GRAS Notice Inventory > Agency Response Letter GRAS Notice No. GRN 000242
`
`Page 1 of 5
`
`Archived Content
`The content on this page is provided for reference purposes only. This content has not been
`altered or updated since it was archived.
`
`Agency Response Letter GRAS
`Notice No. GRN 000242
`
`Return to inventory listing: GRAS Notice Inventory (http://www.fda.gov/grasnoticeinventory)
`
`See also Generally Recognized as Safe (GRAS) (/Food/IngredientsPackagingLabel-
`ing/GRAS/default.htm) and about the GRAS Notice Inventory (/Food/IngredientsPackag-
`ingLabeling/GRAS/NoticeInventory/default.htm)
`
`CFSAN/Office of Food Additive Safety
`October 14, 2008
`
`Robert S. McQuate, Ph.D.
`GRAS Associates, LLC
`20482 Jacklight Lane
`Bend, OR 97702-3074
`
`Re: GRAS Notice No. GRN 000242
`
`Dear Dr. McQuate:
`
`The Food and Drug Administration (FDA) is responding to the notice, dated January 18, 2008, that
`you submitted on behalf of Neptune Technologies and Bioressources (Neptune) 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 February 4, 2008, filed it on February 4, 2008, and designated it as GRAS Notice No. GRN
`000242.
`
`The subject of the notice is krill oil. The notice informs FDA of the view of Neptune that krill oil is
`GRAS, through scientific procedures, for use as a direct food ingredient in various foods as
`described in Table 1 (below). Neptune views this use of krill oil to be "as an alternative or substitute
`for fish oil."
`
`Table 1. Neptune's intended conditions of use
`
`RIMFROST EXHIBIT 1091 page 0001
`http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/ucm154...
`10/19/2016
`
`

`

`GRAS Notice Inventory > Agency Response Letter GRAS Notice No. GRN 000242
`
`Page 2 of 5
`
`Food
`
`Milligrams (mg) Per Serving
`
`Breakfast Cereals
`
`Cheese
`
`Beverages (Nonalcoholic)
`
`Fruit Juices
`
`Frozen Dairy Desserts
`
`Milk Products
`
`Medical Foods
`
`300
`
`300
`
`150-200
`
`150-250
`
`300-500
`
`300-500
`
`300-500
`
`As part of its notice, the notifier includes the findings of a panel of individuals (Neptune's GRAS
`panel) who evaluated the data and information that are the basis for the notifier's GRAS
`determination. Neptune considers the members of its GRAS panel to be qualified by scientific
`training and experience to evaluate the safety of substances added to food. Neptunes's GRAS
`panel evaluated estimates of dietary exposure, method of production, and product specifications
`as well as published and unpublished studies. Neptune's GRAS panel concludes that krill oil
`produced in accordance with good manufacturing practices is considered to be generally
`recognized as safe when used as a substitute for fish oils.
`
`Krill oil is obtained from krill which are small, pelagic, shrimp-like crustaceans of the family
`Euphausiidae. Krill oil is a reddish, opaque, lipid extract of marine krill (Euphasia superba). The
`major components of krill oil are triglycerides and phospholipids, and include the fatty acids
`eicosapentaenoic acid (EPA, C20:5 n–3), docosahexeanoic acid (DHA, C22:6 n–3), and cis-11-
`octadecenoic acid (vaccenic acid, C18:1 n–7). The combined concentration of EPA and DHA in
`krill oil is approximately 26 percent, with a ratio of EPA to DHA of approximately 2:1. Krill oil also
`contains naturally-occurring esterified astaxanthin.
`
`Neptune describes the manufacturing process for krill oil. Frozen Antarctic krill are crushed and the
`lipids and proteins are extracted using acetone. Following extraction, the krill proteins and lipids
`are filtered through an organic solvent-resistant filter under reduced pressure to enable physical
`separation of lipids and proteins. Excess acetone is evaporated and water is separated from the
`oil. The oil is subjected to additional filtration and purification to remove impurities and is packaged
`in a modified nitrogen-containing atmosphere and stored. The notifier provides product
`specifications for krill oil, including specifications for fatty acids, total phospholipids, esterified
`astaxanthin, saturated fatty acids, and trans-fat (<0.1 percent). Specifications also include limits on
`residual acetone (<10 milligrams per kilogram (mg/kg), lead (<0.1 mg/kg), mercury (<0.1 mg/kg),
`arsenic (<0.1 mg/kg), cadmium (<0.1 mg/kg), pesticides, and microbiological contaminants.
`
`Neptune calculates an estimated daily intake (EDI) of krill oil based on minimum and maximum use
`levels listed in Table 1 and reported food consumption data from the 1994-1996, and 1998 USDA
`Continuing Survey of Food Intakes by Individuals (CSFII). Neptune reports the mean EDI as 3.1 to
`4.1 grams per person per day (g/p/d) and the 90th percentile EDI (mean multiplied by two) as 6.2
`to 8.3 g/p/d. Neptune notes that at a combined level of 26 percent of total EPA and DHA, the
`maximum daily consumption of EPA and DHA would be 2.2 g/p/d. Neptune states that the
`maximum expected daily consumption of EPA and DHA from krill oil is within the recommended
`intake for menhaden oil (less than 3 g/p/d).(1)
`
`RIMFROST EXHIBIT 1091 page 0002
`http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/ucm154...
`10/19/2016
`
`

`

`GRAS Notice Inventory > Agency Response Letter GRAS Notice No. GRN 000242
`
`Page 3 of 5
`
`Neptune discusses FDA's recommendations regarding safe levels of exposure to EPA and DHA,
`noting that krill oil is intended as an alternative or substitute for fish oil. Consequently, dietary
`intake of total EPA and DHA from krill oil will be substitutional and not additive to that which would
`be ingested from fish oil. Neptune also notes that the use levels of krill oil in foods will be self-
`limiting due to the strong taste that begins to be detected at use levels between 300 and 500
`milligrams per serving, depending on the type of food.
`
`In its discussion of the safety of krill oil, Neptune provides a compositional comparison between
`krill oil and other marine-derived oils in the marketplace, including menhaden oil, tuna oil, salmon
`oil, and anchovy oil. Neptune concludes that the composition of krill oil is similar to marine oils
`commonly consumed. Neptune also summarizes the results of published and unpublished studies
`supporting the safe use of krill oil in foods. Neptune describes published rodent and human clinical
`studies examining nutritional and clinical utility, which also provided evidence that krill oil was well-
`tolerated. Neptune discusses results from an unpublished human clinical study as well as an
`unpublished rodent study that corroborates Neptune's conclusion regarding the safe use of krill oil
`in food. Neptune also provides a discussion of the evidence supporting the safety of the krill oil
`components astaxanthin and vaccenic acid concluding that the presence of these substances does
`not affect the safety of krill oil.
`
`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.
`
`Standards of Identity
`In the notice, Neptune states its intention to use krill in several food categories, including foods for
`which standards of identity exist located in Title 21 of the Code of Federal Regulations. 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
`FDA notes that krill oil has the potential to impart color in food products that contain it. 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
`(2)
`used) 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
`
`RIMFROST EXHIBIT 1091 page 0003
`http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/ucm154...
`10/19/2016
`
`

`

`GRAS Notice Inventory > Agency Response Letter GRAS Notice No. GRN 000242
`
`Page 4 of 5
`
`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, beta-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, beta-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.
`(3)
`
`Medical Foods
`In its notice, Neptune informs FDA that one intended use of krill oil is use 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 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 Neptune'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
`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 Neptune's
`notice that krill oil is GRAS for use in certain foods, 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 Neptune, and other information available to FDA, the agency
`has no questions at this time regarding Neptune's conclusion that krill oil is GRAS under the
`intended conditions of use. The agency has not, however, made its own determination regarding
`
`RIMFROST EXHIBIT 1091 page 0004
`http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/ucm154...
`10/19/2016
`
`

`

`GRAS Notice Inventory > Agency Response Letter GRAS Notice No. GRN 000242
`
`Page 5 of 5
`
`the GRAS status of the subject use of krill oil. As always, it is the continuing responsibility of
`Neptune 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
`000242, as well as a copy of the information in this notice that conforms to the information in the
`proposed GRAS exemption claim (proposed 21 CFR 170.36(c)(1)), is available for public review
`and copying on the homepage of the Office of Food Additive Safety (on the Internet at
`http://www.cfsan.fda.gov/~lrd/foodadd.html).
`
`Sincerely,
`
`Laura M. Tarantino, Ph.D.
`Director
`Office of Food Additive Safety
`Center for Food Safety and Applied Nutrition
`
`FDA has affirmed the GRAS status of menhaden oil for use as a direct food ingredient (21 CFR
`(1)
`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 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).
`
`(2)
`
`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
`(3)
`be safe and 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 000242 does not constitute a "finding of the Secretary" within the meaning of section 721(b)
`(4) of the FFDCA.
`
`More in GRAS Notice Inventory
`(/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/default.htm)
`
`RIMFROST EXHIBIT 1091 page 0005
`http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/ucm154...
`10/19/2016
`
`