Monograph: Fish Oil

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This monograph is intended to serve as a guide to industry for the preparation of Product Licence Applications and labels for natural health product market authorization. It is not intended to be a comprehensive review of the medicinal ingredient. There are many N-3 polyunsaturated fatty acids, popularly known as omega-3 acids/omega-3 fatty acids (Ph.Eur. 2012). This monograph is specific to eicosapentaenoic acid (C20:5 n-3, EPA) and docosahexaenoic acid (C22:6 n-3, DHA). Notes: (i) Text in parentheses is additional optional information which can be included on the Product Licence Application and product labels at the applicants' discretion. (ii) The solidus (/) indicates that the terms are synonyms or that the statements are synonymous. Either term or statement may be selected by the applicant.

Date: 2018-09-25

NHPID name

Fish Oil

Proper name(s)

Common name(s)

Fish Oil

Source material

Route Of administration

Oral

Dosage form(s)

The acceptable pharmaceutical dosage forms include, but are not limited to capsules, chewables (e.g. gummies, tablets), liquids, powders, strips or tablets.
This monograph is not intended to include foods or food-like dosage forms such as bars, chewing gums or beverages.

Use(s) or purpose(s)

Statement(s) to the effect of:

General

Helps to reduce serum triglycerides and maintain/support cardiovascular health.
Helps support cognitive health and/or brain function. (EFSA 2012, van de Rest et al. 2008, Freund-Levi et al. 2006, Fontani et al. 2005b, Haag 2003, Morris et al. 2003, IOM 2002)
Helps support the development of the brain, eyes and nerves in children up to 12 years of age. (Marszalek and Lodish 2005, Haag 2003, IOM 2002, Giedd et al. 1999, Mills 1999)
Helps to promote healthy mood balance. (EFSA 2012, Nemets et al. 2006, Sontrop and Campbell 2006, Fontani et al. 2005b, Zanarini and Frankenburg 2003, Peet and Horrobin 2002, Stoll et al. 1999)

For products providing per day

Source of omega-3 fatty acids for the maintenance of good health. (EFSA 2012, Simopoulos 2007, Oh 2005, IOM 2002, Simopoulos 1999)
Source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for the maintenance of good health. (EFSA 2012, Simopoulos 2007, Oh 2005, IOM 2002, Simopoulos 1999)
Helps maintain/support cardiovascular health. (EFSA 2012, Oh 2005, Wang et al. 2004, Leaf et al. 2003, Kris-Etherton et al. 2002)
Helps to reduce serum triglycerides/triacylglycerols. (EFSA 2012, Oh 2005, Balk et al. 2004, Hooper et al. 2004, Nilsen et al. 2001, Sirtori et al. 1998)
In conjunction with conventional therapy, helps to reduce the pain of rheumatoid arthritis in adults. (EFSA 2012, Volker et al. 2000, Skoldstam et al. 1992)

Dose(s)

Duration of use

No statement is required

Risk information

Statement(s) to the effect of:

Caution(s) and Warning(s): No statement is required Contraindication(s): No statement is required Known Adverse Reaction(s): No statement is required

Non-medicinal ingredients

Must be chosen from the current Natural health products ingredients database and must meet the limitations outlined in the database.

Storage conditions

For all products, except those encapsulated: Refrigerate after opening (Wille and Gonus 1989).
For all products: Store in airtight container, protected from light (Ph.Eur. 2012, USP 34).

Specifications

The finished product specifications must be established in accordance with the requirements described in the NHPD Quality of natural health products guide.
The medicinal ingredient must comply with the requirements outlined in the Natural health products ingredient database (NHPID).
Peroxide, anisidine, and totox values of fish oil or omega-3 fatty acids derived from fish oil must be in accordance with the methods set out by the Association of Analytical Community (AOAC) and/or Pharmacopoeial analytical methods. These specifications are necessary to ensure the oxidative stability of the fish oil and the omega-3 fatty acids from seal oil (HC 2007). The maximum peroxide value (PV) must be 5 mEq/kg, the maximum anisidine value (AV) must be 20 while the maximum Totox value must be 26 (calculated as 2 X PV + AV). (Refer to Appendix 1 Table 3)
The dioxins, polychlorinated dibenzo-para-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), and the polychlorinated biphenyls (PCBs), which include the dioxin-like polychlorinated biphenyls (DL PCBs), and the non dioxin-like polychlorinated biphenyls (NDL-PCBs) are contaminants in oils from marine sources. 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). The maximum limits from EU1259/2011 are: for dioxins (sum of PCDDs and PCDFs) -- a maximum of 1.75 pg/g, for the sum of dioxins and DL-PCBs -- a maximum of 6 pg/g, and for PCBs -- a maximum of 200 ng/g. The maximum limits from USP 35 are for dioxins (sum of PCDDs and PCDFs) -- a maximum of 1.0 pg/g, and for PCBs -- a maximum of 0.5ppm (Refer to Appendix 1 Table 4) [(i)Maximums levels are expressed in World Health Organization (WHO 2005) 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).(ii) Sum of dioxins: WHO-PCDD/F-TEQ (USP 35~ EU 2011) (iii) Sum of dioxins and dioxin-like PCBs: WHO-PCDD/F-PCB-TEQ (EU 2011) (iv) Sum of PCB congeners 28, 52, 101, 118, 138, 153 and 180 (USP 35~ EU 2011) (v) Equivalence: 0.5 ppm = 500 ng/g.
The medicinal ingredient must comply with the requirements outlined in the Natural Health Products Ingredients Database (NHPID). In addition, the medicinal ingredient may comply with the specifications outlined in the Fish Oil, Rich in Omega-3-Acids Monographs published in the European and British Pharmacopoeias or Fish oil containing Omega-3 Acids from the USP (Refer to Appendix 1 Table 2)

References cited

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Appendix 1

Table 1 Daily dose for eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) in fish oil
Subpopulation		EPA + DHA (mg/day)
Subpopulation		Minimum ^{Table 1 Footnote 1}	Maximum ^{Table 1 Footnote 2}
Children	1-8 y	100	1,500
Adolescents	9-13 y 14-18 y	100 100	2,000 2,500
Adults ^{Table 1 Footnote 3}	≥ 19 y	100	5,000
Table 1 Footnotes Table 1 Footnote 1 Restrictions to minimum dose may apply according to Use(s) or Purpose(s) section above. Return to Table 1 footnote 1 referrer Table 1 Footnote 2 Adult maximum dose supported by US FDA 1997. Children and adolescent maximum doses, calculated as a fraction of the adult dose, are relative to body weight and caloric intake. Return to Table 1 footnote 2 referrer Table 1 Footnote 3 Includes pregnant and breastfeeding women. Return to Table 1 footnote 3 referrer

Table 2 Fish Oil Monographs published in the American (USP), British (BP) and European (Ph.Eur.) Pharmacopoeias
Pharmacopoeia	Monograph
BP	Fish Oil, Rich in Omega-3-Acids
Ph.Eur.	Fish Oil, Rich in Omega-3-Acids
USP	Fish Oil Containing Omega-3 Acids

Table 3 Maximum values of oxidative stability parameters for fish oil (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 4 Maximum levels of dioxins, dioxin-like polychlorinated biphenyls (DL PCB) and polychlorinated biphenyls (PCBs) in oils from marine sources
Dioxin, DL PCB, and PCB contaminants	Maximum level
Dioxin, DL PCB, and PCB contaminants	EU 1259/2011	USP 35
Dioxins (sum of PCDDs + PCDFs) ^{Table 4 Footnote 1} ^{Table 4 Footnote 2}	1.75 pg/g	1.0 pg/g
Sum of dioxins and DL-PCBs ^{Table 4 Footnote 1} ^{Table 4 Footnote 3}	6.0 pg/g
PCBs ^{Table 4 Footnote 4}	200 ng/g	0.5 ppm ^{Table 4 Footnote 5}
Table 4 Footnotes Table 4 Footnote 1 Expressed in World Health Organization (WHO 2005) 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 4 footnote 1 referrer Table 4 Footnote 2 Sum of dioxins: WHO-PCDD/F-TEQ (USP 35; EU 2011) Return to Table 4 footnote 2 referrer Table 4 Footnote 3 Sum of dioxins and dioxin-like PCBs: WHO-PCDD/F-PCB-TEQ (EU 2011) Return to Table 4 footnote 3 referrer Table 4 Footnote 4 Sum of PCB congeners 28, 52, 101, 118, 138, 153 and 180 (USP 35; EU 2011). Return to Table 4 footnote 4 referrer Table 4 Footnote 5 Equivalence: 0.5 ppm = 500 ng/g Return to Table 4 footnote 5 referrer

Monograph: Fish Oil

NHPID name

Proper name(s)

Common name(s)

Source material

Route Of administration

Dosage form(s)

Use(s) or purpose(s)

Statement(s) to the effect of:

Dose(s)

Duration of use

Risk information

Statement(s) to the effect of:

Non-medicinal ingredients

Storage conditions

Specifications

References cited

References reviewed

Appendix 1

Table 1 Footnotes

Table 4 Footnotes