carotene:vitamin A, on a weight to weight basis (HC 1990; FAO/WHO 1967).

Example:

As per Appendix IV, the minimum dose for the vitamin A deficiency claim for adults (excluding breastfeeding women) is 900 µg per day. This is based on the highest RDA for all adult subpopulations (i.e. 900 µg for adult males). There are three potential ways this dose can be achieved:

1. Vitamin A alone (900 µg RAE (from vitamin A) per day);

2. beta-Carotene alone (5400 µg beta-carotene per day); or

3. Combinations of vitamin A plus beta-carotene (e.g. 500 µg RAE (from vitamin A) + 2400 µg beta carotene = 900 µg RAE per day).

Note: The depiction of beta-carotene in RAE is to demonstrate the efficacy of the combination of vitamin A and beta-carotene only and must not appear on the product documentation form or label.

Mitigating the risk of hypervitaminosis A:

In products containing both vitamin A and beta-carotene, the risk of hypervitaminosis A is to be mitigated by ensuring that the combined doses of these two active ingredients is not excessively high. Therefore, the combined dose of vitamin A plus beta-carotene must not exceed the maximum dosage value for vitamin A, measured in μg RAE (See Table 8). The conversion factor of 6 μg beta-carotene = 1 μg RAE (HC 1990; FAO/WHO 1967) can be applied for the specific purpose of ensuring safety of the combined dose. The example below illustrates how the 6:1 conversion factor can be used to determine the safety of combinations including beta-carotene and vitamin A:

Example:

The maximum dosage value of vitamin A for adults is 3000 μg RAE per day. If a product contained 2800 μg vitamin A (i.e. all-trans-retinol, vitamin A acetate, vitamin A palmitate), then it could contain no more than 1200 μg beta-carotene. See calculation below:

2800 μg vitamin A + 1200 μg beta-carotene (200 μg RAE) = 3000 μg RAE.

Note: The value of 3000 μg RAE is to demonstrate the safety of the combination of vitamin A and beta-carotene only and must not appear on the product documentation form or label.

Appendix VI

Conversion factors

1. Pantothenic acid [Source note 47]:

2. Vitamin A [Source note 48]:

The quantity of vitamin A must always be provided in terms of retinol activity equivalents (RAE) (i.e. μg all-trans-retinol), irrespective of the source ingredient used.

International Units (IU) may be provided as optional additional information on the product documentation form in the "additional quantity per dosage unit" field and on product labels.

Examples using the vitamin A conversion factors:

Converting vitamin A activity into quantity of RAE (µg)

Convert 500 IU of vitamin A activity from all-trans-retinol into μg RAE:

• = 500 IU x 1 μg RAE/3.33 IU vitamin A

• = 150 μg RAE

• = 3000 IU x 0.87 μg RAE/2.91 IU vitamin A

• = 897 μg RAE

3. beta-Carotene:

The quantity of beta-carotene must always be provided in weight amount (i.e. μg).

IUs may be provided as optional additional information on the product documentation form in the "additional quantity per dosage unit" field and on product labels.

1 IU beta-carotene = 0.6 μg beta-carotene [Source note 49]

4. Vitamin B₁₂:

1.5 μg of vitamin B₁₂ = 0.06 μg of cobalt

5. Vitamin D:

The quantity of vitamin D must always be provided in weight amount (i.e. μg).

IUs may be provided as optional additional information on the product documentation form in the "additional quantity per dosage unit" field and on product labels.

1 IU of vitamin D = 0.025 μg cholecalciferol [Source note 50]

• = 0.025 μg ergocalciferol

6. Vitamin E [Source note 51]

The quantity of vitamin E must always be provided in terms of alpha-tocopherol (AT) (i.e. mg 2R-alpha-tocopherol), irrespective of the source ingredient used.

IUs may be provided as optional additional information on the product documentation form in the "additional quantity per dosage unit" field and on product labels.

Examples using the vitamin E conversion factors:

1. Converting vitamin E activity into quantity of AT (mg)

   Convert 400 IU of d-alpha-tocopheryl succinate activity into mg AT:

   • = 400 IU x 0.67 mg AT/IU

   • = 268 mg AT

2. Converting vitamin E source ingredient quantity into quantity of AT (mg)

   Convert 200 mg of dl-alpha-tocopheryl acetate into mg AT:

   • = 200 mg x 0.45 mg AT/mg

   • = 90 mg AT

7. Folate [Source note 52]:

Folic acid in supplements is to be represented in mcg of folic acid. Factors for converting mcg of dietary folate equivalents (DFE) to mcg for supplemental folate have not been formally established by source authority but conversion factors established by other regulatory agencies can be used if DFE is listed as additional information on the label.

Following conversion factors established by the US Food and Nutrition Board and also included in the Codex nutrient reference values can be used for conversion between food folate and folic acid (supplemental form):

• 1 DFE = 1 µg food folate.

• 1 DFE = 0.6 µg folic acid from fortified food or from a supplement consumed with food (factor of 1.7).

• 1 DFE = 0.5 µg folic acid from a supplement taken on an empty stomach (factor of 2).

Note: The bioavailability of L-5-Methyltetrahydrofolate (5-methyl-THF) in supplements is the same as or greater than that of folic acid. However, conversion factors between mcg and mcg DFE for 5-methyl-THF have not been formally established. The US FDA allows manufacturers to use either a conversion factor of 1.7 to be comparable to folic acid, or their own established conversion factors not to exceed 1.7 [Source note 53].

Appendix VII

Zinc and copper interaction

Zinc supplements can cause a copper deficiency. In order to mitigate this risk, applicants are encouraged to supplement high dose zinc products with copper. Table 24 below outlines how much copper is sufficient to mitigate this risk based on both the subpopulation and zinc daily dosage. Products which do not fulfill the zinc and copper quantity guidelines below require an additional risk statement. See Section 7.0 Risk Information.

Examples using Table 24:

1. Question: Product A is targeted to adults only. The product provides a daily dose of zinc of 30 mg but does not contain copper. Is a risk statement necessary on this product? Answer: No. According to Table 24, for an adult subpopulation, there is no need for copper supplementation at a dose of 30 mg zinc per day. Therefore, no risk statement is required.

2. Question: Product B is targeted to adults and adolescents ≥ 12 years. The product provides zinc and copper at daily dosages of 20 mg and 500 µg, respectively. Is a risk statement necessary on this product? Answer: Yes. According to Table 24, for an adult subpopulation, there is no need for copper supplementation at a daily dose of 20 mg zinc. However, for adolescents ≥ 12 years, products providing daily doses of zinc between 16-23 mg need at least 920 µg copper per day. As the product in this example provides 500 µg of copper per daily dose, the following risk statement is required: "Zinc supplementation can cause a copper deficiency. If you are unsure whether you are taking enough copper, consult a health care practitioner prior to use".

Appendix VIII

Guidance on labelling for specific mineral supplements: calcium, iron, magnesium and zinc

Health care professionals and consumers have reported confusion in distinguishing between the quantity of the element (i.e., the active ingredient) and the quantity of the salt (i.e., the source information) of the above four mineral supplements when reading the product label, which has led to medication errors in Canada including dosing errors. In the case of these minerals, dosing errors may lead to serious health consequences (ISMP 2021a, b, c). Health care professionals may recommend or prescribe to consumers calcium, iron, magnesium or zinc by either the elemental quantity or the salt quantity. The active ingredient quantity listed on the label should be clearly associated with the elemental mineral.

a) Single ingredient mineral supplements

The quantity of the element must be clearly associated with the element name, so that it is not confused with the quantity of the salt. In addition, the quantity of the element and the salt may both appear on the label. Anhydrous salts should be clearly identified in order to account for their element-to-salt ratio. Note that the label generated by the web-based product documentation form has not been adjusted to represent single ingredient products as recommended above; however, the information on the marketed label should be represented as clearly as possible based on this guideline.

• • Examples

  • Each tablet contains:

  • Calcium.....500 mg (calcium carbonate 1250 mg)

• • Each tablet contains:

  • Calcium.....500 mg (derived from calcium carbonate 1250 mg)

• • Each tablet contains:

  • Iron..........60 mg (from anhydrous Iron (II) sulfate 190 mg)

In cases where a mineral supplement is derived from mixed source ingredients or complexes of the same element, the quantity of the salt(s) does not need to be identified. However, the addition of a note clarifying that the quantity of the mineral represents the amount of the element is recommended.

As per the label generated from the web-based product documentation form:

* For minerals, the active ingredient quantity represents the amount of the element per tablet.

b) Multi-ingredient mineral supplements

The quantity of the element(s) must be clearly associated with the element name, so that it is not confused with the quantity of the salt(s). The quantity of the salt(s) does not need to be identified. However, the addition of a note clarifying that the quantity of the mineral represents the amount of the element would be recommended.

As per the label generated from the web-based product documentation form:

* For minerals, the active ingredient quantity represents the amount of the element per tablet.

Appendix IX

Most multi-vitamin/mineral (MVM) claims are associated with ongoing use, as they relate to maintaining health, preventing deficiencies, or supporting normal body functions over time. Regular consumption of the MVM ingredients is required to support the efficacy of the majority of these claims. For this reason, they are generally not considered appropriate for products intended for occasional use.

However, the claims included in Table 25 are factual statements about product composition, their mechanism of action, or they describe more immediate metabolic functions that do not depend on continuous use.

Note: As defined in the reference Combination Guide, source authority considers the statement "For occasional use only" to represent a duration of use that applies to products intended for supplementary use, when needed, (for example: on a specific occasion), but not typically to products intended for long-term continuous use. Products intended for occasional use may be used a few times per month (for example: caffeine at a dose higher than 400 mg/day to help temporarily promote alertness) or for a short, defined period of time (for example: bearberry as a mild diuretic to help relieve symptoms associated with minor urinary tract infections).

¹Note: This claim is also applicable to niacine/niacinamide, vitamin B₆, pantothenic acid, riboflavin, thiamine, magnesium and zinc; however, the part "/(and) tissue formation" should be removed.