GR
`
`Illllilillllllilllll
`
`000001
`
`NEPN 2009
`
`NEPN 2009
`
`

`
`gvnm’ 8: Qszutiatezi Elm.
`
`749 46”‘ Square
`Vero Beach, FL 32968, USA
`Te1evhone=7v2-299-0746
`Facsimile: 772-299-5381
`E—mail: sonim@bellsouth.net
`
`December 14, 2010
`EEEHWE
`
`
`
`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 20740-3 835
`
`
`
`Subject: Notification of GRAS Determination for Krill Oil
`
`Dear Sir/Madam:
`
`DEC i520
`
`Division of
`
`I0
`
`fl
`
`Biotechnology and
`GRAS Notice Review
`
`
`
`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.
`9
`
`Superbam 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.
`
`Singer l I KW
`
`\
`
`kl
`
`Madhu G. Soni, Ph.D.
`
`Enclosures:
`
`www.soniassociates.net
`
`O 0 0 0 0 2
`
`NEPN 2009
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`NEPN 2009
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`
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`@0111’ 8: Qssnttatez film.
`
`749 46th Square
`Vero Beach, FL 32968, USA
`Te1ephone=772—299-0746
`Facsimile: 772-299-5381
`
`E—mai1: sonim@bellsouth.net
`
`GRAS NOTIFICATION
`
`1. Claim of GRAS Status
`
`A. Claim of Exemption from the Requirement for Premarket Approval Reduirements
`Pursuant to Proposed 21 CFR § 170.36(c)(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.
`
` Date
`
`ill \4\ \O
`
`Madhu G. Soni, Ph.D., FACN
`
`Agent for:
`
`Aker Biomarine Antarctic AS
`
`Fjordalleen 16, 0115 Oslo
`Norway
`
`wwwsoniassociaIes.net
`
`OOAOOO3
`
`NEPN 2009
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`NEPN 2009
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`

`
`B. Name and Address of Notifier:
`
`Hogne Vik, M.D., Ph.D.
`EVP Documentation
`Aker Biomarine Antarctic AS
`
`Fjordalleen 16, 0115 Oslo
`Norway
`Tel: +47 24 13 00 00
`Fax: +47 2413 01 10
`
`Email: hogne.vik@akerbiomarine.com
`
`C. 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 Superbam Krill Oil extracted from
`Antarctic krill, Euphausia superba. Superbam Krill Oil is rich in omega-3 fatty acids,
`most of which are attached to phospholipids. Superbam Krill Oil also contains
`astaxanthin ester.
`'
`
`D. Conditions of use:
`
`High phospholipid krill oil is intended for use as asubstitute or alternative to fish oils in
`the following food categories: 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 Superbam 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 Superbam Krill Oil will provide a maximum daily
`consumption of up to 2.20 g/person/day of eicosapentaenoic acid (EPA) and
`docosahexaenoic acid (DHA).
`
`E. 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 Superbam 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.
`
`Krill oil GRAS Notification
`
`000004
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`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 46”‘ Square,
`Vero Beach FL, 32968
`Phone: (772) 299-0746; E—mail: sonim@bellsouth.net
`
`II. Detailed Information About the Identity of the Notified Substance:
`
`A. Trade Name:
`
`_
`
`The subject of this notification will be marketed as Superbam Krill Oil
`
`B. Physical Characteristics
`
`Superbam Krill Oil is dark red colored viscous oil
`
`C. Chemical Abstract Registry Number:
`
`Not available
`
`b
`
`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.
`
`0)
`
`H
`
`1
`
`<1
`
`5
`
`8
`
`11
`
`14
`
`17
`
`6
`
`3
`
`1'
`
`20
`
`CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CI-ICH2CH=CH(CH2)3CO0H
`
`Eicosapentaenoic acid (EPA)
`
`
`1
`_
`4
`7
`1o
`13
`16
`19
`
`H
`
`CH3CH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)2COOH
`
`Docosahexaenoic acid (DHA)
`
`Figure 1. Chemical structures of EPA and DHA
`
`Krill oil GRAS Notification
`
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`F. Typical Composition and Specifications
`
`Typical compositional analysis and specifications of Superbam 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 Superbam Krill Oil are triglycerides and phospholipids high in omega—3 fatty acids
`suchas 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 Superba” Krill Oil will be 23.5 i 2 g/100 g of the oil.
`No processing aids or additives, with the exception of residual amounts of ethanol solvent,
`are included in the final Superba” 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 enviromnental 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 II.
`
`Table 1. T ical com ositional anal sis and s s ecifications of Sn erbam Krill Oil
`
`Assa method
`
`Dark red viscous oil
`
`
`
`
`
`
`
`
`
`
`Total hosholiids (g/100 g_)
`- Omega—3 phospholipids of
`total PL2% w/w)
`Tri cerides ; 100 ;
`Fat
`acid - rofile
`
`43 :l: 3
`>70
`/\ O5
`
`Total omega-3 (expressed as
`; 100 g)
`-C 20:5 n-3 (EPA)(expressed as
`
`23.5 3: 2
`
`14 2!: 2
`
`N A88 /AM—AKMB-012
`Calculation
`‘
`N A88 /AM-AKMB-012
`
`AOCS Ce lb-89/AM—ABM-013
`
`AOCS Ce lb-89/AM-ABM-013
`
`6.5 :i:l
`
`AOCS Ce lb«89/AM-ABM-013
`
` as :, 100 )
`
`
`
`
`
`<3.0
`A
`<2
`
`AOCS Ce lb-89/AM-ABM-013
`
`AOCS Cd 8b-90/AM-058
`
`20 minimum
`
`N A233/AM-ABM-Oll
`
`AOAC 978.18
`GC
`_
`
`<0.5
`<3.0
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Total omea-6
`Stabili
`index
`Peroxide value (mEq
`
`- roxide/k)
`Antioxidants
` 100
`Astaxanthin m ;
`
`Water and Ethanol
`Water activi
`at 25°C
`Ethanol content (% w/w)
`
`Microbiolo
`
`Salmonella negative (PCR) (1
`
`samle at 10 ;
`
`AES10/4-025/04
`
`Based on Homan and Anderson (1998) and Moreau (2006)
`2Omega-3 phospholipid: defined as phospholipid where on average one out of two possible
`positions is occupied by an omega-3 fatty acid.
`3Based on Schierle J. & l-lardi W. (1994); ‘Expressed as astaxanthin diols.
`
`
`
`
`
`
`
`
`Krill oil GRAS Notification
`
`000006
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`Page 4 of 38
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`».. ,m».-«-ma...
`
`mam -.4p.nw«~4.n ..»,-em...’ ..
`
`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 II). These results show that while the
`total arsenic levels in krill oil ranged from 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.
`
`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 lrans—fatty acids from four different batches revealed the
`presence of total trans-fatty acids of <0.2% (Appendix III).
`
`Table 2. Lipid profile, including phospholipids
`Percent Oil
`
`~ 2--.
`
`Triacylglycerol
`Diacylglycerol
`Monoacylglycerol
`Free fatty acids
`Cholesterol
`Cholesterol ester
`
`Phosphatidylethanolamine
`Phosphatidylinsotol
`Pho hatid lserine
`Phoshatid lcholine
`
`L sohoshatid lserine
`Total olar liids
`
`Table 3. Details of re - resentative fat
`
`acid a rofile
`
`Hm
`
`Total neutral li - ids
`
`
`000007
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`Page 5 of 38
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`
`
`+(n—5)
`
`n-7)
`
`'T +
`
`fl
`
`Acids
`Total Fa
`*Percent oftotal oil; Data from representative batch (A)—U30 l/006/A10
`
`Krill oil GRAS Notification
`
`
`
`.I
`
`i
`
`<0.1
`
`0.1
`
`C18:3n-3
`
`C18:4n-3
`
`<o.1
`
`
`
`NEPN 2009
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`

`
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`
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`
`H. Manufacturing process
`
`of
`from shrimp—like, marine crustaceans
`derived
`is
`Superbam 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 Superbam Krill Oil are naturally occurring
`organisms fished fiom 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 l. 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 2-8°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 Superbam
`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
`
`000008-
`
`Page 6 of 38
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`
`_,.,
`
`..
`
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`
`-
`
`1. Manufacturing of Superba““ Krill Oil Process Diagram
`
`Krill meal
`
`1. Raw material storage
`
`Ethanol
`
`2. Ethanol extraction
`
`3' Filtration
`
`Residual powder
`
`4. Concentration
`
`Ethanol
`
`5. Storage
`
`6. In-process analyses
`
`7. Blending
`
`8. Centrifugation
`
`Salts
`
`9. Final concentration
`
`0
`
`Ethanol
`
`10. End product analyses
`
`1 1. Packaging/shipping
`
`SuperbaTM Krill Oil
`
`Figure 2. Manufacturing process of Superbam Krill Oil
`
`Krill oil GRAS Notification
`
`000009
`
`Page 7 of 38
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`NEPN 2009
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`
`,
`
`., - .
`
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`
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`
`.. ,.-«am m »~-~—.~.-....,-«....-m--»«s—».t....»....»«.~e<4va-a.-~u»ux.«-»~e-an-~u~v-a.-~s:-»1 '« -
`
`J.
`
`Intended Technical Effects
`
`Superbam Krill Oil is intended for use as a nutrient supplement as defined in 21 CFR
`l70.3(o)(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 fruit 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 0.30-40.50 g/serving. It is intended to be used as a replacement for fish
`oil. The intended use of Superbam 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 Superbam Krill Oil in
`foods is not intended to function as a color additive as defined in 21 CFR 70.3(f).
`
`III. 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 fruit and fi'uit 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
`
`000010
`
`Page 8 of 38
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`.
`
`..v . ..
`
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`
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`
`IV.
`
`Basis for a Conclusion that SuperbaTM Krill Oil is GRAS for its Intended Use.
`
`TABLE OF CONTENT
`
`I.
`
`INTRODUCTION........................................................................................................ 10
`
`1.1.
`
`- 1.2.
`
`1.3.
`
`1.4.
`1.5.
`
`1.6.
`
`1.7.
`
`Background .................................................................................
`
`.............................. 10
`
`Chemistry and Biological Activity..........................................................
`
`................. 11
`
`Description, Manufacturing Process and Specifications .......................................... 11
`
`Similarity with Fish oils ........'....................................................................................... 12
`Technical effects ...............
`.......................................................................................... 12
`
`Current Uses ............................................................................................................... .. 13
`
`Intended Use Levels and Food Categories ............................................................... .. 13
`
`1.7.1.
`
`Estimated Daily Intake from the Intended Uses ......................
`
`...................
`
`........ 14
`
`2.
`
`2.1.
`
`2.2.
`
`2.3.
`
`2.4.
`
`2.5.
`
`2.6.
`
`2.7.
`
`2.8.
`
`3.
`
`4.
`
`5
`
`6
`
`7.
`
`8
`
`9.
`
`DATA PERTAINING TO SAFETY .......................................................................... 15
`
`Absorption and Metabolism........................................................................................ 16
`
`Human Studies .............
`
`..................................................................................
`
`........ 17
`
`Animal Studies ..................;.......................................................................................... 19
`
`Safety of Omega-3 fatty acids- EPA and DHA.......................................................... 21
`
`Astaxanthin ................................................................................................................... 22
`
`Trans—Fatty acids .......................................................................................................... 22
`
`Other Safety Considerations ....................................................................................... 23
`
`Allergenicity and Other Related Concerns................................................................ 24
`
`COMMON KNOWLEDGE ELEMENT................................................................... 24
`
`SUMMARY .................................................................................................................. 24
`
`CONCLUSION .............................. ..'............................................................................ 27
`
`REFERENCES ............................................................................................................. 28
`
`APPENDIX I ................................................................................................................ 31
`
`APPENDIX II ............................................................................................................... 33
`
`APPENDIX III ............................................................................................................. 36
`
`10.
`
`APPENDIX IV ............................................................................................................. 38
`
`Krill oil GRAS Notification
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`.
`
`..
`
`.
`
`.
`
`.
`
`.-..
`
`......~..-up ta 4--..4 wqm-pqo.;;1\«.I>6v$1r4a".-I0.mIH0v»:I~I>a¢,vug0'4d»\|!~2‘fPN...ap1Ifi4&YOJ$VPv/N».
`
`DETERMINATION OF THE GENERALLY RECOGNIZED AS SAFE (GRAS)
`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 l70.3(o)(20)]3 in non—alcoholic beverages; breakfast cereals; cheeses; frozen dairy desserts;
`milk whole and skim; processed fruit and fruit juices; and m medical foods at use levels ranging
`from 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
`
`is the common name given to the order Euphausiacea of sl1rimp—like marine
`Krill
`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 19”‘ 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).
`
`2 See also attachments (curriculum vitae) documenting the expertise of the Panel members.
`3 “Nutrient supplements": Substances which are necessary for the body's nutritional and metabolic processes.
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`Krill oil GRAS Notification
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`Table 4. Classification of Eu hausia su I erba
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`Species Euhausia sugerba
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`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 omega-3 fatty acids. One, on-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 A
`major marine omega-3 fatty acids are EPA (2025) and DHA (2226) (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
`
`Superbam Krill Oil is a dark red colored viscous oil with a seafood odor. Typical food
`grade specification and composition of Superbam Krill Oil produced by Aker Biomarine
`Antarctic AS are summarized in Tables 1, 2, and 3. The primary constituents of Superbam 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
`manufacturing are described earlier in Section II. Analytical results of five different batches
`indicate that the product consistently meets the specifications (Appendix I). The results of
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`Krill oil GRAS Notification
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`pesticide, PCBs and dioxins, and furans analyses are presented in Appendix II. The trans-fatty
`acid profile from four batches of Superbam Krill is presented in Appendix III.
`
`liquid
`(2010) used high performance
`In an extensive study, Winther et al.
`chromatography-electrospray tandem mass spectrometry to elucidate the phospholipids in
`Superbam 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 1yso-
`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 i 5 g/100 g oil (n =
`5). The results of this study reveal the composition of phospholipids of Superbam Krill Oil and
`the presence of long chained, heavily unsattnated 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.
`
`Table 5. Comparison of fatty acid profile of Superbam Krill Oil with
`tuna oil and menhaden oil"
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`14:0 T
`16:0
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`18:0 1111
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`*Values for tuna and menhaden oils adapted from FDA response to
`(FDA, 2002)
`
`109
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`1.5. Technical effects
`
`Superbam 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
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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 Superbam Krill Oil in foods may impart a color to food products. However,
`the intended use of Superbam 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
`Superbam 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 Superbam
`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 703(1)].
`
`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 Feb