Document 6wEwBO7n4jNJE0xKrOZdpraRm

none . DFKoiirnvaenr 330)s3K707n545Bd ai sa Makin 1 04 AR 226-0461 * CORNING Hazleton Spansor: ! 3M Vi St.Paul, Minnesota ECEIV =i1 FINAL REPORT APR 30 B37 I Study Tite: : 5-Daily Dose Dermal Absorpion/Toxicty StudyofT-6564 in Rabbits i Author: F.Bud W.McDonald : Study Completion Date: . April 28,1997 Performing Laboratory: -: M3a3dC0io1smonKi,inngWsiHmsaacznolneBstoiounnleI$nvc3a.7r0d4 : Laboratory Project Identification: CHW 6329-185 Page 10750 4 EBi [-- - a 2976 cuweszss 3 QUALITY ASSURANCE STATEMENT This report hasbeenreviewedbytheQuality Assurance Unitof Coming Hazleton Inc. in accordancewiththe Food and Drug Administration (FDA) Good Laboratory Practice S{toatnhdearSdtsu,dy21DiCreFcRto5r8.anTdhmeanfaoglleomweinntg.inWspreicttieonssawteurserecpoonrdtuscoftiendsapnedctfiionndsinagsndrefpionrdtiedn.gs ae issued to Coming Hazleton management according tostandardoperating procedures Inspection Dates From. --To Phase ReDpaotreedio SwdvDirector RepoDnaiteed to Management 09/30/96 09/30/96 Protocol Review 10/01/96 10/01/96 i 1012//0032//9976 0112//0032//5976 ProStaomcpolleAHmaennddlimnegnt 011/20/032//9976 0112/0032//9976 4i 01/13/97 01/14/97 Data/Report Review 01/14/97 0114/97 i Orie fo Dror Representative, Quality Assurance Unit -28-77 Date i ; . 2 NR C0977. " -_ cchHwwe9m-a18s5 : STUDY IDENTIFICATION ot} 5-Daily DoseODferTm-a6l36A4bsionrRpatbiboint/sToxicity Study Test Material T6564 Sponsor 2 i M ToMxeidcioclaolgyDeSpearrvitcmeent 3P.M0.CBenotxer3,3B2l2d0g. 220-2E-02 St.Paul, MN 551333220 : i4 Sponsor's Representative RMoger G. Perkins, PAD, DABT Tosicology Service 1 1 Medical Department 3M Center, Bldg. 220-2E-02 : P.O. Box 33220 2 St1.2P)au7l3,3M-3N22255133-3220 "4 Study Director :i } F. Bud W. McDonald CP.oOm.iBnogxHa7z5l4e5ton Inc. M(6a0d8i)so2n4,2-W7I50153707-7545 : Study Location 4 C33o0m1inKginHsamzalnetBoonuIlnec.vard ) Madison, WI 53704 2 Study Timetable : Study Initiation Date Experimental (In-ife) Star Date October 25, 1996 October 28, 1996 ! ElxovplefreimEenndtaDlatTeermination Date: NAporvielm2b8e,r19295,7 1996 Study Completion Date April 28, 1997 | 4 3 A 02978 . -_ KEY PERSONNEL chcwweenswsess - Acute Studies Laboratory Animal Medicine . MaSnteavgeenrM. Glaza CDiipnldoymaJ.teC,arAy,CDLVAMM Francis (Bud) W. McDonald Supervisor Study Director Anatomical Pathology JIne-flrifeeySBu.peHrivcikssor Thomas E. Palmer, PHD : Rose M. Bridge Anatomical Pathologist i: Administrative Supervisor IDenbkorSsehrfLo.rPirkel/ ii Toxicology Support SNuepcerrovpissyors MKaanthaygeMryers - CSaulpveirniLs.orHorton : Quality Assurance ) SMhaenrargyeRr. W. Pecsl 3 ii 4 : } _i ] 02979 CONTENTS cH e-1ss : QUALITY ASSURANCE STATEMENT ccm STUDYIBENTIICATION wuss CITEE sEssmTmmVmmensmmmssmmsmnsmsssmasmsmmmmmmons' i REGULATORY COMPLIANCE wv 3 TE ANDCS ONTT ROL MATERIALS... 3 FE) i FE : SH08017dRERCTEIONE rrr 10 SAEPICCUIONS.0ocrerresensneneeroene 10 Si Animal Dit... wmm---- aol) Selectionof Test Animals. mm----------)1 . StudyDesign........ " an mmm} : JustififcoraStpeicoiens Selection nmn----------l ; DROCEDRRIS ummm] jEi PDOESEPAAAMTIOAIfSEITXPIROUSOOUINNE ATEe R. r re e es s e]12. : ReasonforROU OfAGTIRISURION.......vrereoeneerrneeoron 12. : OBSEIVAIONSOFARMAS roses 13 :i BPlRoUoRdOISOaRmYplev COllr ecionSSHIPMEDL......eorroroerer--ee--reroeoc13 ! ShipmentofBileandTissues.. msn 14 3i LF ocatofiRoanw Data, Records, and FinalReP port .....v.ororvrrrrroorrr 14 HA = - Ce 5 ee " 02980 ! cH gs29-155 CBHOIYCWAEOIGBHSSE.IcViAIsInOsRSs.mcsrrsremmsmoennsmmnnoomssnssonnssnenss er een 18 13 . DIEIR-- S nmmmmmm--mn--m--am--a--mo--n--mm--m--a--mmy--l DISCUSSION... 16 : TABLE } E) 1 2 IIndnivdidiuavlaiCnRddIMuGeAaallnSIBoGdNySWer ights (8o )... vers or 118 ii 3 Individual Derma Iiation Scores Group I (Control-) Distilled Water (0.0 ME/Kg/day).....ccvcvcvcrvrcrvrvsvneeld i 4 Individual Dermal Imitation Scores - Grup 2 - T-6564 (10.0 MFKGAY) ccs20 : APPInEdNivDidIuXalA Animal Patv holOgyDatao ren versiso wsmnmmnsndl2l2 i i ADPADOIEOCNO!DTIPBE,3SsTppmr ommsssesnr sssmmmmasr mmmn essA es : Amendment N1o0t.he PIOIOCO! rrr ssmmmem---- A HN1 6 - - 02981 0 cw 620.185 - SUMMARY "This study was done to assess the systemic absorption/toxicty and relative skin iritancy ofT-6564 when applied to the skin ofrabbits for 5 consecutive days. `The study was conducted using three male and three female acclimated rabbitsofthe Hra:(NZW)SPF strain for each treatment group. TC T owl DoseLevel" NumboefrAnimals Group TestMaterial _(mgkg/day) -- Males Females L 1 (Co2ntrol) DistTil6l5ed6w4ater 10000 33 3 3 2 a Administered at a dose volumeof0.5 mLkgofbody weight. : "Thebackofeachrabbitwasclippedfree ofhair andasingledose oftherespective control or test material was administered 0 the skinofthe rabbits for 5 consecutive days. `The treatment sites remained inact. Theareaofapplicationwas covered witha gauze patch secured withpapertapearound aledges and overwrapped with Saran Wrap and Elastoplast tape to provide an occlusive dressing for each approximate 23-hour exposure i period. Clinical observations were conducted predose on Day 1andat proximately 1, 2.5, and ; 4 hours afer each control or test material administration on Days 1 through 5. Morality : checks were conducted twice daily on Days 2 through 29 (a.m. morality check only on . Day 29). Additional clinical observations were conducted daily on Days 6 through 29. 1 Body weights were determined on Day -S for randomization purposes, before the first control or test material administration (Day 1), and atthe scheduled sacrifice interval (Day 29). Theinital dermal iritaton reading was made before the frst controlo test material administration (recorded as the Day 1 reading). Subsequent readingsof dermal imitation were made afier each patch removal on Day2s through 6 and on Day 13. A blood sample (approximately 4 mL) was collected from each animal on Days -3, 8, 15, K and 22. In addition, at the time ofnecropsy (Day 29), approximately 20-40 mLofblood was obtained from each control animal and approximately 20 mLofblood was obiained 4] 7 - .- ---- . 02982 7 cH 69.185 - fromeach Group 2animal. Allsampleswere centrifugaend separate samplesofserum `and cellular fractions were obtained and sent frozen on dry ice to the Sponsor. On Day 25, the animals were anesthetized with sodium pentobarbital, bied via the posterior vena cava, exsanguinated and necropsied. The whole liver, bile, an approximate 1-cm x i 1w-eermesceocltlieocntoedfftrhoemdealrlmaanliampapllsi,cawteiionghseidte,(vaonldubmoetohnkliyddneetyesrm(icneodlfloreabcislteo)en, deansdamsepnlte) frozen to the Sponsor. `Applicationof T-6564 did not result in any test material-related changes in body weight gain or macroscopic findings at necropsy. All animals appeared normal throughout the study. In the distilled water control animals, no dermal iitation as observed in one. animal and slight to severe dermal iitation was observed inthe other five animals. In the animals treated with T-6564, slight dermal irritation was seen in tree animals, and : `modetorsaevteree dermal irritwaatsiseoenninthe other three animals. The reason for | the unexpected dermal irritation in the distilledwater control group was not determined. J 5 -- C02983 1 CHW 6329-185 3 OBJECTIVE : "The objectiveoftis study was 1 assess the systemic absorption/toxiity and relative : skin iritancy ofa test material when applied o the skinofrabbits for consecutive days. REGULATORY COMPLIANCE `Thisstudywas conducted in accordancewiththe United States Foodand Drug `Administration Good Laboratory Practice Regulations for Nonclinical Laboratory Studies, 21 CFR 53, with the exception that analysisofthe test material mixtures for . concentration, homogeneity/solubility, and stability was not conducted. All procedures i used in ths study were in compliance with the Animal Welfare Act Regulations. In the i `opinionofthe Sponsor and study director, the study did not unnecessarily duplicate any 3 previous work. All procedural times presented in this report fall within the acceptable. 3 ranges as specified in the Wisconsin facilityof Coming Hazleton Inc. (CHW) Standard ` Operating Procedure (SOP). i TEST AND CONTROL MATERIALS : Identification "The test material was identified as T-6364 and was described as clear, colorless liquid : "The control material was distilled water (Neensh Springs; Expiration May 20, 1997) and 1 was described as a clear, colorless liquid. tH Purity and Stability ; "The Sponsor assumes responsibilty for test material purity and stability determinations : (includingunder test conditions). Analysisof the test material mixtures for N concentration, homogeneity/solubilty, and stabilitywasnot conducted. The purity and 4 stabilityofthe control material were considered to be adequate for the purposesofthis i study. wd 3 9 : we : 02984 vy cHwes25-185 : Storage and Reteation : `The control and test materials were stored at room temperature. A reserve sampleofthe 3 controlandtestmaterialswastake andstoredin afreezerset to maintain atemperature f-20C +10". The control material reserve sample will be retained at CHW for one i yearinaccordancewith CHW SOP. Thetetmaterial reserve sawmaspsentl0tehe . Sponsor. Any unused test materialwasretunedtothe Sponsor according to CHW SOP. Any remaining control material may be used for othr testing and will not be discarded after issuanceofthe final report, . Safety Precautions `The control and test material handling procedures were according to CHW SOPs and 1 policies i TEST SYSTEM ; Test Avimal Adult albino rabbitsofthe Hra:(NZW)SPF strain were received from HR, Inc., 2 Kalamazoo, MichoinOgctaobner 16, 1996. : Housing After receipt, the animals were acclimated for a periodofat least 7 days. During 4 acclimation and throughout the study, the animals were individually housed in suspended : stainless seel cages. Environmental controls for the animal room were set to maintain a t temperature of 19 10 23C, arelative humidityof 50% +20%, and a 12-hour : light/12-hour dark lighting cycle. In cases where variations from the required. i temperature and humidity conditions existed, they were documented and considered to : have had no adverse effect on the study outcome. 3 i . en 10 ar wanes C02985 i i : . : i : : < : "i ' cw 9-185 Avimal Diet `The animalswereprovidedaccesstowateradlibitum and a measuredamountof Laboratory Rabbit Dict HF #5326, PMI Feeds, Inc. The feed is routinely analyzed by the manufacturer for nutritional componentsand environmental contaminants. Samples of thewaterareperiodicallyanalyzed. Therewerenoknown contaminanitnsthefeedor water at levels that would be expected to interfere with or affect the resultsofthe study. Selectionof Test Animals `The animals were identified by animal number and corresponding car tag and were placed into study groups using a stratified body weight randomization program. The randomization body weights were determined on Day 5, Study Design Animals weighing from 2,038 to 2,270 g and approximately 14 to 18 weeksof age at initiationof treatment were placed int the following study groups: TCT omoV DoseLevel Dose Volume NumberofAnimals Group Test Material (mg/kg/day) _(mlikg/dsy) Males Females 1 (Con2trol) DistTil6l5ed6w4ater ~~ 0.0 100 os 05 33 53 Justification for Species Selection Historicaltlhy,e New Zealand White albino rabbit hasbeenthe animalof choice because ofthe large amountof background information on this species PROCEDURES Preparationof Exposure Area On the day before the first conto! or test material application, the back and, ifnecessary (10 obtain unblemished skin), the flanksof each rabbit was clipped freeofhair with an n Co Tom C0986 --_-- ocvHe9-n1ass electric clipper. The clipped area made up approximately 20%ofthe total body surface . area. The test sites (intact skin) were inspected for interfering lesions, imitation, or deftehactwotulsdprecludethe useofanyofthe animals. The animals were clipped as needed throughout the study (Days 4, 13 and 29). Dose Administration All animals received five consecutive daysofadministrationofthe respective control or test material. Thefirst dayoftreatment was designated as Day 1. Group 1. An individual dose was calculated and measured based on each animal's body weightonthe first dayoftreatment. The control material (distilled water) was applied to the test site ata dose volume of0.5mL/kg ian thin and uniform layer. i `The rateofapplication was approximately 0.04 mLie'. | Group 2. An individual doseofhe test material mixture (T-6564 and distiled : water) at a concentrationof20 mg/mL. was calculated and measured based on each animal's body weight on thefirstdayoftreatment. The test material mixture was applied tothe test sit at a dose volumeof0.5 mLUofKbogdy weight in a thin and uniform layer. The rateof applicationwas approximately 0.04 mL/cm'. : Each area ofapplication in Groups 1 and 2wascovered with a 4-ply 5-cm x S-cm gauze } patch. Each gauze patch was secured with paper tape around all edges and overwiapped : with Saran Wrap and Elastoplast tape to provide an occlusive dressing. Collars were used to restrain the animals during each approximate 23-hour exposure period. 4 `Approximately 23 hours after each control or test material application, the restraining collars and patches were removed and the application sites were rinsed with tap water and ! dried with disposable paper towels. Reason for RouteofAdministration 3 `The dermal route is apotential outeof exposure in humans, 3 12 : a 02987 cH es29-185 4 ObservationsofAnimals . Clinical obsewerrecovndua ctet d pri edosoe onnDas y1and at approximately1, 2.5, and 4 hours after each control or test material administration on Days | through 5. Morality checks were conducted twice daily on Days2 through 29 (a.m. mortality check only on Day 29). Additional clinical observations were conducted daily on Days 6 through 29. Body weights were determined on Day -5 for randomization purposes, before the fist control or test material administration (Day 1), and a the scheduled sacrifice interval (ay29). : `The initial dermal irritation reading was made before the first control or test material p application accordingt the Draize! technique (recorded as the Day 1 reading). ! `Subsequent readingsof dermal irritation were made within 30 to 37 minutes after each I patch removal (Days2 through 6) and on Day 13. : Blood Sample Collections/Shipment : A blood sample (approximately 4 mL) was collected from a marginal ear veinof each animal on Days -3,8, 15, and 22. In addition, atthetimeofnecropsy (Day 29), approximately 20 to 40 mLofblood was obtained from each control animal end approximately 20 mLofblood was obiained from each Group 2 animal via the posterior of vena cava. All samples were stored a room temperature until centrifuged. After i centrifugation, separate samplesof serum and celular fractions were obtained and stored 1 inafreezer set to maintain a temperatureof-20C +10C until shipped to the Sponsor. `The serum and cellular fraction samples obiained on Days -3, 8, and 15 were shipped . frozen (on dry ice) to the Sponsor (James D. Johnson, 3M E-T. & , Bldg. 2-36-09, 935 i Bush Avenue, St. Paul, MN, $5106) on Day 17. The serum and cellular fraction samples : obiained on Days 22 and 29 were shipped tothe Sponsor one week afte the experimental 7 (in-ife) dateoftermination in the same manner as the samples obtained prior to Day 22. H The Sponsor is responsible forth retention and dispositionofthe samples. CHW does not accept any responsibility for the analysisofthe samples collected in this study nor are these resulis presented in this report g 3 COR98S i CHW 6329-185 Pathology At terminationofthe in-ife experimental phase (Day 29), animals were anesthetized with Sodium pentobarbital, bled via the posterior vena cava, exsanguinated, and necropsicd in random order. The sitesofcontrol or test material application were washed with warm ap water before the necropsy procedure. All animals were subjected to an abbreviated gross necropsy examination and any abnormalities were recorded. The whole liver, bile, an approximate 1-cm x 1-cm sectionofthe derma application site and both kidneys : (collected as one sample) were collcted from all animals, weighed (volume only determined for bil), and immediately placed in a freezer set to maintain a temperature of "20C 10, After necropsy, the animalswerediscarded. 3 ShipmentofBile and Tissues i `One week afier the dateofin-life experimental termination, the tissues (whole livers, i dermal application sits, and kidneys) and ble were sent frozen (on dry ice) to the i `Sponsor (James D. Johnson, 3M E.T. & S, Bldg. 2-3E-09, 935 Bush Avenue, St. Paul, ! MN, 55106), along with documentation ofthir corresponding weights or volumes. The Sponsor is responsible for the retention and dispositionofthesamples. CHW does not `accept any responsibility for the analysis ofthe samples collected in this study nor are 2 these results presented in tis report i i Statistical Analyses i No sutistical analyses were required by the protocol. : Location of Raw Data, Records, and Final Report R The raw data, records, and an orginal signed copyofthe inal report will be retained in : the archivesof CHW in accordance with CHW SOP. i 14 : ee - 02989 cHw 65-185 - RESULTS : Body Weights Individual and mean body weights are in Table 1. All animals, with the exception of `Animal No. F60987 (Group 2 male), exhibited a weight loss from randomization to initiation (in-ife). This weight loss can be attributed to the acclimation ofthe animals to resrining collars conducted for 3 days (approximately 23 hours/day) before the initial `control and test material administration. All animals gained weigh from initiation (Day 1) to termination (Day 29). : Clinical Observations Individual clinicalsignsare in Table 2. All animals appeared normal throughout the i study. Dermal Irritation in Individual dermal iritation scores are in Tables 3 and 4. The control material (distilled # wate) did not produce derma irritation in one animal, Four other control animals A exhibited slight to moderate erythema, slight edema andor slight desquamation reactions. . Slight to severe erythema and edema reactions and slight desquamation were observed in i the other control animal. No explanation for the unexpected dermal imitation in the : distilled water control group was found. The tetmaterial,T-6564, produced slight to ! moderate erythema and edema reactions in five animals. Oneofthese animals also had slight desquamation on the application site. Slight to severe erythema and edema ! reactions (with subcutaneous hemorrhaging), light desquamation and coriaceousness, . and moderate issuring were observed in th other anima treated with T-6564. ] Pathology Individual animal pathology data (tissue weights, bile volumes, and gross pathology observations) are presented in AppendiAx. Observed at necropsy on the liverof one Group 2 female was a single, firm, green, pedunculated mass (0.7x 0.3x 0.3 cm) atached to the ventral surfaceofthe right median lobe near the gallbladder. The findings i 1s ! - Cine ag 02930 ' Hw e185 4 in this animals was not considered 10 be test material related. No visible lesions were seen in anyofthe other animals at necropsy. DISCUSSION "The acute systemic absorptionftoxicty and relative skin iritancyofT-6564 was evaluated inmaleand female albino rabbits when administered dermally for 5 consecutive days. Applicationofthis material did not resiunalnty test material-related changes in body weight gain or macroscopic findings a necropsy. All animals appeared : normal throughout the study. Slight 0 severe dermal iritation was observed in the distilled water control animals and in the animals treated with T-6564. 1 4 : SIGNATURE F7FBu.dBWu.dMc1D)o.nralddomate) Dat4e -28-91 : Study Director 1 Acute Studies REFERENCE : 1. Draize,J. H, "Acute Dermal Toxicity (Single Exposure), In: Appraisalof the Safety ofChemicals in Foods, Drugs and Cosmeics - Dermal Toxicity, AssociationofFood and Drug Officialsof the U.S., pp. 54-56 (1959). i 16 Ed 02991 chess i Table1 : Individual and Mean Body Weights (8) : Animal Ranwdoame Day Animal RanFdeomma Diy Number ization 1 79 Number ization T_35" Group 1 (Control) - istled Water (00 mg/kg/day) FFG09982 22221035 22,019173 22677634 FFeASeSs 22204967 22000412 22761747 FOB 2255 2002 2646 G90 2298 2014 278 : Mean 2225 2004 2694 Mean 2280 2,119 2725 3 Group 2 -T-6564 (10.0 mg/day) FFGEOO9S8BSS 22119969 22003886 2255987 FFGC0SSI 22128110 22,004678 22657096 FOBT 2263 2210 28 FGM 2269 2207 2835 . Mem 2219 203 2668 Men 220 2107 267 5i " } } 02992 cH 6529-185 Taner a dau lscSigs soins eT ew eHT oeawTe FoumTr eHorw on) MeSmxbOnseeriron_ TTTT TIT TI9%THT THT T TT H 0 ES PE ---- FO M Aspesebsomd 44 LLL IIL 0 ss sss ER RY AA J IN A . : TP PPR A AA JI PR A : J PR A Group3. Tse 108mpgs 3 RRPR PRA AAA : ERPRAIA - FAB WM Apeadromil 0 LS SILLS Sst 4 ts RR RR PR AAA : RE RR RR AAA RR PR AAA ti 7= Contvoncipny ewo comeWR 18 = : i : :. : : : # -_ ccHav9e-18s5 Table3 Individual Dermal Irritation Score-s Group 1 (Control)- Distilled Water (0.0 mg/kg/day) TT DeDmeamlaRleRsecatcioonn Mas TSTudyby 11 22 33 4& 55 661153 Animal No. F60982 Erythema Edema 0111220 0111111 Ania 0000000 Desquamation ~~ Coriaceousness 0 0 0 0 0 0 0 0 0 0 0 0 1 0 Fissuring 0000000 Animal No. F60983 Erythema Edema 0000000 0000000 Avonia Desquamation ~~ 0000000 0000000 FiCssuorinrg ia~c~0e00o0u00s00n0 0e00s0s0 Animal No. F60984 EdEreymthaema 00000001 122110 Avonia Desquamation ~~ 0000000 000000I FiCssuorinrg iac0e0o00u00s00n00e0s00s0 Femm -- SudyDy T1327353 44 5 5661055 Animal No. F60988 0111221 0011110 0000000 0 0 0 0 00 0 0 00 00 0 0 0000000 Animal No. F60989 01 11121 001 1110 0000000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0000000 `Animal No. F60950 0111231 0011331 0000000 00 000 0 0 00 0 00 01 0000000 <5 1 02994 " pr 5 Tabled IndDiermvaliLritdatioun Scaorels- +! Group 2- T-6564 (10.0 mg/kg/day) DermalReaction Shy Males 1 2 3 45 613 Sway Females 1 2 5 45 613 Animal No. F60985 Animal No. F60991 EdEreymthaema 00 0110 111000 0000 0010101 11100 ;i DCAeosqnouamartiosn ~e~o0 0u00 0s00 n000 e000s000s000 00000000000000 00000 00 q Fissuring 000000 0 0000000 Animal No. F60986 Animal No. F60992 . EErdoyemtmhaaema 0 00000000001 202202101 0001101023022303033012 ! Desquamaion 0 0 0 0 0 1 0 00 00 01 : Coriaceousness. 00000 0 0 00001 10 ] Fissuring 0000000 000000 2 ; AnimalNo. F60987 `Animal No. F60993 1: EEArdoyentmhaema 0 00000001101101101000 0 001101022 10102 102001 } CDesoquarmsioan c~~e00o00u0s0 0n0 0e0 0s0s00 0000000000000 Fissuing 0000000 0000000 + Subcuaneoshemoraging 5 2 . : - a 02995 : CHW 6329-185 APPENDIX A Individual Animal Pathology Data | i i # 2 |o 02996 22 :i 8& S Hg 3 : g a S8 4; 8 g : 2g := 3 H gg = RB I iis 2 8g8 8 wre &: 3g3oo i:= ggs 2:2 2  & 8 EEE weSd SET 3g : i 8 & : i ERT JRE onBo egOT ET 8gga3 2 Hc 4 _-- ocwweesm1sms APPENDIX B : AmendmePrnottoNcoo.l T1 Pt63tShe1Protocol 3 3 i 03009 i ' Seton. CHW 6329-185 CORNING Heron Sponsor St Paul,mMMiron *3 PROTOCOL TP3S1 : Study Tite: f Daily Dose DemAbsTxicky Syof T-6564 in Rabbis : Dre 7 Ocuber 25, 195 : Fetorming Laboratory: ! 33C0orKiniHsieBonvinrcud Nadon, Waser $3704 3 Laboratory Project demicaion: cw zsans 2 . . Coes Patna eis 35 - 03010 CHW 6329-185 cH 5p.1e8n5 Page2 STUDY IDENTIFICATION 5-Day Dose Dermal Absopio/Toxicity StyofT6564 in Rabbis CH No os.ass Test Maria Tass : Sponsor aToMicology Sevice i 3MMedCicealnDeBpladrgme1n2t0-2602 i SPCPO BoxM3N322$081339220 ' Sponsor's Reprsesive aRwogeGr. Peskin, PAD, DABT ToMxeidcioclaolgyDeSpearvmeent : 3POM.CBeonexr3,2B2i0ds 22025.02 : St puml MoNm$31333220 ::: Sty Director FCo.r5nidngWH.asMiceDoonnaIlncd. PO Box 7545 i (M6a0d8i)so2n4,2.W3I50155707-7545 i:. Study Locsion C33o0m1iaKginHsumsalneaBnounlce.vard Madison, WI 3704 : PrEoxpposeerdmcSnualdSTainmDeaes Wek of October 28, 1986 y DExrpaekriRmeepnotratlDTaetremination Dae Weeeekk ooff JNaonvueamrbye6r, 2159,971996 A 4 03011 rss CHW 63T2r9.e1a8s5 Pages 1 S5-uDdayy Dose Dermal Absopion/Tosicy Sy in Rabbis : 2 TPoursgees the systemicabiorpionand oxic andrelivesin iinof 8 tsk materialwhenspied10 heskinof bis orfiveconecuive days . 3. TRheigsulsautdoyrwyiClolmbpelcioanndcuected in ccerdancewith he followingGoodLaborsory 52 } Pn1or6tacbmiecaecrRioeganodlmnieixoenssStfondacrodn/eGnuriadieolni,nssolwuibtihlitthy,e ehxocmeopgteinoenittyh,ataand smaboiflatew.ill 5i [[X1]]2C1onCdFucRt5185 2(FNDoAw)regulaed Sy [[1]]4400 CCFFRR116902 EEPPAAFTISFCRAA)) : {[11)59 CNo6h1S3a(nFiNno.) 3(9O5E0CDs)pans MAFF) {1NodfisionNos 313 1nd 70 (apance MOH) i! ARunengeupclreuosicsoeadnriuslryesIdnuitpnhliehcioastpepinrynoopcrfevtaihroeuisSnwcpookm.nplainsndcsae wyrithithee rAn,imtahle WeclfyardeoAccstot 3: 4 "QTuhaeliptryoAtssourdanyce conduc, 0d the final epors will be audited by he Quality i AInscur(nCcHeW)UnSiuinndaaccoOrpdearnacienwg iPrtohceeWsissco(nSsOinP)[canidtypoolficCieosrning Hasieon 5 Tes Materia -t A. TMeansietrieston 4 B. PThoybseicdaloDecscruipmtioenthnertwedtds ui 3 Kl 03012 cw ens caw sEaasots . roTPeueirmyngarne,SnraisRyomornieplyaomr psdyoasodba silatybn dsewmihhodsb)e TrraetoessfiamrwiaonsvBge nnsssbyepeSp. ; 5 suucme-- hd E RR--es-eerveeh Samples of eh bcos se will en ox 1 heTenvnt msFeipstaeoaeSmEopCf) wilwbehrdrnCHbVei Sporersr . F. fRuceeiondetet mal wil be re te Samer campeon of - G. RA ne Safety Precautions. sors we eis :: -- Bisse ! 6. Control Material ! B. Sa Physical Description ii; C. Pusndorse ivsytayaysaois commerettyy.site mis odd : 5. SRurogepCoenssors 4 5 . . 03013 ; cnwessass aw ea ons] ERoeneSSuomtp mswmm msn -: Ti ocmlTmetrev me) ile rd CHVin re : F. L Rietenatioin nsnndn Tatl ayabeweed oot ving edwi sb G. SS te pesoEseL sors odpts 7. peo Deen Np, sfpiion @ Speeitne e, worg iin " 3) Age at Initiation h ----e , -- est entoeue @ oy PA -- fi 3 - ---- . . c03014 cw emss .. awaTpnreosdn] EoroamtTinttocsnmofpbos8aoRaabltoirBea452to6 n3e } ClweaarnecefdodmswSeonpntsbeoss.mtea,SeSpmotsGe,evn4 : frente ii @ [ Cominar ns aE -- :: ESSnLmotnoTsfv he io rs oamowislcebbsoa0poof : n a we itpts |: aNcianin : :] t eo SsteoFmefyo TnsoteemsheFahscS oacrinHnd OgTSOPswil il . aocsno payetegonstSoodyvny w.e : -3 0 sfooicecniontfaotepoefibSsesteasctwioetiooeaatnuseenotonwie 3 r . 03015 aves foo ---- A : MEARE Control/ DoseLevel NumberofAnimals of CcooerT| oaT| ooer TT] 4: iLootlioy r e ie TerSLacetiin -- na et -- bSe--dt f i nSaphntToi:n . ii pees rGeepdayee B l dlen a .: B TpeeEeea rR naTreies BielinCT e pmeat vie Sele lsptpd 3; Se doeyfTi eyd edrSee neeCna . LS R node hSien p l , e te Pipi Be ee potTeper " 4 Wd 03016 " . -_ cHCwHWe6n32a9-s18s5 Hw e3T2e8a.1s8t5 Pages (0) TRheeadseornmafolrrRoouuttee o3Apdoteeinatiiasltrroatteonof exposure in humans. (9 hRApeepmrpooavxtaiclhmeaostfeTalenyds2tc3oltlheaorrusrisawlis:lhebsearcehmotvesetdosrdcontteolremsaitdeurailaml paprliscatwiiolnl, abSepeswraotf eetreptmraiunosrditonogctvvhoatuseeoumardetaernoilaallpeppcrphooipncrapirioocsneodwluivrleenl.tb,eifweacseshaywi.lh Twhae r =o . Observation of Anus 2]t : 0) 4BC7ledifnoircheaolcuoOrnbstsaoelfrevorarttiaeoctnhsmatmeiriiasltaamiioinosnficon,oaaannpptretomxiaomrall1,o2n5, : dDaalyys (115m.or12cd ipma)fsoig,mdoruallyih ty threoughDa faoycl2ir 9nicuaml.sgmno,ranlidtytwice : sonuldyyodneDcaoyr.25) Observationsmaybe extended when drcied by the @ BReefaodriengtheofiDiearmaclotreonrotenst maria admiiscation, the dena . i(Ataicohnenre:ad1i).ng Awidldboenmsaddeeaanld rierciokrdieodnssretsheinDsaywi|lrbeeadmiangde i fSwoitrtuhdciyhneD3asy00n1l3.6,0 Iindoivuisduasledreermxaclhpiancihonremroevcoarlds(Dwailylsb2e-6)maindsono : ) FBoordyadWoemiigzhatison, before te nia esto contol mei spplicsion : (Day 1). on Day35,ot st dest (when sari exceeds 1 dn) Blood Sample Cllections . @ FPrrcedqouseenacnyytime frmuptofur days before the nial dose tsdemrivmiisinraaio(nDay D29a)y 1), on Days 8, 15, 2, and at expermersl 2 . .- ass - 03017 4 cv smns : aw TsTaansns . . BSBln a ptea m ay r m-- w e tss sc nfmomh : TrJ ieniGnlo.m awh Soi--3 e-- 40 o--ofnsst wil i; a firysnpcdsofiooeapcployrssoeoreewdeeirtheclnereCdotosafoayrc3iy0 ; ES =:5 "CTheeoboted sdtamploep s mwillabe s sored aStir1n o0aemltTesmpseehirateoandphoedn imiatte oancTSpoosot donwkraehleDoFko1pcoranp ostn en :: Oa L13hibeepameeeontn, tdTeeeSpieeeSapomp ene | hesee ndcele Fin swu ll il ps : ii : JBaimseeasiDnr. aJeeohensson : rae Sos 3: Ja ames D. Jehnoneois llr ill be noid regaithne iFl ; - . a . 03018 cw 6329-185 Hw eTse.a1s8t8 Page 10 D. Pathology .i (UnsAcnhyedauilleddySiacnrdiufriicnegs tahnedsDedstosacrificedinmoribund cm`ocnoadsmiuiianoadniwoicnlolannbddeesunulbjsweiblcoltoebrdeal1aini2sehssebwirizlelevdibnewiiretedhcorsdooesddi.unmeAcprneopoisbysibini+l (via 2 csicniguninitneda.e Tmhe whaocleril vvee,),blde (uil aivln,can,appnodsite i" (dTcoeulmlercxttheiIed s3mnudogsneeocrsoansmopflcet)hwreildlfiebneai4lmcoocalrplielecibtcueaddntdiroocnomsnidatieli3oann,diewmessighdKeyiidndge.rs i3l i h(feselci iemsse tnm ltwysilmdeata bieenrdimiinsncl e3adrtdfeeordmbpile),rsnodf m20eCd1i0cC.pscAeed simeocr+opsy. {} @ SOcnheDdauyle2d6,Stahreiainciemals wible anesthized with sodium pesiobrbal . (evxianngeucitniioen,inintdhesmuabjregciend 1caranveanb,oebviindtvdia tcse vneecroapvsys camnaion. The animals will be ncropied in random ordersndall =' SanonscpmraolxiimeastewilLlebme rxec1oradmeds.ecTohneowfhotlhee idverem,albilaeppulilcaativoanisatbel.eand both Kidneys (collected a on sample) will be collec, weighed ii i fh(eelcunemsieasntll1y0wimdlebeaermdiiis3ncnadtredfeoamdrp.beiirla)n,ne1dofi2m0mC e1d0iC.paAcfetdeirieosr3opey, . ) sTeThoteswsfeaumSzpaelmeopsnl(evderSyrh,iipbeim1lee0,nttdheerSmaplapnloircwaittihoinnsotn,ewaenedkkaid1neys)olweilcliobne, +:1 Tshhieppseda10mthpaenplderetshosensicsoemdspianSdeicnognw7.Ce.(0oi(4r)v.oglTuhmheeSswptiolnslsboeirs responsible for th re1nnddiisposintionofth samples 3 i E NSwoissiaciaslicAamsyyss we revel ! a" I 03019 .: cw sss cw mrTasreasn + agTean pn nin ts sd ow wi be mbind 1 DDFesoicripeieon oof f crt 1nnd cnt mci : TeDisevoofrcpoefofimmooernasaylbish eiboyn1iad idientet :: TGeetrdootPnpAoofpRnmcoodnseosywweeiggsh ndydtSsyekhmeedesntdyseDeviev) 5. CSLarctmonnoifanRgra Doarts,hgRecldorda rRseesSeumsitoG,foo2wndfFlpreriohnn . 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