Document reN248YKwbGdzjZdjrq13kya

AR 426 _ 0661 N-Et FOSE alcohol Teratology - le @ LABORATORIES AMVERCA INC 1. Study 2. purpose 3. Test Material A. Identification 8. Purity . Characteristics 0. Reserve Samples 4. Compliance 5. Quality Assurance . PROTOCOL Rat Teratology Study (Segment IT) Tiocitdyetaenrdninteerattheogeenmibcryop/ofteenttailaltoxo-f gaavtaegset tmoateprrieaglnanatdmirantisstedruerdingbythe period of fetal organogenesis. 7-3352 Assume 100% tIhnefsoirsmatainodnsotnabitlhietym,ethaosdswelolf assyncdahtaaraconterciosmtpiocssitiwohnichordeoftihneer the stepsotnsomra.terial, are on file with the cRoensterrovle saarmtpilcelsesofwiltlhebetesttakeanndat sianmiptlieast,ionas awnedllretaas inaendy. remTahiesneing ttheest smpaotnesrorialu,ponwililssbueancreetuofrnetdhe to final report. cThoimsplisatnucdey wwiiltlh baellcoFonodductaendd Dirnug AtdheminGoiosdtraLtaiboonratgouriydelPirnaecsticiencluding DReegduelnabteiron2s2,, TFHedEeraln Regir ster, Tthhee pfrinoatlocorle,poritn-wliilfle bpehasaeu,ditaendd by the Office of Quality Assurance in parcoccoerdduarnecse watithHazslteatnodnardLaboopreartaotriinegs. 000452 @HaziETon 5. Experimental Design A. Aninals (1) species (2) strain/Source (3) Age at Receipt (4) Number/Sex (5) Identification (6) Husbandry (2) Housing (6) Food (c) water Rat Sprague-Dawley C0/Charles River Breeding Laboratories, Inc. Sexually mature, 8-10 weeks old (females) and 12-14 weeks old ws(iimlgalnlsesb)ea.ncdu/olRrlaetdsbodphryaivoiwrnegigthoctlmianetixictnargle.mes 100 females/100 males Individual eartags Individual housing, except during mating when wciatgehs.one mal one e, infemhaalneginigs placed wire Purina Rodent Laboratory Chow 5001, 2d libitum. Sufficient quantities olifontitnoiuoamdtbieowrnillotfo befeenesrduerteaisintehadavtaialttashbetluesdaymfeor tahnealydzuerdatioonna opfrotshpeecsttiuvdey. basFiesedfoirs mceotnaclesn,traatnitoinbsiotoifcss,pecaiffliateodxihne,avy pesticides, and nitrosamines. Tias prwoautteirn,1aydanlailbyitzuend. on Thae rweattreormoserptgeaaclntsii,svmesa,fbkaasplieissntiiftcoyir,dessap,nedcihfehiaaevldyogemnisc.ro- 000453 @HazeeTon (d) Contaminants (e) Environment (F) Quarantine (7) Rendomization Procedures, 3s sTiphneotnesrsoftreurdiyhnagvdeisruecbcostntosarindceaernsedd/poporotsetsnhteiibalelly pirnecsleunditnginthaenimtaelst fmeaetderainadl waittesre,lf mloaritsetpreoidsasliisnblea(sb)swtearlnuldctau(scr)atlanlbayovrieet.elmastNeodne aofblytheexspeecctoendtamtoinbaentspreasreentreainson. faniicnieelnt fteoedionrterwfaetreer waitthletvneilss suf. study. tEavienryteamtpteermaptturweisll atbe7m2e+de69tFo main- w2i0%t.h a Trheelatpirvoejechtumciodoirtdyinoafto5r0 + will tbeempneortaitfuireed eixmceedeidastealyranigfetohfe room c5y0c-l9e007w.ill Abe12m-ahiounrtailniegdh.t-dark Minimum of two weeks. Upon observation of sperm or uvasasigsniignganleadtplatubogl,eexoptfehreirmafenendmtoaamllesnugmrwboielurlpss.be tAlrleatamneinntalswitwhiilnl baetwpol-awceeedkonperiod. cPersiaorreatno steercmtiinoanl onsacdrayifi2c0eofand 2Bg1ee1stapasetsriisogonnn,endeallrlapnedsorumfrovrnimuviminbngegrscdeasmsasoretwaihnlalt wssikelecllteitobaenlsuneaaxnwadamrieenxattoefironnatlh,eof dvotishseecerflaeeltve,ulseosr dferroinvewdh.ichThtehenuamnbiemrasls wwilelrebe abanesigsniiagnlnneidnagndbywciotrnhatnidtnohuemincfgainrrudsmtedrGrraiowcuapll1y 000454 Q@HAZLETON (8) Justification -a- ctehsraorueghanGrsoeucptio4.ns The order of on any given day wniulzlberbe asdseitgenrmmeinnte,d bbyegitnheninrganwdiotmh the lowest continuing code number through the and highest for tinhatcesdaayr.ean Thsiesctimoentshodbeiwnilgl result wpietrhfoourtmedknoiwnleadgreanodfomamcatunzn]ar animal tihdeenctoidteyd ordamdosneumbleervsel.willCobpeies of cfoorowradridneadtorto atndhe toprotjheectsponsor by the group leader of the study. Cthoede numbers will be recorded on prepartum examination records, Fetal Tent examination Fication records, tanadgs,skevliestcaelral ecoxmapmlientaitoinonofrecaollrdsd.ataUpcoonllection paendrmatneernattolaongiimacl eviadleunattiifoincsa,tiotnheand dtorsaensclreivebled astosigalnlmendtasta wirlelcorbdes. Raagtesntsarewhiscehnsiarteiveknotwon a tnoumbeber of Reamtbsryohtiosxtiocricaanldl/yorhatveeratboegeneniucs.ed in tsyapfeetyandevaalrueatrieoqnuirsetdudibeys thoef this Ianppraodpdritiiaotne, rebagcuklgartoournyd agteenrcaiteosl.ogy ocfonttrhoel prdaotpaoseadre starvaaiinlabalned sfoorurcrea.ts 000455 @HAZLETON Tt 3a 8. Group Designation, Dose Levels, and Dosing Schedule Group No. DLoesveelr Dosing Schedule Forks Dgayesof tation NoF.enaolfe MaRattesd 1 (Control) 6-15 2 2 (Low) 1 6-15 2 3 (mia) 10 6-15 2 4 (High) E) 6-15 2 "dBuarsiedngontheinddoisviidnugalperbiooddy. weiDgohsets laetvelesachwilwleigbheindgeteirnmtienravdal upon review of the pilot teratology study data by the sponsor. C. Dosing Procedures (1) etAhdmoidniosftration Ttheeredtesbty moraatleriianltuwbialtlionbedaaidlmyiniosnDThaey 6dostehroaudgmhiniDsatyer1e5doftogeeascthation. freemcaelnetlywilrlecobredebdaseidndoinvidtuhael moasntimal bpeordiyodweiagnhdtwidlulrinbeg gtihveendosating adapyp.roxinately the same time each (2) RReoasuotnefor Dosing Otrheal reilnattuibvaetioenaseisofuseddosibnegcauasned of assurance of the dose emount. (3) PSroelpaurtaitoinosn/of Dosing Suspensions cSeonlturtaitoinosn/suwsipllensbieonpsreopfareedachfrecsonh- wVeeheikcllye inandDuskaem'pslescoronf oil. each dosing s48oluhtouirosn osfhouplrdepabreatsihoinppetod: within 000456 @HazLETon, -6- KToixlilcioalnogCi.stMcCormick, 111 MTeodxiiccaolloDgeyptS.e/r3vMices S2t2.0-2P6aul3,M MCNent5e5r101 Freezing is not required. (4) AnaSloylsuitsionosf/SDuosspienngsions (2) stability (3) Homogeneity (c) Routine Analyses 0. Mating Procedures To be conducted by the sponsor. To be conducted by the sponsor. To be conducted by the sponsor. (1) Breeding Opnleacemdalein aandbroneeedifnegmalceagewilulntible a sisufofbitciaeinntednu(mmbaexrimuonf mbarteeeddinfgemales period 1s two weeks). (2) vaginal Examinations eDuxraimnignatmiaotnisng,wildlailbey mvaadgeinaflor the pthreesepnrceesenacned ovfiabailciotpyulaotforsypeprlmugo.r DisayDaofy o0bsofervgaetsitaotnioonf. sperm or plug (3) Disposition of Males Tshaecrimfailcesed,wilalnd bedisacnaersdtehedtiwzietdh,out mnaetcirnogp.sy upon completion of the E. Observation of Animals (Dems) (1) Observations Adlalilyanfiomralmsorwtilallitbye eanxdamimonreidbutnwdiictey. 000457 @HAZLETON (2) Body Weights (3) Food Consumption F. Termination (1) sickD/eMaodrDiabmusnd/Found -7- Ad1a1ilyanitnharlosughwiolult bgeesotbasteirovnedforonce ocnlsienti,caldegsriegen,s ainndclduudirnagtiotnimeofof eifnfcelcudte., Cbuatgesniodtebeobsleirmviatteidontso, will mcuhcaonugsesmeimnbrsakniens,andresfupri,raetyoersy and sayusttoenmo,micciracndulacteontrryalsysnteermv,ous sbyeshtaevmi,or.somatomotor activity, and oIbnseardvdaittiioonns, cwialrlefuble mcaldienicaatl each weighing interval. oSbisgensrvewdi.ll be recorded as they are A6n,i8n,als12,wil1l6,beandwei2g0heodf ognestDaatyison0., Aprmoevaisduerdedonqugeasnttaittiyonof dafyood0,wialnld be fonoodgesctoantsiuomnptidoanyswi6l, l 8,be 1m2e,as1u6r,edand 2g0e."statAinoynfoiondteravdadlesd wduirlilngbethe recorded. Dbaencsausfeounofd dseiacdkneosrs saorcrmiofriicbeudndity waiblnlormbael extahomrianceidc,forabdaonmyingarlo,sslory pvieslcveircaviwsicllerab.e reHtoaianbendormuenlless ranedqueosvtareidesbywitlhle bseponesxoarm.inedUtefroir riemsppleacnttiavteiloyn.s and corpora lutea, Findings will be recorded. 000458 @HAzZLETON,, -8- (2) Dams Showing Signs of Abortion or Premature Delivery sDaamcsrifeixcheidbitbiyngcartbhoense disiogxnisdewiilnl be halation. Any grossly abnormal tvhiosrcaecriac,wilalbdboeminnaolt,ed.or pelvic No abnormal viscera will requested by be retainzd unless the sponsor. Uteri ainmdploavnatraiteisonswilalnd becorepxoarmaineldutefao,r respectively. Findings will be recorced. (3) Terminal Sacrifice On Day 20 of gestation, all surviving dams will be weighed and sacrificed by carbon dioxide inhalation. ~The fetuses will be taken immediately by cesarean section, see Section G.(1) below. G6. Postmortem Procedures (1) Cesarean Section A cesarean sacrificed section will on Day 20 of be performed on gestation. Any those females grossly abnormal 2tbhnoorramcailc, `vaibsdcoemrianawli,ll orbe psealvveidc viscera will be noted. unless requested by the No sponsor. eTxhaemiunteedrusforfrotmhe enaucmhbefremaalnde pwlilalcembeentexocfiseudt,eriwneeighed, and implantation of early and lsaittees,resnourmbbienrg offetluisvees,andanddeaadny faebtunsoersm,alintuimebse.r bTeheen utreemrouvsedw.ill Thneotovbaerireeswewiiglhledbeafetxeramitnhead cofonrtentthse have number of corpora lutea. Findings will be recorded. (2) Fetal Evaluations Each fetus will be abnormalities, and sexed, weighed, identified with examined a tag. for external 000459 @ ABCATORES AnERCA NC Lo. wAiplplroxbeimasteellecyteodne-antdhirpdrocoefss2e1d1 floirvevifsecteursaels efrxoammineaatcihonlitbyter DtuhreinWgilsvoinsceTreaclhnieqxuaeminfaotrioanssoefssitnhge fseofttusetsi,ssupeartdiecvuellaorpment. Taetntse,nti2nodn rielt]inab)e, ppaaildatteo, thaendexbraamiinnat(itohnirdofantdheleayteesral(size, sveecnttiroincliensg).procSetdauirnelse.ss Asbteneolrmarlaiztoiresblwaidlels bweilldesbecriubseedd fasor anomalies or variants. sThkeelerteamlaienxianmginfaettiuosnesuwsiilnlg tbeheeAvliiszcaerriantedRedanSd sptraoicneisnsged for msektuhlold,.`ToTnhgisboneevsa,luavteirotnebrwailll coilnucmlnu,deriedxamciangea,tioenxtroefmitthiees, oafndospescitfoircaaltioanndwiplellvibce agisrsdelsesse.d. BAobnenoramlailgintmieenst wainldl debegree described as anomalies or variants. eFxeatmuisnesatiwoinll inbethseelfeocltleodwifnogr mvainsnceerr:al or skeletal cBoengtiinnnuiinnggatpastthethoevarciearnvixendintoof tthhee rliegfthtutuetreirnienehohronrn,antdhe vfiisrcsetraa]vaielvaalsulaetifoent.us wTihlel nebxetfitxwoedfeitnusBeosuinw'isll sobelutpirooncesfsoerd ufnotrilskeallletaalvaielvaablluaetifoent.usesTnihsaveseqbueeennceselweilcltedb.e repeated Dead fetuses will be discarded without examination. (3) Tissue Preservation nTheeutrfaolllobwuifnfegretdissfuoersmalfirno:m each dam will be preserved in 108 ovaries uterus oArI glfyectuesreisne.will be retained in alcohol, Bouin's fixative, 000460 @ LABORATORIES AMERCA. NC "10 7. Final Report ATtowitnegrmiinnaftoiromnatioofn twniellstbuedy,preapafriendal anrdepsorutbmiwthtiecdh: includes the fol- A. Experimental Design and Methods B. Results (1) tMaatbeurlnaarl foDramt.a - Arranged by test group and supplied in (2) Data for each animal showing: dfisdpoisefitiicnoantito(nprneugmnbaenrcy csetsataurseanandsecdtaiyonof or sacrifice) fooidntecrovnaslumption at each bodiyntewreviaglht at each weighing daily clinical signs (b) Data for each dose level showing: numpblearcedof onanismtauldsy npurmbeegrnaanntd percent numSbuerrvivainndgpetrocecnetsarean dseacyti2o0n on gestation numtbheart aanbdortpeedrce(nitncluding meapnrenbaotduyreweidgehltivearty)each weighing interval mean body weight change for 6g-e1s6t,ati1o6n-20d,ays0-200-,6, an6d-8,6-20 meaant efaocohd cionntseurnvpatl isn mea(nindtievrimdiunaall tbeordmyinwaelighbtody wuetiegrhitnse wmeiinguhstsg)ravid smeuamnnaruyteriinnceidewnecieghtofs sucmlairnyicailncisdigennsce of gross pathology (2) fFeotraml. Data - Arranged by test group and supplied in tabular (a) Data for each litter showing: niudmebnetirfiacnadt_ipoenrcennutnber numobferTiovfe efaecthusessex numlbaetre raendsorpbeirncegntfetofuses numtbotearl arndesoperrbcienngtfeoftuses 000461 : Q@UAAZZLLEETTOONN Sue nmeuawmneeirgThitvaengbyfpeetsarelcxent of dead fetuses numcbaerry arndesoprebricnegnt feoftuses nnuummbbeerr ooff ciomrpp1oarntaatluitoensa fnglantation efficiency (implantations X 100 corpora lutea) (b) Abnormality data for each litter showing: niudmebnetr.ifiofcatfieotnusensumebexramined for external abnormalities; Pnuummbbeerr ooff ffeettuusseess wwiitthhina pnoarrmtailcullairmitesxternal variant numnnubumembrbeerr.ofoofffetffueestteuussseessexawwmiiitthnheidna nfpooarrrmtasilkceullleaitrmailtesxtaebrnnoarlmaalniotmiaelsy RHuummbeerr ooff ffeettuusseess wwiitthh a& ppaarrttiiccuullaarr sskkeelleettaall avanroimaanlty numHnbuumembrbeerrofoofffetffueestteuussseessexawwmiitithnheidna pnfooarrrmtaivlciuslc1aeirrmailtvsisacbenroarlmalviatriieasn;t inRciudmeenrce ofandfedteussecsripwtiitohn a ofparetacihcultayrpe voifscearbsnlormaanloimtayly (c) Cumulative data for each dose level showing: nSudnebnetrifoifcatliiotnterosf eexsacmhingerdoup Pmmeeeaaannn runeeuiimdgb]netrvioafanpdillpiiveetrycefnettusoefs lbiyvesefxetuses (live fetuses X100 MmeeaainnmpnnYuuammnbbteearr.tioaannnsdd)ppeerrcceenntt Mean number snd percent ooff of edeaardlyferteussoersbing fetuses Tate. resorbing fetuses eMeaann nnuummbbeerr oafndcoprerpcoernat loufteatotal resorbing fetuses mmeeaann niummpblearntaotfiiomnpaenfftiactieinocnsy Nunber and percent of 1itters with any external variant nnuumembxbteeerrrnaaannldd pvpaeerrrccseeannnttt ooff lliitttteerrss Wwiitthh aanyparetxtiecrunlaalr anomaly numebxteerrnaanld paenrocmeanlty of litters with a particular 000462 @ LABORATORIES AMERICA NC S12. nnuummbbeerr aanndd ppeerrcceenntt ooff lliitttteerrss wwiitthh eannyy sskkeelleettaall vaanroimaanlty numsbkeerletaanld vpaerricaenntt of litters with a particular nunsbkeerletaanld paenrocneanlty of litters with a particular nnuunnbbeerr aanndd ppeerrcceenntt ooff lliitttteerrss wwiitthh aannyy vviisscceerrael] avnaormiaanlty numvbiesrceraanld pvearrcieanntt of litters with 2 particular nunvbiesrceraanld paenrocmeanlty of litters with a particular nnuumnbbeerr aanndd ppeerrcceenntt ooff lliitttteerrss wwiitthh aannyy vaanroimaanlty C. Statistical Analyses Ttheestesdignuisfinigcanacpeproofprisautgegessttiavteistiinctaelrgrtoeuspts.difference will be Banoidmyalwseigdhutrincghantgheestraenadtmteonttalanfdoodposcto-ntsruemapttmieonntofphapsreesgnawniltl be aonnael-ywzaeydANbCyOVoAn.e-waIfy aApNpOrVoAprainadtef,etaDlunnweetitg'hsts tw-itlelstbewilalnalbyezed by ftperesortnf,ortmhweeildlcotnoutnrdioedlre.gnotiHfaeytseegrrriooegusepsneoofwuistthradanstsiafg,onrimfasaitciadonenttsleyrmtiodniefadfcehribeaynvteLevmeenaen'ss homogeneity of variances prior to performing the above analyses. KFriusshkearl--EHrawlilnisE'xacntonTpeasrta,metdreipcendoinneg-woany AthNeOVAnatourrea mofodithfeieddata, wnIionlnclpidaerbneacneepterrdifactosrmteetdsotboenforainntacrlieydnzedendcewiildnlactlabu.edepetIhrnefoarfdmodelidltoiwooinnn,gt:haese data. (1) Percent males/litter (2) percent fetal viability (3) Percent resorptions (4) ePxetrecrennatl,ofvitsotcaelralf,etoursesskeelxeatmailnedanowmiathlyaorparvatriicaunltar 000463 @BLE ABORATORIES AVERCA. INC. aT (5) Porercveanrtianotf t(oetxatlernlailt,tervsisceexraamli,nedorwistkheleatapla)rticular anomaly (6) percent of total fetuses examined with any anomaly or variant (7) Percent of total litters examined with any anomaly or variant AYeNvelt,esttswo-ftorailseidgnfiofricatnhceegraoruepmacdoempaartistohnes 5.an0d% ponreo-btaabiilleidtyfor Leven's F-tests and trend analysis. TShpeonsfoirnalwitrheipnortt,hreoer maondtrhasftofcopryeceofipts.uch,Anywilrlevibesiornesvieowredcombymentthse will be submitted to Hazleton within this period. 560/829/883 000464