Inspection Guides > GUIDE TO NUTRITTON LABELING AND EDUCATION ACT
`
`4 0f=-4
`
`
` .1: v"rJ;>..gov,’FD.4\goviIC:ECI,"Ensr:e-:rior:s_!Inspecticr:G::i¢1e::,"L1e:‘;2LxIt Mr‘-'2
`
`http :/',/V\«‘ww.f<ia.. gm’/TCECL/’T1:1spectie11s,/Ensp§:<:ti0nGuides/ucmT 1 4098 him
`
`3/ 1 6/20 1 2
`
`00000114
`
`

`
`U,S.S.N. 95./'00”? ,3774
`Declaration of D1‘. Fer:3id00n Shahidi
`
`A§§3€§E§§X C
`
`4:;
`
`
`Nsfticxs far Aksr Bigmarim Antarctic:
`
`AS, D€C1$EfE1b€1° M3 2010
`
`00000115
`
`00000115
`
`

`
`GR
`
`i§§§iEiE§§§3E§W§
`
`
`
`gamfi,wmmfimmfi
`
`fifififiéléi
`
`00000116
`
`00000116
`
`

`
`
`
`uiii Se fieeeiiuiee Eiiui
`
`749 46“? Square
`Vere Beach, FL 32968, USA
`7v2~2ii~«>74<i
`Facsiniilez 772-299-5381
`E—maii: sonim@beEIsuutii.net
`
`
`
`
`H W7
`V
`
`EEC 3 5 2%
`
`"”"7‘:I‘{§5£§é13;}Tgi
`Bsotechnoiugy am:
`GRAS Notice Review
`
`December 14,2010
`
`Officu 0:; Food Additive Safety (}~i'FS-255)
`Center fer Food Safety and Appiied Nutrition
`Food and Brag Administration
`5100 Paint. Brunch Pari~:way
`College Park, Pi/EB 207403835
`
`Subject: Neiifieiiiieu iii‘ {ERAS Betermiuetiuu fer Kriii GEE
`
`Dear ‘Sir./1\/iadaui:
`
`in ziccerdiinee wit}: pmpeseii 21 CFR £70.36 {Notice of a ciaim for exempiiun
`based en a GERLAS deteimiiiaiien) pubiished in Fecierai Register (62 FR 18938-18964;
`April ‘E7, 1997), I am submiuiiig in uipiieate,, as the agent of the notifier, Aker Biumarine
`Aiitarctic AS, Norway,
`:1 Geueraiiy Recognized As Safe QGRAS)
`Iiotificuiiuu for
`Superba® Krill Oi}.
`
`Seuperbafl“ iiriii 0i? extracted fmm Antarctic kriii, Euphmzsia superba is imteiided
`fur use as :i food ingredieiit in iiui1—ulc0hoiic beverages; breakfast cereals; cheeses; frozen
`siairy desserts; milk whale and skim; processed fruit and fruit juices; and medical fiiiiiis,
`at use levels ranging fmui (3.05 to (3.50 g pea‘ serving (reference amounts eustuiiiariiy
`ceiisuuieii, 21 CFR 301.12). The iiiieuiieci use of Superba® i‘:l‘iii {iii is estimated to
`result in a maxiiuum daiiy iniaiae of S928 g/peiseu.
`
`if yeu have any qi:.esi'iui:1s or require aiiditienai infermatieii, piease fee} free to
`euutacié; me by phone at 772—299~0746 or by emaii at seuim@beiisuuih.uet.
`
`Singn-en! v /
`
`
`
`Madiiu G. Soui, Phfi.
`
`Enciosuresz
`
`Y1’)!YzizfiQfiiéfi§i§§l£2§§§§_§.;§}Si
`
`5 Q Q g Q 2
`
`00000117
`
`00000117
`
`

`
`$333‘ gig mmiam Eiiii.
`
`749 46*“ Sqiiare
`Vero Beach, FL 32968; USA
`Wvhone:7v2~-2990746
`Facsimile: 772--299--5381
`
`E-—mzail: sonim@belisouih.net
`
`{ERAS NO'.E"fl¥‘E§CA'.E‘i€§N
`
`Chaim flf (ERAS Swims
`
`A. Ciaim «sf Eflxemptiim fmm flm Requirenimt fin‘ E’i*en'§a2'§<et Agigimvai Requireiiients
`Pursuant in PI‘0§9S§3(§ 3}. C.‘§.7R§ i7€~.36{a:}(§}
`
`Aker Bimnairine Antarctic AS, Noxway, has deite:i*min<~>d that high phesphcelipid kriii oi} is
`Generaiiy R6C<)g)“1iE:’.Ed As Safe, and therefore, exempt from the raquirement of premarkei’
`approvai, under the condiiions of its imended. use. This £§.€:tf3I’I1‘iiI1£§'ii{}I1
`is based on scicntific
`pI‘O(.5€d11t‘6S
`riescribed in the failowing sections, under the C0i’1difiOIl-S sf krill 0ifi’s intended
`use in fomi, ammig sxpsrts quziiiiied by sciemific training and expertise.
`
`
`
`Madhu G: Semi, Phil, FACN
`
`Agent for:
`
`Aker Biomarine Antarctic AS
`
`Fjarciaiiéen 16, 01 15 Oslo
`N03wa.y
`
`wxmw.s::>masss>ciaIes.ncE
`
`00000118
`
`iiiiiiififlfi
`
`00000118
`
`

`
`8.. Name and A€l8.‘l¥‘£§S ill" illlstllierz
`
`lleghe Vile, lVl.D., Phi).
`EEZVP lllocumentalieh
`
`Aker Biomarine Antarctic AS
`
`FjS1‘Cl.;':lllé€ll
`Norway
`
`lfi, 0115 (isle
`
`Tel: +47 24 l3 {)0 00
`Fax: +47 2-4 l3 (ll l0
`
`Email: hognes/illficijalqerbiomarine.eom
`
`C. Csmmeii er usual name ill the notifies substance:
`
`Tlie eonmimi name of the sulistalice of this netifieaiieii is high plitisplmlipid lerilll oil. Tlie
`specific substance ml” this GRAS 4.l€‘€€lll’ll.Fl‘c'lIlOll
`is Superbam Kri.ll Oil exttaeleal {mm
`Antarctic: liiill, Euphazisia .superba. Supetl:-al“ Krill Oil is rich in Gmc-:ga~3 fatty acids,
`most of which are altaellezl
`lo phospliolipicls. Stiperham Krill Oil alse contains
`astaxantliiii ester.
`
`ll. Cendiliims ill" use:
`
`High phosphelipicl krill ell is intehiiecl far use as a substitute 01' alternative ta fish ails in
`the lbllmving feed categories: mmnalcolmlie beverages; ibreaklast cereals; cheeses; iirozen
`e.la.ii"y desserts; milk whale and skim; pmcessecl limit and {mil juices; and meclical fO<3(.lS1,
`as‘. use levels ranging from 0.05 ‘lo 0.50 g per serving (ie;l’ei'enee amounts eustamarily
`consumed, 2l CPR llll.l2). The intended use of Superbam Krill Gil, in the aheve
`mentiimecl feed categuries,
`is estimated ta result in a maximum daily intake of 8.23
`g/person. Tile prepesecl use of Supeibam Krill. Oil will fpl”0Vli‘l<'3 a maximum «éslly
`€.‘3Ol"lSi.lIl‘lp‘ilOl’l
`sf up to 2.20 g/pel’s0n/'e.lay of eicosapehtaenclic acid (EPA) and
`ClOCGS§il’lf3X§:l€3IlQlC acid. (DHA).
`
`E. Basis fill’ GRAS Betermiiiatlma:
`
`In accordance with Lil CPR 'l?'0.3{l, high phospholipicl krill oil has been clelenninecl to be
`Genemlly Recegiiizeel As Safe (GrRAS} ‘based en scieiitific pmeetluies. A cemprellensive
`Search ef the scientific literature was also UlIlllZۤl
`far this determination. ".l7liere exists
`
`incluiiilig human and animal
`sulliciezlt qualitative and quantitative selentilie f3V’l€.l§3Il€3€,
`data to Cli°:l'f3l“ll’llI‘l§‘3 safety~iii~use for Sup€l“l”l&lTM Krill Oil. Recently, high phosphelipld krill
`oil {GRN 000242) has been the subject of 3 {ERAS notitleatiehi while two all its
`impnrtaiit cmnpenent fatty acids, E’l7“A and Dlli-lA as part of fish or algal ail, have been the
`suhjecl of multiple GRAS llollllcalitms.
`in response to these notices, FDA did net
`questitm the C€)l1ClllS'l0l’lS that the use fif high phospholipicl krill oil or sources of fatty
`acids {EPA and BEA) is GRAS tmclei" the conditions described in the 1'lQllC€S. The safety
`
`is
`‘ Under Section 5(3)) of the Orphan Drug Act (Ol)A), a Medical Food is claimed as a food that
`fomiulsted to be consumed or administered euterally under the supervision of a physician and that is
`intended far the specific: dietary management of a disease or comlillon for which allstlnctlve nutritional
`requirements, based are recognized scieiitillc principles, are established by medical evsluatioil. The
`intended use of lqill oil in medical foods will be as per these anti other 3.pplles,hl(: regulations.
`
`Krill oil GRAS Ncilifieatien
`
`000001 19
`
`llilfillll/l
`
`Page 2 of 38
`
`00000119
`
`

`
`dertermination Qflligh phospllollpid krill all is based an {ha mlalily of available scirzntific
`evidence tlml:
`includes lmman Qbservations and a variety of preclinical and clinical
`stiidles. Based. on the available s.al7cty—related llifflmlatlflll, Ella esstianatecl daily intake? if
`ingesled daily over a lifetime, is safe.
`
`F. Availability‘ 0f lnlbrmatlonz
`
`The data and lnlbmnatian that farms the basis for this €3:RA.S gletarminaiion will be
`
`pmvided ‘:0 the Food and limlg .Ad;mlnisl;ml.i0n upon l”f3(.}i.3.r3Sl. and are lacated at the ofllcas
`of:
`
`Madhu G. Semi, Pl1.D., FACN,
`Sam’ &; Associates lzm,
`74:9 46:3‘ Square,
`Vaam Beach FL, 32963
`Phone: (1772) 299~0746; Email: sonim@.bellsouth.n.et
`
`ll. lfielallafi linlbrmallazn Alwmt film ltlemity ef the Nallfiecl Sulusstmme:
`
`A. Trades Name:
`
`The subjezct 0f this ncfliillcatlon will be 3.’i‘la;l'l{€3’E€Cl as Sup:=:rba,TM Krill Gil
`
`B. Physical Chsimetterlsllcs
`
`Sl1p€§I‘l3'c1TM Krill Oil is alarli red calmed viscsms all
`
`C. Clwmlml Abslraetl Rgaglstry Number:
`
`Noll agvallafible
`
`ll. Cllemical Fmmula:
`
`Not. a;ppl.ical_>le
`
`E. Slramliurez
`
`ll}:-3 important wns‘a;i.tuam's of high plmsplmlipld krill oil are: the fully anicls, EPA and
`DHA. Tllfii slructurezrs of ‘Elissa twa fatty acids presemsecl in Figure l.
`
`
`
`
`
` “ 1 8 ‘ g H 14
`
`
`CH3CH;3CH=CHCl-lgCll_==CllCll;Cl€l$Cl€lCCllgCll==CHCH2Cl§==€H(Clil3)3C(}{}H
`
`Eimsapentameie acid (EPA)
`
` 1
`
`ll
`
`4
`
`0
`
`l
`
`0
`
`13
`
`0
`
`‘S6
`
`0‘
`
`0
`
`CH3CH;;CllmCllCll;Cll==ClFlCl-l2CllfmCllCllgflllflCllCH2CHmCHCllg,Cll==Cll(Cl{E;)2C0OH
`
`liamsalaemenois: acid (BEA)
`
`Figsxre l. Chemical struciuzrsas 01:‘ EPA and DHA
`
`Krill oil (ERAS Nctificatiem
`
`00000120
`
`llllfillllfi
`
`Page 3 0138
`
`00000120
`
`

`
`F, Tyeieai Cempesitiee amt Speeitieatirrrts
`
`Typieai eempesitienai analysis and specifications ef Superba'“"‘ Krill Oil are presented in
`Table 1.
`.Anaiytiea1 results of five tots from nor}-eortseeutive batches (Appendix 1)
`indicate that the produett consistently meets these specifieatirms. The tneier components
`(sf SuperbaTM Krill} Gil are trigiycerides amt phos.p‘ne}.ipids high in err1ega,~3 fatty acids
`such as EPA ((3. 20:5 11-3 fatty aeid) and DHA (C 22:6 r1~3 fatty acid). The maximum
`ameurtt ef ESEJA DEA present in Super'ba"'M Krill Git. wiii be 23.5 i 2 g/100 g of the oil.
`Ne preeessing aids or additives»‘., ‘with. the exception 01’ residual amounts at‘ ethanei solvent,
`are ineiud.ed in the firral Srzperbam Krill Oi} product. ’t,i1<ewise due tr"; natmejiy eeeurring
`astaxanthin esters that aid in its preservatierr, adriitien of an exogenous arrtiexitiant is net
`required; Based on an 18 month s‘tabiEi'ty test at different storage temperatures, the sheif
`Eite of Superrra Krifl Oil
`is set te 38 months when stored at 2~3°C. The results ef
`pesticides and other envimrrmentai eentaminants ineiudirrg PCEC-Es, diexiras, furans and
`tiiexin like PC3353 organeehierirre pesticides, PBDES, ?AHs., and eiements and heavy
`metal anaiyses from multiple batches of the product are presented in Apperrriix It.
`
`Tame 1., T ieet mm usitiemsi anaivsis and as eeifieatien§_s;=i° Sugerbasm‘ Kriii Oi}
`
`
`._B§_¥‘_’§‘_‘§tE?§_‘;mm_.-.-.
`“W33
`5 Assafnlfiflfld
`
`....................................................,.........
`..............................._.._._.,...........
`._.....__.................._._.____................._._.._..................
`3 A earance
`
`..:e:a3_rz_t2srr:>3:rr:§<s«'1é<>
`= ~ Omega-3 phosptroiiigaids of
`
`.............. _..........
`
`.........._......_.......................................................
`
`
`‘K ;K »
`
`Calculation
`._....._...............;
`.........................................................................
`."AM—AKMB -0 12
`
`AOCS Ce 1b»S9/AM»ABE‘v’i-(3 1 3
`
`
`
`
`AOCS Ce 1b~89/'AM~ABM~013
`g
`:“é"é€i:'§ rr»3 (E?A)(ex;3ressecI as
`;..ei.t9;(P. >
`________________________________________= ____________________________________________________________________________________________
`g —c 22:5 n—3 (r>r»r«tj;(expressed.
`AOCS Ce 1'tt—89/A1\/l—AB1\«t-O13
`5.5 zti
`..........mm.“............-
`...............................mm...........0.
`<3.0
`AOCS Ce 1b—89/AM-ABM-O13
`"fetal omegaré
`Stab_i_§ttr_tt:§t§_______________________________________________________________________mm._______mm__________.
`g Peroxide vaiue (mEq
`A0<::::'«3 Cd Sb-913/AM~{¥58
`
`neroxide/kg}
`_.
`§,._£§.t"_‘_3§_i:‘_‘*_‘_xmmm.‘3‘i“‘*§,mm.‘~“_
`Lfi$§§§§E§Et§tt:_§1l3§§;<.%}__________
`5 Water maxi Etisarmfi
`_
`§:___Y€§_\§§_l_‘ activity at 25°C
`.........
`Lfithanoi content (“/23 w/w)
`
`§I;9¥§.§l*i§t§__E§:Ett¥_iE;f§1/e)
`______
`5<25ft<?
`wit <1 samrje as it e________M_________________0,____________________.
`§___§_§_3j_t_"g_1_'§; bacteria, 37°C (cfu/g)
`§ <10
`N<>rdVai Refi No. 014
`Salmcanellcz negative (reg) (1
`Negative
`ABS m/4-925/04
`J
`L§§£‘_E‘taa.t.tQ. .
`Mold and Yeast (efuzfgg________
`___________________________________§__§{g§§‘y:2_g_§_ef:_}:e.mtL1_§_____
`___
`Based on Herman and Anderson (1998) and Moreen: (2006)
`?‘Omega»3 phosphoiipiciz defined as phospheiipid where on average one out of twe possible
`positions is occupied by an 0mega~3 fatty acid.
`3Based. on Sehierie J. & Hétrdi W. (1994); 4E.-xpressed as estaxanthén diets,
`
`
`
`_
`
`mm
`
`,
`.£.}_t13_0 =* 20 tei.!2i;m>N:.mmmA?>3/’AM*Ammm_B1‘«W1____ mm...
`
`______»_
`»__
`________w_m__m_______
`__
`
`E <<>.5 AOAC 978.18
`.........,..
`.5.
`.........
`..........
`
`
`
`Kriii oi} GRAS Notification
`
`00000121
`
`980908
`
`Fage 4 0:638
`
`00000121
`
`

`
`As avaiiabie research highiights the petentiai for seafood ‘:0 cemtain substan’:ia.i amounts
`ef arsenic, an extensive chemical amalysis of bath organic and inorganic arsenic was
`undertaken fmm multiple batches (see Appendix II). These results shew that whiie the
`totai arsenic levels in kriii nil ranged fmm. 4 to 6 ppm? the vast inajerity as? this arsenic
`was in organic farm. The inerggmie arsenic as measured in the farm sf arsenite and
`arsenaie was beiow the Eevei of qiaantifieatien at 0.05 ppm.
`
`1. Lipid am} Fatty Add Pmfiie:
`
`The lipici profiie composition and fatty acid profiie of kriii oii is presented in Table 2 and
`3, respectively. Anahysis of zmns—faE.ty acids from fem‘ differem beeches revealed the
`presence of total rrar2s«—fatty acids of <{).I2% (Appendix H1).
`
`’E'zsE:9Be 2. Lipid pmfiie, inciusiing ghasgziaoiipiais
`Egmercent Oil
`Limes
`Txiacylgiycezfol
`3 Diseylgiycerei
`Monoacyiglyceroi
`Free fatty acids
`
` ‘ Cheiestemi
`
`.
`
`n_______________________»
`Cholesterol ester
`Phosphatidyiethanoiangiaxei‘EV
`Pimsphatidyiinsami
`W‘
`93
`Phoshatidxgsgqjge______________________v
`__________
`Phos hatidvicholine
`_________W 3.,’/'
`L soheshatid rlsgrjge__________________
`Total
`§_>__1_§;‘__§_ig_i____________________________MW;
`44 . ".7
`333??‘1“3U;;.E.F..%.*.1.Eieids
`,
`:’:§_-_§____________..
`
`_____________A
`
`‘
`______________>_
`
`__:lf§}_;§e_§3_§§e_§a_§§§_9f re resemative fat: acid mfiie __________________________
`Fercem*
`
`5 C1$:1(n~9)5+(n-7}
`§_...
`:f_<_i!:§}
`:
`
`
`
`«
`mW._"i"<3¢=i=%_E?_a_;§¥;2i_—_e£Ms
`.
`_
`.
`“‘Percent of tetsi oi}; Data frmzra represemative batch {A)—’U‘301/’006."Al(}
`
`Krill oil GK/XS Notification
`
`00000122
`
`3 8 3 {E {B ‘E’
`
`Rage 5 of 33
`
`00000122
`
`

`
`\/ .. 1.: ...,
`
`44):)»n>\\>~#V4<“4(‘».-)1/\5\r/«*1?)/37V|§/&\’>»Y U, '9,’-JK ..~.:o/~-»~n., ».,.;c1,~.v.~.~ <6\gw.«nm>r~~‘m«*r'£:4«1\““#"*"\w&$4v<*1’«)4?
`
`V ~
`
`H. Manufacturing giroeess
`
`of
`from stiriinolilte, marine crustaceans
`derived
`is
`Superliam Kicill Oil
`the order Euphausiacea, Eupizaussia superba.
`lltese organisms have a eireutnpclar
`distribution with the highest concentrations found in the Atlantic sector. Antarctic krill
`exist in large nuntbers in the open sea and are consented as food by littmzitis. The
`Antarctic krill used in the production of Superl;ia.TM Kriil Gil are tiétturaliy ocenning
`organisms fished from the wild. "Elie ltarvested Antarctic krili is cooked and dried on the
`vessel to prepare krill meal. The steps involved in the manufacturing are sunimarized in
`Figure l. The raw material that is extracted, kriil meal, is 82. biomass composed of lipids,
`cariioltydrstes, and proteins. By using a solvent extraction process, the proteins and free
`CE12‘l)()l.’i}’ti2'fiii€S are removed. Thus the oil is produced by subjecting the krill meal to
`ethanol extraction. The solvent used is food~grsde quality and is removed from the
`product in accordance with current good rnannfeeturing practice.
`
`Following extraction, the defetted krill meai and the ethanol oii solution are separated.
`lite etiia.nol.~oii solution is then concentrated by evaporation and stored. The ethsnol—oii
`solution is siialyzetl. for ethanol, neuttei and. polar lipids, and astsxentliin content. Several
`batches are blended and the etltanoloil solution is clarified by centtiiitgaticn. The etlisnoi
`is tlieri evaporated from the oil solution and the fins} product is analyzed to Verify the
`conformity witlr product specifications. llie final product is tilled into suitable containers
`and stored at 2-8°C and can be sliipped ‘by tend, air, or boat. Prcicessing aids. including
`solvents (wliieit is removed by e’w's1‘§ioration} used in the manut‘a<:.tt1ring process are tood—
`grade quality as specified in the 5 ‘ Edition of Food Chemicals Codex. The St!_p€l‘bf:tTM
`Krill Oil production process is controlled under the Hazard Analysis Critical Control
`Points (HACCP) system and eoints for likely contsinirtation of the oil are strictly
`monitored. Additionaliy, the qiiaiity of the final product and production lots are routinely
`tested for specifications ineludirtg solvent residue? nrieroorgenisms, heavy metals, and
`pesticides.
`
`Krill oil GRAS Notification
`
`00 0001 23
`
`tiiiiltlfld
`
`Pttge 6 of 38
`
`00000123
`
`

`
`,
`
`/.,..‘» 3\4!k_A\’l\fl—‘)5l|7 T «Wu,
`
`..«:.ms;>~\‘k‘~vw:’~w4>~.«
`
`~
`
`Ra-:si<i’uaE pcewdcr
`
`Eihanni
`
`L Manufaemring «sf Su§m:°haTM Kriii 0&3 Pmcess Eiagram
`
`Kriii meai
`
`.E5
`
`1. Raw matarial smrage
`.a......
`
`
`
`Ethanol
`
`2. Etilanoi extraction
`..........................—......a
`
`
`
`
`I 3. Fiitratien
`
`4. Concsnimtion
`
`Salts
`
`9. Fina} c:Gncentmtio11
`
`5
`
`Eithanci
`
`E»
`
`""""""'""”"“““"g
`_
`a
`3 19. End prmiucr: analyses
`*
`
`
`
`
`1 1. P21ckaging:"shipping
`
`Super&a'§’M Kriii 3:”!
`
`Figure 2. Msmufactaxring process sf Supesrbssm Km} 0&3
`
`will 0&1 GRAS ‘Nmification
`
`Fags
`
`O O O O O 1 24
`
`00000124
`
`

`
`-«s»-<s>zg«-§~‘~<*1\,v.~rr+l;2*;-.«<'hm~»-aw<-><=--‘ meam ' x
`
`-
`
`.l.
`
`intended Technical Etieets
`
`Surierham Krill Oil is intended. for use as a nutrient. supplement. as defined in Zl CFR
`l7tl.3(o)(20). it is iiitended for use by the general population at levels ranging from 0.05
`to 0.50 g/serving for addition to the following feed categories: non-alcoholic beverages;
`breakfast cereals; cheeses; frozen dairy desserts; rnilk products; processed fruit and fruit
`juices; and in rneclieal.
`foods.
`it
`is recogniszed that
`there are Standard ct‘ ldentity
`requirements for some of these foods,
`located in Title 2i ot‘ the Code of Federal
`Regula‘tioiris, if used in such foods, the name will he changed so as not to he contiised
`with the standardized food. Available information indicates that use levels are selfs
`
`limiting hecanse of their strong taste that can be detected, depending on food type, at
`levels greater than 0,30-0.50 g/serving‘, lt is intended to he used as a replacement for tish
`oil. The intended use of Superham Krill Gil is in the
`foods and at the same levels of
`addition as those described in GRN 242 ‘for ltrill oil. The use of Sriperham Krill {iii in
`foods is not intended to l’nn.c‘tion as a color additive as defined in 2i CPR ’70.3(t).
`
`ill. Summary of the liasis for the Notit"ier”s lleterniination that Krill Oil is GRAS
`
`An indepen.dent panel of recognizzed experts, qualitled by their scientific training and
`relevant national and internatiomil experience to evaluate the safety of food and food
`ingredients, was requested by Alter Biornarine Antarctic AS to determine the Generally
`Recognized As Safe (GRAS) status of high plinsphciipid krill oil. A comprehensive
`search of the scientific databases for safety and toxicity i_rtt7orrnatiori on krill oil and its
`component oinega—3 fatty acids (Iii-IPA and l)l?lA} was conducted through August 2010
`and was utilized for this assessment. Based on a. critical evaluation of the pertinent data
`and inforrnation summarized here and employing scientific procedures, the Expert Panel
`members have individually and collectively determined hy scientific procedures that the
`addition of high niiospholipid. lnill oil to the foods {rion«alcoliolic beverages; breairlast
`cereals; cheeses; frozen dairy desserts; rnillc; processed fruit and fruit juices) containing
`no other ingredients that are good sources of EPA or l)l§lA, when not otherwise precluded
`hy a Standard of identity, and to Medical Foods, meeting the stiecilication cited above
`and manufactured in according. with current Good M'an1iiacturing Practice, is Generally
`Recogrnzeii As Safe (Gl?’;AS} under the conditions of intended nseg as specified herein.
`
`in coining to this decision that lrrill oil is GRAS, the Expert Panelists relied upon the
`conclusions that neither high pliosphoiipid krill oil nor any of its eonstitu.erits pose any
`tozticological haz.ard.s or safety concerns at
`the intended use levels, as well as on
`published toxicology studies and other articles relating to the safety of the prodnest. it is
`also the opinion of the Expert Panelists that other qualified and competent scientists,
`reviewing the same publicly available toxicological and safety intbrmation, would reach
`the same conclusion.
`
`Krill oil GRAS Notification
`
`00000125
`
`Page 8 ei‘38
`
`00000125
`
`

`
`~« .
`
`0.
`
`.
`
`V (J
`
`¢
`
`.,
`
`.\
`
`.»,
`
`-'!.\)‘y“:U.w«:1r-¢.L«<».a;;»>«v» ,¢», 1..
`
`,»..
`
`I’r:.\¢1*"V,V‘\‘,‘n~’\\.«I'|s»IA_1.mN‘§‘-
`
`,.n»;§m>»;qem»a-«ex~»w,~<-awrswe«m»»«:
`
`EV.
`
`Basis Em" 21 C§_5flcs‘.§.uS§{§§3. ma: S:.aper§aa“m Kriii 03E is GRAS Em‘ Em intended Hsge.
`
`TABLE OF CGNTENT
`
`Backgmund
`
`Chemistry and Biaieagicai
`
`ii}
`
`11
`
`B§ss.:ri§fi.~:m, Manufacturing Frmresfi and S§ms:i‘§ie:a§§9Ii§...........,............................... 11
`
`LE.
`
`1.2.
`
`L3.
`
`1.4.
`
`1.5.
`
`1.6.
`
`1.7.
`
`Simifiarity wfith Fish
`
`T&3€£’§fil§§&23§
`
`1
`Currant 1.
`
`a
`
`iimemied Use Lewis and Fwd
`
`1.7.1.
`
`Estimated Baiiy intaim fmm the imemdeai ‘Uses
`
`2-.
`
`DATA PERTAENENG T0 SAFIETY
`
`12
`
`‘£2
`
`13
`
`13
`
`14
`
`15
`
`E6
`
`17
`
`E9
`
`21
`0
`
`22
`
`2.1‘
`
`2.2.
`’
`
`.
`23
`
`.
`
`‘*4
`.0.
`
`.
`
`2.5.
`
`2.6.
`
`2.7.
`
`2.8.
`
`3.
`
`3..
`°°
`
`Q
`
`..
`
`Abserptian and
`.
`Human.
`ax163$
`5
`§t ii
`h‘
`tu1&5
`d’
`
`X mama
`K '
`
`ES
`
`SE’
`£9
`or %fttv “d E A: dm-EA
`we a mega-.. 3 M an s- R. an
`.
`.
`.
`
`“ii
`F
`T
`ram* atty am22
`
`Qikesr Safety
`
`Afiiergenifiity and Qiher Rssiated
`n
`'
`‘E EE_.EW§ENT
`0
`0
`0 W
`A
`.0FVER’K§l“‘>3 K; {BWEEBG
`-
`
`i
`
`_,
`L
`-
`KEVCLETSEGN
`
`.....um.........M..5ma....9.M.......4..no.NeH......9.....-....7...M...9........9..H.........u.......m.......
`
`'
`.4.‘
`M .
`_.i
`R? FFRF VCES
`
`orcha-canowasannounce3oea2omacatowaeoaaascses-Q:9!on9sauna:-a9anonovemlwavso5weatwaeokaaoanItaswtoawowvomzoaooeoawtoacao
`
`.
`A?FEND§X H
`
`.......................................9...9......mm....................m...............................m.......
`
`95? N X HE
`
`23
`
`24
`
`24
`
`27
`
`23
`
`..
`33
`
`'
`
`.
`
`.
`A3’P‘ENE}EX H?
`
`«ureaatseaarotognawaanmyagoes9macawnoaeaem!9nossrsaqovaosu-van.-ooeasrnawaoaosroe95owe0moanvurtwaoa-ozone-or-navaotsono .
`3
`
`Kriii oi} GRAS Natification
`
`00000126
`
`{H§{}€}i1
`
`Fage 9 of 38
`
`00000126
`
`

`
`
`
`§E'i‘ERh’iihiA'l‘l0l“«l QF THE G~ENERALL‘i’ RE-CQGNEZEEF AS SAFE {GRAS}
`STATUS Oi?‘ KRELL {BEL AS A NUTREENT
`
`l. ENTRGDECTEQN
`
`The tntdersigned, an independent panel of recognized experts (hereinafter referred to as
`the Expert l’anel)2;. qualified by their scientific training and relevant national and international
`experience to evaluate the safety of food and food ingredients, was convened hy Soni &
`Associates inn, at the request of Alter Biornarine Antarctic AS, Norway, to deterrnine the
`Generally Recognized As Safe (GRASE status of high phosphoiipid krill oil as a nutrient {2l
`CPR l7{3°3(o){2t))}3 in nonalcoholic lieverages; breakfast cereals; cheeses; frozen dairy desserts;
`mills Whole and sltim; processed fruit and fruit juices; and in rnedicai foods at use levels ranging
`frotn £3.05 to £3.50 g./sei'ving resulting in rnaxirntim estimated daily intake of 8.3 g/person/d.a.y. A
`comprehensive search of the scientific li.teratnre for safety and toxicity information on krill oil
`and ornega~3 fatty acids was conducted through August 2010 and made available to the Expert
`Panel. The Expert Panel independently and critically evaltiated materials stihrriitted hy Alter
`iiiornarine Antarctic AS and other information deemed appropriate or necessary. Following an
`independent, critical evaluation,
`the lilxpert Panel conferred and nna.n;irnot1sly agreed to the
`decision described. herein.
`
`i .1. Baeitgroiind
`
`is the eoninion name given to the order Eupliansiacea of shriinpmlike marine
`liiirill
`crustaceans. The current taxonomic placement of E. superba is summarized in Table 4. These
`small invertebrates, also known as euphausiids, are fotnid in oceans around the world. The name
`krill is a Norwegian word that means "young try of fish", which is also oiten attributed to other
`species of fish. ilshill.
`a vital oornporient of the marine food chain tor haleen whaiesg whale
`sharks, seals, and a few seabird species. in Japan and Russia, krill is also used for human
`consnrnption. Since the i933 century or may he even earlier: krill has heen harvested as a food
`source for hitinans (oiriami) in Japan. Antarctic krill
`is closely related to shrimp and are
`eonsutned as human food in a similar way. Cornrnercially, krill. is used for aqttacttltnre and
`aqéitariniti feeds, as bait in sport iishiiig, or in the pharrnaceutleal industry. in the Southern Ocean
`one species, Eupitazrsia supezha is abundant. Commercial fishing of krill is done priinarily in the
`Southern Qcean and in the waters around. Japan. Approximately 4(}‘3’o of the Japanese Antarctic
`krill catch is processed for ht1rn.an consnrnption, and Antarctic i{l’ll.l has heen sold as a food for
`human consumption since the inid~l 973s.
`
`in recent years, ltrill has received considerable attention hecanse it is a rich source of
`highqnality protein, with the advantage over other animal proteins ofheing low in fat and rich in
`ornega~3 fatty‘ acids (Ton er a!._, 2007). Antioxidant levels in krill are higher than in fish,
`suggesting henefits against oxidative damage. Antarctic krill oil has heeri reported to contain
`high levels (30%) of EPA and DHA as well as astaaanthin esters in concentrations offztltl to 490
`ppm (Zhu et mi, 22008; Kidd, 2007). Additionally, krill oil is also a rich source of phospholipids,
`vitarnin A3 and other nutrients (Ruben 83i1si., 7.2003).
`
`«----«—-———~——m-~
`2 See also attachments (curriculum vitae) documenting the expertise of the Panel mesnlaers.
`"‘ “Nutrient supplcrnents”: Substances which are necessary for the body's nutritional and metabolic processes.
`
`ii%Glii2
`
`Krill oil GRAS Notification
`
`00 0001 27
`
`Page ll} of 38
`
`00000127
`
`

`
`is-.v< ;'rR}L\Nf‘ib/“s"4A1,:‘»iA/‘.""-.
`
`(Xvi ¢.=r.»,«ry«;«~\»;.«-'v>»:«:,~>v;-ew:.~»\., em.» mw~;u'w¢~‘?tru&br#¢:v»\>v§:r;‘zi54vHO~3~eA‘\1V2»Wr‘£\*+‘ V/‘,4 ,
`
`Tahiti 4. Classification of Eu imesis sugerlzre
`l
`
`* Kixisdom
`,e_ttim_"s}it=_mmWmm_W_.mmm____
`
`
`
`
`Order
`
`:
`
`Ezicarida.
`
`Eu haausisiceat
`E
`
`
`
`iEu»t=.»s_tsis_m............mm......,_m_i_
`i____________Wm_______~_‘:‘:t=.:¢cies Eezlswsiawserta
`
`1.2. Chemistry’ end Bielogicsi Activity
`
`The iniportsnt constituents of hill oil, emega~3 fatty‘ acids, also known as ii—3
`polyunsatmated fatty acids (PUFA) belong ‘((3 an essential fatty acid family clisracterizecl by their
`‘first dcuble bond at cerlmii stem number 3 counted fiem the iiietliyl or emege earl of tlie Cai‘l3t')i’l
`chain cetistitutiiig the i}£t(3.l{i’3OI.‘le of fatty acids. Omega-3 fatty acids are t‘:l‘l€3li73.lCali‘_§/’
`and
`biologically distinct fteni emegemé fatty’ acids, where the first cieuble bond is at csilioii atom
`number 6. There are two subgroups ot‘omega~3 fatty acids. One, f)'.~liIl0lt.3IllC acid (ALA), derived
`frem plant oils such as canola oil, rapeseed oil said linseed oil, is composed of i8 cerboii stems
`with three deuible ltsoiids (iiomenclstute; 13:3). The ether group is derived from seafood, and tlie
`major marine omega—3 fatty acids are EFA (2025) and DHA (2216) (i'*‘igu.i‘e l). in humans, ALA
`can, to s limited extent, lie elongated and dessttiiated te EPA and DHA. Otlieiwise, EPA and
`DHA are only acquired from seafood.
`
`iii 3, recent review Etfliti-it), Calder (2005:) discussed the biological role and ineclienism of
`seticii cf lo1ig—clte.in omega-=3 fatty acids.
`it
`is well known that
`the emegs-6 fatty acid,
`srsciiidoeic acid, gives rise to the eieesanoid fsiiiily eteiediaters (prestaglsiidiiis, ttiromboxsnes,
`leukotiieiies, and related metabolites). "l‘liese mediators liave iriiistmtistory éictieiis in their own
`iiglit and also regulate the production ei" other medieters iiicludirig intlsmmatery cytelciiies.
`Consumptien of long chain omega-=3 fatty acids decreases the amount of sracliidoiiie acid in cell
`inembranes and the availability for eieeseeoid preduetion. Additionally, these fatty acids also
`decrease the prodtietion of tlie classic ititlsniiiiatcty eytolcines, such as tumor necrosis teeter,
`ii1i'€3I'l€:tll{i3‘.1-l.
`arid iil.i£:3flt3i1i(iil-6, and the expression of sdiiesion meiecules iiiveived in
`iiiilaziiiiiietety interactions between leiilcecytes and eridotlielial cells. Tliese letter effects may
`eecur by eicosstioid~iiidepemient meclieiiisms including iiioitulstieii cf the sctivatieii of
`trsiiseriptieii factors involved in ie.l'l2immstei"y processes, Because of their peteiitisl health
`benefits, omega—3 fatty acids have been commonly eetisuitied and extensively’ studied for their
`physiological effects.
`
`L3. iiesetiptien, ltiseiiisctttrieg Pteeess amt Speeii’iestiees
`
`Superl'ie,TM Kflil Oil is a cleric; red coleied viscous eii Willi ti sesteed odor. Typical food
`grs;.l.e speciiicstioii and composition cf Superbam Krill Oil produced by Aker liiomeritie
`Aiitaietic A3 are summarized iii Tables it 2, and 3. Tlie primary constituents ei‘ Stipetbsm Krill
`Oil are triglycerides and plicsspiiolipids wliicli are iicli in EPA anal DHA fatty acid. Detailed
`intieitnstien altseut
`the ideiitity ei‘ krill oil along with specifications, composition, and
`manufacturing are described earlier in Section ll. Analytical results of five different batches
`indicate that the plf‘0f.l?.lC'l.' eetisisteiitly meets the speeificstioiis {Appendix l). The results ei’
`
`Krill :3-ii GRASS Notification
`
`00000128
`
`llfiilslii
`
`Page ii of 38
`
`00000128
`
`

`
`eestieide, PCBS and dioxins, and fumes analyses are presented in Appendix H. The trtms~fatty
`acid profile frettt fem‘ batches of Supe1‘baTM Krilt is presented in Appendix Iii.
`
`(ittiiti) used high perietntenee Ziquid
`at’.
`ea‘
`in an extensive study, Wintiter
`ettremetogtepity-eiecttesptay teitttem mass spectrometry to elucidate the phespitelipids in
`Supet‘t3a’“‘"3 Ktiti Oi} extracted from Etgpkausia sz.tperE2a. The study was ezmried out in order te
`map the species of the eheEitte~eenteitti1tg phespttelipid eiasses: pttespttetidyteheitine and tyse—
`pttesphetidyieheiine. A total of 69 ehetine—eet1tainittg phespholipids were detected, whereof {St}
`pttespttstidyieiteiine substances, among ethers seven. with ptebebte omega-3 fatty eeids in bet}:
`sit-i and sn—2. The pitesphatidyieitoiitte eeeeettttetiett was estimated te be 34
`5 g/108 g eii {tt
`S). The results ef this study reveal the eompesitien ef phespheiipids of S'ttpetbaTM Kriii Di} and
`the presence of long ehaitted, heaviiy tmseturated fatty acids. '}Chi.s study else verifies pt‘€:‘\:’:i0’ttS
`tindirtgs and effer new insights into the eempesitiett of ktiii eii. in addition to EPA and DHA,
`the ether meter fatty eeids present in krill eii are pettnitie £tCit'i., mytistie acid, eieie eeid, and
`peimiteieic acid.
`
`1.4. Simiterity with Fists eits
`
`The available itifemtatien suggests at eensidetebte simiiatity, pat'tieu.Eetdy emege_3 fatty
`acids? between krill tail and fish oil from different fish sources. In tespettse tn 8. number ef GRASS
`notices, the FEEA has eeitnewiedged the GR!-XS status ef different tbtftns of tish eii. As per 21
`CPR E84. 1472,, tttenitedee eii has been et‘.timtett as GRAS. Ad.ditieneity,
`the FDA has met
`questioned GRAS notifications sttbtnitted on tuna eit (FDA, 2092), seimen oil (FDA, 29643),
`and anctzevy oil {FBA3 266433). in FDAIS review of ttma eii, the fatty acid content ef tune eit was
`compared te menhedetz eii (FDA, 2002). The fatty acid eomposition of kriii oil is eempered with
`these ef Fil}A’s eemparisett ef time and menheden Gil in Teiztie 5. Krill oi} eettteitts it high level
`of the desirebte n»3 urtsetutatedt fatty zteids that is eetnperebie te ether eiis.
`
`Tetste 5. Cemtaerisett ef fatty eetd pretite ef Stteet°t)aTM Kiri}! Git with
`tee}: ed and tttenhsdett at? I 3 "L
`
`
`
`west, 2002)
`
`1.5. Teehttieei effects
`
`Supettvam Ktiti Gil is intended fer edditien te a limited ttutttbet' of eettventitmet tends es
`e.mtttitiet1zd ingredient. it is intended for use as at dietary ingredient
`a source ef 0mege.~3 fatty
`acids, which are fettttd in their phesptteiipid term. Supptemetttetien with the emega~3 -fatty acids
`EPA and BSA has been shewtt to have :5. wide Variety ef bioiegieai effects. Ttte itttetided use is
`tea‘ the general poputatiett at teveis ranging from 3.05 to 9.56? g./setvittg fer addition te the
`
`tififidiéi
`
`Kritl eii {ERAS N'ot1'fieati0n
`
`O0 000 1 29
`
`Page 12 et” 38
`
`00000129
`
`

`
`i
`
`troaen dairy
`foiiowing food categories: noneicchoiic beverages; breakfast cereals; cheeses;
`desserts; niiiir products; processed fruit and fruit juices; and rnedicai foods, it is recognized that
`there are Standard of identity requirements for some of these foods, and as such, Aker Bionrarine
`Antarctic AS does not intend to refer to them by the cornmoniy recognized names such as rniiic,
`or yogurt.
`
`The use of Superham Kriii Oii in foods may irnpart a color to food products. However,
`the intended use of Superham Kriii Oi} wonid fail outside the definition of “color additive”
`because: the intended use ieveis are tow enough to impart a significant coior to food products,
`consistent with the “non~apparent coior” Exerriptiori
`[21 CFR 7ti.3{i)}; the intended use of
`Stiperham Kiiii Git as a nutrient wouid contrihu‘te a coior in a manner consistent with the
`“unimportant coior” exeniption addressed in 21 CPR 7t).3(g); and the intended use of Superham
`Kriii Oii is to provide consumers with an additional source of a nutrient in the diet and does not
`reiate to any use of the