10/15/2018
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`GRAS Notice Inventory > Agency Response Letter GRAS Notice No. GRN 000371
`
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`The content on this page is provided for reference purposes only. This content has not been altered or
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`
`Agency Response Letter GRAS Notice No.
`GRN 000371
`
`Return to inventory listing: GRAS Notice Inventory (http://wayback.archive-
`it.org/7993/20171031011218/http://www.fda.gov/grasnoticeinventory)
`
`See also Generally Recognized as Safe (GRAS)
`(/7993/20171031011218/https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/default.htm) and
`about the GRAS Notice Inventory
`(/7993/20171031011218/https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/def
`ault.htm)
`
`CFSAN/Office of Food Additive Safety
`July 22, 2011
`
`Madhu G. Soni, Ph.D
`Soni and Associates, Inc.
`th
`749 46 Square
`Vero Beach, FL 32968
`
`Re: GRAS Notice No. GRN 000371
`
`Dear Dr. Soni:
`
`The Food and Drug Administration (FDA) is responding to the notice, dated December 14, 2010, that you submitted
`on behalf of Aker Biomarine Antarctic AS (Aker Biomarine) in accordance with the agency’s proposed regulation,
`proposed 21 CFR 170.36 (62 FR 18938; April 17, 1997; Substances Generally Recognized as Safe (GRAS); the
`GRAS proposal). FDA received the notice on December 16, 2010, filed it on February 7, 2011, and designated it as
`GRAS Notice No. GRN 000371.
`
`(1)
`The subject of the notice is krill oil.
` The notice informs FDA of the view of Aker Biomarine that krill oil is GRAS,
`through scientific procedures, for use as a food ingredient in non-alcoholic beverages, breakfast cereals, cheeses,
`frozen dairy desserts, whole and skim milk, processed fruit and fruit juices, and medical foods at use levels ranging
`from 0.05 to 0.5 grams (g) per serving.
`
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`GRAS Notice Inventory > Agency Response Letter GRAS Notice No. GRN 000371
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`As part of its notice, Aker Biomarine includes the report of a panel of individuals (Aker Biomarine’s GRAS panel)
`who evaluated the data and information that are the basis for Aker Biomarine’s GRAS determination. Aker
`Biomarine considers the members of its GRAS panel to be qualified by scientific training and experience to
`evaluate the safety of substances added to food. Aker Biomarine’s GRAS panel discusses identity, specifications,
`method of manufacture, dietary exposure and safety, and concluded that krill oil is GRAS under the intended
`conditions of use.
`
`The notifier states that krill oil is manufactured in accordance with current good manufacturing practices and meets
`appropriate food grade specifications. The marine organism known as krill (Euphasia superba) is first cooked and
`dried. The oil is extracted from the resultant krill meal using food grade ethanol, and the ethanol-oil solution is
`concentrated by evaporation and clarified by centrifugation. The ethanol is then evaporated from the oil solution.
`The major components of krill oil are triglycerides and phospholipids, which include esters of the fatty acids
`eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). The notifier provides product specifications for krill
`oil, including levels of fatty acids, total phospholipids, and astaxanthin. Specifications also include limits for lead (<
`0.10 mg/kg), mercury (< 0.05 mg/kg), arsenic (< 0.05 mg/kg), residual ethanol (< 3.0 %), and trans-fatty acids (<
`0.3%).
`
`Aker Biomarine calculates an estimated daily intake (EDI) of krill oil using food consumption data from the 1994-
`1996 USDA Continuing Survey of Food Intakes by Individuals (CSFII) and intended use levels in their notice. Aker
`Biomarine states that average EDI calculations were doubled to approximate 90 percentile EDIs. Aker Biomarine
`th
`reports an average EDI of 4.1 g per person per day (g/p/d) and an approximated 90 percentile EDI of 8.3 g/p/d.
`th
`Aker Biomarine calculates that, based on the 90 percentile EDI for krill oil, the combined maximum EDI for EPA
`th
`and DHA would be 1.95 g/p/d. Aker Biomarine states that use of krill oil in medical foods would be meal
`replacements for patients whose diets would consist solely of these foods for 3 meals per day. Total krill oil
`consumption in these patients would be 0.90 to 1.50 g/p/d.
`
`Aker Biomarine discusses FDA's recommendations regarding safe levels of exposure to EPA and DHA, noting that
`krill oil is intended as a substitute for fish oil. Consequently, dietary intake of total EPA and DHA from krill oil will be
`substitutional and not additive to that ingested from fish oil. Aker Biomarine states that the daily intake of EPA and
`(2)
`DHA estimated from krill oil does not exceed 3 g/p/d set for EPA and DHA for menhaden oil in 21 CFR 184.1472.
`
`In its discussion of the safety of krill oil, Aker Biomarine provides a compositional comparison between krill oil and
`other marine-derived oils in the marketplace, including menhaden oil and tuna oil. Aker Biomarine concludes that
`the composition of krill oil is similar to other marine oils commonly consumed.
`
`Aker Biomarine summarizes the results of published and unpublished human and rodent data from GRN 000242, in
`addition to considering more recently published human data which further support the safe use of krill oil under the
`intended conditions of use. Aker Biomarine also provides a discussion of the evidence supporting the safety of the
`krill oil components astaxanthin and the trans-fatty acid, vaccenic acid, concluding that the presence of these
`substances does not affect the safety of krill oil at their current concentrations in the final product.
`
`Allergen Labeling
`The Food Allergen Labeling and Consumer Protection Act of 2004 (FALCPA) amends the Federal Food, Drug, and
`Cosmetic Act (FFDCA) to require that the label of a food that is or contains an ingredient that bears or contains a
`"major food allergen" declare the presence of the allergen (section 403(w)). FALCPA defines a "major food allergen"
`as one of eight foods or food groups (i.e., milk, eggs, fish, Crustacean shellfish, tree nuts, peanuts, wheat, and
`soybeans) or a food ingredient that contains protein derived from one of those foods. Issues associated with
`labeling food are the responsibility of the Center for Food Safety and Applied Nutrition's Office of Nutritional
`Products, Labeling, and Dietary Supplements.
`
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`Standards of Identity
`In the notice, Aker Biomarine states its intention to use krill oil in several food categories, including foods for which
`standards of identity exist located in Title 21 of the Code of Federal Regulations (CFR). We note that an ingredient
`that is lawfully added to food products may be used in a standardized food only if it is permitted by the applicable
`standard of identity.
`
`Potential Requirement for a Color Additive Petition
`In its notice, Aker Biomarine describes krill oil as a dark red-colored viscous oil. As such, the use of krill oil in food
`products may constitute the use of a color additive under section 201(t)(1) of the FFDCA and FDA’s implementing
`regulations in 21 CFR Part 70. Under section 201(t)(1) and 21 CFR 70.3(f), the term color additive means a
`material that is a dye, pigment, or other substance made by a process of synthesis or similar artifice, or extracted,
`isolated, or otherwise derived from a vegetable, animal, mineral, or other source, and that is capable (alone or
`through reaction with another substance) of imparting color when added or applied to a food; except that such term
`does not include any material which the Secretary,
` by regulation, determines is used (or intended to be used)
`(3)
`solely for a purpose or purposes other than coloring. Under 21 CFR 70.3(g), a material that otherwise meets the
`definition of color additive can be exempt from that definition on the basis that it is used or intended to be used
`solely for a purpose or purposes other than coloring, as long as the material is used in a way that any color
`imparted is clearly unimportant insofar as the appearance, value, marketability, or consumer acceptability is
`concerned. Given the construct of section 201(t)(1) of the FFDCA and 21 CFR 70.3(f) and (g), the use of a
`substance that is capable of imparting color may constitute use as a color additive in addition to use as a food
`additive or GRAS substance. For example, β-carotene is both approved for use as a color additive (21 CFR 73.95)
`and affirmed as GRAS for use as a nutrient supplement (21 CFR 184.1245); in some food products, β-carotene is
`used for both purposes. Importantly, if the use of krill oil constitutes use as a color additive within the meaning of
`section 201(t)(1) of the FFDCA and FDA’s implementing regulations in 21 CFR 70.3(f) and (g), section 721(a) of the
`FFDCA requires premarket review and approval of that use by FDA. Under section 402(c) of the FFDCA, a food
`product that contains an unapproved color additive would be deemed adulterated.
`(4)
`
`In its notice, Aker Biomarine states that use of krill oil in foods is not intended to function as a color additive as
`defined in 21 CRF 70.3(f). Aker Biomarine further states that the addition of its krill oil to the various food products
`occurs at a level low enough to be consistent with the “non-apparent color” exemption 21 CFR 70.3 (f); the intended
`use of krill oil as a nutrient would contribute a color in a manner consistent with the “unimportant color” exemption
`addressed in 21 CFR 70.3 (g); and, the intended use of krill oil does not relate to any use of the ingredient as a
`color additive (21 CFR 70.3 (f)). In its review of Aker Biomarine’s notice that the ingredient krill oil is GRAS for the
`intended uses, FDA did not consider whether section 201(t)(1) of the FFDCA and FDA’s implementing regulations
`in 21 CFR Part 70 apply to the use of krill oil in foods. Accordingly, this response should not be construed to be a
`statement that the use of krill oil in foods is lawful under section 721(a). If, after receipt of this letter, Aker Biomarine
`has any further questions about this issue, we recommend that Aker Biomarine contact the Office of Food Additive
`Safety.
`
`Medical Foods
`In its notice, Aker Biomarine informs FDA that one intended use of krill oil is in medical foods. Section 5(b) of the
`Orphan Drug Act (ODA) defines a medical food as a food that is formulated to be consumed or administered
`enterally under the supervision of a physician and that is intended for the specific dietary management of a disease
`or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established
`by medical evaluation. Section 403(q) of the FFDCA lays out the statutory framework for nutrition labeling of food
`products. Section 403(r) of the FFDCA lays out the statutory framework for health claims and nutrient content
`claims. Under section 403(q)(5)(A)(iv) of the FFDCA and FDA's implementing regulations in 21 CFR 101.9(j)(8), the
`requirements for nutrition labeling do not apply to medical foods as defined in section 5(b) of the ODA. Under
`
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`section 403(r)(5)(A) of the FFDCA and FDA's implementing regulations in 21 CFR 101.13(q)(4)(ii) and 21 CFR
`101.14(f)(2), the requirements for nutrient content claims and health claims, respectively, do not apply to medical
`foods as defined in section 5(b) of the ODA. For your information, FDA's response to Aker Marine’s notice that krill
`oil is GRAS for use in medical foods does not address the question of whether any particular food product that
`contains krill oil as an ingredient would be a medical food within the meaning of section 5(b) of the ODA and, thus,
`would be exempt from the requirements for nutrition labeling, nutrient content claims, and health claims.
`
`Section 301(ll) of the FFDCA
`The Food and Drug Administration Amendments Act of 2007, which was signed into law on September 27, 2007,
`amends the FFDCA to, among other things, add section 301(ll). Section 301(ll) of the FFDCA prohibits the
`introduction or delivery for introduction into interstate commerce of any food that contains a drug approved under
`section 505 of the FFDCA, a biological product licensed under section 351 of the Public Health Service Act, or a
`drug or a biological product for which substantial clinical investigations have been instituted and their existence
`made public, unless one of the exemptions in section 301(ll)(1)-(4) applies. In its review of Aker Marine’s notice that
`the ingredient krill oil is GRAS for the intended uses, FDA did not consider whether section 301(ll) or any of its
`exemptions apply to foods containing krill oil. Accordingly, this response should not be construed to be a statement
`that foods that contain krill oil if introduced or delivered for introduction into interstate commerce, would not violate
`section 301(ll).
`
`Conclusions
`Based on the information provided by Aker Biomarine, as well as other information available to FDA, the agency
`has no questions at this time regarding Acker Biomarine’s conclusion that krill oil is safe under the intended
`conditions of use. The agency has not, however, made its own determination regarding the GRAS status of the
`subject use of krill oil. As always, it is the continuing responsibility of Aker Biomarine to ensure that food ingredients
`that the firm markets are safe, and are otherwise in compliance with all applicable legal and regulatory
`requirements.
`
`In accordance with proposed 21 CFR 170.36(f), a copy of the text of this letter responding to GRN 000371, as well
`as a copy of the information in this notice that conforms to the information in the GRAS exemption claim (proposed
`21 CFR 170.36(c)(1)), is available for public review and copying via the FDA home page at
`http://www.fda.gov/grasnoticeinventory.
`
`Sincerely,
`
`Mitchell A. Cheeseman, Ph.D.
`Acting Director
`Office of Food Additive Safety
`Center for Food Safety and Applied Nutrition
`
`(1)
`FDA notes that krill oil was the subject of GRN 000242 for the same uses. The primary difference between the
`subjects of these notices is that the solvents used in manufacturing the oil were acetone and ethanol for GRN
`000242 and GRN 000371, respectively.
`
`(2)
`FDA has affirmed the GRAS status of menhaden oil for use as a direct food ingredient (21 CFR 184.1472)
`provided that the combined intake of EPA and DHA from consumption of menhaden oil does not exceed 3 g/p/d.
`FDA had raised concerns about the consumption of high levels of EPA and DHA and possible adverse effects of
`consumption on bleeding time, glycemic control, and low-density lipoprotein cholesterol levels (62 FR 30751 at
`30757; June 5, 1997). FDA subsequently revised the menhaden oil rule to reallocate the uses of menhaden oil in
`
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`conventional food, while maintaining the 3 g/p/d limit on EPA and DHA, and to require that menhaden oil not be
`used as an ingredient in foods in combination with another added oil that is a significant source of EPA and DHA
`(70 FR 14530; March 23, 2005).
`
`(3)
`The Secretary of the Department of Health and Human Services.
`
`We note that section 721(b)(4) of the FFDCA provides that a color additive shall be deemed to be safe and
`(4)
`suitable for the purpose of listing under section 721(b) of the FFDCA while there is in effect a published finding of
`the Secretary declaring that the substance is exempt from the definition of “food additive” because of its being
`generally recognized by qualified experts as safe for its intended use as provided in section 201(s) of the FFDCA.
`Importantly, FDA’s response to GRN 000371 does not constitute a “finding of the Secretary” within the meaning of
`section 721(b)(4) of the FFDCA.
`
`More in GRAS Notice Inventory
`(/7993/20171031011218/https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/default.htm)
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