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Drugs and Health Products

COD LIVER OIL

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This monograph is intended to serve as a guide to industry for the preparation of Product Licence Applications (PLAs) and labels for natural health product market authorization. It is not intended to be a comprehensive review of the medicinal ingredient.

Notes
  • Text in parentheses is additional optional information which can be included on the PLA and product label at the applicant's discretion.
  • The solidus (/) indicates that the terms are synonyms or that the statements are synonymous. Either term or statement may be selected by the applicant.
  • The use(s) or purpose(s) statements in this monograph are based on the efficacy of vitamins A and D, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that are present in cod liver oil. The references used to support these statements refer to the efficacy of these individual constituents and are not specific to cod liver oil.
  • Consult Appendix 1 for Adequate Intake (AI), Recommended Dietary Allowance (RDA) and Tolerable Upper Intake Level (UL) definitions for nutrient intake. Refer also to Table 8 in Appendix 2 for RDA and AI values for vitamin A, and to Table 9 in Appendix 3 for RDA and AI values for vitamin D.

Date

July 18, 2017

Proper name(s)

Cod liver oil (Ph.Eur. 2012; USP 35)

Common name(s)

Cod liver oil (Ph.Eur. 2012; USP 35)

Source material(s)

Oil from one or more of the following sources in its natural triglyceride/triacylglycerol form and/or its concentrated esterified form:

  • Liver of Atlantic cod, Gadus morhua L. (Gadidae) (Ph.Eur. 2012; USP 35; ITIS 2004)
  • Liver of Greenland cod, Gadus ogac Richardson (Gadidae) (Ph.Eur. 2012; USP 35; ITIS 2004)
  • Liver of Pacific cod, Gadus macrocephalus Tilesius (Gadidae) (Ph.Eur. 2012; USP 35; ITIS 2004)
  • Liver from Arctic cod, Arctogadus glacialis Peters (1872) (Gadidae) (Ph.Eur. 2012; USP 35; ITIS 2004)
  • Liver from all species of Gadidae (Cod family) (BP 2012; Ph.Eur. 2012; USP 35)

Note

  • "Atlantic cod, Gadus morhua", "Greenland cod, Gadus ogac", "Pacific cod, Gadus macrocephalus", "Arctic cod, Arctogadus glacialis" or any other species of Gadidae must be indicated on the PLA and label as source material information.
  • Refer to Appendix 4 for a complete listing of species in the Family Gadidae (Cod).

Route(s) of administration

Oral

Dosage form(s)

This monograph is not intended to include foods or food-like dosage forms such as bars, chewing gums or beverages.

Dosage forms by age group:

  • Infants 0 - 12 months, and Children 1-2 years: The acceptable dosage forms are limited to emulsion/suspension and solution/drops (Giacoia et al. 2008; EMEA/CHMP 2006).
  • Children 3-5 years: The acceptable dosage forms are limited to chewables, emulsion/ suspension, powders and solution/drops (Giacoia et al. 2008; EMEA/CHMP 2006).
  • Children 6-12 years, Adolescents 13-17 years, and Adults ≥ 18 years: The acceptable dosage forms include, but are not limited to capsules, chewables (e.g. gummies, tablets), liquids, powders, strips or tablets.

Use(s) or Purpose(s)

For products providing daily doses of vitamin A at or above the Recommended Dietary Allowance (RDA) or Adequate Intake (AI ) (adjusted for the life stage groups):

Helps to prevent vitamin A deficiency (IOM 2006; Shils et al. 2006; Groff and Gropper 2000).

For products providing daily doses of vitamin D at or above the Recommended Dietary Allowance (RDA) or Adequate Intake (AI ) (adjusted for the life stage groups):

Helps to prevent vitamin D deficiency (IOM 2011, 2006, 1997; Shils et al. 2006; Groff and Gropper 2000).

For products providing 138-3,000 µg retinol activity equivalents (RAE) (µg vitamin A/all-trans retinol (palmitate)), per day:

  • Helps to maintain eyesight, skin membranes and immune function (IOM 2006; Shils et al. 2006; Groff and Gropper 2000).
  • Helps in the development and maintenance of night vision (IOM 2006; Shils et al. 2006; Groff and Gropper 2000).
  • Source of vitamin A, a factor in the maintenance of good health (IOM 2006)

For products providing 1.15-25 µg vitamin D3 (cholecalciferol), per day:

  • Helps in the development and maintenance of bones and teeth (IOM 2011; Shils et al. 2006).
  • Helps in the absorption and use of calcium and phosphorus (IOM 2011; Shils et al. 2006; Groff and Gropper 2000).
  • Source of vitamin D, a factor in the maintenance of good health (IOM 2011).

For products providing 100-1,360 mg eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), per day:

  • Source of omega-3 fatty acids for the maintenance of good health (Simopoulos 2007; Oh 2005; IOM 2002; Simopoulos 1999)
  • Source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for the maintenance of good health (Simopoulos 2007; Oh 2005; IOM 2002; Simopoulos 1999)

For products providing 100-1,360 mg EPA + DHA including at least 100 mg DHA, per day:

Helps support cognitive health and/or brain function (van de Rest et al. 2008; Freund-Levi et al. 2006; Fontani et al. 2005a,b; Haag 2003; Morris et al. 2003; IOM 2002).

For products providing 150-1,360 mg EPA + DHA including at least 150 mg DHA, per day (maximum doses of EPA + DHA in Table 4 below will apply):

Helps support the development of the brain, eyes and nerves in children up to 12 years of age (Agostini 2008; Helland et al. 2008; Ryan and Nelson 2008; Marszalek and Lodish 2005; Haag 2003; IOM 2002; Giedd et al. 1999; Mills 1999).

Dose(s)

Note

The potencies of vitamin A, vitamin D3 and/or EPA+DHA must be indicated on the PLA and label, in addition to the dose of Cod liver oil.

Quantities

Table 1 Daily dose for cod liver oil Table 1 Footnote 1
Life stage group Cod Liver Oil
Minimum Table 1 Footnote 2 Maximum Table 1 Footnote 4
(ml/day) Table 1 Footnote 5 (g/day) (ml/day) (g/day)

Table 1 Footnotes

Table 1 Footnote 1

BP 2012, Ph.Eur. 2012 or USP 35 grade Cod liver oil must be used to ensure that potencies of vitamin A, vitamin D3, and EPA + DHA listed in Tables 2, 3 and 4 are met.

Return to Table 1 footnote 1 referrer

Table 1 Footnote 2

The minimum dose of Cod liver oil is based on the minimum quantities of EPA + DHA required for efficacy.

Return to Table 1 footnote 2 referrer

Table 1 Footnote 3

Includes pregnant and breastfeeding women.

Return to Table 1 footnote 3 referrer

Table 1 Footnote 4

For all subpopulations, the maximum dose is based on the quantity of Cod liver oil providing the maximum daily amount of Vitamin A, in μg RAE, according to the UL (IOM 2006).

Return to Table 1 footnote 4 referrer

Table 1 Footnote 5

Based on the specific gravity of Cod liver oil (USP 35).

Return to Table 1 footnote 5 referrer

Infants 0-12 mo 0.83 0.77 0.87 0.80
Children 1-3 y 0.83 0.77 0.87 0.80
4-8 y 0.83 0.77 1.3 1.2
Adolescents 9-13 y 0.83 0.77 2.4 2.2
14-18 y 0.83 0.77 4.0 3.7
Adults Table 1 Footnote 3 ≥ 19 y 0.83 0.77 4.3 4.0

Potencies

Table 2 Potency Table 2 Footnote 1 for vitamin A/all-trans retinol (palmitate) in cod liver oil
Life stage group Vitamin A (μg RAE/day)
Minimum Table 2 Footnote 2 Maximum Table 2 Footnote 3

Table 2 Footnotes

Table 2 Footnote 1

References for the potency of vitamin A are: BP 2012, Ph.Eur. 2012, and Tischer 1938.

Return to Table 2 footnote 1 referrer

Table 2 Footnote 2

Calculated as the minimum amount of vitamin A available in 0.77 g Cod liver oil, which is the based on the minimum quantities of EPA + DHA required for efficacy.

Return to Table 2 footnote 2 referrer

Table 2 Footnote 3

Maximum potency based on the UL (IOM 2006).

Return to Table 2 footnote 3 referrer

Table 2 Footnote 4

Includes pregnant and breastfeeding women.

Return to Table 2 footnote 4 referrer

Infants 0-12 mo 138 600
Children 1-3 y 138 600
4-8 y 138 900
Adolescents 9-13 y 138 1,700
14-18 y 138 2,800
Adults Footnote 4 ≥ 19 y 138 3,000
Table 3 Potency Table 3 Footnote 1 for vitamin D3/cholecalciferol in cod liver oil
Life stage group Vitamin D3 (μg/day)
Minimum Table 3 Footnote 2 Maximum Table 3 Footnote 3

Table 3 Footnotes

Table 3 Footnote 1

References for the potency of Vitamin D3 are: BP 2012, Ph.Eur. 2012, and Green 1951.

Return to Table 3 footnote 1 referrer

Table 3 Footnote 2

Based on the minimum amount of vitamin D3 available in 0.77 g Cod liver oil, and supported by the RDA and AI for vitamin D3 (IOM 2011, 2006). See Appendix 1 for definitions and Table 9 in Appendix 3 for RDA and AI values.

Return to Table 3 footnote 2 referrer

Table 3 Footnote 3

For all subpopulations, the maximum potencies are based on the amount of vitamin D3 available in the quantity of Cod liver oil which provides the maximum daily amount of vitamin A, in μg RAE, according to the UL (IOM 2006).

Return to Table 3 footnote 3 referrer

Table 3 Footnote 4

Includes pregnant and breastfeeding women.

Return to Table 3 footnote 4 referrer

Infants 0-12 mo 1.15 5.00
Children 1-3 y 1.15 5.00
4-8 y 1.15 7.50
Adolescents 9-13 y 1.15 14.06
14-18 y 1.15 23.12
Adults Table 3 Footnote 4 ≥ 19 y 1.15 25.00
Table 4 Potency Table 4 Footnote 1 for EPA + DHA in cod liver oil
Life stage group EPA + DHA (mg/day)
Minimum Table 4 Footnote 2 Maximum Table 4 Footnote 3

Table 4 Footnotes

Table 4 Footnote 1

References for the potency of EPA + DHA are: BP 2012 and Ph.Eur. 2012.

Return to Table 4 footnote 1 referrer

Table 4 Footnote 2

Restrictions to minimum potency may apply according to Use(s) or Purpose(s) section above.

Return to Table 4 footnote 2 referrer

Table 4 Footnote 3

For all subpopulations, the maximum potencies are based on the amount of EPA + DHA available in the quantity of Cod liver oil which provides the maximum daily amount of vitamin A, in μg RAE, according to the UL (IOM 2006).

Return to Table 4 footnote 3 referrer

Table 4 Footnote 4

USP 35; Rajakumar and Thomas 2005; Stene et al 2003; Linday et al. 2002.

Return to Table 4 footnote 4 referrer

Table 4 Footnote 5

Includes pregnant and breastfeeding women.

Return to Table 4 footnote 5 referrer

Infants Table 4 Footnote 4 0-12 mo 100 272
Children 1-3 y 100 272
4-8 y 100 408
Adolescents 9-13 y 100 765
14-18 y 100 1,258
Adults Table 4 Footnote 5 ≥ 19 y 100 1,360

Duration(s) of use

No statement required.

Risk information

Caution(s) and Warning(s)

No statement required.

Contraindication(s)

No statement required.

Known adverse reaction(s)

No statement required.

Storage condition(s)

For all products:
Store in airtight container, protected from light (Ph.Eur. 2012; USP 35).

For all products, except those encapsulated:
Refrigerate after opening (Wille and Gonus 1989).

Non-medicinal ingredients

Must be chosen from the current Natural Health Products Ingredients Database (NHPID) and must meet the limitations outlined in the database.

Specifications

  • The finished product specifications must be established in accordance with the requirements described in the Natural and Non-prescription Health Products Directorate (NNHPD) Quality of Natural Health Products Guide.
  • The medicinal ingredient must comply with the requirements outlined in the NHPID.
  • The medicinal ingredient may comply with the specifications outlined in the pharmacopoeial monographs listed in Table 5 below.
  • Peroxide, anisidine, and totox values of cod liver oil and omega-3 fatty acids derived from cod liver oil must be in accordance with the methods set out by the Association of Analytical Communities (AOAC) and/or Pharmacopoeial analytical methods. These specifications are necessary to ensure the oxidative stability of the cod liver oil and the omega-3 fatty acids from cod liver oil (HC 2007). Refer to Table 6 below.
  • The dioxins, polychlorinated dibenzo-para-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs); the dioxin-like polychlorinated biphenyls (DL PCBs); and the polychlorinated biphenyls (PCBs) are contaminants in marine oils. Testing for these contaminants are required and must be performed using either the analytical method of the European Commission Regulation EU 252/2012 (EU 2012) or the U.S. Environmental Protection Agency’s method 1613B for PCDDs and PCDFs and method 1668A for PCBs (USP 35; US EPA 2010, 2008,1994). Applicants are advised to consult the Council of the European Union document on these contaminants for further information (EU 2011). Refer to Table 7 below.
Table 5 Cod Liver Oil Monographs published in the American (USP), British (BP) and European (Ph.Eur.) Pharmacopoeias
Pharmacopoeia Monograph
BP Cod-Liver Oil (Type A)
Cod-Liver Oil (Type B)
Ph. Eur. Cod-Liver Oil, Farmed
Cod-Liver Oil (Type A)
Cod-Liver Oil (Type B)
USP Cod Liver Oil
Table 6 Maximum values of oxidative stability parameters for oils from cod liver (HC 2007)
Oxidative stability parameter Maximum value
Peroxide value (PV) 5 mEq/kg
p-Anisidine value (AV) 20
Totox value 26 (calculated as (2 x PV) + AV)

Table 7 Maximum levels of dioxins, dioxin-like polychlorinated biphenyls (DL PCB) and polychlorinated biphenyls (PCB) in oils from marine sources
Dioxin, DL PCB, and PCB contaminants Maximum level
EU 1259/2011 USP 35

Table 7 Footnotes

Table 7 Footnote 1

Expressed in World Health Organization (WHO) toxic equivalents using WHO-toxic equivalent factors (TEFs). Analytical results relating to 17 individual dioxin congeners of toxicological concern are expressed in a single quantifiable unit: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxic equivalent concentration (TEQ) (USP 35; EU 2011).

Return to Table 7 footnote 1 referrer

Table 7 Footnote 2

Sum of dioxins: WHO-PCDD/F-TEQ (USP 35; EU 2011)

Return to Table 7 footnote 2 referrer

Table 7 Footnote 3

Sum of dioxins and dioxin-like PCBs: WHO-PCDD/F-PCB-TEQ (EU 2011)

Return to Table 7 footnote 3 referrer

Table 7 Footnote 4

Sum of PCB congeners 28, 52, 101, 118, 138, 153 and 180 (USP 35; EU 2011)

Return to Table 7 footnote 4 referrer

Table 7 Footnote 5

Equivalence: 0.5 ppm = 500 ng/g

Return to Table 7 footnote 5 referrer

Dioxins (sum of PCDDs + PCDFs) Table 7 Footnote 1 Table 7 Footnote 2 1.75 pg/g 1.0 pg/g
Sum of dioxins and DL PCBs Table 7 Footnote 1 Table 7 Footnote 3 6 pg/g
PCBs Table 7 Footnote 4 200 ng/g 0.5 ppm Table 7 Footnote 5

References cited

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  • Stene LC, Joner G. 2003. Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study. The American Journal of Clinical Nutrition 78(6):1128-1134.
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References reviewed

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  • Helland IB, Smith L, Saarem K, Saugstad OD, Drevon CA. 2003. Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children's IQ at 4 years of age. Pediatrics 111(1):e39-e44.
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Appendix 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 Recommended Dietary Allowance (RDA) cannot be determined (IOM 2006).
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 (IOM 2006).
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 (IOM 2006).

Appendix 2: Recommended Dietary Allowance (RDA) and Adequate Intake (AI) Values for vitamin A

Table 8: RDA and AI Table 8 Footnote 1 values for vitamin A based on life stage group (IOM 2006)
Life stage group Vitamin A (µg RAE/day)

Table 8 Footnotes

Table 8 Footnote 1

The AI is indicated by an asterisk.

Return to Table 8 footnote 1 referrer

Infants 0-6 mo 400*
7-12 mo 500*
Children 1-3 y 300
4-8 y 400
Adolescent males 9-13 y 600
14-18 y 900
Adult males ≥ 19 y 900
Adolescent females 9-13 y 600
14-18 y 700
Adult females ≥ 19 y 700
Pregnancy 14-18 y 750
19-50 y 770
Breastfeeding 14-18 y 1,200
19-50 y 1,300

Appendix 3: Recommended Dietary Allowance (RDA) and Adequate Intake (AI) for vitamin D

Table 9: RDA and AI Table 9 Footnote 1 values for vitamin D based on life stage group (IOM 2011)
Life stage group Vitamin D (µg/day)

Table 9 Footnotes

Table 9 Footnote 1

The AI is indicated by an asterisk.

Return to Table 9 footnote 1 referrer

Infants 0-6 mo 10*
7-12 mo 10*
Children 1-3 y 15
4-8 y 15
Adolescents Males 9-13 y 15
14-18 y 15
Adult Males 19-30 y 15
31-50 y 15
51-70 y 15
>70 y 20
Adolescent Females 9-13 y 15
14-18 y 15
Adult Females 19-30 y 15
31-50 y 15
51-70 y 15
>70 y 20
Pregnancy 14-18 y 15
19-50 y 15
Breastfeeding 14-50 y 15
19-50 y 15

Appendix 4: Species of the Family Gadidae (Nelson 2006)

Subfamily Gadinae

  • Genus Arctogadus (Dryagin, 1932)
    • East Siberian cod (Arctogadus borisovi) (Dryagin, 1932)
    • Arctic cod (Arctogadus glacialis) (Peters, 1872)
  • Genus Boreogadus (Günther, 1862)
    • Polar cod (Boreogadus saida) (Lepechin, 1774)
  • Genus Eleginus (Fischer, 1813)
    • Saffron cod (Eleginus gracilis) (Tilesius, 1810)
    • Navaga (Eleginus nawaga) (Koelreuter, 1770)
  • Genus Gadiculus (Guichenot, 1850)
    • Silvery cod (Gadiculus argenteus argentus) (Guichenot, 1850)
    • Gadiculus argenteus thori (Schmidt, 1914)
  • Genus Gadus (Linné, 1758)
    • Pacific cod (Gadus macrocephalus) (Tilesius, 1810)
    • Atlantic cod (Gadus morhua) (Linnaeus, 1758)
    • Greenland cod (Gadus ogac) (Richardson, 1836)
  • Genus Melanogrammus (Gill, 1862)
    • Haddock (Melanogrammus aeglefinus) (Linnaeus, 1758)
  • Genus Merlangius (Garsault, 1764)
    • Whiting (Merlangius merlangus) (Linnaeus, 1758)
  • Genus Microgadus (Gill, 1865)
    • Pacific tomcod (Microgadus proximus) (Girard, 1854)
    • Atlantic tomcod (Microgadus tomcod) (Walbaum, 1792)
  • Genus Micromesistius (Gill, 1863)
    • Southern blue whiting (Micromesistius australis) (Norman, 1937)
    • Blue whiting (Micromesistius poutassou) (Risso, 1827)
  • Genus Pollachius (Nilsson, 1832)
    • Atlantic pollock (Pollachius pollachius) (Linnaeus, 1758)
    • Saithe (Pollachius virens) (Linnaeus, 1758)
  • Genus Theragra (Lucas in Jordan & Evermann, 1898)
    • Alaska pollock (Theragra chalcogramma) (Pallas, 1814)
    • Norwegian pollock (Theragra finnmarchica) (Koefoed, 1956)
  • Genus Trisopterus (Rafinesque, 1814)
    • Norway pout (Trisopterus esmarkii) (Nilsson, 1855)
    • Pouting (Trisopterus luscus) (Linnaeus, 1758)
    • Poor cod (Trisopterus minutus) (Linnaeus, 1758)

Subfamily Ranicipitinae

  • Genus Raniceps (Oken, 1817)
    • Tadpole fish or tadpole cod (Raniceps raninus) (Linnaeus, 1758)

Subfamily Lotinae (cuskfishes)

  • Genus Lota (Oken, 1817)
    • Burbot (Lota lota) (Linnaeus, 1758)
  • Genus Brosme (Oken, 1817)
    • Brosme (cusk) (Brosme brosme) (Ascanius, 1772)
  • Genus Molva (three species) (Lesueur, 1819)
    • Blue ling (Molva dypterygia) (Pennant, 1784)
    • Mediterranean ling (Molva macrophthalma (Rafinesque, 1810)
    • European ling/drizzie (Molva molva (Linnaeus, 1758)