~ont & ~ssociates Jnc.
`
`7 49 46th Square
`Vero Beach, FL 32968, USA
`Telephone: 772-299-0746
`Facsimile: 772-299-5381
`E-mail: sonim@bellsouth.net
`
`December 14, 2010
`
`Office of Food Additive Safety (HFS-255)
`Center for Food Safety and Applied Nutrition
`Food and Drug Administration
`5100 Paint Branch Parkway
`College Park, MD 20740-3835
`
`Subject: Notification of GRAS Determination for Krill Oil
`
`Division of
`B1otechnology and
`GRAS Notice Review
`
`Dear Sir/Madam:
`
`In accordance with proposed 21 CFR 170.36 (Notice of a claim for exemption
`based on a GRAS determination) published in Federal Register (62 FR 18938-18964;
`April 17, 1997), I am submitting in triplicate, as the agent of the notifier, Aker Biomarine
`Antarctic AS, Norway, a Generally Recognized As Safe (GRAS) notification for
`Superba® Krill Oil.
`
`SuperbaTM Krill Oil extracted from Antarctic krill, Euphausia superba is intended
`for use as a food ingredient in non-alcoholic beverages; breakfast cereals; cheeses; frozen
`dairy desserts; milk whole and skim; processed fruit and fruit juices; and medical foods,
`at use levels ranging from 0.05 to 0.50 g per serving (reference amounts customarily
`consumed, 21 CFR 101.12). The intended use of Superba® Krill Oil is estimated to
`result in a maximum daily intake of 8.28 g/person.
`
`If you have any questions or require additional information, please feel free to
`contact me by phone at 772-299-0746 or by email at sonim@bellsouth.net.
`
`\
`
`Madhu cf. Soni, Ph.D.
`
`Enclosures:
`
`rroY::VY'\
`~
`I. Io · 1 0
`
`P-P
`
`www.soniassociates.net
`
`000002
`
`RIMFROST EXHIBIT 1089 page 0001
`
`

`

`@mi
`
`749 46th Square
`Vero Beach, FL 32968, USA
`Telephone: 772-299-0746
`Facsimile: 772-299-5381
`E-mail: sonim@bellsouth.net
`
`GRAS NOTIFICATION
`
`I. Claim of GRAS Status
`
`A. Claim of Exemption from the Requirement for Premarket Approval Requirements
`Pursuant to Proposed 21 CFR 5 170.36(~)(1)
`
`Aker Biomarine Antarctic AS, Norway, has determined that high phospholipid krill oil is
`Generally Recognized As Safe, and therefore, exempt from the requirement of premarket
`approval, under the conditions of its intended use. This determination is based on scientific
`procedures as described in the following sections, under the conditions of krill oil's intended
`use in food, among experts qualified by scientific training and expertise.
`
`Sig
`
`Madhu G. Soni, Ph.D., FACN
`
`Agent for:
`Aker Biomarine Antarctic AS
`FjordalEen 16,O 1 15 Oslo
`Norway
`
`Date iq 'y\ \o
`
`RIMFROST EXHIBIT 1089 page 0002
`
`(b) (6)
`
`

`

`B.
`
`C.
`
`D.
`
`E.
`
`Name and Address of Notifier:
`Hogne Vik, M.D., Ph.D.
`EVP Documentation
`Aker Biomarine Antarctic AS
`Fjordallken 16,0115 Oslo
`Norway
`Tel: +47 24 13 00 00
`Fax: +47 24 13 01 10
`Email: hogne.vik@akerbiomarine.com
`
`Common or usual name of the notified substance:
`The common name of the substance of this notification is high phospholipid krill oil. The
`specific substance of this GRAS determination is SuperbaTM Krill Oil extracted from
`Antarctic krill, Euphausia superba. SuperbaTM Krill Oil is rich in omega-3 fatty acids,
`most of which are attached to phospholipids. SuperbaTM Krill Oil also contains
`astaxanthin ester.
`
`Conditions of use:
`High phospholipid krill oil is intended for use as a substitute or alternative to fish oils in
`the following food categories: non-alcoholic beverages; breakfast cereals; cheeses; fiozen
`dairy desserts; milk whole and skim; processed fruit and h i t juices; and medical foods',
`at use levels ranging from 0.05 to 0.50 g per serving (reference amounts customarily
`consumed, 21 CFR 101.12). The intended use of SuperbaTM Krill Oil, in the above
`mentioned food categories, is estimated to result in a maximum daily intake of 8.28
`g/person. The proposed use of SuperbaTM Krill Oil will provide a maximum daily
`consumption of up to 2.20 g/person/day of eicosapentaenoic acid (EPA) and
`docosahexaenoic acid (DHA).
`
`Basis for GRAS Determination:
`In accordance with 21 CFR 170.30, high phospholipid krill oil has been determined to be
`Generally Recognized As Safe (GRAS) based on scientific procedures. A comprehensive
`search of the scientific literature was also utilized for this determination. There exists
`sufficient qualitative and quantitative scientific evidence, including human and animal
`data to determine safety-in-use for SuperbaTM Krill Oil. Recently, high phospholipid krill
`oil (GRN 000242) has been the subject of a GRAS notification, while two of its
`important component fatty acids, EPA and DHA as part of fish or algal oil, have been the
`subject of multiple GRAS notifications. In response to these notices, FDA did not
`question the conclusions that the use of high phospholipid krill oil or sources of fatty
`acids (EPA and DHA) is GRAS under the conditions described in the notices. The safety
`
`Under Section 5(b) of the Orphan Drug Act (ODA), a Medical Food is defined 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. The
`intended use of krill oil in medical foods will be as per these and other applicable regulations.
`0 0 0 0 0 4
`Page 2 of 38
`RIMFROST EXHIBIT 1089 page 0003
`
`Krill oil GRAS Notification
`
`

`

`determination of high phospholipid krill oil is based on the totality of available scientific
`evidence that includes human observations and a variety of preclinical and clinical
`studies. Based on the available safety-related information, the estimated daily intake, if
`ingested daily over a lifetime, is safe.
`F. Availability of Information:
`The data and information that forms the basis for this GRAS determination will be
`provided to the Food and Drug Administration upon request and are located at the offices
`Of:
`
`Madhu G. Soni, Ph.D., FACN,
`Soni & Associates Inc.,
`749 46th Square,
`Vero Beach FL, 32968
`Phone: (772) 299-0746; E-mail: sonim@bellsouth.net
`
`11. Detailed Information About the Identity of the Notified Substance:
`A. Trade Name:
`The subject of this notification will be marketed as SuperbaTM Krill Oil
`B. Physical Characteristics
`SuperbaTM Krill Oil is dark red colored viscous oil
`C. Chemical Abstract Registry Number:
`Not available
`D. Chemical Formula:
`Not applicable
`E. Structure:
`The important constituents of high phospholipid krill oil are the fatty acids, EPA and
`DHA. The structures of these two fatty acids presented in Figure 1.
`
`6
`
`3
`
`03
`1
`
`CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH( CH2)3COOH
`Eicosapentaenoic acid @PA)
`
`0
`
`H
`7
`19
`16
`10
`13
`4
`1
`CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH( CH2)2COOH
`Docosahexaenoic acid @HA)
`Figure 1. Chemical structures of EPA and DHA
`
`0 0 0 0 0 5
`
`Krill oil G U S Notification
`
`Page 3 of 38
`RIMFROST EXHIBIT 1089 page 0004
`
`

`

`F. Typical Composition and Specifications
`Typical compositional analysis and specifications of SuperbaTM Krill Oil are presented in
`Table 1. Analytical results of five lots from non-consecutive batches (Appendix I)
`indicate that the product consistently meets these specifications. The major components
`of SuperbaTM Krill Oil are triglycerides and phospholipids high in omega-3 fatty acids
`such as EPA (C 20:5 n-3 fatty acid) and DHA (C 22:6 n-3 fatty acid). The maximum
`amount of EPA + DHA present in SuperbaTM Krill Oil will be 23.5 f 2 g/lOO g of the oil.
`No processing aids or additives, with the exception of residual amounts of ethanol solvent,
`are included in the final SuperbaTM Krill Oil product. Likewise due to naturally occurring
`astaxanthin esters that aid in its preservation, addition of an exogenous antioxidant is not
`required. Based on an 18 month stability test at different storage temperatures, the shelf
`life of Superba Krill Oil is set to 18 months when stored at 2-8°C. The results of
`pesticides and other environmental contaminants including PCBs, dioxins, furans and
`dioxin like PCBs, organochlorine pesticides, PBDEs, PAHs, and elements and heavy
`metal analyses from multiple batches of the product are presented in Appendix 11.
`
`d l 0 0 g)
`-C 22:6 n-3 (DHA)(expressed
`as g/lOO g)
`Total omegad
`Stability index
`Peroxide value (mEq
`peroxidekg)
`
`6.5 *1
`
`<3 .O
`
`<2
`
`AOCS Ce lb-89/AM-ABM-013
`
`AOCS Ce 1 b-89/AM-ABM-O13
`
`AOCS Cd 8b-90/AM-058
`
`<2500
`Negative
`4 0
`Negative
`
`NJ? EN IS0 4833/CQ-MO-23 1
`Total plate count (cfdg)
`E. coli (1 sample at 10 g)
`Petrifilm Select EC
`NordVal Ref. No. 0 14
`Coliform bacteria, 37°C (cfdg)
`SuZmoneZZu negative (PCR) (1
`AES 10/4-025/04
`I
`sample at 10 g)
`I NordVal Ref. No. 016
`1 4 0
`Mold and Yeast (cfidg)
`'Based on Homan and Anderson (1998) and Moreau (2006)
`*Omega-3 phospholipid defined as phospholipid where on average one out of two possible
`positions is occupied by an omega3 fatty acid.
`3Based on Schierle J. & H2rdi W. (1994); 4Expressed as astaxanthin diols.
`
`0 0 0 0 0 6
`
`Krill oil GRAS Notification
`
`RIMFROST EXHIBIT 1089 page 0005
`
`Page 4 of 38
`
`

`

`As available research highlights the potential for seafood to contain substantial amounts
`of arsenic, an extensive chemical analysis of both organic and inorganic arsenic was
`undertaken from multiple batches (see Appendix 11). These results show that while the
`total arsenic levels in krill oil ranged fiom 4 to 6 ppm, the vast majority of this arsenic
`was in organic form. The inorganic arsenic as measured in the form of arsenite and
`arsenate was below the level of quantification at 0.05 ppm.
`G. Lipid and Fatty Acid Profile:
`The lipid profile composition and fatty acid profile of krill oil is presented in Table 2 and
`3, respectively. Analysis of trans-fatty acids from four different batches revealed the
`presence of total trans-fatty acids of <0.2% (Appendix 111).
`
`Table 2. Lipid profile, including phospholipids
`
`Triacvlrrlvcerol
`Diac y lgl y cero1
`Monoacvlglvcerol
`Free fatty acids
`Cholesterol
`Cholesterol ester
`PhosDhatidvlethanolamine
`Phosphatidylinsotol
`
`38
`0.8
`<1
`5.4
`1.1
`< O S
`1.6
`<1
`
`I Phomhatidvlcholine
`Lysophosphatidylserine
`Total polar lipids
`Total neutral lbids
`
`I
`
`I
`
`39
`3.7
`44.7
`45.6
`
`Percent*
`7.7
`15.4
`0.9
`<0.1
`
`Fatty acid
`C14:O
`C16:O
`C18:O
`c20:o
`
`C16:l n-7
`C18:l (n-9) + (n-7)
`+ (n-5)
`C20: 1 (n-9) + (n-7)
`
`I
`
`I
`
`Fatty acid
`C20:4 n-6
`c22:o
`C22:4 n-6
`C18:Z n-3
`C18:4 n-3
`C20:4 n-3
`C205 n-3
`
`C21:5 n-3
`C22:5 n-3
`
`Percent*
`0.4
`<o. 1
`0.5
`1 4
`
`I
`
`I
`
`Total Fatty Acids I
`68.2
`*Percent of total oil; Data fiom representative batch (A)-U301/006/A10
`
`Krill oil GRAS Notification
`
`8 0 0 0 0 7
`Page 5 of 3 8
`RIMFROST EXHIBIT 1089 page 0006
`
`

`

`H. Manufacturing process
`
`shrimp-like, marine crustaceans of
`from
`is derived
`SuperbaTM Krill Oil
`the order Euphausiacea, Euphausia superba. These organisms have a circumpolar
`distribution with the highest concentrations found in the Atlantic sector. Antarctic krill
`exist in large numbers in the open sea and are consumed as food by humans. The
`Antarctic krill used in the production of SuperbaTM Krill Oil are naturally occurring
`organisms fished from the wild. The harvested Antarctic krill is cooked and dried on the
`vessel to prepare krill meal. The steps involved in the manufacturing are summarized in
`Figure 1. The raw material that is extracted, krill meal, is a biomass composed of lipids,
`carbohydrates, and proteins. By using a solvent extraction process, the proteins and free
`carbohydrates are removed. Thus the oil is produced by subjecting the krill meal to
`ethanol extraction. The solvent used is food-grade quality and is removed from the
`product in accordance with current good manufacturing practice.
`Following extraction, the defatted krill meal and the ethanol oil solution are separated,
`The ethanol-oil solution is then concentrated by evaporation and stored. The ethanol-oil
`solution is analyzed for ethanol, neutral and polar lipids, and astaxanthin content. Several
`batches are blended and the ethanol-oil solution is clarified by centrifugation. The ethanol
`is then evaporated from the oil solution and the final product is analyzed to verify the
`conformity with product specifications. The final product is filled into suitable containers
`and stored at 243°C and can be shipped by land, air, or boat. Processing aids, including
`solvents (which is removed by eva oration) used in the manufacturing process are food-
`grade quality as specified in the 5 Edition of Food Chemicals Codex. The SuperbaTM
`Krill Oil production process is controlled under the Hazard Analysis Critical Control
`Points (HACCP) system and points for likely contamination of the oil are strictly
`monitored. Additionally, the quality of the final product and production lots are routinely
`tested for specifications including solvent residue, microorganisms, heavy metals, and
`pesticides.
`
`Krill oil GRAS Notification
`
`0 0 0 0 0 8
`Page 6 of38
`
`RIMFROST EXHIBIT 1089 page 0007
`
`

`

`I. Manufacturing of SuperbaTM Krill Oil Process Diagram
`
`Krill meal
`1
`1 1. ~ a w material storage
`Ethanol -I 2. Ethanol extraction
`4
`3. Filtration
`
`I
`
`1
`I
`
`1
`
`Residual powder
`
`1 4. Concentration
`I- Ethanol
`I 5. Storage F 6. In-process analyses
`7. Blending G Z
`Salts ,
`r - t-+
`I 9. Final concentration
`I 10. End product analyses c
`I
`I 11. Packagingkhipping
`
`8. Centrifugation
`
`Ethanol
`
`I
`
`.t
`SuperbaTM Krill Oil
`
`Figure 2. Manufacturing process of SuperbaTM Krill Oil
`
`Krill oil GRAS Notification
`
`8 0 0 0 0 9
`Page 7 of38
`RIMFROST EXHIBIT 1089 page 0008
`
`

`

`J. Intended Technical Effects
`
`SuperbaTM Krill Oil is intended for use as a nutrient supplement as defined in 21 CFR
`170.3(0)(20). It is intended for use by the general population at levels ranging from 0.05
`to 0.50 g/serving for addition to the following food categories: non-alcoholic beverages;
`breakfast cereals; cheeses; frozen dairy desserts; milk products; processed h i t and fruit
`juices; and in medical foods. It is recognized that there are Standard of Identity
`requirements for some of these foods, located in Title 21 of the Code of Federal
`Regulations. If used in such foods, the name will be changed so as not to be confused
`with the standardized food. Available information indicates that use levels are self-
`limiting because of their strong taste that can be detected, depending on food type, at
`levels greater than 0.30-0.50 gherving. It is intended to be used as a replacement for fish
`oil. The intended use of SuperbaTM Krill Oil is in the same foods and at the same levels of
`addition as those described in GRN 242 for krill oil. The use of SuperbaTM Krill Oil in
`foods is not intended to function as a color additive as defined in 21 CFR 70.3(f).
`
`111. Summary of the Basis for the Notifier's Determination that Krill Oil is GRAS
`
`An independent panel of recognized experts, qualified by their scientific training and
`relevant national and international experience to evaluate the safety of food and food
`ingredients, was requested by Aker Biomarine Antarctic AS to determine the Generally
`Recognized As Safe (GRAS) status of high phospholipid krill oil. A comprehensive
`search of the scientific databases for safety and toxicity information on krill oil and its
`component omega-3 fatty acids (EPA and DHA) was conducted through August 2010
`and was utilized for this assessment. Based on a critical evaluation of the pertinent data
`and information summarized here and employing scientific procedures, the Expert Panel
`members have individually and collectively determined by scientific procedures that the
`addition of high phospholipid krill oil to the foods (non-alcoholic beverages; breakfast
`cereals; cheeses; frozen dairy desserts; milk; processed h i t and h i t juices) containing
`no other ingredients that are good sources of EPA or DHA, when not otherwise precluded
`by a Standard of Identity, and to Medical Foods, meeting the specification cited above
`and manufactured in according with current Good Manufacturing Practice, is Generally
`Recognized As Safe (GRAS) under the conditions of intended use, as specified herein.
`
`In coming to this decision that krill oil is GRAS, the Expert Panelists relied upon the
`conclusions that neither high phospholipid krill oil nor any of its constituents pose any
`toxicological hazards or safety concerns at the intended use levels, as well as on
`published toxicology studies and other articles relating to the safety of the product. It is
`also the opinion of the Expert Panelists that other qualified and competent scientists,
`reviewing the same publicly available toxicological and safety information, would reach
`the same conclusion.
`
`Krill oil GRAS Notification
`
`0 0 0 0 1 0
`Page 8 of 38
`RIMFROST EXHIBIT 1089 page 0009
`
`

`

`..
`. . . . . . . . . . . . . . . . *idr^irrr*-* .-... *.* ... ~ . ~ , ~ ~ ~ ~ ~ ~ ” ~ ~ ~ , ~ . , ~ ~ ~ ~ ~ ,
`
`lix.”*lu..*-r.Xilr....r.x..
`
`IV . Basis for a Conclusion that SuperbaTM Krill Oil is GRAS for its Intended Use .
`
`1 .
`1.1.
`1.2.
`1.3.
`1.4.
`1.5.
`1.6.
`1.7.
`1.7.1.
`2 .
`2.1.
`2.2.
`2.3.
`2.4.
`2.5.
`2.6.
`2.7.
`2.8.
`3 .
`4 .
`5 .
`6 .
`7 .
`8 .
`9 .
`10 .
`
`TABLE OF CONTENT
`INTRODUCTION ........................................................................................................
`Background ..................................................................................................................
`Chemistry and Biological Activity ..............................................................................
`Description. Manufacturing Process and Specifications ..........................................
`Similarity with Fish oils ...............................................................................................
`Technical effects ...........................................................................................................
`Current Uses .................................................................................................................
`Intended Use Levels and Food Categories .................................................................
`Estimated Daily Intake from the Intended Uses .......................................................
`DATA PERTAINING TO SAFETY ..........................................................................
`Absorption and Metabolism ........................................................................................
`Human Studies .............................................................................................................
`Animal Studies .............................................................................................................
`Safety of Omega3 fatty acids- EPA and DHA ..........................................................
`Astaxanthin ...................................................................................................................
`Trans-Fatty acids ..........................................................................................................
`Other Safety Considerations .......................................................................................
`Allergenicity and Other Related Concerns ................................................................
`COMMON KNOWLEDGE ELEMENT ...................................................................
`SUMMARY ..................................................................................................................
`CONCLUSION ............................................................................................................
`REFERENCES .............................................................................................................
`APPENDIX I ................................................................................................................
`APPENDIX I1 ...............................................................................................................
`APPENDIX I11 .............................................................................................................
`APPENDIX IV .............................................................................................................
`
`10
`10
`11
`11
`12
`12
`13
`13
`14
`15
`16
`17
`19
`21
`22
`22
`23
`24
`24
`24
`27
`28
`31
`33
`36
`38
`
`Krill oil GRAS Notification
`
`8 0 0 0 1 1
`Page 9 of 3 8
`RIMFROST EXHIBIT 1089 page 0010
`
`

`

`DETERMINATION OF THE GENERALLY RECOGNIZED AS SAFE ( G U S )
`STATUS OF KRILL OIL AS A NUTRIENT
`
`1. INTRODUCTION
`The undersigned, an independent panel of recognized experts (hereinafter referred to as
`the Expert Panel)2, qualified by their scientific training and relevant national and international
`experience to evaluate the safety of food and food ingredients, was convened by Soni &
`Associates Inc., at the request of Aker Biomarine Antarctic AS, Norway, to determine the
`Generally Recognized As Safe (GRAS) status of high phospholipid krill oil as a nutrient [21
`CFR 170.3(0)(20)]~ in non-alcoholic beverages; breakfast cereals; cheeses; frozen dairy desserts;
`milk whole and skim; processed fruit and fruit juices; and in medical foods at use levels ranging
`fiom 0.05 to 0.50 g/serving resulting in maximum estimated daily intake of 8.3 g/person/day. A
`comprehensive search of the scientific literature for safety and toxicity information on krill oil
`and omega-3 fatty acids was conducted through August 2010 and made available to the Expert
`Panel. The Expert Panel independently and critically evaluated materials submitted by Aker
`Biomarine Antarctic AS and other information deemed appropriate or necessary. Following an
`independent, critical evaluation, the Expert Panel conferred and unanimously agreed to the
`decision described herein.
`
`1.1. Background
`Krill is the common name given to the order Euphausiacea of shrimp-like marine
`crustaceans. The current taxonomic placement of E. superba is summarized in Table 4. These
`small invertebrates, also known as euphausiids, are found in oceans around the world. The name
`krill is a Norwegian word that means "young fry of fish", which is also often attributed to other
`species of fish. Krill is a vital component of the marine food chain for baleen whales, whale
`sharks, seals, and a few seabird species. In Japan and Russia, krill is also used for human
`consumption. Since the 19fh century or may be even earlier, krill has been harvested as a food
`source for humans (okiami) in Japan. Antarctic krill is closely related to shrimp and are
`consumed as human food in a similar way. Commercially, krill is used for aquaculture and
`aquarium feeds, as bait in sport fishing, or in the pharmaceutical industry. In the Southern Ocean
`one species, Euphausia superba is abundant. Commercial fishing of krill is done primarily in the
`Southern Ocean and in the waters around Japan. Approximately 40% of the Japanese Antarctic
`krill catch is processed for human consumption, and Antarctic krill has been sold as a food for
`human consumption since the mid- 1970s.
`In recent years, krill has received considerable attention because it is a rich source of
`high-quality protein, with the advantage over other animal proteins of being low in fat and rich in
`omega-3 fatty acids (Tou et al., 2007). Antioxidant levels in krill are higher than in fish,
`suggesting benefits against oxidative damage. Antarctic krill oil has been reported to contain
`high levels (30%) of EPA and DHA as well as astaxanthin esters in concentrations of 200 to 400
`ppm (Zhu et al., 2008; Kidd, 2007). Additionally, krill oil is also a rich source of phospholipids,
`vitamin A, and other nutrients (Ruben et al., 2003).
`
`0 0 0 0 1 2
`* See also attachments (curriculum vitae) documenting the expertise of the Panel members.
`"Nutrient supplements": Substances which are necessary for the body's nutritional and metabolic processes.
`
`Krill oil GRAS Notification
`
`Page 10 of 38
`RIMFROST EXHIBIT 1089 page 0011
`
`

`

`.Y x,
`
`1
`
`Table 4. Classification of Euphausia superba
`I Animalia
`Kingdom
`I Arthroaoda
`Phvlum
`Subphylum
`Crustcia
`Malacostrasa
`Class
`Eucarida
`Superorder
`Euphausiacea
`Order
`Euphausidae
`Family
`Euphausia
`Genus
`Euphausia superba
`Species
`
`1.2. Chemistry and Biological Activity
`The important constituents of krill oil, omega-3 fatty acids, also known as n-3
`polyunsaturated fatty acids (PUFA) belong to an essential fatty acid family characterized by their
`first double bond at carbon atom number 3 counted from the methyl or omega end of the carbon
`chain constituting the backbone of fatty acids. Omega-3 fatty acids are chemically and
`biologically distinct from omega-6 fatty acids, where the first double bond is at carbon atom
`number 6. There are two subgroups of omega3 fatty acids. One, a-linolenic acid (ALA), derived
`from plant oils such as canola oil, rapeseed oil and linseed oil, is composed of 18 carbon atoms
`with three double bonds (nomenclature; 18:3). The other group is derived from seafood, and the
`major marine omega-3 fatty acids are EPA (205) and DHA (22:6) (Figure 1). In humans, ALA
`can, to a limited extent, be elongated and desaturated to EPA and DHA. Otherwise, EPA and
`DHA are only acquired from seafood.
`In a recent review article, Calder (2006) discussed the biological role and mechanism of
`action of long-chain omega-3 fatty acids. It is well known that the omega-6 fatty acid,
`arachidonic acid, gives rise to the eicosanoid family of mediators (prostaglandins, thromboxanes,
`leukotrienes, and related metabolites). These mediators have inflammatory actions in their own
`right and also regulate the production of other mediators including inflammatory cytokines.
`Consumption of long chain omega-3 fatty acids decreases the amount of arachidonic acid in cell
`membranes and the availability for eicosanoid production. Additionally, these fatty acids also
`decrease the production of the classic inflammatory cytokines, such as tumor necrosis factor,
`interleukin- 1 and interleukin-6, and the expression of adhesion molecules involved in
`inflammatory interactions between leukocytes and endothelial cells. These latter effects may
`occur by eicosanoid-independent mechanisms including modulation of the activation of
`transcription factors involved in inflammatory processes. Because of their potential health
`benefits, omega-3 fatty acids have been commonly consumed and extensively studied for their
`physiological effects.
`1.3. Description, Manufacturing Process and Specifications
`SuperbaTM Krill Oil is a dark red colored viscous oil with a seafood odor. Typical food
`grade specification and composition of SuperbaTM Krill Oil produced by Aker Biomarine
`Antarctic AS are summarized in Tables 1,2, and 3. The primary constituents of SuperbaTM Krill
`Oil are triglycerides and phospholipids which are rich in EPA and DHA fatty acid. Detailed
`information about the identity of krill oil along with specifications, composition, and
`Section 11. Analytical results of five different batches
`manufacturing are described earlier in
`meets the specifications (Appendix I). The results of
`indicate that the product consistently
`0 0 0 0 1 3
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`Krill oil GRAS Notification
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`pesticide, PCBs and dioxins, and furans analyses are presented in Appendix 11. The trans-fatty
`acid profile from four batches of SuperbaTM Krill is presented in Appendix 111.
`In an extensive study, Winther et al. (2010) used high performance
`liquid
`chromatography-electrospray tandem mass spectrometry to elucidate the phospholipids in
`SuperbaTM Krill Oil extracted from Euphausia superba. The study was carried out in order to
`map the species of the choline-containing phospholipid classes: phosphatidylcholine and lyso-
`phosphatidylcholine. A total of 69 choline-containing phospholipids were detected, whereof 60
`phosphatidylcholine substances, among others seven with probable omega-3 fatty acids in both
`sn-1 and sn-2. The phosphatidylcholine concentration was estimated to be 34 f 5 g/100 g oil (n =
`5). The results of this study reveal the composition of phospholipids of SuperbaTM Krill Oil and
`the presence of long chained, heavily unsaturated fatty acids. This study also verifies previous
`findings and offer new insights into the composition of krill oil. In addition to EPA and DHA,
`the other major fatty acids present in krill oil are palmitic acid, myristic acid, oleic acid, and
`palmitoleic acid.
`1.4. Similarity with Fish oils
`The available information suggests a considerable similarity, particularly omega-3 fatty
`acids, between krill oil and fish oil from different fish sources. In response to a number of GRAS
`notices, the FDA has acknowledged the GRAS status of different forms of fish oil. As per 21
`CFR 184.1472, menhaden oil has been affirmed as GRAS. Additionally, the FDA has not
`questioned GRAS notifications submitted on tuna oil (FDA, 2002), salmon oil (FDA, 2004a),
`and anchovy oil (FDA, 2004b). In FDA’s review of tuna oil, the fatty acid content of tuna oil was
`compared to menhaden oil (FDA, 2002). The fatty acid composition of krill oil is compared with
`those of FDA’s comparison of tuna and menhaden oil in Table 5. Krill oil contains a high level
`of the desirable n-3 unsaturated fatty acids that is comparable to other oils.
`
`14:O
`16:O
`18:O
`16:l
`18:l
`22: 1
`18:2
`18:3
`205 (EPA)
`
`(FDA, 2002)
`
`20.3
`20.0
`6.0
`4.5
`15.0
`1 .o
`1.5
`1 .o
`6.0
`
`9.0
`19.0
`3 .O
`12.0
`13.0
`1 .o
`1 .o
`14.0
`
`7.7
`15.4
`0.9
`4.9
`12.1
`0.6
`1.2
`0.2
`14.7
`
`~~
`
`1.5. Technical effects
`SuperbaTM Krill Oil is intended for addition to a limited number of conventional foods as
`a nutritional ingredient. It is intended for use as a dietary ingredient as a source of omega-3 fatty
`acids, which are found in their phospholipid form. Supplementation with the omega-3-fatty acids
`EPA and DHA has been shown to have a wide variety of biological effects. The intended use is
`for the general population at levels ranging from 0.05 to 0.50 g/serving for addition to the
`ab00014
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`following food categories: non-alcoholic beverages; breakfast cereals; cheeses; frozen dairy
`desserts; milk products; processed fruit and fruit juices; and medical foods. It is recognized that
`there are Standard of Identity requirements for some of these foods, and as such, Aker Biomarine
`Antarctic AS does not intend to refer to them by the commonly recognized names such as milk,
`or yogurt.
`The use of SuperbaTM Krill Oil in foods may impart a color to food products. However,
`the intended use of SuperbaTM Krill Oil would fall outside the definition of “color additive”
`because: the intended use levels are low enough to impart a significant color to food products,
`consistent with the “non-apparent color” Exemption [21 CFR 70.3(f)]; the intended use of
`SuperbaTM 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 SuperbaTM
`Krill Oil is to provide consumers with an additional source of a nutrient in the diet and does not
`relate to any use of the ingredient as a color additive [21 CFR 70.3(f)].
`1.6. Current Uses
`Krill oil has been reportedly used in human food in Japan, Russia, Ukraine, and France
`since the 1970s. Based on information described in FDA dockets, in 2003 a New Dietary
`Ingredient Notification was submitted on the use of krill oil as a dietary supplement (FDA, 2003).
`The FDA filed the notice without any objections. The supplement is sold in 300 and 500 mg
`capsules with a recommended dose of 1 to 2 capsules/day. Krill oil has been available as a
`dietary supplement in North America for several years, European Union, Norway, and Taiwan.
`In the GRN 242 (FDA, 2008), it is stated that a total of 120,000 kg of krill oil has been
`consumed by customers as a dietary supplement without any reports of serious adverse effects.
`Based on information from FDA’s GRAS Notice Inventory4 website, in February 2008
`Neptune Technologies submitted a GRAS notification to the FDA on krill oil (FDA, 2008). The
`notice indicated that krill oil obtained from krill is intended to be added to a limited number of
`different food categories. The notice informed the FDA that krill oil is GRAS, through scientific
`procedures, for use as a food ingredient in non-alcoholic beverages, breakfast cereals, cheese