Document OEBGKDpQVzLbagak7oyDpejaM

foHseon vefntne,13.305137i07.m75a45Bld,Madcon, I 608.241.4471 608.241.7227 Fax Sponsor: 3M St. Paul, Minnesota AR1X)%60-0420 `CORNING Hazleton FINAL REPORT Study Tide: Acute Oral Toxicity Studyof T-6669 in Rats (OECD Guidelines) Author: Steven M. Glaza Study Completion Date: January 10, 1997 Performing Laboratory: Corning Hazleton Inc. 3301 Kinsman Boulevard Madison, Wisconsin 53704 Laboratory Project Identification: CHW 61001760 Page 1 of 35 NEGEIVER SNC ET 00051 -_-- cCwHWe610o017m60 (COMPLIANCE STATEMENT `Acute Oral Toxicity Study ofT-6669 in Rats (OECD Guidelines) a`TnhdisDsetvuedlyowpamsenctonadnudctPreidnciinpalcescoorfdGaoncoedwLiatbhotrhaetoOrrgyaPnriascatticieo,n Cf(or81E)c3o0(nFoimniacl)Cwoiotphertahteion exception that analysisofthe test material mixtures for concentration, homogeneity/solubilty and stability was not conducted. StevenM. Glaze, Study Director Acute Studies Coming Hazleton Inc. Date 19-7) 2 00052 -_ cHCwHeWl61o00m17e60 QUALITY ASSURANCE STATEMENT `aTchciosrrdeapnocret whaisthbetheenOrregvaineiwseadtiboyntfhoer EQucaolniotymiAcssCuoroapnecreatUiniotnoafndCoDrenvienlgoHpamzelnetto(nOEInCc.D,)in PcroinndcuicplteesdoafnGdofoidndiLnagbsorreaptoorrtyedPrtaocttihcee,StC(u8d1y)3D0i(rFeicntaolr).andThmeanfaoglleomweinntg inspections were Inspection Dates From To Phase 10/24/96 10/24/96 Necropsy 12/29/96 12/30/96 Data/Report Review Date Reported to Study Director 1024796 12/30/96 Date to Management 10724796 12130096 ZL ho Doth Representative, Quality Assurance Unit 1-10-97 Date 3 C0053 -_ 00 cHCHwWe6o10o017m60 STUDY IDENTIFICATION Acute Oral Toxicity Study ofT-6669 in Rats (OECD Guidelines) Test Material Sponsor `Sponsor's Representative Study Director Study Location Study Timetable Study Initiation Date Experimental (In-life) Start Date In-life End Date Experimental Termination Date Study Completion Date T6669 3M Toxicology Service Medical Department 3M Center, Bldg. 220-2E-02 P.0. Box 33220 St. Paul, MN 55133-3220 Roger G. Perkins, PhD, DABT 3M Toxicology Service Medical Department 3M Center, Bldg. 220-2E-02 P.0. Box 33220 St. Paul, MN 55133-3220 (612) 733-3222 Steven M. Glaza Corning Hazleton Inc. P.O. Box 7545 Madison, WI 53707-7545 (608) 241-7292 Corning Hazleton Inc. 3301 Kinsman Boulevard Madison, WI 53704 October 9, 1996 October 10, 1996 November 14, 1996 January 10, 1997 January 10, 1997 4 eeesa _ Acute Studies Steven M. Glaza Study Director Manager Steven R. Sorenson Study Coordinator JeffreBy. Hicks In-lfe Supervisor Rose M. Bridge Administrative Supervisor Toxicology Support Kathy Myers Manager Calvin L. Horton Supervisor KEY PERSONNEL Quality Assurance Sherry R. W. Petsel Manager cCHHWw61e00o176w0 Laboratory Animal Medicine Cindy J. Cary, DVM Diplomate, ACLAM Supervisor Anatomical Pathology Thomas E. Palmer, PhD Anatomical Pathologist DeboraLh. Pirkel/ Jack Serfort Supervisors Necropsy Anne Mosher Supervisor Pathology Data 5 Q0055 - CONTENTS cHweowm COMPLIANCE STATEMENT................ corremasvermassenmasy ee unl `QUALITY ASSURANCE STATEMENT ................... ervnasserass ton 3 STUDY IDENTIFICATION ................... rteeeproro S-- wn KEY PERSONNEL.................. reerommpie" toni wrrennd OBJECTIVE..... sa rvs sono 8 TESTMATERIAL.................. Identification................ Purityand Stability... Storage and Retention. Safety Precautions ....... a ssresnassors - BI rererenpiem-------- ccrsrernass reesei rstrasseness rririasei Bo ee rserasveriasen wd annS rein 8 wisneS TEST SYSTEM er Test Animal... . aitsnesassion Housing. " ren AnimalDiet ......... Sririni: Animal Selection and Grouping............ Justification for Species Selection ieerseprpini rte WR a espa -- wasn) aun end psn nsrnrinmied puss 30 PROCEDURES........ Grote Preparation and Administration ofTest Material Reason for Route of Administration................ Observations... " = Pathology " StatisticalAnalyses. E J LocationofRaw Data, Records, and Final Report. en eteepmespimtiatet SO e serraeion re ttseseprote pe -- 10 -- wuunell 11 assess 11 RESULTS. oetresoo Mortality sts Body Weights. itt ClinicalSigns............ Pathology ss" rerio a -------- ers rt stv ctreerassererassoerasssnn ST ssevnsonnss Bl wali 1 n well DISCUSSION................... rrestaererssinasin assim 12 00056 -_-- SIGNATURE........... S------------ cCHHWW610l01o76e0 - enensrsmmnenen 15 PATHOLOGYREPORT.......... eso ---- -- cn 14 TABLE 1 Mortality Summary...... csr ry 2 Individualand Mean BodyWeights/ BodyWeightGains (g) -- -- lS wr 16 3 Individual Clinical Signs. ener 4 IndividualPathology Comments............. esses wo 18 -- ener nl APPENDIX........ tne Protocol TP2069 ............... Protocol Amendment No. 1 Protocol AmendmentNo. 2 Protocol Amendment No. 3....... cess esos wonernsllS cweses ener S-- wes esses nin 33 -- ss nin 34 I S-- onnaS 7 C0005? -_-- cChHwWe61i00u17m60 OBJECTIVE `Theobjectiveofthis study was to assess the acute oral toxicity produced when the test `material is administered bytheoral route (gavtaograets)." All procedural times presented in this report fallwithinthe acceptable ranges as specified in the Wisconsin facility of Coming Hazleton (CHW) Inc. Standard Operating Procedure (SOP). TEST MATERIAL Identification The test material was identified as T-6669 and described as a white powder. Purity and Stability `The Sponsor assumes responsibility for purity and stability determinations (including under test conditions). Analysisofthe test material mixture for concentration, `homogeneity/solubility and stability was not conducted Storage and Retention The test material was stored at room temperature. Any unused test material will be returned to the sponsor afer issuance of the final report according to CHW SOP. Safety Precautions The test material handling procedures were according to CHW SOPs and policies. 8 00058 TEST SYSTEM CHW 61001760 Test Animal Young adult albino ratsofthe Crl:CD (SD)BR strain were procured from Charles River Laboratories, Inc. on September 23, October 7, October21, 1996 (Portage, Michigan facility) and on October 1 and October 15, 1996 (Kingston, New York facility). : Housing Afer receipt, the animals were acclimated for a periodofat least 7 days. During acclimation and throughout the study, the animals were separated by sex and group housed in screen-bottom stainless steel cages. Environmental controlsforthe animal room were set to maintain 2 temperature of 19 to 25C, a relative humidity of 50% 20%, and a 12-hour light/12-hour dark lighting cycle. In cases where variations from these conditions existed, they were documented and considered to have had no adverse effect on the study outcome. Animal Diet The animals were provided continuous access to Laboratory Rodent Diet #5001, PMI Feeds, Inc., andwaterexcept for approximately 17 to 20 hours before test material administration when food, but not water, was withheld. The feed is routinely analyzed by the manufacturer for nutritional components and environmental contaminants. Samples of the water are periodically analyzed by CHW. There were no known contaminants in the feed or water at levels that could be expected to interfere with or affect the results of the study. Animal Selection and Grouping Ten male and 10 female healthy, acclimated rats, weighing from 208 to 269 g and approximately 8 to 12 weeksof age, were assigned to two treatment groups of 250 and 500 mg/kgof body weight. Each dose level consisted of5 male and $ female rats. The animals were identified by animal number and corresponding ear tag throughout the study. 9 C0059 -_-- cHCHwWe61l00a17m60 Justification for Species Selection Historically, rats have been used as a representative ofa rodent species and are preferred by various regulatory agencies. PROCEDURES Preparation and Administrationof Test Material The test material was mixed with distilledwaterto a concentrationof0.025 g/mL for the 250 mg/kg dose level and 0.050 g/mL for the 500 mg/kg dose level. The prepared test material mixtures appeared to be solutions. An individual doseofthe respective test mixture was calculated for each animal based on ts fasted body weight and administered by gavage at 2 volume of 10 mL/kg of body weight. The test material mixtures were stored at room temperature until administered. Reason for RouteofAdministration Historically, the oral route has been the routeof choice for administering a known amount oftest material Observations Clinical observations and mortality checks were conducted at 1, 2.5, and 4 hours after test material administration and daily thereafter for 14 days. Mortality checks were conducted twice a day (morning and afternoon) for 13 days after test material administration and again the morningof Day 14. Body weights were determined before test material administration (Day 0). Additional body weights were determined at Day 7, at terminationof the in-life phase (Day 14), or at death when survival exceeded 1 day. Pathology At termination of the respective in-life phase for each dose level, all surviving animals `were euthanized. All animals, whether found dead during the study or euthanized, were 10 00050 _-- cCiHwW e61o00m176m0 sreucbojredcetde.d tAofatenranbebcrreovipastye,dtghreoasnsinmaelcsrowpesryeedxiasmcianradteidonanadndnoantyisasubensorwmearlietsiaevsedw.ere Statistical Analyses No statistical analyses were required by the protocol LocationofRaw Data, Records, and Final Report The raw data, records, and an original signed copyofthe the archivesof CHW in accordance with CHW SOP. final report will be retained in RESULTS Mortality A summaryof the observed mortality is in Table 1. No mortality was observed at the 250 mg/kg dose level. Two males and all five females treated at 500 mg/kg were found dead within 4 days of test material administration. No other mortality was observed. Based on the observed greater than 500 mg/kg mortality, for males the estimated and between oral 250 LD values were determined and 500 mg/kg for females. to be Body Weights Individual and mean body weights and body weight gains are in Table 2. All surviving animals exhibited body weight gain throughout the study. Clinical Signs Individual clinical signs are in Table 3. All animals treated at 250 mg/kg appeared normal `dwuertinugrotgheenisttauldayrweiatwhitthheinex2c4ehptoiuornsooffttewsto mfaetmearlieaslwahdmiicnhisetxrhaitbiiotn.ed rCeldin-isctaalinseidgnfsacoefand/or toxicity observed in the animals treated at 500 mg/kg included red-stained face, yellowstained or wet urogenital area, hypoactivity, hunched posture, staggered gait, excessive " 00051 salivation, and death. `appearance by Day 7. we The surviving animals treated at 500 `mg/kg returned to a normal Pathology Individual gross necropsy pathology findings are in Table 4. A summary report by the study pathologist is on Page 14. There were no test material related lesions observed at DISCUSSION `The acute oral toxicityof T-6669 was evaluated inmaleand female rats when administered asa single gavage dose at levels of250 and 500 mg/kgof bodyweight. Based on the observed `mortality, the estimated oral LDs, values for male rats was determined to be greater than S00 `mg/kg and between 250 and 500 mg/kg for females. All mortality occurred at the 500 `mg/kg dose level within 4 daysoftest material administration. All animals treated at 250 mg/kg appeared normal during the study with the exceptionof two females which exhibited red-stained face and/or wet urogenital area `within 24 hoursoftreatment. Clinical signs oftoxicity observed in the animals treated at 500 mg/kg included red-stained face, yellow-stained or wet urogenital area,hypoactivity, hunched posture, staggered gait, and excessive salivation. Animals surviving to the end of the observation period exhibited body weight gain during the study. The grossnecropsy `examinations did not reveal any test material related lesions. MW StevenM. Glaza Study Director Acute Studies SIGNATURE feo Date 12 C00052 _-- cCHHWw610O017m60 REFERENCE 1. "Acute Oral Toxicity," Organisationfor Economic Cooperationand Development Guidelinesfor Testingof Chemicals, Section 4, Health Effects, Number 401, Paris Cedex (February 24, 1987) 13 C008] --_-- cCHHWwe61w00o176m0 PATHOLOGY REPORT Therewere 10rats (five male, five femeacahflromedo)se levels of 250and 500 mg/kg snuercvroipvsiinegd.aniAmlallsanwiemraelseguitvheanniSze0d0 amngd/knge,creoxpcseipetdfaotrtthhereteermmailneast,iodnioefdtohnetesstt.udyT. heThe dose level, Individual dayofdeath, and gross observations Pathology Comments that follow this recorded report. for each animal are in the uAntrenleactreodpstyo,tthheetreestwemarteerfiaelw. fiInnditnhgesaannidmaalllsofthtahtedsieedwoenretecsot,nsoindeermeadlienwciadsenptaarltiaanldly cannibalized, one female had multiple, dark brown areasofvariable size in the glandular cmluecarosflauoidf. tThheestpoemlavicsho,fanbdotbhoktihdhnoerynssoinfontheefuetmearluesgiinvaenno2t5he0rmfge/maklgewwaesreobfsiellrevdewdittho be large. There were no visible lesions in the remaining animals. Thomas E. Palmer; Pathologist (61001760.fin) 12169 Date/=v0-F7 14 00054 ' -- Table 1 Mortality Summary CHW 61001760 Dose Level (mg/kg) 250 250 Sex No.MoDriteadl/itNyo.ResDuolstesd Mos Fos 500 500 M25 Days3', 4! F 5/5 Days0', 1, 3%, 42 * `Saunpiemraslcsrfioputnndudmebaedroinndtihceatiensduicmabteedrdaoy.f 15 000s5 -_-- cCHHWw61e00o176m0 Table 2 Individual and Mean Body Weights/ Body Weight Gains (g) Animal Day0 Number Weight classi 269 C2550 cull 269 2a ci612 259 cisl3 253 Mean 260 Day? Weight _Gain Males (250 mg/kg) 330 61 325 56 307 59 296 37 29 3 31 s1 Day 14 Weight Gain 38 14 339 70 3715 127 354 95 315 a2 365 106 Females (250 mg/kg) C137 261 C1267 248 clases 23s C2369 259 cnn 22 294 3 285 37 280 45 303 a 287 35 315 54 294 46 285 50 309 50 288 36 Mean 251 290 39 298 47 * Gain from Day 0 body weight 3 00056 _-- cHCHwWe61w00a17m60 Table 2 (Continued) Individual and Mean Body Weights! Body Weight Gains (g) Animal Day0 Number __Weigh csr a3 ci227 221 CC22222298 208 217 C230 21s Mean 215 Day? Weight __Gain Males (500 mg/kg) 249 36 ant. 168)" - 2m 54 274 59 265 50 Day 14 Weight _ Gain 302 - 8.9 - - 320 103 34 119 319 104 Females (500 mg/kg) C12276 ci277 248 3 C127 24 C1279 246 C1220 236 Mean 235 a(1rs.t- @a as). -- - - - . - - - - - - - - = Gain from Day 0 body weight Animal was required. found dead on the dayofdosing. No body weight (1) cVoanlsuiedienrepdariennctahlecsuelsatiisnga tdheeadmebaon.dy wSuepiegrhstcrainpdtwnausmbneotr indicates the day the animal was found dead. = Not applicable. 17 00087 -_-- cChHwWe61n00w17m60 ates [-- EMmEeOwevwin i TOWTTTTr rrmw mom Miastomrae COS Mpesivomd 4S REI LLL rts t rs ss ss, II F A I E RE C0 Npastvomil 4 LL I I A AE Ltt stv rss, Fen@sa0mlense CeSMpoanteeesA 4 4 ooA oo L LA us1 sA s uA s0 s As 0 R , Ces pivot CeSpeirs 4 LL SLs ttt dr sss, 4 fs sus ssss rs, RWeevwgsewie .cL LTLIT0 TLLTI01I1NI Ld FREE I A A AVIA 18 00058 _-- cCHWwe61o00o17m60 Table (Contract) Indien Cline Signs TMEeNummbberObuevoamion ETECO2WE1wNH0TTSE3N 3Tv TSV mW BEE Male (500mg) Cm AVB epleloswi-snsneemdd 4E 4coL TIE T T u LLA n , n A RA rogeers CmspRpeetrriinoedeemes 4 TL . L HHoipnocabseidvipyose L- LLSL Ls L SFuogugnedsdtodgt s 0d 1, cms A[pewaeimnerems 4O 40 A . HVoeploouwcsisvinyes opereas PE PE Founddent oo PE BLr rBEE A AA A A A A Re RA RA A AA A A T7 Ceomn--mdt--eoinn 1 00089 -_-- cCHHWWe61l00m17m60 Table (Continent) IndddenClic signe NHuoEmbmEeerObwevesniioonn T0O35E3w 000TT F3T75 T%e7r TS ST WnwnmE Fem(a00lmeeres) Rebmocatis LLA LJ VHypeo geta Hudgens L - LL REL) ] Found de sii. Cm [Arpomeourritn 4 ss a HVpaoswcgivmiiyiua SLL LLT 4 FHouucndhddepsotmwe L olL 7H0a EI cesvenivien , Founddod T cm [srpermeirnont 4 4 . HWyeptoursogievriy wea : DDod StFauggnedreddepdaite Cineloer) |[az crm RAepbspameedatore 4 40s.o HVyepowgetiun Hunchdporre LSLet 0 5e) PE. SaFogugnededdespat So ilisv, T7 CConnkoevidnent mW 20 Table 4 Individual Pathology Comments Dose Level: 250 mg/kgof Body Weight CHW 61001760 Amma Number Sex cissi Mm cso M cis Mm cis M cies M cm F ci367 F clases F 12369 F cnn OF "Notapplesble Tey Died Sacrificed - 14 - 14 - 14 - 14 - 14 - 14 : 1" - 14 - 14 - 14 Necropsy Observation No visible lesions. No visible lesions. No visible lesions. No visible lesions. No visible lesions Bpeolvtihso.fthe kidneys haavlarege No visible lesions. No visible lesions. No visible lesions. No visible lesions. 21 00071 ) CHW 61001760 `Table 4 (Continued) Individual Pathology Comments Dose Level: 500 mg/kgof Body Weight Aum Number Sex cs M ci27 M cls Mm C2220 Mm cso M cz F ci OF cz OF cz OF ci OF ST Netappliable. Teby Died Sacrificed - 14 4 - 3 - - 14 - 14 3 - a - 0 - 1 - 4 - Necropsy Observation No visible lesions. The right flank was cannibalized. No visible lesions. No visible lesions. No visible lesions. The glandular mucosaofthe astomrauchpehta0as2mxusl|timp,lme dark brown No visible lesions. No visible lesions. `tThheeulteurmuesn iisnfitlhleedbiwliatthercalleharorfnlsuiod f No visible lesions o0072 2 --_-- cCHHWW610l0u17m60 APPENDIX Protocol TP2069 Protocol AmendmentNo. 1 Protocol Amendment No. 2 Protocol AmendmenNot. 3 2 00073 _-- ene ro zw cCHwWe61o00u176m0 w= { | I fC Sarmo pyloveeo AbSeutbSmteisitrc tOu apealrrrFnnotramoynymoaAr is fC5SHcWgKrSaoa rysenNoeSe .o_d_dsC1nOdD260 Summa Coromy 300 Eons FAGL Corres: Lv ron Tsaorm NorbarlPupo Pong. 3 -- el sumoio ame: _T-L0od ony Toeramroc1n) = rr= SPouacliHOaunraontePnr:ocess:__i_STEe onSo06 TO-ZVOL imaa rrseis0CHyon tncoo ng ur oors)on --ewvon.ty vere yo CA GolBeer = Saple SorageRaqukermens: h5s33e500 Jin CoE Rh YT Xneoentdampates -- ---- Oto ctnrg co some * ME 143 cr o Speer Cweyi [ro] eteOrtToibn tts ePaoPn e ttsava atstan i rEC0 Ronmrsaccdm0oe3dy0apaeocsrno,ns. 50585 ToIprrNinGsPetacSonrnnaaaersnaenhaseitn (ense Okco ote S KrioosCCSroEp amnwtdeosyrr eyVos th Cneoe vmeu5a5g3tyge | -- _ ---- ns ---- ee tyenaton ArciutreEDaunmaPEohTnensseermneasuasrtawszogng TT Trmoaan w aan eian sine3mr ame meevt ous f T C iSaEnn E hedn uy iebgaty2 cm i0oPlgYy scram a a ------------ ee TWO cr n rese e--a rconT esmatin I Proc suOt: ua. | SSormeaen Re amastress CoC otocorny mm 2 00074 _ @HAZLETEN Ha Sa NSN sonar: st. pan"homens roroca Tass KesterTStTudodtyTtiiytlet:ay 1 bts aneDa1t,e:1593 drSattr,eSniweiasscornBsnoinw,eSntess. Coane LabPorojrectaIdetntioficr atiy on: eawweoaoorrrswo 00075 25 _-- cere cHw61001760 eF2e0z6 STUDY ToENTIFICATION Acute OraolcTcosGteuittyasitnudey fn Rats No. Test Matertal Sponsor Sponsor's Representative Study Director Study Location PrEopooesredieSnttudly STiseTtabBre FiExnpaelriRmeepnotratl GTaetremination Date creoines (see sample submittal form) THe0x-i5cEo-tten0o8nysseeCrrvainceers Shad, Sian JEToodshtenoloLn.y Butea, pO Services Ssi2a0E)-3,7E3.-310i54062C"anStiear H#sat6zetveeStnoonnK.TWicaslicaornasin, Inc. Raasdi)con2s01U7T25253707-7565 Ssa6az0ft2iectiPonangcketWori.sscAovnseinnu,e Inc. Hadison, ui s3704 peek ar 1200 MVeaeekk ooff a/r2.%e.5 00076 26 _-- cCHwWe6n10u017m60 TPa2g0e8'9s 1 SActuutye oral Toxicity Study fn Rats (OECDGutdel nes) 2. PTaduoarinsnasistseetsesretdhebyacutthee oorraall rtoauxtie.cit(y3uvpargoed)ucesdo rwhaesn the test material 1s 3. BLTehasibusolraastttoourrdyyyCPIorTmaTpcltiibceaenCRcoeengduulcattefdonfsn/Satcacnocradradnsc/ecuwtidtehl tinhees:following Good [[1]1a4C0oneCdrukcstleaos"da(oEoPtAn-rre1geumlna)ted Study {J [[1 ] aCdot1t1cfr3ei0css(eiFion(naElth)oAT(as0E6aRD),) nat to, tao otiication Ko. 313, March 31, 1962, 41cdaaps essenadryby Notification No. &70. October 5, 1568 {ospancee Horm) d4i1e1rlefcaptrroeorc,AecdttuhreeRsegsutilunadtytihodinosse:sprontaIokncoutlhneneacorepesisnfainroincloymopfld{utaphnelciecSaptoweintshsornthspenrdeAsnsiiimouant]sy 4 2F[Q4eoutprhiorrttHeeagziuAllTsea)sttuoerndbaenWsciatesuucddoiinetsse,idnbtyh(eWtIph)erQoSuttoaaclonldI,airydsAtOsupsdeuyrraactnoicnnedgucUtnP,irtocaen1ddnurtsehtsecorf(diSaonranelt)e and policies. 5. lest materis A J(eSenetisfaimcpalteiosnubmittal form 8. Ph(SuesetcSaalmpleescsrciboatritoian) fom) dapTehtereurStapiaarnennastdoriSirotinaassbtasiu(lmiliyentscsylurdieisnpgotnusnidbyeirlitLye1stfocsronptduirtiiitoyn)sa)n.dosrSteaebpitlaistyof aIcSfpoTtonTencrseobnreet.xrpatetariTkiohennene,snebtesafsoloalrumetbpeillreaimsdtiaynt(,a1ntfiisotthnoarskaoetfgnoie)ronncwpiiot1lsyl,siarbbenleqedsesaesstanntbiltaeityldytosb.iyst.hteheaSnpaolnyssoers 00077 27 _-- cwCHeW o610w01m760 TPra2g0e6'9s 0. STtEoEreSsapte subateen form) EfShrtauvedeinerseSsoeifrmvpeTleesssa;sptlheisn retwseienkesd.in experimental duration will not dRLiaerksaeetnrivoeinF.stahsipsle(sst)udyof15exmcohrebattchhanyTa4teocfkstesItn emaxtpeerriiamlentwailll be sTfhiregerpeozttseeirsttisomentateSroiniTaima)ecacionnrrtedastaisnnrocveea wWitsthaemmppTleterhaewtCuirs)epoprobnoefperbsietalotSorewedtr0eagCtuelWfaaEatror1nIy0n TJ+earrs Laboratory practices: 4 F fAtonhtyeenuftinniuaoslnedretpeosrtt,matuenrfieasls WGIiIr)ectbseddicsicraerrdiesdeabfyterthefsSspuoamnsceer.of 6 SRaaferteyqupirreecdaubytiMonls S075 and policies 6. ExmertmentalDesion A tatmis ) sRaotecies @ sFTtCWoraiyrcsCiharatess Rivenr eLarboratrortiess, MInic.e, oc ) fnYaoeturatsti3dauTtt ion (4) aZitioa3ta0I'nsibtiattion (5) fumsmaiblleeerssannagansoe$rxteSmafteemsalefsorftohreanfyaftaida)iticoonsse]Tdevoesle levels (5 required) (6) LIendnitviitdiucaaltsnounmbered ear tag 28 00078 _-- cCwHeWls1o0w01m760 eF2e0s8 0) tushangry @) SSfteoapuiasnriianetgsesd sbhyeestexcaagneds"gr(orupenhosueseemds){n screen-botton ) aERfdoomndsietntnitst(Crhoaomtviooun1t.5r0i0g1hhet(Pufuroiofndao1WsiATrelossu,stiknTienl.ya)sapadly1ziebditubny etnhveirmoanumaencttaulrenrtafnoirmannottei:ons] comments' sg aRwateredTrrnoetsatsr:eenIannrdaolSyspzeeacdifsbiyedmImiccfroorbsiototlanolg,ica1lsssucootenetesedntoofiarige, aTrogranSceplhaotsupehdaetleesn,inntds', chiovryinemettesdrsR.drocarbons. TTCRhoEenErteaw"moaiuTnlead"nntssSntkenrowTnerscownittahmitnhanetsssfinntdhe food ar water () rfsEeuetluaitrTNiaovmemmaeEiRnnotmtadilnceoysntortfoelmsBp0e%rfaostr5u0rt%eh,eofaann1dt5aet1o2r3hus9oecCksi1l be TIGhe/13-hou dare crete. HE. () 7Sas03dseeeSqdnuialmtoaen1eRoneu"fIamncTTbGteehhrtsvitaoianfudnteiotbxymoedanspysooI`vrnetlthoaehlLtsTEaRRcIcT1o]4rdxpilnagcpeotsrochaWaeIsessaSsOsPosa.theAtn ) JHrJoiadSuretnoitrsiicSaahtetcilyii,s'foraarntidsSpcdheracevaieperssteSefeeesilrerscoeitdeidnoibnaysvarerpiroessenrteaptuiivseioosf a 8. 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Feo2e0s6 FRoTGCoL APPROVAL l SEdponsaolers a Represental tive l sStheWveeneihr.ercGtTaa,rzs MN Bue HaczilteetonToxWiicsoconsin, Inc. QRueaplreEsZyenitRaasetuirvnaenceunitAllyn Hazleton Wisconsin, Tn. (rv2065.) qui ex [2 es we wst0: 00082 32 so _-- cCHwWe610o017m60 ve. _creizes PROTOCOL AMENDMENTS |I AendaentHo. _1__ | Effective _ crocs9 90, | [{ Proferotocoa einmoet: I ogc cet ton at he pag I |l |[| rvviCsnnoflro esse)teeinnS:ooTTroo dsgeenpt hante e cain e SnMenme apfr-- | f| -- SSaoraiRvarhrazaleStoonnnIinncg.com || eae I I l Study Director dpprovat: ___ 3Nia 1 Mop os | (621/01-07-91) -- - -- - 000S3 33 " wom CHW 61001760 he. _eresins PROTOCOL AMENDMENTS ( | Effective feendeent vo. _2_ _Oxnagen9, ro lportion of protocol Being Modified: Pace4, 6. Expertoenta) Desion:A, | pevcsateotretosmoaranee, mstcl pat0 te sm7 e soe Er -- -- --fealice thissectionwith thefollwing change: -- [ L @m Study Director Approval Rou, - Moe | Anima . | | | wan | = se 00034 Ioh _-- cwemm PROTOCOL AMENDMENTSOMe. _clooug [ riento. 2 | | fro of Protocol Being Madified: _E_paxge p5. 6.erioeestann: ta)| reason for moatication: | treated intianiy im ion aamn odiication: Lm i i eee eS | (1701-07-50) - i 00085