Document aBnprV3GMKGegg8gnYvz2mo3R

Repeat Application 28 bay Pexcutansous Absorption seid inwiRtuhbiTn-o26R1a8bCboiCts Te SO ---- . snes 972 -- SFEreOsermpratpoteens-- aor Getaber 9, 197 to becenber 10, 197 S Toroaiwra e, oh pra s f-- aw E A wcE nm E o(e z XL setry2 3o4ra 01707 ann 1. A repeat application 28 day percutaneous absorption study with T-2618CoC was conducted from October 9, 1979 to December 10, 1979 at Riker Laboratories, Inc., St. Paul, Minnesota using male and female albino rabbits ranging in body weight from 2.05 to 2.64 kg. A preliminary rangefinder study vas conducted to determine the appropriate dosage to be used in this study. The test article was administered by dermal application to ten male and ten female rabbits each at dosage level of 100 mg/kg body weight for a 6 hour exposure period on five consecutive days a week for two weeks. No mortalities or untoward behavioral reactions were noted during the 28 day study, however, body weight losses were noted in wo animals at the end of the study. An interim scarificed was performed on day 14 on four male and four female rabbits and necropsy revealed no visible lesic Necropsies were also performed on surviving animals upon termination of the | study with no visible lesions noted. Preliminary serum analysis (see Appendix V) indicates dermal absorption of T-2618CoC in albino rabbits, however, due to the Limited number of samples analyzed by the sponsor, no concrete conclusion may be drawn. Introduction The objective of this study was to determine the percutaneous absorption potential Of T-2618CoC in male and female albino rabbits after repeated application. The study, which was initiated at Riker Laboratories, Inc., St. Paul, Minnesota on October 9, 1979 and completed on December 10, 1979, was not conducted to support a government submission or marketing permit and is, therefore, not regulated by the Good Laboratory Practice Regulation of 1978. The raw data generated by the Study Director and the final report are stored in the conducting laboratory's archives. 2 Riker Toxicity Experiment No.: 0979ABO4ES, Test Method 699 01708 : 2 Method and Results Young adult albino xabbits of the New Zesland breed vers used in this test. ALL animals were held under quarantine for several days prior to testing "ith only anisals which appeared to be in good health and suitable as test aninals at the initiation of the study used. The rabbits vere housed individsally in stainless steel, wire-bottomed cages and maintained on a standard laboratory ration with food and water available ad libitun. An initial rangefinding study as conducted using two male and two female rabbits for each dosage level. he trunk of each animal was clipped free of hair and the test article placed on the surface of the intact skin which covered approximately "0% total body surface area. After administration of the test article, a flexible plastic collar was fitted on each animal and the trunk weapped with fnpervious plastic shesting vhich will occlude the test articie. | The aninals vere retumed to their cages for a 24 hour period after which tine the test article was removed from the dermal surface of theanimals. This procedure was reposted several times during the First half of the 14 day rangefinder to further characterize the toxicity of the test article. The animals were chserved for pharmanotonts esctions both during the initiel exposure period (mediately post dose administration, one and two hours) and after removal of the test article (daily for 14 days following initial dose adninistraion) with all reactions recorded (rable 3. Initial and final body weights were also recorded (Table 1). he information derived from the initial rangefinder was used in determining the dosage Level for the repeat application 28 day percutaneous study. Prepaxation of the 10 male and 10 female animals for dosing and the actual application of the test. article vere conducted in the same mamer as the rangefinder study. Blood samples were collected from the ombital sinus ples prior to the initial applica tion and again on days 7, 14, and 28 after initation of the study for 2 sFealrinFareeRsabbTinsc..chofuo,gerRsa,lsatnon Purina, St. Louis. HO < ASTnioitrmieacnlisespofpnrlodimvaaytshie6ona2sn0d0o0n7aunandaiyl1e01+00th5emga/anknigm0adloss.agreongrotuhpes1w0e0rmey/ruegadmgrionuipstererceCediovtehLde7teesnt 3 serun which was frozen for sponsor analysis. After each 6 hour exposure period the test article was removed from the dermal surface. The application procedure was repeated for 5 consecutive days a week for a two week period. An interim sacrifice of four male and four female animals was conducted on day 14 with the remaining animals continuing for observation through the end of the 28 day study. Initial, 7, 14 and 28 day body weights were recorded (Table 2) as vere any pharmacotoxic signs noted during the 28 day observation period (Table 4). A gross necropsy was conducted on all animals which died during the conduct Of the study as well as all animals which were sacrificed on day 28 and all findings recorded (Table 2). The protocol, principal personnel involved in the study, composition characteristics, and Quality Assurance statement are contained in Appendices I - IV. 01'710 TABLE 1 hd ACUTE DERMAL RANGEFINDER TOXICITY STUDY = ALBINO RABBITS wien 5-2616000 Mortality ana Body Weight Daca mtree e ------------ee-- r daoksee?) 5% aunmibneary IndivJiedsutalgBayaByuwmE epBiegrehts (iq) RNuummbbeerrTDeesatdederpeberscaent 000muPoo sSamaeassmseaor HH 222540a08 ((a6 bpbaaayyys)s) (ea Goa a 100 000 [onIwo oonmseas Pom 22i1o5450(0 vo1ayey a ow sr 0 0 ouPww oromnersssses 21i090as8 p22.0t1s0 os o Po ome pt HEY 2 test. article as dosed as a water slurry Note: Figures in parenthesis represent time of death 01711 -- s. ACUI PUKCUIANEOUS ASSORFIEON TOXICESY STUDY ~ ALBINO RABBITS Mortalivtiythan1d-2o6d1y800W0eight Data T bEorSedS E anima ToS dviviiddeul BodyS oideights (ka) T vumber . esd escent o(ng/ki g) . Nuper SfS estR Day . NuSmbOe.rWSi oii ledsDead 00 WWoow ooSseenaas ad3sass 2a23335 nazsa nbndee orto wWwoo omomammenn dddema aaaaam aa1ahm dhheem wNPoI ommiemeRe2s5oA iims FI FR Noms das ies : = worP omsGeemmeeen: za2esa l2ie3is9 22s3o0s 22r5ea ono o PvToo omaooemeemsess a2a1s37 zslaassarazl;iess aasgoees PEPo ommmmeees 22d33a a22aba F>5 R Pome ass 2m ER Nnseaecccrrroiopfpaisscyeesppereirofdormreedveoanledsnnionalvsisiubploen lteesrimoinnsa.tion of the study and also at the interim EB ithneaitesstsearetriictliecewdasonaddumrini14stered as a water siursy 01712 ms ACUTE SERIAL NKGEPINOR TORICIT soy- asi masies wien T1000 Sumacyof mscticns EconD sex pescien ebteirAottescten Tpaontiianmtianregirbwioosn GmFMoolrmtioasmtnisamtpioosene m won memrooarrsreres i7ann orareo7 wnnrtte ddeennn Poms ua our? 0 nmairen 72 owwe7 ne doen oRwEe denn roertamarleoan aAin onEEyhR2 owleioithdseennn 0 Poow wenceliosnn tmated - B riosleliofngsutaotshe ore ora ors ay $ TThiomn twhheenn frsntioaandteisn t1hthSeoedo3e0gmreoxhephiitbeidcehdethFeeorceinocntion Yo siomicnt sesctions ) 328 >: 538 . me + CUTE DELL PERCUTANEOUS ASSORPTION TOXICITY sith 72610000 STUDY - obi Raaains Sumary of Reactions anfosien) sex maction WM HubmbaerratfefeetchtedTFhmoolalta osviiangniR Daorsee FAonlilnoiwsitnigatbiaosne ----Fio--slleov--iongf --ouab--tonse-- doresacitginointsicnaonted -- FN signteican: -- en reactions noted -- = - Mo Significant Reactions noted (-) S8 3 >= KO bn wn os GUSH snd APPENp D sden, Acute Dermal toxicity Rangefinder study 5 CSOPNONDSUOCRT:ED 3BMY--:----SCafoetmyuEmvaelnuactisosn eLabCowraetmorpye,nReiker Laboratories, Inc., St. oo paul, Mimmewstc TCOENSTTHOALRFAICRLTEI:CLEE : 72E 26P18e62a0 PIOIUSKD STAKTING/CONPLETION HST SYST AND SOUL: ow DATE OF Zealand STUDY White Albino Zoo Rabbits: ZZ Sex: Male/Female a PIMBCHIVIS TLhosstulabcjtuicctliovefoorf uhuibsucsqtuundty dwill bo te NBuomdbyerW:eig1h/ts:ex2/.l0e0ve=l dotenmine 4 dose level range 3.00 kg for uns JOF lthaondLiensgt asnydstuannefcoarl tahvoaiirlaesbreimnlauilictyLi,DvSiOcydeotferrmeisnpaotnisoens.hisRtaobrbiicteslwaemsaeeeloemeced Mimo: atlnihuienmiaadlniitmWyaillcslontbwerilolalluebidognhreoodouwssoadwndiuntmhbesrtfcaodnoddacsradranwdtaigwr,aet-ewmrhoischohffcawarigcledls Ce aidn Ltiebmipeeurma.turesaacnnd Sorsogon too nard [fAofrEoor2sofa2dmhfiahonioiruHsrutarncadxotpuiottoshsnueicdoeetfeopsfettrhieatorhdteeiaccslaeges.ipnlgalcTeehdedootsnreutnhlkeovoefalbsrcaaocdfhednSd0i0s0nuraafnaacweil20lo6f0btemhecyhhisspr.pred oiSnnibnabaallusEtnwhiedllly tiboettdoubssibecurvrGeoadmgoevsfeodrfomfrsortroatmaa2lcr4ihtteihycodlueoerrnmlaoaysxlpfoaossruurrstfeahalecpieenfreooilofsdll.otuwhreeayba.ineistmhaoalshs:nminTcehiiesn.eou|iiilll ing 14 days. uLprnionietudKianbahlieacbhroaws,iontsalwsitloln bPeurminaad,e the exposure site sufficiently deep Satp.protxouitmsa,teWliysseovuerriy ten centimeters to disrupt the epidermal Layer: sue alon sufficient to cause bleeding. noc : LL a Sponsor Z 7/20/29 Date Staay Diredtor 257: Bate 01715 APpPrEoNvDoIcXor1 R(iCkoenrtiEnxvpeedr)iment No.: S OY1THU Lc/SsR "-- ny TEST: Repeat Application 28 Day Percutaneous Absorption Study SPONSOR: 3M Levens, Conic i CEOSNTTHOALRTIACRLTEI,CLE 7 ryign er rE Division. TRUSESYSTEa N ANN D SOUCROCRE:LLNPeelw-PZrcRoaAclaEa,ndI7WnchS.iu,tseeRoAgLeBrEsR,STAFrRekEaBnTsEaRs LeNeerweirioercTe Body Welsht Rage: 2.0 - 3.0 ONECTIVE: OtTPFhoheteehntotebdisjatelclstoyifsv4tenetdmhoefGfoottnrehcsirtstahlaesirtrtvuilachylilesiltloielrnidciabealeylb.itnuoaoedTeatibnebridmteiern.mealtRhAaebbbpsieerrrecputwtieaerneeosumesrlmoaibeesoosrtpCoCeolitoen MEHlon: awrEsahrsneoidlgioancnnedlidymarlaohsoo,mnususmesbdweeilrtuiehncdtefsdctoaaornfddrtaoaarmgnd,dauwwilahratierec-grhnoerwsoihfclfolelcroaengdyesabdiynLhietnaetlmvtpehenr.aatnudrBeabcohdanydwwremeinegshst,iatcwlilbolnnbe ZaonuidtnsitdSheeYeotrfeisnttghaerotucipacrgool.reinaapTthpeolliyctdr4uan0sk Grilar? ill be Fitted on aof sienagclheacndoiormsraaelgsepwooinfldl tObaeDaciciamcmhreenrae/firrienievgeoitiinlmhe2oinr otal body surface Sear Eieciire mietie p5StlehaaeCstnotniabcretisrcheoltoeutrinwneigdl,l twboheitcrhheemiwovielecdlaa.cgohecscaTlnhfueiodmreaalpapthlaein6cdathechosiuetornaeSrbexcrupionoccksleuedwr.ueeraspppeswermidiesewidiatcbfheiemseessrierpewrrreieicilhestthhee cfeedsutreasretrcieucptleieavceecdodnatayassctdaewewimeteehdk eight changes on a weekly nfeorcesasatrwyo tshcehesdkiunl.e bwTyeheekthdpeoesrseitsouddwyiwldilitrhbeectthorere-hssasgiireissnieeeninriyefio1erotohcionoorre during the two week spati isoPnr8rtbuioidortyrianlftoorssaitcnshrueeisrfufimpiclreeWsxhtuoisfca,hpfpoWlauiinrldclamtaaibgloeaeni,nfarnoobdnzleonodadyfosra7,nsppl14oe,nssaewnridlaln28ab.leyssceioeslriaansestieeeedsiesieftoroiniemmrcicrorrigs.est!heen 1zF608otsfhe nteshectruodspytsuydayswiwwleilltlhbeatshecaolnrledmuaacnitinemidanlgosnafnasoilaunlcrarliafsfneiimcmcaeaoldlnestoiannnhuiiimdcnaahgylsmo1va4niylasldtniudebdoeyrdswee3se0si.sieecsAtcereoysnh ooan. dayoL Scoonmdeuss Df2enuidtnurdrbeieocnnogermsdimecwdraiorlsrlascoowbpweie(clrsletecexaorsanrmudmiae)nndaytwaiipnolhdnla.rtmbiaescsIounfteiiotxxiesiadalcm,pislnie7,gs1n0s8o14f,bAouLfaivfneedrr,e2d8sdpfaloyemeanbt.oidnybuusfeionir.ghpeebsmicowimiieii)e RtSihhkeeerrsetLusdapybo.onrsaitbAoiLrlLiietrsyauAorfdcahttiah,veesos,tphonSetsr.ort,Phaauanln,dthMetihnbenleofsoiondeasla.nartelepydosriStusridwnaiyclal twhoeniccstnooserretidse inborrthe PiTuhnregienscatoilolrnaarbobfiwitlrleCshibowde,uwaolRranltessfttoonrartPhuteriicndlaue,r.atSti.onLooufist,heMisstsuoduyrito reduce oral Sponsor Mn = SeaySDirtelct / falas = o1716 AEE Conta TO Me Cg : LN Ne Go AmendmentEoProtocol bev haed Co See ens 10. 4, 2encoptien, ton wo Jb, Sole snjegbider actos of ty did, --- 2 Fb), nm ce be.2 Pale situs lucie Ble dey! 4 Lex Logs, 0 bled cpt Study Director 08 {0 ent elie sngafuel, LN Date St5udy DDeirveectnors Ho pon - l`nDgace Tle seadie Sh ky A ~3cc. CC, nd gi, py CU cen Study Director seiskl cope wirl be ES cchhiled acho of44 ule, EE ! Fla dee desi -- r0rBrDiarsec-- t este neni te ding at `YasjzaD__ate 2000 ree fun i. re be cepted derinol Goede +, Bonu one aC -- _ 0 Pnallien Poin 6b Ned. dil (I Y StudyDirector y Tate Ste EE ---- 7. The YS ioCc doadn SRE 8. ee Study Di} boCoiche,0OectCdoingeduoeny (a=g) Gx trgamed: Date LSotudSy aDirnectee) isate 0 --_-- c01717 Exineipal Nam Kt bens, us [Lt 0. o'Maatllteey, ss ve. V. Potnapragada G. c. Pecore Aven ex 1x tarticipating Persone) Involved in the stu a, Function Supervisor, Acute Toxicology SevaatnceadeTeotxiocsolioegis Comercial Chemicals Chemist ASnuipmearlviLsaobroratory 01718 CompositAivoneecnhoarraxct1e1r1istics 12. This study is not regulated by the Good Laboratory Practice Regulation of 1978 and therefore information pertaining to composition characteristics is not applicable for inclusion in this study. 01719 APPENDIX Tv 13. Quality Assurance Statement This study is not regulated by the Good Laboratory Practice Regulation of 1978 and therefore a statement signed and prepared by the Quality Assurance group is not applicable. This study was, however, audited by the Quality Assurance group. In addition to the data audit, different significant phases for studies underway in the Toxicology Laboratory are inspected weekly on a recurring cycle, and the facilities are examined by Laboratory Quality Assurance on a three month schedule. 01'720 : tes Contest 10. /i AppENDIX v / "K. L. EBBENS - RIKER SAFETY EVALUATION LAB - 203-1 tun PU uFSuwCKn,-Ie1Noc2,82A,5UM,SCOTCCRaO.PRg1TMa2II5OCNKunS-gtMupEneDtrIssCgAoL DFEePTt,es,TOrXIeC.OLOFGCY-9S9E,RVFIGC-E1S34-, 220-28 Feuizs, SN mPoolnnetaicsoenoecdmoncsocimdpeeoruontdyhnsi/'siskaeinnaSubtahcorrpitzafotniosntufdoiredyoeuarielbabooIrSatteorrythteo arboolveease : PChFoooenvrpeaa'omanondzaasofyfi"aeerSooaoCr3dOiRntPhLseheaatmLfepldluteoharemnondcsahtieWuynidliilcoaslmoararespesb'iesisantgsiAimzseosluuteesdd,SiSenErIuamnresipanomcrpotlm.epslete E hCF oencaenipE atfoE alS8TetyeoucoNnacvleuspieonnesraacltoson"dceisrnnqdidinrcgattacesesomrvuparisrtci,icivinee,.tthtooexx=eincoiuttghyhe. toHowever, 7 Shel Thank ou completion Should for your putience nox hoTlHs opipaE ri EieL n? anySloinnTg'ear.barnoaaldyezred in this matter, selon. wa:kan 01721 a onan .' 15. APPENDIX V (Concluded) ACOMNMERACIALLTCAYHBEMRTIECPAOLIRSTCfDIlVIAiSIOLN To W. C. MCCORMICK - 220-28-02 Fim V. POTHAPRAGADA AND V. BUNNELLE - 236-34 Sec RIKER SKIN ABSORPTION STUDY Cw June 9, 1980 CET ing, . 2I oSnv 0. Loot Reference: C#o15m6m6e5rcial Chemicals Division Analytical Request . Fanoarlylzaecdk. of time, only a selected set of serus semples vas Compound co129 ve-134 ve-120 Fe-98 Fe-135 rcs rc-99 re-143 Held 6 TOTAL , pon DeylFeasleDsay2s pay1Malesbey 2s 6.1 69.6 02 sa uns 2a 18.8 2. ah 26s 264 93.1 16 ams aos es 69 20.8 0.9 128.0 23 7.6 10.3 10.2 4521.5 mnailse w2e7a egelss vemales Day 7. Deyl Dey28 Day? Hates Day 16 payze 04 12a 35 sa 08 aw Aunty: 0Ox.y7is.onHaBgoewn,/GAGnaTle.cBtioicahemC:lo8n7,el54l5,e1978). re )) "VA Bunnelle abe Co Vo Fochapraguda Rexd and Reviewed by bu b, winter nt Lo 01722