Document JNaJBw1p4M0XEavNwn5q4MbYX

AR RAE -- 331] 493 H2r_ 3300 | . Report on the results of 28-day repeated administration toxicity study using a mammal 1. General items |Nameof novel chemical C TL e----] _----|| weiri|GE-- | (IUPAC nomenclature) iI a pti m orn| e ] He 2 putnc|osti=ce|n ~ tat |3 mo | po Loto, 1 f= -- -- -- | ---- |-- -_ _- - Company Sanitized. Does not contain TSCA 3 2. Acute toxicity test ~~ Test| Kindofiest | Animal | No.ofanimals| Adminisvation| Dose | LDSOor NOEL No. | andierm | species | per group path (mgs) (mfg) 1 Laday repested admission est Male 3 head onl | (megs) Female 3head| adminisraion | 1.000 500 250 0 beomwol | Avormal | Avwormat | 2 Aboormal | 5 Noma | Noma | NOsomEpgLs| re soap, gent| cosion, | semmwiogiaties, | & open, |B -- doin | 8 Hopstopiat * NOEL: No-Observed-Effect Level # Purified water @ Test carried out on the kidney of the male medium-control group, 50 mg/kg group and 1000 mg/kg group. General condition (Male) 250 mg/kg group: soft stool (2/3) . 500 mg/kg group: soft stool (2/3) 1,000 mg/kg group: soft stool (3/3) (Female) 500 mg/kg group: soft stool (3/3) 1,000 mg/kg group: soft stool (3/3) -- -_-- Lompany Sanitized.DoesnotcontTaCiAn . rr 3. 28-Day repeatedadministrattoixiocnity test FEEL =e FE Bodyweight JHE LE elelolslale|ale|olelole|als |} wBoayvee ign wan[| L| [[ =ITT TLT 1 EC TI] ] rassa |A [| T LT TTT T T P5T ] _ weetiPr [ e T|[ELEEEEEELLTAT TT ete [=[T=T=T=T=Taoefla] =|=e] 0] EE EET esphospatase TE HHT Co HEE pen [EET =] wiayze]aE I EYE EERE PYES --_ _-- BompanySanizad,Dossnotcontain Tscacar | . wlE fubsiance| | mere | 0 wo | 0 | a | mw | o Loo EEEELE eleleielaielai2lalelaig|als eb LLL ETT [ire | A -A- I - 1 P [== === Ta] FpEer [ [T LF F] F wnsession|-[|=[=[==Ts|=[=T=[=[=[-]]| entriobular hepatic osllhypertrophy 5 [m sroe mestmcssio) --[=F ToF Fo To [Tue [=[= uo]|=|+] ~ Ee S fPyelectasia } ELee LTe T) J -- pm Tle Le = Spi mm Le oT fo Tle eeono[=[=[ww]=] _ _-- `CompanySanitized Doesno containTSCACBI s --- ~: no abnormality Lor T: tendency Vora: risk factor (P) <0.05 Vora: isk factor (P) <0.01 *: not tested 4. Other Repested sdminisraion toxicity Address| 3-822 hicho, Hit City, Ohita Prefecture, Telephone 097324721 Test implementation fei [romme [ome [rons ew | _ J `CompanySenitized. Does notcontTSaCAiCnl ; `Work assignment table ~~ Tie: 28-Day repeated oral administration toxicity test ofQUIN r=ts [Name [ Wocowew | Testmanager: | to cary out work such as test planing, test work management, overall Keiji Shiraishi | analysis and evaluation of the results, report reparation, etc. and have general responsibilities for all work caried out for the est Person in charge of| to cay out quarantine inspection as wel as conditioning and rearing testing; management of animals, test substance preparation, administration, general Naomi Kawazu | condition observation, bodyweight measurement, feed intake measurement, etc. and have responsibilities for animal experiment work. Person in charge of|tocarry out work such as dissection, tissue collection, organ weight pathological testing:| measurement, histopathological tet, et., and have responsibilities for Kazutoshi Shinoda_| pathological and morphological work. Person in charge of | to cary out work such as hematological tests, hematobiochemical tests, urine clinical testing: | tests, ec., and have responsibilities for work related o biochemical analyses Keiji Shiraishi | of biological samples -- 0 carry out work such as test substance stability determination, confirmation analysis: of stability and uniformity of test substance solutions prepared, et., and have Takaharu Hara ponsibilitis for work related to analyses. -_-- Company Sanitizod. Doss not contain TSCA CB ` Statement ~~ Chemical Evaluation & Research Institute, Hita Laboratory Test requestor: DuPont KK. Title: 28-Day repeated oral administration toxicity test ofWRRNNNNY in rats test. This final report (copy) is an accurate transcription of the final report of the above titled December 5, 2003 Operation Manager: Shigeharu Yamasaki --_ --~ Company Sanitized. Does not contain TSCA CB4 ' Final Report 28-Day repeated oral administration toxicity test oSEND in rts December 2003 Chemical Evaluation & Research Institute, Hita Laboratory [Seal] ~ `Company Sanitized. Does not containTSTCSACA CE! 0 --~ Statement Test requestor: DuPont KX. Chemical Evaluation & Research Institue, Hita Laboratory Tite: 28-Day repeated oral adminisration toxicity test of(NNERin rcs `The test described above was carried out according to "Testing facilities specified in `Ministry Ordinance Article 4 stipulating items, and evaluationof toxicity related to designated etc., of test related to chemical substance" novel (GLP) chemical substances [Environmental Protection Notification 39, Notification No. 229 of Pharmaceutical Affairs Bureau and MITT Basic Industry Bureau Notification No. 85 dated March 31, Showa 59 (1984), amended on March 1997), 1, Heisei 12 (2000)] and "OECD Principlesof Good Laboratory Practice (November 26, ~ In addition, this final report has been confirmed to reflect the raw data accurately, and the test data obtained are confirmed to be effective. December 5, 2003 Test Manager: Keiji Shiraishi --~ Company Senitizad, Dogs not contain `TscACBI u Quality Assurance Certificate ~~ Chemical Evaluation & Research Institute, Hita Lab. Test requestor: DuPont KX. Tie: 28-Day repented oral admiisstion toxicity tet of(ND in rcs `The auditing and inspection of this test were carried out by the QA department of Chemical Evaluation & Research Institute, Hita Lab. The date of auditing or inspection and date of the results reported to the person in chaofrsgtudey or operationmanagerare as follows _ Dateofauditing or | Da> te of auditing or Study protocol chang Recordofreceiving animals [TuJuly l18.y 20032[1 3 ju,lJu2 yly220 32,,2200000353|| July 28, 2003 July 28, 2003 [TSetsudtysupbrsottaoncoclecphraenpgaerat(iNoon. 2) |JJuullyy2390,,22000033| JJuully y3300,.22000033 | [Animalgrovping record |Juy30,2003 | July30,2003 | -- Study protocol change (No. 3 [Dissection ~~ [AuguJusly t311,12,0200303 | July 31, 2003 August11,2003 | | Augu27,2003 |August27.2005 [PrStoufdyileprotocol change (No. 4 OScetpotbeembre3r1,2,22000033 || SNeopvteemmbbere43r,, 22000033 Study protocolchange (No. 5 [Clinical testresults October 31, 2003 | Novem4b,2e00r3 | November 19, 2003_| November 15, 2003 Pathological test results [Animal experimentresults November 25, 2003| November 25, 2003 |November 27, 2003_| November 27. 2003 Clinical test result, Test substance and 2 time rearing conditions records | NNoovveemmbbeerr 2278,, 22000033|| November 28, 2003 | NNoovveemmbbeerr 2288., 22000033 November 25. 2003 + [Physicochemical test reportdraftreevaluation Final report draft reevaluation | _ NDoevcemebmebre32r,8.22000033 || December 5, 2003 | NDoevceemmbbeerr238,,22000033 Decembe5r, 2003 - [nalreport| December. 2005 | December5. 2003 This report describes the method and procedures used in the test accurately, and the results reported reflect the raw data accurately. ~~ --- December 5, 2003 Person in charge ofquality assurance: Keiji Shiraishi SSB i ~ Test substance code No.: HR5158 `Title: 28-Day repeated oral administration toxicity testof(SEER in rats Test requestor: DuPont KX. 1-8-1 Shimomeguro, Meguro-ku, Tokyo, 153-0064 Test facility: Chemical Evaluation & Research Institute, Hita Lab. 3-822 Ishii-cho, Hita City, Ohita Prefecture, 77-0061 Object: the object is to elucidate varity, extent and reversibility of toxic signs developed and to determine no-observed effect level (NOEL) by observing changes in the function and. morphology ofanimal body in the case of 28-day repeated oral administration of the test substance. Testing method: the method according to "28-day repeated administration toxicity test to use ~ mammals" specified in the "Partial amendment, et, of "Novel chemical substance testing method" (Environmental Protection Notification No. 700, Notification No. 1039 of Pharmaceutical Affairs BureauandMITT Basic Industry Bureau Notification No. 1014 dated December 5, 1986" and "407, Repeated dose oral toxicity ~ rodent: 28-day or 14-day study" specified in "OECD guideline for testing of chemicals" (May 12, 1981) was carried out. `GLP applied: "Testing facilities specified in Ministry Ordinance Article 4 stipulating items, etc, of test related 10 novel chemical substances and evaluation of toxicity related to designated chemical substance" (GLP) [Environmental Protection Notification 39, Notification No. 229 of Pharmaceutical Affairs BureauandMITI Basic Industry Bureau Notification No8,5 dated March 31, 1984, amended on March 31, 2000] and "OECD Principles of Good Laboratory Practice (November 26, 1997) was used. Test schedule Start of study July 16, 2003 Experimental animal received July 22,2003 -- Start ofexperiment stat of substance administration) July 30, 2003 Dissection at the end of administration term August 27, 2003 ~ompany Sanitizod. Dossnotcontain TSCACB 1 Startofrecoverytest ~ Dissection at the endof recovery term August 27,2003 September 10,2003 Endofexperiment (end ofhematological test) October 31, 2003 `End of study December 5, 2003 Document storage site and storage term The raw data, study protocol, test request, test substance brochure, final report, QA inspection documents, other recordsordocuments and specimens are to be stored at the document storage room of the Hita Laboratory of the Institution, and the test substance samples by lot were stored in the test substance `storage room for 10 years from receiving a notification of the Chemical Substance Control Law, Article 4, Clause 1, No. 1,2 0r 3 `being applicable. The date test receiving requester. the The notificationisto be contacted to the Hita Laboratofotrhey handling after thestorageterm requires approval from the Institution by test requester. th In e thecase of specimens, test substances, etc, the qualities of which are liable to be changed during dtihsepsotsoarlagree,qutihreesstaoprpargoevtaelrfmriosmfotrhethteesdturreaqtuieosnteor.f the qualities being able to be evaluated, and the Storageoforiginal documents ~~ The originalofthe study protocol and amendments is to be stored at the HitaLaboratory of the Institution. Furthermore, its copy is to be stored by the test requester. `The original final reporti to be stored at the Hita Laboratoryofthe Institution. Furthermore, its copy is 10 be stored by the test requester together withastatement (certificate of the content being not different from the original) issued by the operation `managerofHita Laboratoryofthe Institution attached. Study Study manager and manager: Keiji other persons Shiraishi involved in the study and their work assignments (Carrying out work such as test planning, test work management, overall analysis and evaluation of the results, report preparation, etc, and having general responsibilities for allworks carried out for the test) Person in charge of testing: Naomi Kawazu (Carrying out quarantine inspection as well as conditioning and rearing management of animals, test substance preparation, administration, general condition observation,bodyweight rr measurement, feed intake measurement, etc. work) and having responsibilities for animal experiment Ld Gompany Sanitzed. Doss notcontain TSCACBI 1 f~~ Person in charge of pathological testing: Kazutoshi Shinoda (Carrying out work such as dissection, tissue collection, organ weight measurement, histopathological test, ec., and having responsibilities for pathological and morphological work) Person in chargeofclinical testing: Keiji Shiraishi and havi(Cnagrrreysipnognsoiubtilwitoireks fsourchwoarskhermelaattoeldogtoicbailoctehsetms,ichaelmaatnoabliysoecsheomfibciaollotgeisctas,l usraimnpeleesst)s, ctc., Person in charge of analysis: Takaharu Hara (Carrying out work such as test substance stability determination, confirmation of swtoarbiklitryelaantdedutnoifaonramliytseyso)f test substance solutions prepared, etc. and having responsibilities for Approval by final report author Study manager: December 5, 2003 Keiji Shiraishi [signature] --_ Affiliation: Hita Laboratory, 2* Department for Testing --- (Company Saniized. Doss not contain TscA cay 1s -- Abstract Table of Contents re Material and method 1. Test substance 2. Experimental animal 3. Rearing environment 4. Group configuration 5. Stability of test substance 6. Test substance preparation 7. Substance administration 8. Observation and test 9. Statistical method Factors affecting the study Results ~ 1 General condition 2 Body weight 3 Feedintake 4. Hematological test 5. Hematobiochemical test 6 Urinary test 7. Organ weight 8 Dissection 9. Histopathological test Discussion ~ Sm Company Saiz. DossotconTtSCiACnE 16 ~~ Fig1uresBodyweights 2 Foodnakes JE sprmseetaieny 3 : Tables 1 2 Sumofmcliaicarlsiygns Sumofmboadywreigyhts +++ erenneenienins +++ rere 3 3 Sumomffoaodirntakyes "+++ evereenennenenens 4 Summaryofhematologicalexaminations S Summaryofbloodchemicalexaminations +++ -.eveves <+++--r-rveies Summaryofwinalyses vrereeereereniiierienion 10 7 Summaryofabsoluteorganweights| ++---vcvcrvrriin 1p 8 Summary of lativeorganweights +++ runeenens 9 +10 SSuummmmaarryyooffimsatcorpoastchoopliocgeixcaamlienxaatmiionnastions:+:+-o--iei-iie+ness 3 14 Photos ~ 1 Clienaesigns of indiiviadniumalls ~----++vcrerrerrs 2"Bodyweigofhintdisvidual simals +--+-vveecrerrn 3 * Foodintakesofindiviadiugalls~~ ++++-novcnisss 4 Hemaodatlaoofingdviidusol aanimlals +--+ cvesn 1p $ Blood chemical ditaofindividualspmals +++ o-eocss 16 6 Uridaanofilndiviydualtanimoals +--+ 7 Absoluteorganweighsofindividual animals ++ vse -ooos 20 2 Relativeorganweightsofindividualanimals +--+ 24 9 Pathfiondinlgsoofingdiviiducalsanimlals +--+ o or 26 Attached documents Physicochemical test report -_-- 2c oanySanDioaslnoticonztaienTSdCAG.B} " ~ Fo(r INN. 2 5 -day Abstract repeated oral administration oxic test and 4-day rraetcsoovfer5ywteesetkwseorled.caTrhreieddoosuetsbuyseudswienrge6 4helaedveplesrfgrroomup1,o0f0C0rjm:g/CkDg/(dSaDy)aIsGtShemmaalxeiamndumfedmoaslee followed by 200, 40, and 10 mg/kg/day. Incidentally, control group were allowed to have recovery groups. the 1,000 mg/kg/day group and medium substancIen athdemipnriessternattisotnu.dyM,ortheeorveerw,asthneorefwatearecansoetcooxnisciodleorgiecdatloebfefeactttsroibfutthaeblteesttostuhbestteasntce haedmmiantiosltorgaitciaolntoebstsse,rhveemdadtuorbiinogchtheemiwchaolletesatdsm,iunriisntarraytitoensttsearnmdwdiitshsercetsipoenctcatroritehde roeustulatfsteorfthe administration term. or higheWristhhorweesdpescotftosttohoel,geannedratlhicsofnidnidtiionng,wtahsosceonmsaildeesreadndtofbeematlheesefwfietchtaofdotsheeotfes2t 0su0bmstga/nkcge administration. inhibition from In addition,the males day 12 to day 28. in the 1,000 mg/kg group showed body weight increase of the Inthecase of organ weight measurements, the 1,000 mg/kg group was foundtobe increased. relative weight of the liver in the females As a result of histopathologieal examination, centrilobular hepatic cell hypertrophy and ~~ single cell In necrosis in theliver the recovery test, all were observed in males of the 1,000 mg/kggroup. changes observedduringthe administration term and at the end of the administration terms showed recovery. inhibiti`oTnhaenrdescuhltasngaessdeisnctrhiebelidvearbaosveansuegegecsttoed tmhainaldymisnoifsttsrtaotoilo,nboofd(ywReigEht iNncrEeaseE. and from all of those changes, it was considered to be recoverable. Incidentally, the NOEL of O mg/kg/dN ay becau: se of softhsctocoolndoibtsieornvsedusiendmianltehseapnrdesfeenmtaslteusdoyfwgarsouepsstiwmiatthedatdoobsee 4of0200 `mg/kg/day or more. -- Company Sanitizad. Doss not contain TSCA C8! 1 _ Materials and Methods 1. Test substance (information provided by the test requester) 1.1 Name CAnAoSthNeor. QE -- 1.2 Lot No. 13 Source DuPont KK. 1.4 Structural formula 15 Purity oo 1.6 Name and. ---- 1.7 Physicochemical property State ata room temperature: brown viscous solid Stability: unknown Melting point: - Boiling point: - Vapor pressure: - Parition coefficient: - -- Hydrolysis: unknown -- ed. Doss not conTtSaCAiGnE}  Dissolution: oil soluble and water soluble rm Solubility: Water Less than 50 mg/mL. (measured at the institution) DMSO Less than 50 mg/mL (measured at the institution) Acetone - Other Ethanol Soluble (unknown solubility) 1.8 Storage conditions 1.9 `The storage was Handling precaution at aroom temperature (experimental storage, cabinet 6). Protective gloves, mask, cap and white lab coat were worn. 2. Experimental animals Shiiku CCern:teCr,D73(5SDK)oImGaSturakt,s H(iSnPoF-)cwheo,reGpaumrocuh-agsuend,frShoimgNaiPprpeofencCtuhraerl5e2s9-R1i6v3e3r),K.A.fte(rFino qseulaercatnatniinmeailnssopefcntioornmaalndgrcoonwdtihtiaonndinggo,otdhegernaenrdalomcoenxdtirtaicotni,onanmdetthheodanbiymawlesigwhetrewagsrouuspeeddtsoo ~ tithmaetotfhethmeeasntarbtoodfywsuebisgthatncweasadampipnirsotxriamtaitoenlywassam5ewieneekascohldg,rotuhpe.mTahlee bagoedyofwetiheghatniwmaaslsianttthhee `raannigmealofid1en4t1i.f7i-c1a5t9io.n9wg,asanwditthheeafremtaaglse. bodyweight was in the range of 115.5-132.9 g. The 3. Rearing environment period, Tthheroaungimhaolustwteherewhkoeplteirneaarbianrgriteerrmsyisntcelmurdeiangritnhgerqouaormanstienatet ianstpeemcpteiroantuarnedicnonthdeirtainongieng f21-25C, relative humidity in the range of40-70%, numberofventilation in the range of 10- o1f5datyi)m.esT/hhreaancdtulailglhyt-mdeaarskucryecdlerewsiutlhts1o2fhtrheintteemrvpaelra(tliugrhet atnurdnreedlaotniv7e%hhuomuirdiatnydwoefrfoe n21.199-2h3o.9urC and 54.6-71.8% respectively. min On due t0 the da2y being hit of by the recovery term, the function lightning causing the humidity of to the rise air-conditioner (the maximum was suspended for humidity of 71.8%), Awassaroebsseurlvteodf,thaendstuhbeseiqnuceidnetnotbwsaersvcaotnisoindoefrtehdengoetnteoraalffceocntdtihteiornesoulfttsheofanthiemasltsu,dyn.o abnormality floor caPgreisor(2to6g0rWouxp3in8g0,Dt1h8e 0anHimmaml,s wTeorkeikaepKta5ghaekaud/Kciakagie iKn.Ks.t)a,inalnesdsasftteeerlgarnodupmientgalthmeesh ~ animals were individually kept in stainless steel and metal mesh cages (165Wx300Dx150H mm, = `Company Saniized. Does not containTSCA Gat, 0 Tokiwa Kagaku Kikai K.K.). The bottom trays were exchanged once a week before grouping ~ and2 times a week after grouping. dose group and high dose group as Incidentally, because of soft stool well as high dose recovery group, observed th trays in the medium were exchanged eavnedr2y tdiamyesfraowmedeakyf2rooftmhdeaa4ydmoifnitshterarteicoonvetreymtetrom.daTyh3eoffetehdeerrs,eccoavgeersyatnedrmrafcokrstwhoesreegroups gerxocuhpasngoneldy)o.ncInecicdaecnhtaallyt,hettheimreaocfksgraonudpcianggesanwdereendtaogfgtehdefaodrmiidneinsttirfaictaitoinont. em (recovery the drinTkihnegfweaetdeursweadswtaaspawastoelirod ffeHeidta(MCFi,tyLo(tchNloor.in0e30a5d1d0e,d)OrailelnotwaeldYteoabset ItnadkuesntfrryeKelKy.f)r,oamnadn (a1u2to1maCtfeodr w3a0tmerinf)eebdeefro.rTehuesifnege.dFoanrdthreeafreiendg,etqhueiapnmaelyntticaanlddattoaolsdewteerremianuetodbclyaveJ-asptaenriFliozoedd WRietsheianrcthheLsatbaonrdaatrodriveasluweesoreftobhteaiUnSedEfnrvoimrotnhmeemnatnaulfParcottuercetri,oannAdgtehenciytReemgsulwaetrieoncso.nfIinramdeddittioonb,e LtahbeomriastcoerlylaonfetohuesIinnsctliutustiioonns,oifndornienkoifntghwosaetetreswtse,rtehteeesntiedretw4i6ceitaemyseaorfbwyattehre Kquuarliutmyedescribed 1im99t3hewMeirneistterstyeod,fiWnelthfearseecaonnddHteeastl,th32OridteimnsanacmeoNnog. t6h9em(bweecroemitensgteedf,feacntdivtehoenreDseulctesmwbeerro 1, confirmed tobewithin the standard values. ~~ period, Throughout the whole rearing term those rearing environmental factors including the quarantine inspection showed no variations considered to andconditioning affect the results of the study. 4. Group configuration The group configuration used wasa in the following table. "Dose Dose Dose: MeMeddiiuummccoonntrol rgercoouvpery group| 00 Low dosegroup 10 010 10 00 01 6500--162)) 603-15) 6S04E9-54) . MeMeddiiuumm ddoseo(21))sggrrooeuupp Highdose group 2"00 1100 0240 100 | 10 100 660@95--2340)) 601-36 6660515--6660)) 667637--7782)) dRoesaessonosf 5f0o,r 2d5o0s,es50us0eda:nda 11,40-0d0aymgr/ekpge/adtaeyd.orAasl aadrmeisnuilst,trtahteiroenwteorxieccithyantegsetswianstchaergreienderoault with 4 ~~ Tchoenrdeiftoiroen,obsethrevepdreisnentthes2tu5d0y,mtgh/ekhgiggrhoduopsaenwdassusseptecatte1d,0t0o0bemga/ttkrgi/bdutaayblfeoltolotwheedtebsyt 2s0u0b,st4a0nce -_-- Company Saitized. Doss not contain TSCA CBA 21 ~~ saentdfo1r01m,g0/0k0gm/dga/yk,g/tdhaatyias,ntdhemetodtialuomfc4ondtorsole.s being used. Incidentally, the recovery groups were 5. Stability of test substance Hita The stability of the test substance Laboratoryofthe Institution. during the administration term was confirmed at the spectruTmhbeefsotarbeiltihteysotfartthaentdesatfstuebstthaenecnedwoafstchoenafdimrimneisdtbraytmieoanstuerrimn.g is infrared absorption transforTmheinifnrfarraerdesdpaebcstorroppthiootnosmpeetcetrr(uMmomdeealsFuTreSme1n35t,sNwieprpeocnarBriioe-dRoaudt LbayboursaitnograieFsouKrKi.er) in the raonf4g,0e00 cm ~ 400 cm'. with a sBpeefcotrreumthpersotvairdtoedftbhyetahdemtiensitstrreqauteisotne,r,thaeniddeinnttifhiecamteiaosnuwraesmecnartriceadrroiuetd bouytcaofmtperaring `completing the administration term, the spectrum before the administration was used to compare 0 find any change. 6. Test substance preparation 6.1 Medium ~ `The stateofsuspension in selected was pure water(LotNo. pure water was A168, Takasugi found to Seiyaku be good, K.K.). and thus, the medium 6.2 Preparation method small amTohuenttesotfspuubrsetawnacteerwaats actciumreatientloy awneaiggahteedmaonrdtasrustpoepnrdeepdarien 0p.u1r,e0w.a4t,e2r.b0yanadd1d0i.0nagwivdh solutions. Incidentally, the test substance preparation was carried out once a week. 63 Homogeneity test and stability test stabilityFaonrdthuonsiefotremstitsyubtsesttasnwceerseolcuatriroinesdproeuptaaretdhebHyitthaeLparbeopraartaotiroyon fmtehtehoIdnstdietsuctrioinb.edAsabaove, result, the place for 7 10.0 and 0.05 w/v days. Furthermore, solutions prepared were confirmed to be the homogeneity was found to be good. stable in a cool and dark w/v soFlourtitohneshiommmoegdeinaetietlyyoaffttehrethteesitr spruebpsatraantcieonssolwuetiroenssapmrepplaerdeda,t ttohpe,1m0i.d0dwle/va%ndabnodt0t.o0m5 cloanyecresntwriatthionn=w3asfomreeaascuhreldaybery,utshiensgahmipglhespewrefroermdainlcuteedliwqiutihd cmherthoamnaotlo,grtahephtyest(HsPubLsCt)a,ncaend the ~~ homogeneity was confirmed from the relative standard deviation of the test substance Corzany Sanitized. Doss not contain TSCAC51 2 ~ 0c.o0n5cewntirva%tisoonlsuattiornesspweecrteivseosraemdpliinancgosoitles.anFdordatrhek sptlaabciel,itsyacmopnlfeidrmratoimont,htehmei1d0d.l0ewl/ayve%r awintdh `nc=on3cenaifrtate3irondawyassamnedas7udraeyds,btyhuessianmgphliegshwpeerrefodrilmuatnecdewliitqhuimdecthharnoomla,tothgeratepshtys(uHbsPtLaCn)c,e and the. psrtaebpialriattyiwoans(rceosnufltisromfedhobmyofgienndeiintgyanteysc)hange from the concentrations immediately after `HPLC analysis conditions (1) Instrument used (HPLC1) Interface: Model D-7000IF (Hitachi, Ltd.) Pump: Model L-7100 (Hitachi, Lid.) Autosampler: Model L-7200 (Hitachi, Ltd.) RI detector: Model L-7490 (Hitachi, Ltd.) Column oven: Model L-5020 (Hitachi, Ltd.) Date processor: Model D-7000 HPLC System Manager (Hitachi, Ltd.) (2) Measurement conditions Column: Shodex Asahipak GF-310HQ 7.6 mm LD. x 300 mm Column temperature: 40C ~ Mobile phase: methanol Flow rate: | mL/min Amount injected: 50 uL 7. Administration to carryAoustyrfionrgceed(oTrearluamdomiCnoirspt.r)atwiiotnheaveNreyldaatyonincatthheemteorm(iTnegrurmeopeCaotrepd.l)y fcoorn2n8ecdtaeyds.was used Subsequently, a recovery term of 14 days was set. 8. Observations and tests . administTrhaetidonaywaansdsewteaeskdcaaylc1u,latthieodnasyysbetfeomreistahsefdoalylotwos.stTarhtesudbasytatnocsetaartdmsiunbissttarnacteion was set n2esdxtadya--y1,ofatnhde tfhienawledeaky wohfesnubtshteanacdemiandimsitnriasttiroantiwoanswsatsarsteetd awsadsasyet1 a(srweceoevkery1.),Fuarntdhetrhemowreee,kthoef starting the recovery term was set as week 1 (recovery). ~~ 8.1 General condition -- Company Sites. bos otenrn 23 ~ "The general condition was observed 3times a day before substance administration (in the moming), during and after substance administration and in the afternoon everyday from daylto day 28. During every day from the recovery tem, the observation was day 1 (recovery) to day 14 (recovery). carried out once a day i the morning animal Incidentally, the symptoms observed showing a symptom was recorded in were summarized every week, the animal No. an individual table (Addendum). Furthermore, of the sinytmhpetroemcsovoebrsyertevremd,waenrde tchleasnsuifmibeed raosfthcoasseesobosbesrevrevdedduirnienagcthhgeraodumpinwiastsrarteicoonrdteedrminaandgrtohuospe table (Table). 82 Bodyweight measurement administ`rTahteiomne,adsauyre1m,e3n,t8,wa12s,c1ar7r,i2e1d,o2u6taonndd2a8yd-u2r(iantgtthheetiamdemionfisgtrroautpiionng)tebremfaonreddsuabysta1nce. (recovery), 5, 10, and 14 during the recovery term. carried Ionuctiadtentthaelleyn,dtoofctahlecualdamtienriesltartaitvieownetiegrhmt aofndoregnadnso,ftthheebroedcyowveeirgyhttermme.asurement was 8.3 Feed intake measurement ~ 22, and `The measurement was carried out 28 during the administration term once before substance and da4y (recovery), administration, and 14 during on day 3, 8, 15, the recovery term. -_-- "canary Sanitized. Does notcontain TSCA 31 2 8.4 Hematological test ~ collecteTdhfermomeatshueraebmdeonmtisnaolf tahoertfaolulnodweirnegtihteremasnewsetrheesciaarraifetderoouvteornnibglhotofdatorin`gp(l1as6m-a20sahmr)plaetsthe end of aAdsmiannisatnriat-icoonagtuelramn(,eaxc3l.ud2i%ngaqtuheeoruescosvoelurtyigornooufpss)odainudmatcitthreateenwdaosfutsheedriencotvheercyasteeromf `mweaassuusreedmefonrtsotohferprmoetahsruormebmiennttsi.me, and activated partial thromboplastin time, and EDTA.2K. Fre [DRedbioadcellcomiBO) 2) White blood cll count WB) TT | 1070) | lec rapes tio | | x[0%1) | Blecric resistance mana | a method oe 36))MMeeaannccoormppusuctulearrvhoelmuogmleo(biCnVco)ntent (MCF) | f0y 10 | FiHeori rsossancsmii | RBC [32) PRleaitutteccyouintrQopaoertlieondFee) He | ()T0750) T|RFoevoasrunnesgmti] od | ~ H112O1)LAPecouttkiiovcraytotenedbppiarrnottpiioarmlteirooPnmTb()oDpilfaesrteinntamtoen(oPfTleTu)kocyte)|||(((se%ee)c)) | Magueiicsonore] |M"aWgrnigehttisctasienimnogrsytem | SBeagnmdennetuetdronpehuitlrso(pNh-iBla(nNd-)Seg) `EBoassionpohpihsil(sB(asoos)inc) LMoynmopchyotceyt(eMson(oL)ymph) Instrument used LABORA1-T8O)RAIutEoSm)ated general hematological analyzer (Model CELL-DYN 3500, ABOTT 910),Ge1n1)erAaulthoemmaatteodlobgliocoadlctoeasgtuinlgatdieovnimceet(eMro(dMeoldAeDlVKIC-A1102A0,, ABaMyEeLrUMeNdGi)cal) 12) Microscope (Model VANOX, OLYMPUS) 8.5 Hematobiochemical test and the Fmreaosmutrheemebnlotosdocfotlhleecftoeldlaotwtihneg siatemmes twiemreeacsarirnietdheoustecftoironse8r.4u,mtsheamspelreusmprweapsariesdo.lated, -- _- CompanySanitized. pe96snotcanTtSCaAicany || 2 ~ Foor Be Be TT mms Wh vam oSCChmitmn 3Slefshasec GIF_[ ((UUDL 2 Cholineserue CUE) | UL) T|Omp-VNimtveopehhetny(]oSpCoCdbsaed-fo--rmat--s -------- |Sunytochoineoid metmd---- Rr Fo Toul oleae 0h) |UD | (mgd) T|LCODgAiDnPam.ctabdo,4sivoss -------- ied Fppasheeide 10) |(moll) |GPOADP peso rismio --] [ptpron(Protein) | (pi) EC Bremod FpaGmio WGmil [| Album ProtTenrAlu-- n (eal | los] [Gm Gm) {OCCmethod (12 Chlorine @ 1 my) |Conlometric irsionmtd --------] Instrument used 13),6:8), 12), 13), 15), 16) Automated biochemical analyzer (Hitachi Model 7170 --_ 4,5),9), 10), 14) Automatic Analyzer) Automated biochemical analyzer (Hitachi Model 7150 17-19) Automatic Analyzer) Electrolyte analyzer (Model PVA-III, A&T) 8.6 Urine test (excludiTnhgermeecoavseurryegmreonutpsw)asancdarornicede o(udtayon1c4e((rdeacyov2e8r)y)d)urdiunrgintghethaedmrienciosvterraytitoenrmt.erm (150W>F2o0r0aDuxr2in6e3sHammpml)e,(tshbeoautmo1u6nhtraancdcucmoulolraattiioonn)wceolrleecmteeadsuinreadn,iannddivtihdeuamlemaestuarbeomleinctcsaogfe uBsHi,ngprtoetsetipn,apkeerto(nNe-Mbuoldtyi,stbiixliruBbaiyne,rocMceudlitcabll)o.od, glucose and u:robilinogen were carrid out by 8.7 Pathological test 1) Dissection All cases were observed in detail. 2) Organ weight measurement - Company Sanitizec. Doss notcontain Tsc car |2 ~ For al case, the weight measurements of the following organs were carried out, Furthermore, relative weights were calculated based on the bodyweight measu Liver, kidney, testicles, ovaries, brn, splen and acrenal gland red at the end. 3) Histopathological examination (1) For all cases, the following organs and tissues were collected Classification Organ or tissue Respiratory system Digestive system Trachea, lung Tncisors, esophagus, stomach, intestines (duodenum, return), Cardiovascular system pancreas, liver Heart Urinary system Kidney, bladder Reproductive system testicle, epididymis, prostate gland, seminal vesicle (including Nervous system coagulating gland), ovary, uterus and vagina Brain (cerebrum and cerebellum) Hematopoietic system tbhoynmeumsagrlraonwd (femur), mesenterium lymphatic nodes, spleen, ~~ Endocrine system paidtrueintaalryglgalnadnd, thyroid gland (including parathyroid gland), Sensory organ eyeball solution.ThIencoidregnatnasllayn,dthiesstuesetsiccloelalencdteedpiwdeirdeymfiisxewdeirneafi1x0e%d wnietuthraBloluyibnu'fsfesorleudtfioonr,malin s@t)aiFnoerd wtihethfohelmoawtionxgyloirng-aenossianndstiasisnuiensg,apnadroabfsienr-veemdbuendddeerd asnecotpitoincaslpemcicirmoesncsopwee.re prepared, Study group Medium control group Organ or tissue Stomach (anterior stomach and glandular stomach), imetine - Medium control recovery (dvodenum,jejunum, ileum, cecum, colon heart, Kidney, spleen and adrenal gland and rectum), iver, Liver (male only) group 200 mg/kg group ~ 1,000 mg/kg group Liver (male only) Stomach (anterior stomach and glandular stomach), intestine | `BompenySanitzec.Doesnotcontain 5a car | n --_ (duodenum, jejunum, ile, cecum, colon and rectum), liver, heart, kidney, spleen and adrenal gland 1,000 mg/kg recovery group Liver (male only) 3) Following organs and tissues examined as naked eye-observed morbid portions Study group (animal no.) Organ or tissue 40 mg/kg group (No. 22) Kidney 200 mg/kg group (No. 30) Spleen 1,000 mg/kg recovery group (No.42) Spleen 9. Statistical method `The results on bodyweight (except at the time of body removal), feed intake. `Hematological tests, hematobiochemical tests, amount of urine and organ weights were tested for equality of variance by the Bartlett method, andifthere was equal variance observeadt a 5% significance level, a one-way analysis of variance was carried ou. If the results of analysis of variance showed a significant difference,a test by the Dunnett method was carried out between the medium control group and respective administration groups. --~ Ifno equal variance was observed, a Kruskal-Wallis test was carried out, andifthere was a significant difference observed, a test was carried out between the medium control group and respective administration groups by using the non-parametric Dunnett method. Factors affecting study 1. Unpredictable incident suspected to affect the reliability of the test results In the hematobiochemical test of one case (No. 2) in the medium control group, the blood `glucose showed an abnormally high value. The result was far higher than the background value of the Laboratory. The result was considered as a reference value because ofa risk of affecting statistical processing and excluded from the statistical analysis. Incidentally, this was nolmsorset) considered to show any effect on the result of evaluation in the study. `The function of the air-conditioner was temporarily suspended for min due to alighting strike on da2yofthe recovery term causing the humidity elevation (maximum humidity of 71.8%) intherearing room. As a resultofthe observation of the general condition carried out subsequently, no abnormal finding was found, and the incident was considered to have no effect on the results of the study. ~~ 2. Violation of the study protocol Lo ompany Sanitized. Doss notcontain TSCA CBI x ~ According to the study protocol, the bottom tray exchange was to be carried out twice a week, but in the medium and high dose groups as well as high dose recovery group, soft stool `was observed, and the tray exchange was carried out every day from day2 of the administration termto day3 ofthe recovery term. This incident was notisofses2) considered to cause any effects on the results of evaluation in the study. 3. No environmental factor considered to affect the reliability of the resultsofthe study was observed Test results 1. General condition (Table 1, Addendum 1) 1.1 During the administration term Male: soft stool (6/6) in the 200 mg/kg group and soft stool (12/12) in the 1,000 mg/kg groups <Stateof appearanceofsoft stool> In the 200 mg/kg group, sporadically or continuously observed from day 15 to day 28. In the 1,000 mg/kg groups, sporadically or continuously observed from day 2 to day 28. Female: soft stool (2/6) in the200 mg/kg group and soft stool (12/12) in the 1,000 mg/kg groups ~ <Stateofappearanceof soft stool> In the 200mg/kg group, sporadicallyobservedfrom day 16today 28. In the 1,000 mg/kg groups, sporaodricocntainuloulslyy observed from day 2 to day 28. 1.2 During the recovery term Male: soft stool (6/6in) the 1,000 mg/kg group <State of appearance of soft stool In the 1,000 mg/kg group, observed from day 1 to da3y Female: soft stool (5/6) in the 1,000 mg/kg group <Stateofappearanceofsoft stool> . In the 1,000 mg/kg group, observed from day 1 to da3y . 2. Bodyweight (Figure1, Table 2, Addendum 2) 2.1 During the administration term Male: in the 1,000 mg/kg group, low value observed on day 12 and low valuetendency observed from day 17 to day 28 ~ 2.2 DuriFnegmatlhee:rencoovaebrnyortmearlmity observed Boman Senitze Dosspo cont --_-- |. --_ Male: in 1,000 mg/kg, low value observed from day 1 to day 14 | Female: no abnormality observed 3. Feed intake (Figure 2, Table 3, Addendum 3) 3.1 During the administration term Both males and females showed no abnormalities. 3.2 During the recovery terms Male: no abnormality observed Female: in the 1,000 mg/kg group, high value observed on day 4. Hematological tests (Table 4, Addendum 4) 4.1 At the endofthe administration term Male: in the 200 mg/kg group, shortened activated partial thromboplastin time observed Female: no abnormality observed 4.2Atthe end oftherecoveterrym --_ Both males and females showed no abnormalities. 5. Hematobiochemical tests (Table 5, Addendum 5) 5.1 At the end of the administration term Male: in the groupsof200 mgo/rhkighger dose, reduced albumin observed. In addition, in the 40 mg/kg group, increased alkaline phosphatase observed. Female: no abnormality observed. 5.2 At the end of the recovery term Male: in the 1,000 mg/kg group, reduced blood glucose level observed Female: no abnormality observed 6. Urine tests (Table 6, Addendum 6) 6.1 At the endofthe administration term Both males and females showed no abnormalities 6.2 At the end of the recovery term ~~ Male: in the 1,000 mg/kg group, increased amount of urine observed Female: no abnormality observed (Company Saniized. Dae not contain TSCA! 0 -- 7. Organ weight (Tables 7 and 8, Addendums 7 and 8) 7.1 At the end of the administration term Male: no abnormality observed Female: in the 1,000 mg/kg group, increased relative weight of the liver observed 7.2 At the endofthe recovery term Male: in the 1,000 mg/kg group, increased relative weights of testicle and brain observed Female: no abnormality observed 8. Dissection (Table 9, Addendum 9) 8.1 At the end of the administration term Male: in the medium control group, pyelectasia (1/6) of the kidney; in the 40 mg/kg, group, pyelectasia (1/6) of the kidney; and in the 200 mg/kg group, whitened section (1/6) of the spleen observed Female: no abnormality observed --_ 8.2 At theendoftherecoveryterm Male: in the 1,000 mg/kg group, node in the spleen (1/6) observed Female: no abnormality observed 9. Histopathological examination (Table 10, Addendum 9) 9.1 At the endofthe administration term Male: in the 1,000 mg/kg group, centrilobular hepatic cell hypertrophy (+, 3/6) and single cell necrosis (+, 4/6) in the liver observed. In addition, in the medium control `group, pyelectasia of the kidney (+, 1/6); in the 40 mg/kg group, pyelectasia of the Kidney (+, 1/1); and in 200 mg/kg group, small granuloma (+, 1/6) in the liver and ~ local necrosis (++, 1/1) in the spleen was observed. Female: single-ocourrence cyst (+ 1/6) in the medulla of the kidney was observed in the `medium control group. 9.2 At the endofthe recovery term Male: in the medium control group, small granuloma (+, 1/6)ofthe liver and in the 1,000 `mg/kg group, follicle hypertrophy (++, 1/1) of the spleen observed ~ Female: no examination carried out | a-- Company Sanitzed. 000s not contain Tc cg 31 -- Discussion `The forced oral administration ofWs carried out to Crj: CD (SD) IGS rats at4 dose levels of 1,000, 200, 40 and 10 mg/kg/day to carry out 28-day toxicity test and 14- day recovery test In the present study, no fatal case considered to be attributable to the test substance: `administration was observed. Moreover, no effects by the test substance administration were observed on the results of feed intake during the administration term, hematological tests, urinary tests and dissection carried out at the end of the administration term. In the general condition, both males and females of those groups with a dose of 200 `mg/kg or higher showed soft stool considered to be caused by the test substance administration. However, no effects were observed on the results ofpathological test for changes in the digestive tract, etc. Furthermore with respect to body weight, the increaseswere observed to be inhibited in malesofthe 1,000 mg/kg group from day 12 to day 28. As aresult of the hematobiochemical tests carried out, the males of the 200 mg/kg or higher groups showed reduced albumin, but the changes were all fluctuations within the background value range of the Laboratory, the dose-dependencyofthe results was found to be poor, and consequently, the changes were not considered as an effectofthe test substance ~ administration. In the measurements of organ weights, the relative weightofthe liver was observed to be. increased in the femalesofthe 1,000 mg/kg group. Furthermore, as a result of the histopathological examination, centrilobular hepatic cell hypertrophy and single cell necrosis of the liver were observed in the malesofthe 1,000 mg/kg group. Those changes were considered 10 be attributable to the effects of the test substance administration on the liver. In addition, there were changes other than those described above observed at the end of the administration term, but they were observed only sporadically, no dose-dependency was observed, and they were considered to be accidental changes. In the recovery test, the soft stool in both males and females of the 1,000 mg/kg group `was continued during the recovery term, but both males and females showed no soft stool on day 4 showing that it was a recoverable change. In addition, the bodyweight was found to remain low in the males of the 1,000 mg/kg group, but the increases were found to be roughly the same as those observed in the medium control group, and consequently, it was considered to be a recoverable change. In addition, several items showed sporadic changes, but they were not observed at the endof the administration term; furthermore, no related changes were observed, `and consequently, they were considered to be accidental changes. ~ As effects of the administration o soft stool, bodyweight increase inhibition and changes in the liver were suggested from those results obiained, and those changes . `Company Sanitized. Dos notcontainTSCA GBE 2 --_ were considered all recoverable changes. Incidentally, the NOEL of(Nn ras under the conditions of the present study was estimated to be 40 mg/kg/day because of soft stool observed in both males and females of the groups with a dose of200 mg/kg/day or higher. 1) Background value of the Laboratory (at the end of the administration term): medium/pure Water (containing gum arabic and CMC) -- fIetemm SSexx onn MMeemansa2sSDD,. --AlbomiAlnbu@mi/n d(dlL)) MaMallee 2288 2277420022 -- `Company Sanitized. Doss not contain TSCA cat 5 --~ o 53333 I SsEEzEERr =o oBase ~ s| Lo 3 | ch) 2 3 CN 2 g 8g 2 zg : | --- Company Sanitized. Does not contain TSCA CBI - I \ ~ . 2z 5535 25558. [ REEF g onaoe " i z 2 2 8 = `Company Sanitized. Does not contain TSCACBI ~[ --~ 5 z a[ErEEea |of | Torr | 3 : ~ gy . I iz (hepjaesys) Company Santzd, Dossnotcontin TSCA 71 ~1 - % v0 x& sEEEE = FE FIEErEEr o23| | 4 Sse - : ~ . z 3 z (epjaveayy) iz T Company Sanitized. Does not contain TSCA CBI 5 --_ Table 1 TSwusomftinyiere-spresscds-idosgeorahstit-y dcyenys P sSeigns TT mme iistm ionPe ied -- Reco--r P--eed menH VC VC WW TTR Wim ME Foe sore i e ccd EE CE 8w6 w sw w h&w TeShwe Es ww ww awai No stmorites duaeed e6o6 6eu6 ie -- FmStomaef-- m e-- d ------------ VGVianildscpo,l 3,Reson. -- ~~ - Company Sanitized. Doss not contain TSCA GEY | , . bI Bevnndennss | preaans ge | FEEEEREz EEE i i jp raat 8 Hels |r fi  --~ }H| o | i Znon ;| | EEE If Mezagazs 1 ~ HSErlg.ile =o | igE iE: 5 H$3)i835mEs E(5E2s i 27 | i ~ CompanySntzad Dos nccota TSCACBI  ~ | el | | Blom ees ang Hlrasaes 7 seomenon FRR RR Aman aaa P| RREEE 5 Erb alak #g Erreosensy H $ TLL LL Blygle oo cnfae oon i Iz|1t N if HlefgfgfEaaegsg i|33 F iE: --_ Company Sanitized. Doesnot contain TSCA CBI a --~ i [m | i ; os Hz |EJ || | i | iE [7[57 fa a it IE L7 Company Sanilized. Dossnotcontain TSCACBE  _ ' j ls 2m am Eo ad rs don em we eed oo 8 SC AlanaY asses anata 33 ASAT FEISS Rp Baap apie Boer fEefRmmEmumsl mmanaam naa anyn 33loaoe arr ae om selon noe me aol ou oof FI EEEE BEES Ey EEE SEs nan un seEEED manera an - p [sErfEmEEsEE mSHsEeEsaEvasd anane PliEEsEnsgnsnnnnn S1f0p |mae sana; sal 87 i$illsg3lererenennT n semen mT ango T pegs] 00 fBlE le cco el| e ee eee aiSe]EEE FEE ils EIEIIENPCY PE IE 2 Fa s ky 3: ly = |E ~, -y CompanySanitzsd. Dossnot contain TSCA GBI 5 ~ I] bo Po | imnnnn snEannn 3 BlEeiesensanan ssnanil n artedestarn 4e13 fg afEssasssg| smd | an JET RTC R RTT CRo R scuT cy 2R 2oy Ele |galensoarEmsaEE cs loaan e g ead uenn ~ fit | LE EAE EE EE i | i 22 BBS lle,BuT l ossoi rT oac usnne T g a E HIHig5i|sB3|E= 2 CgR Eglgm3iEsET(FEe 5 ag i5 B 3gE)s|l _ ny CompanySanizad. Doss nolcontain TSCACBI " _ sIs E|| msRzssEsnss| sssNsl|eEc RseRc EseNan| EseYu| S$8SlRrasr Ros Nfan a enon]E aa a| ay RR EE EEE EE H 20s E oxE go onl se EEE C]ETPY o8:|enssen en og| ox nglas ae mas oe| aman BEjmmzensnan amene a ax ges sas Eas nz 20 a9 no alow an an ay ae) --~ :|3B|eremSaEn Eesos seIsneloen nsnapsagraanngaaonnang 3 : | |af4femssd. sengyj { svnesnanWgEsLnEnIaRsDisoEmAaD 5|: Si#pllsE jena snan en| i snanfaz ag ay amanq ] dren]aS[EIH 3i3|ss8frnenrnennsi engl snag en vel| snag] i3H0 EEE F32E[8l3leHe 5 5 TTT] 5 0| ogg (fH = gg Ei g | se UFEi Hs Ips SIE 5: 3 il i = 2282 i iE -- - compe Stn Dos tHTORCH ss ~ I| Lo || li FREESE yo EREREE dmzungaahoann an dren nares ee Smunng uganda SEEszaannasan 34 I 3 |z8|szsszzenss dnnnnn sss eanlEen nniaan nsn rnn sm ne an -- HIE i BeanIa| nRRRNg ay 3 Eo HHl o i) rvorn|oorenrs oy E 1 B HiteO l oT ooTcl Re Ro R. RA| a BIER ii5)p|izBdFlzEe 9 3 | i5)Lp.e8z.sEs C(l3asFeC5S5 i a f 5 3led Es,c|| iE2E : ; 282 il i i i i _ -~ Company Saritzed.Doss notcontain TSCAGBI ~ I. Io | pplRiioiriiicoliprioneyse: 1 | | resales A SYN DR ~ Bozosisinfioaonioe TRIiio|iIfpiinnn | | se mee alee o DCL jae ey ag fis sl nee yn ~ dlr i -- Company Santzed. Does rot contain Tsca cay a [A Pp | g PlEsEEE S SEE EEEEN aEE | BErrzsesmeros sn FEST ET BY ST EY ZT Av 8[ gr8 gv2 gn Z= ge $3|ssez any mngos sn z ez ay Tx vg fsssisszsses EIR g ssaee nnnsennnges Ha A3 B ol loodi BoEs wvRweEotEaol E42n ~~ 2 I pea | } I| :| P2s|Eesa cHo sNanTodE55NE axlNeE s pReE aEn sEeNneERaEnE i | | 3 FZB| TfsjsEsesEssiiss a ssnslp esssse anus =mens SEhS i Bil x JIc ccc ci| t me mem| e0] ukgzk 5 55) 7 g3|5E= 2 3 | 3 Fg [fEe 2 5 | gi 3ms | 51 BS Iz afst i) a 8 BEd Es i | EERE is: i 333 s . o - = jzis F3EE ER 2 i E54 ~ CompanySailzed. Doo not containTSCACat " Immerse ns i= = Li = & = 7 = = Re J a #| || SBE3[jvamaasnawsv dvriaond S 0m a Tn E a wu E ecns Rod wHu yee SB3o[n3Ec|naaunAr 50% 2 94 oayd 9g onz esglaod rog ances| 8g og 0g 3a4n3y i#25853883532 522 E= R33E&g E28E52E3838 = E32 r85) BiFrive | muoa 1 0n0 0n] avl | me --~ iB| BBE REEF ] 1 :| BslE.ERRE|anmenani an ; PPl2) HleernnT anas sneabT asn aren dnT sre =HF JiElgiBn nSleeemaaeadeige| SacdlieoHHolAe|. TH 5&GhE - HB i25) 3$5|i582 2 5% | H3 8p85 i(382 5 g5 ] I: 5 5i8ts| 2b iH a : 153 gH E: Ci 22 I i2 E2E3E7 _ -~ Corpany Sntizec.Doss nlconanTSCACB | P| N --~ _ - } H-I . gil of =e g[ofelo of oi 8 [ofsfo] of ois H8Es fofelel of oioe S33E8 H] of =! 88[slo] of <i 8 [offs] of iie 8 [aff] of ois 2 32 fe - "i 3 2 [gfele| o eis T|ol [F528H] of =;e H 5: i : ile ' 7 ssl : Company Satized. Doesnotcontain TSCA CBI N 3 | 1h elle ff] Ele) s| s| 5 | 8) 8 s| | sizisis Eafe of of alo of of a] Ebi $10 dof] ei HED 8)s| | 3 8 8 8g sisisix gf} ool of ap af o of sigiss ~ gsc] |5| 5] s| sf 3 8s finigs ' &lelel offal afl] | sisiels glow felel o ofolffff] h i = Jefe of af] ff db i 2 ZE5le|e] of H Fi|o~| 3% i of of] of o] of of 5] 8) 5) 8) 8] 5 LE + sigisis 2 8] sisisis i lei] i Ld 33 3 HIE FEE Hor [dihhynnoini _ J 3:z 2 IA FaoEs4EsEi9E l0Hs4 I9BEeHA dR44D)HeEHd4I asd fil BpEi ERsE]E - mp Sn. centsecmr si ~ i EIS gElele| of hi hn] Eee 8 sisis| sisi] ge] of hn] Boole | hi] bb eae] of hid ld] H4F]o|<| sf sige] size] sll ae] ~ [oo 3 size) sizis) g ale] of hii sisis| 3 [oe] sisis dif g 2 fale of shiii] abd] iI ffie lef nLei ne : i i EH sz] % 22s s8e 3 i 35 iy 3 lg 33H HB E i elE5s Ey :4 [2[I) RRfELisE)NfyH) R3H JEEDH fgd i HEE EE HE Company Sanitized. Dossnot contain TSCA CBI 52 Aached document Physicochemical test report December 5, 2003, Person in charge of analysis: Yoshiharu Hara -- --_ - Company Sanitized. Does not contain TSCA CBI 5 Study object ~ A stability test is to be carried out for the test substance used in "Rat 28-day repeated oral administration toxicity term. Furthermore, the tesot f homogeneity and stability rats"{I during are to be tested for the test the administration substance in ts preparation solutions Testitem Stability test for test substance Homogeneity and stability testoftest substance in its preparation solution Measurement date Test substance stability test June 4, 2003 (before the start of administration) Stability test of test substance in August 27, 2003 preparation solution (after the July end of administration) 1, 2003 Homogeneity test of test substance in preparation solutio-n July8, 2003 July 1, 2003 Test results ~ C"ThR e test suibstN ance used iD n "Rat 28-dfaoyurnedpteoatbeedsotraablleaddmuirniinsgtrtahteioandmtionxiisctirtayttieosnt otefrm. preparatTiohne. tFeustrtshuebrsmtoarnec,e tihnetrheelpatrievpearsattainodnarsdolduetviioantiwoansofftohunedtetsotbseubsstatbalnecefcoo7rncdeanytsraatfitoenrs at various sampling positions was less than 5% confirming th solution has good homogeneity. ~~ --- Company Sanitized. Does notcontain TSCA CSI 2 1. Test materials ~ 1.1 Test substance: 1) Name-- 2) Loto. 3) Source: DuPont KK. 4) Storage condition It was stored at a room temperature (in the test substance storage room, cabinet No. 6). 1.2 Test substance preparation solution 1) Concentration A 2) Medium Pure water 3) Storage condition Stored at a cool and dark place (Biotron Building (7), Test room 3, refrigerator). ~~ 2. Testing method 2.1 Stability test for test substance `The stability of the test substance was confirmed by measuring the infrared absorption spectrum before and after the administration term. `The infrared absorption spectrum measurements were carried out using a Fourier transform infrared spectrophotometer (Model FTS 135, Nippon Bio-Rad Laboratories K.K.) in the range of 4,000 cm -- 400 cm". Beforethe start of the administration, the identification was carried out by comparing with a spectrum provided by the test requester, and in the measurement carried out after completing the administration term, the spectrum before the administration was. used to compare to find any change. . 2.2 Homogeneiatnyd stability test for test substance in preparation solution For the homogeneityofthe test substance solutions prepared, the 10.0 w/v% and 0.05 WIV solutions immediately after their preparations were sampled at top, middle, and bottom layers with n=3 for cach layer, the samples were diluted with methanol, the test substance concentration was measured using high performance liquid chromatography (HPLC), and the homogeneity was confirmed from the relative standard deviation of the test substance ~~ `concentrations at respective sampling sites. For the stability confirmation, the 10.0 w/v and `Company Sanitized. Doss not contain TSCA CBI ss ~ 0.05 11=3 w/v% afte3r solutions days and 7wedraeyss,tothreedsianmpalceosolwearned ddialruktepdlawciet,hsmaemtphlaendolf,rtohme ttheetmsiudbdsltealna,yer with cchonacnegnetrfartoimonthweacsonmceeansturraetidobnsy iumsmiendgiHaPtLelCy,aaftnedr tphreepsatrabaitliiotny (wraessucltosnfofirhmoemdogbeynfeiintdyintgesatn)y 2.3 Standard solution preparation `made In methanol, up to exactly 0.1029 8of the accurately weighed test substance was dissolved, and it was `methanol to 100mL to obtain a prepare standard`solutions. 1.029 pg/mL standard stock solution. It was diluted with Standard solution concentrations: A suitable amountofthe standard 103, 206, and 309 pg/mL stock solution was diluted 500 times with pure water `amnedastuhernemmeentthiannotlheto10obwt/aivn%ap`rmeepdariautmi-oandsdoeldutsitona,ndard solutionfortest substanceconcentration Standard solution A suitable amount concentrations: of the standard 103, 206, and stock solution 309pg/mL was diluted 2.5 times with pure water and then methanol to obtain amedium-added standard solution for test substance. concentration measurement in the 0.05 w/v Preparation solution. --_ `Standard solution concentrations: 103, 206, and 309 pg/mL 2.4 Pretreatment 1) Test substance stability test `The KBr solution film method wasused. pretreatment procedures were carried out, 2) Homogeneity and stability of test substance in Preparation solution The preparation solution was stirred thoroughly with a `magnetic stirrer, and thefollowing (1) 10 w/v% Preparation solution mL. To From 0.5 the mLof the solution Preparation solution, methanol was added to accurately make up to 25 up to 10mL. The prepared, 1 mL solution prepared was taken, and`methanolwas added to accurately make (2) 0.05 w/v% Preparation wasused as solution an HPLC sample (dilution proportion of 500). mL. TheToso4lumtiLonopfrtehpearpreedpwaraastiuosnedsoalsutainonH,PmeLtChasnaomlplweas(daildudteidontporaocpcourrtaitoenlyofma2.k5)e. up to 10 2.5 Measurement condition ~ 1) Infra(r1e)d Ianbsstorrupmteinotn usspeedctrum `measurement condition J EompanySanitizea. Donoscontsain Tscaca s6 ~ Infrated specteophotomete: (2) Measurement condition Model FTS 135 (Nippon BioRad Laboratories KK) Wave number: 4,000 cm - 400 cm! 2) HPLC analysis condition (1) Instrument used (HPLC) Interface: Model D-7000IF (Hitachi, Lid.) Pump: Model L-7100 (Hitachi, Lid) Auto-sampler: Model L-7200 (Hitachi, Lid.) RI detector: Model L-7490 (Hitachi, Lid.) `Column oven: Model L-5020 (Hitachi, Lid.) Date processor: Model D-7000 (2) Measurement condition HPLC System Manager (Hitachi, Lid.) CCoolluummnn:tSemhpoedreaxtuArses:h4i0pakC GF-310HQ 7.6 mm LD. x 300 mm Moving phase: methanol Flow rate: 1 mL/min Amount injected: 50 uL ~ 3- Data processing solution in homogeneity and stability tes for standard substance inpreparation 3.1 Detected value `The peak area wasusedas a detected value. 3.2 Working curve preparation athse dperteepScattraeedndd.vaarlduessolountitohnescwherroemparteopgarraemdsacocboiradiinnegdtaondprkoncoewdunrecosnicnen2t.r5atainodnss,ecatiwoonr2k)i,nagncdufrrveom detected valuesThanedwcohrrkoimnagtcougrrvaempsroefptarhedtpeatsssuebdstthaencoeriwgeinreandidfsfehroewnteddegpoeonddilnigneoarnittyh,ebcuotnttehnet, ofthe medium used the test substance in in the preparation solutions, and thus, the 10 w/vS% preparation solution and forthe quantitative determination 0.05 w/ves, `preparation solution, of smoelduitiuomn-aanddde0d.0s5twan/davrdpsroelpuatriaotnisonwesroelutuisodn.wTehree sptraenpdaarreddsaoclcuotridoinsngofttohpero1c0edwuirves,pirne2p.a5raatnidon section 2), and concentrations, from the working detected values on the curves were prepared. chromatograms obtained and The working curves prepared known passed the origin -- and showed good linearity. Therefore, the quantitative determination of analytical samples was 57 ~ carried out usinag determination. standard Solution ofa medium concentration with one-point weight 3:3 Computation of test substance concentration in analytical samples substancTeh,eanfodltlhoewirnesgufltosrmoufltahewcaosmspuetdattioocnalwceurleatreotuhnedcounpcteont3radtigiiotns.(C: w/v%) of the test C= CsxAXD / Asx10,000 Cs: As: test substance concentration in standard solution peakareaoftest substance in standard solution (g/mL) A: peak area oftest substance in each HPLC sample 1D: dilution proportion of each HPLC sample 4. Test result 4.1 Test substance stability test coincideThwietihnfarnariendfraabrseodrapbtsioornptsipoenctsrpuemct(rFuigmu(rFei1g)urper2o)viodfedthbeytetshtessutbusdtyanrceequmeesatseurrweadspfroiournd0to atnheisntfarratroedf taebsstosruptbisotnanscpeeacdtmriunmis(tFriagtuiroen3a)ttmheeasHuirtaedLaabfioerractoomrpyloeftitohen Ionfsttihteutaidomni.nFiusrttrhaetiromnore, ~ showed no change. 42 Quantitative determination chromatFoiggruarmes4. TanhdeFwiogrukrien5gscuhrovweswosrhkoiwnegdcgurovoeds,liannedarFitiygwuirth6ecaonrdreFlaitgiuornec7oesfhfiocwietnytpiRc=a0l.999, 4.3 Stability test in test substance in preparation solution Table solutions. 1 shows the resultsofthe stability test forthetest substance in preparation concentrFaotriotnheim1m0e,dainadt0e.l0y5awft/rvpreppraerpaartaitoinonwesroeluitniotnhse, rtahnegmeeoafns1o00fthe10te%sotfstubhsetapnrcesecribed v1a0l0u.es5.1I0n%adodfitthieonr,estuhletsteostnstuhbstteasntcseucbosntcaenncteractoinocnesntarfattieo3rn diamymsedainadte7ldyaayfsewreprreepwairtahtiinon. Company Sanitized. Dossnot contain TSCA CF ! 58 -- Table 1_ Chemical stability Nominal ofthe test substance in dose formulations Mean cone. (wv9%) RE. On) [imm|eddaita|taegly| 0 *: after preparation FUP): Raeofthe final concentrationt after preparation the concentration measured immediately 4.4 Homogeneity testoftest substance in preparation preparatTiaobnlseol2utsihoonsw.s the results of the homogeneity test carried outforthe test substance in the The results on the relative standard deviationofthe test substance concentrations sampled at respective layers was less than 5% for all concentrations of 10 and 0.05 w/v%. --_ [ow [os Table2 Physical stabilit of thetestsubstanceindoseformulations Nominal conc. Layer of (Wiv%) `measurement Actual conc. | Mean conc. (wiv) (Wi%) RSD. 6) [mate os] [ omom ios] [wT oow 00 [mad oom | oo | os [oo00sm 37 | RS.D.(%): Relative standard deviation --_ Company Sanitized. Doesnot contain TSCA CB 5 ---- ko - Ce | J [ wl oY Su TH - Tr -I =a "cul St Ps Fig.1 IR spectrumprovidedbythe sponsor " | ii i3 CE Cong : . J! id i =~ ar -- Fig2 IR spectrum measuredpriortotheadministrationperiod Company Sanitzed. Doosnotcontain TSCA CBI  = Ni_ ;. Hp i zx FY daihk2b ar s = ori en 5 suredafterthe end of the adminstrai period ~ 80,000 i "000 : . yeaa R=09%9 0 - . 100.0 2000 -- Fig Calibrationcurvef`Coonc1e0nwtrhationdo(seufgohr)mationanaly [Conagce|rFtoioes] zaes [71365] --_ Company Sanitized. Does net contain TSCA CB a@ ~~ 60000 i 200 J R=0%9 0 00 mo m0 200 Concentration (ug/ml) . Fig3 (Calibration curvefor 0.05w/v% doseformulationanalysis [ConcGaeg/nnl)t|raPt eaikoen] os Ts eT) Coe Tp] ~ wu Signal density (mV) w ] i2 5 - . + CETTE TET, Fig Typical chromatog- Retentiontime (min) or 10 wht os formulation sly - _ `Company Saritzed. Doss not conta TscA car @ --_ Signaldensity (mv) - " = . i ` 3 ' - Poor TTT Fi Retention time (min) Topica chromatogra or 0.05wi dos formalinamy: -- --_ `Company Sanitizod. Doss not contain TSCA CBI  ~ Soa SSReerEn ema a es BEET ame EL eared Z EE OE EEE REE TFeaai m la BSE RE pg EER TeIRTeY Est bs eR Ea R EER Baa da BAe1 Niovrrmaolf le tom bil cntel gro, No. imalx3.6, ~ gopEEalE e alEge rye2 ST EE S oN Ae CoE d PGOe oEo rmaEBa eldiveGRga iEaGay i ee : Fa H SloCE eMiiLeESTh niaeneea inSLrn yaSagtRleeyl : PLI AT SEBeR HAT TBSA Pi00.2 Livro Cone amae rom peop 1a000mspielelyl group sosohss, No.35 sniHmE,ax3l, -- Company Santizad. Doss not contin TSCA CBI o --~ Adder 1CTluiycssigrhs ofnpaedpdaoetsr. itty nyr. Vetscme e Co sn e osoer Tm T ma e------ he-- e -- _ Ny Meg 634 STL S78 s2eis ase neem Mak Fenie S00, S101, MN, SMI LB S4A4L8 6660058,, s O64Ns, Sdsesres Haz oss, mp2 sme Sasasun nSnkw gSaoun a7e wa Addndim 12 TCwelnyi-isghet-oofyoesitosalny dy n a 1 ghey 5 T sx T r e e l Tene e Forbes esis L FaeeiE SE55R0M , STE SR SJeAy ey re ---- me 890 A8g0e0 amm6awa teimeer -- Addin 113CTiwreeysi-gncigvhino-mdiysepisttyesdyoisess. "omghyiny sm osm asses Sm TERA AsiTiT Ta Tomye, RFa ie e sS csiosemS srlesoellGcicieas a BsuAcses ssn des use Addin 14CTloeimynigshmtsdoyfnrepis dsosdiasmivxichysay ns e 2 ogrginy e 5 osm amps Th ES SE:--So --"-- Mig wweFB Sm 61,68,65, 67,6869, 67.70.71, 67,6870, oFmelt nm mong mm7mmLe712 _ fa-- wo -- a --_ Company Sani1200D.o6g8snoot tcongona 7t5a6 icgn | os Adin 15TCresss fp isiy sty Lk Se ST eemrmes1siee,00s0emg/dae y se m FTRT eT m n E e pi ma sonst TTT ree nHem PAR vs Tn sd wy ny JH EE pa:n n -- o. Dreaen, BpAiTer BOA 5, TE m aBIS iva rie a -- : uw TEAL BLE, 818283, 8384 ~ ~~ Compa~;y Saniiizad, Coesnot contain TSCAC8{ - pr `Company Sanitized. Doss not contain sca ca - I LL i res - EEE - I] CompanySanitized. Doesnot contain TSCACBI |r I | f ET Toes | je | Er --~ J Fr || [boI k d T L | 3p i i - RaS se2 snR anE aaRagSanANnnaR =nNeI =nRsRNaAR nYs i: i[Fee2nns83sIYesaneeszs Bulge 5]: --_ ?i = | g 3 2 --- `Company Sanitized.Doss notcontain TSCA Cat ~ | bree] cd V. TH sd af a ---- fi ay HE EEE ps 5 NER SRE gH - J ee ! ju A i -- sss EEE 383223 i JT EEIEE: remem F3gERy : i 3pm ems essafrases : Hl - : Company SanRized. DoesnotcontTSaCAiCnBI QR | sev Loddon bond sensed Ln ed Ege: E 3E) sgprsessesnsfsossssussssbsscssasepsspeeeeesfeesid . -~ compts naTHEA! - I Aprez CO i 5 od nn rrr ss f I - a -- 333323 - Lo - --- Company Sanitized. Does not contain TSCA 1 - I:=A mTnT= 4 I | ia ans - il i ~~ CompanySanitized.Doesnofcontain TSCA CBI 7% ~~ i [+ L i | | | | : f[333r83! os3ammsmsmzsesmsesnsd hnesse segayn EE | ssEa fg smn Jodo 00500 SEIIIRIIIIE IIIa nnn suse I[Hpins| $ma5ma3nsasasesneeze sanssan| sng 3praeas 23essEreIRagIasTS seasabsagas sressd i 3[preven SIaIsTEseaseiseys: kasssazeneas 23335: i RE mm SSissiEennasassaggaiiy tvuxy . aSpeesae EEoErtitiie PERE ERE avin sages { 2 i !EPECEEL Se eSeRELsReIsEaesEs aszamneassn|g i33|, 2lefsrsrosnasn) sneannzaenuFeRsAIRARRRANIINERIIRIRAAN SAAR : H5E 52I-- e2esastjeszesgusanegeasasessysperses seana|yi mg 8 fee] i 1 i. FE {fr osspmesassananna sasas fossa | 3E 28 3 Li i 3 -- i3l*3 H i E: -_p Company Sanitzed. Does ol contain TSCA CBI ~ \ls |prunesj s| o | | t | i sees| i Rass RRR mE is conse sm [i ITT 333533 a3sa8s - 2R2RHAIIARTARNTAR SRE - ss2as: - | pi TT i. . ERatE fate FRE $5885; i ! 5 a S------ a i 5 pees aazazs) TT asxzas a =z288: } i 5 i FE jeg oerpesssggea rpg i proesnlumsntaais JH In $5 i FOE IE = % M < gEg i | `CompanySanitized.Dosnot contain TSCA  x pdzs TTL gsa8sy Ei zany FER 3 o[iEE smERSIIieRaveuasansanunay Sunt er SEER LFS TEER nag ! J 2E |gFlEaRsessess sSuessznsgisEsssssssReisisaInRaIsaLnRssIzaneaseysl iaxaEnag ~~ i i i 3 3punnen sasnadisesstassassenestnanans nner 2] gloomy tassnsisenasersacnhranndenonas sound 33g Flicntin nesundoddidanas oli iia Rass dened ils g: 52 ; --- Compr Santcs. Goss not contin Tscaca  Af E -- J jf | | | i i sh se sn 3 haan iii 33 .3 seas smsssssssssnsssscanara nanan gzs3s | | JI FJ ck RA R NNA n Acg eJzane Jd FE ES pacer --_ F i R -2 E esoE ee S3esasedcesnesddicqsieasadbdssgsisiaasiasssaeisisy $g8a3a389 EH] is Sess Siddiddeaa eaassSEaaae 333533 33g [adass sdangeeta dTIIRINNSNNN SINNED & 1freesvepeaanonaanassoasssstuseanasenaiessazy H3oo3 i-z = Hy 3 2 3 3. 32 -- Company Sanitized.Does notcontain TSCA CBI  ~ Wh ld] jefe ii i i 333353 Il, | i ey cocci i ] wns funn | | | ioonaloood | ofd ann fas anaes) [ree | - | | i Fasss ssssngsssearnsaginsessnsasiy S2z222 i | i iz ana) rors rsaseed azmzer i + k | i Irmo esessemmnaninanunnnasssasanfraness - i no _ Ha - | tle] : #} panySwen eenRTA ) fpr A 333333 1) vey | || trernennnfonnlinsn zy i sss sedans ontisried s3s3ag 2 | 8 fermi mmoles | isin] sires ! Iz a erp] wowngel fy on 1] iHsTloseses|fessussiasasssliaasasliasessiorenrnhfeosasas 3 {5 i i] - `CompanySaniized. DossnotconTtSCiA CnBI ~ i ls] 1 Poanesl | || menamtkesns aienndenidsesaenanl canara)| fH rr Te us E sessed oN ---- En Ft Heprzszs Emmy bi --~ I i i 5 i i= xsres Z fe ssssghsssshans ast ssnoenaael si 28333 Sense He reese Sms ek i HE a isl ; | company Santas,DossrconanTECACEH  JEpr 7 | fed seeded Bru SFiirdiaiia nisin - il hs suse fi i= sscacs Fe3ssmarzsseesssaens a Bn mn ip | | 7] i2iif Idsefepsaezang s3eczesbeessasseseaaEnIaassassaganoniy saxaes: i gE = Frases| 3338Sa5Eeuaezs gosdnezassanes p2a3d3s i 3 i3[ee3ssifrsanarnaasoassSsesesernIsNeRrr EEL Rgkrsaas: BL2l5y3 3 iil ls cle g: i| _ - campy Saiz Dos AEETSCA " ~ Vdd wd i He 3233: CR, 5 Si# EEN| SEE | ta SiE.IE Inmet| pany Hens ssstadesassazassanteresasants 382333 {| Bim mmm snssneuassss roo 5s) S[IEEY HIEIRNCETEEARETsaunananantny sueeny i Hm Issmasanasnaany easy Bl I i3 if 2EIIESE ERIN: peRsRazasEs fhsasey J| | - A Company Sanitized. Does not containTSCA CB ws SMart Fri sreimmnmassmananassay) maven BE Fnaazg sERndissss a saneannnesy S83833 (2134 ii |i BEE ERANEHEa ey es ~| | F$SB |frRuEnNuTnTd MsemoEmnsdIsRnIseRgaeersenaysearreuAnakeasarsi| pparpee:a J5EJE EerEasRe[mEoEneR] RAE RE ce ERE RIE|] Refi _ HE | frend sun $233)! SB3l|o3s3s3n3s3d3 CeeEsEoTrTsRhAzRrAeNsAtAeAnIsTeIeRgIeSsIeAeIsNdAsaaTsasYs= rate: iHI iqlssszes szesezEsessssesasinzage --- 8z325 i 2lesesssfessanbesensnsssahasennnresrs fozzag IE ey 3 5 T s 2 i3): 3 i | i EJ ~ -_ Company Sanitized. Doesnotcontain TSCACBI 56 -- Adie 91 TPwsutyiihsg) tdoyogpuoftaa ddssnoris enya So mem Mr copes [Ee ---- ER Rly Cver,biasderyo,elemlsosvn: lB.romN,epnnb msomi a,ntdormsFoeHosoemeao rocoterd m Simginmp, And 52TFeotsestiddoyorgesposfti e-dse ls ittys sy mre sex Bpgop Au gy, Macroscopicfindings Hisopathologial findings" 5 No miesdecd Tr piceT moninE +slight. Vo nmi et miides Alto 53 Toesopye iesghic-ystdymys -- ecopelbitgdbiviwees --See x. Expgroup BoelFate. `Macroscopicfindings Histopathologicalfindings . emmy. a Ns dralis dd ot mid -- - ompany SanDioosinoztcoentadinT.SCAca 7 Adds 5-4 Toastysightdoy preddss a ity dynts. ~~ Pathologicalfindingsofindividual animals Sex. Bogop olFate. Macroscopicfindings Histopatbological findings" rei " ES Riley SO mwBl 3 meino h.aiacid ieimi te. Addin 95TPocuabyiigchtcnyngpoef tivissoril scysyfas sex Epon pSalm pe Macroscopicfindi:ngs BERN sapiendod Radney i amined Histoputhological Sidings" Thr 5 Sp ~~ SOemi tyc.an Tr me Whitish (83; s+,h mode, Shien tea Focal necrosis++ ~ = Gompany Sanitizod. Doesnotcontaln TSCAGB 5 Addon 5-6 Twesyrepe-atedidosegalhxtity-sandeyfnyts ~ --=--paEnigeneeAEul mEtpoin etvHins cpstai oiogie el de ings"s 31 Ne omanGad Toe Cbeenpttocsye+sypervophyof p HENrmai decd Si cllsgooesof PRfiEveRr RAE Ea [ov -- Male 1000 ST kai deed Su absg enmie sof iCeonrtobaar ypersophoyf RG malsded oCemntos yperophyof bSepsitceolclyg+crroses of 1Or rpeiscionp d lls--S: orSsstomam c, hi ls todmn eas,idose,JomN,oSinuecs,ecmoiiinrdseonoinncd r ~ ptym spe, Addendum 97 PTnaetoocgigihtfdnadiysopfeteinddoisvidn]linoalxysadnrs --E -- EA -- p Hisopabe olegiclaating) TN Se Orgamiad on ls: Eve od mNaocdroes(c47o2pni).c detenmte,ey . SFpoolnlerbypeopb+y+ . --_ CompanySanitized.Does notcontaln TSCA CB o ~ Allin 53 TP wii gddyogpsoo fdedsnotyedyrrs So Poo re Mewes Hiopstologinlfades" Fete Vsdosmol 46 Hedacs ded Tie Crain Samet Flos: SoReni,famiiromdae,eodse,FaSnosepsaelemssdeloend$5 tvir,ttKrids,poe odsrl Saige Abt 99T Publw i nbnei pofsmoit niatsiit tsysany dy es = Brews "re Maerioiin [---- ~ my iN mii dtd Noid Adie 910STuosireysght-idndyigesposfnidodssoril licsy sy nr Sex Egon AgeeFate Macroscopic findings `Histopathological findings Em a aSri dtd Aint 511T Publicv inpoee fisdtidnvoisegr inssiesysd atya Se BRE AE tain i camied opsteopnfotos ee EEE Se 2. a NoVsowomrmaalltliessddeteecdte.d otc Noteowwmied TTT -- E FoSm e det io amet - Gompany Sanilzed.Dossnotcontain TSCA CBI  --_ Addendum 3:12PTuwsoegeictl.Saddayingepoofsntiocslrmeimcysy fs Sx oP ME ry Maceopifades Eistopatbologica Sndings 72___ tw Noabnormalitiesdetected Addeam 313 TPuwlebaoeyp-ii)gidnhyitnrgesoftendidods aaimicsy ady in vs sa Eop AE rr scoping ee Notexamined - Hisopaiologicalfodings rp camiaed lows7: 5rs5shN,oiensalolcdhe,cdcde,eanN,oBmuos,mcmoau:mdeoosendren fir lato-- py ------ ~ Addenda 914FTuloopafiyneg-poofsintohsurts l omn-iiscydsudayneys. a Drm mn, peng [p-- em 84 No sama deed oscami Language ServicesUnit Phoenix Translations PN Febru2,a2r00y4 - `CompanySaniizec. Doesnot containTSCA cay -- 0M5405ff0i2e1]ISCahmeeskaswiatbhotvrea;nsclhaetcokr wtihtihntkratnhsrhetosrhoItuhldinbkeathe`rneots'hionutlhdisbeseant`enncoet.in this sentence. --_~ Company Sanitized. Doesnotcontain TSCA CBI