Document O1LnOLp6Y2VE3rpboLqZqeKdv

28 Day Percutaneous Absorption Study inw'iAeinbirngosRsabbits : 5 Z Srpesinent. Hous Conducted ats Dates Conducted: Conducted By: Reviewed By: wo wEro.on saGamenrei : WC. Wacormick sor9m80632 RSaitkeerpryanLtaE,bvoarlWauitamotmriaiosenost,LsabIoncr.atory October 25, 1979 to December 17, 1979 Diane SFK.eaDy.bDOi'rMeaclilteeoyr, BS Beall tate Err1eiviesorn. houte 7w% eefoef Toxicolosy C03732 1. `Summary A 28 day percutaneous absorption study with FC-95 was conducted from October 25, 1979 to December 17, 1979 at Riker Laboratories, Inc., St. Paul, Minnesota using male and female albino rasbits ranging in body weight from 1.82 to 2.37 kg. (A preliminary rangefinder study was conducted to determine the dosage level to be used in the study) The test article was administered by dermal application to ten male and ten female rabbits each at a dosage level of 5,000 mg/kg body weight for a 24 hour exposure period. No mortalities were noted during the 28 day study. The untoward behavioral reaction which vas noted during the 28 day study consisted of hyperactivity from day 6 to day 7. Body weight loss was noted in one male at the end of the study. Necropsies vere perforned on all animals upon termination of the study with no visible lesions noted. Preliminary serum analysis (see Appendix V), indicates dermal absorption of FC-95 of albino rabbits, however, due to the limited nusber 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 FC-95 in male and female albino rabbits. The study, which was initiated at Riker Laboratories, In., St. Paul, Mimnesota on October 25, 1979 and completed on December 17, 1979, was not conducted to Support a government submission or marketing permit and is, therefore, not regulated by the Good Laboratory Practice Regulation of 1976. 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.: 0979AB0632, Test Method 699 03733 2 Hethoa Young adult albino rabbits of the New Zealand breec were used in this fost. ALL animals woo hold under quarantine for sovoral days prior to tosting with only animals which appeared to be in good health and suitable as tast animals at the initiation of the study used. The rabbits were housed individually in stainless stool, wire-bottosed cages and maintained on a standard laboratory ration with food and water available ad Libitun. An initial rangefinding study was conducted using two male and two fomale rabbits for cach dosage level. The trunk of ouch animal was clipped free of hair ana the test article placed on the surface of the intact skin which covered approximately 40% total body surface area. After adainistration of the test article, a flexible plastic collar was fitted on each animal and the trunk wrapped with impervious plastic sheeting which will occlude the test article. The animals were retumed to their cages for a 26 hour period after which time the test article vas zemoved from the dermal surface of the animals. The animals vere observed for pharmacotoxic reactions both during > the exposure period (immediately post dose adainistraticn, one and two hours) and after removal of the test article (daily for 14 days following dose adainistration) with ald reactions recorded (Table 3). Initial and final body weights were also recorded (Table 1). The information derived from the initial rangefinder was used in determining the dosage level for the 28 day percutaneous study. Preparation f 10 male and 10 fomale animals for dosing and application of the test article were conducted in the same manner as the rangefinder study with the exception of the collection of blood samples from the orbital sinus plexus prior to application and again on days 1, 7, 14 and 26 after initiation of the study for serum which was frozen for sponsor analysis. After the 24 hour exposure 2 vbeurinParocRea,bbintc.C,howH,ogeRrasl,stAonR burina, St. Loui)s, Ho . 03734 5 Period tho test article was romeved from the dermal surface of the animals an the animals retumed to their cages for the following 28 days. Initial, 7. 14 and 20 day body weighs were recorded (table 2) as wore any phacuicotoxic signs noted during the 26 day observation period (Fable 4). A gross neczopsy was conducted on all animals sacrificed on day 28 and all findings recorded (1able 2). The protocol, principal personnel involved in the study, composition characteristics, and Quality Assurance statement aro contained in Appendices 1 = Iv. } 03735 maze 1 . ACUTE DERWAL RANGEFINDER TOKICITY STUDY ~ ALBINO RABBITS with FC-95 Mortality and Body Weight Data dosed (amine IOSDBotsMeldhs (3) ymper besa percent (mg/kg) Number Emre Number Tested Dead 5000 nuu 9om522660030 22.a05 22..2580 Fro osm2m63e9 2.20010 22.00180 ora 1000 uuoo ss22660069 2.20.04 2.203200 FFoo oomneessz 2.20160 22.m2 ora 0 2 est article was administered as a suspension in water. . 03736 mais 2 ACUTE SERCUTAVEOUS ABSORPTION TOKICITY STUDY - ALBINO RABBITS B wich rc-35 Nortaiity ana Body eight Daca bCosoe =(eaR mimgearsr 3divildeesdt3DBaoydyNuwnepieogrrhs Ga) R[ emeerresTtest e-- r he sono NNw o oommsoeis 2a13ms0 Lvvees nrbeees za2de oo o WWooommmeoenm addlee dvdeemm sLsemns 2aaaan WWNo ooommmeossms aasemss dz2osuo 22ssae aadeem Wo omose aa am des an sorPPoosmmmsee 2aa0bn1 addsaes adzouor 2a24ns oo o PPPooommmsse aaDeia Adveoese zzLsea aaamm PPPooommmmmmeee sadxun d2reae naayna 22smaa Poms Le im Le an 2 The test article was dosed as a suspension in water -- He pecfomed upon sermination of the study zevealed no visible lesions. 03737 ACUTE DERMAL RANGEFINDER TOXICITY STUDY = ALDINO RABOITS with re9s Swmary of Reactions T posiae) Sex peaction HWuesbeerrT Afbofseecdted maFaomleilnoivesitnrgestboisoen GeMnFmionlliT mosvtiaznagttioosne iFozlelevoifngdeabtohse 5.00 MPwooesssciitgginnoiinsfsiiccaanntt -- -- -- -- -- -- 100 Merescitginoinssicont -- reactions -- ae ?38 PS&3 -: Riker Experiment No.: QU19ABOL3S- PROTOCOL 8. 57. Single Doss 20 Day Percutaneous Absorption Study rerio SONSOR: 3M bE a Cocamergd iy re Te BRT en Division 35orSr7aToosSA,kRYiTSIaTCESmLMEi:AeEA SROFUoNRC.REE: nEOew ZeBaRtEandOFuWohSeRe,e YAIDS TRA TORTS ea Pek Freon, ners Rogers, nekenas ehalboenr:sameA:etr27a kg AIBCTIVE: Tob: PTThoeetsetnotbsijvaeelctteinovfefotrohfethLteehisists hsatriutsditycolrveiiclailln wbeerlebitomnnedSesautbmebmriemtrien:iebrteRhseapbtpbieiorsncuvteeaernsectossoserleSaoobresseosar2pb2teionne PariEre end generar satiate rTThaoentstoaennditmyarloheao,msssesnwciltoihcntofsdtoarnfagreoarnnddaveilatrreegrremrsoncfoflveoernrsyseabysInhLveieanbltptraherenannudnEeab.cohedydawmepiiagnhnt,wshwiailoolnnbe nSSeudetihtiihneeedotFeasttmhmeabreirveiegcdei..eeaarTphpeitiageTsdrehusico&hfsvisinclrhllescdvooirsoeamrgiPeroonnoadfle5ps0e0a8c.hcramdepeanSrtsseontaeodoLkrtetahctethee FCHrilani"saericEcpvwesirhleiehnteibens.gs,sFriwovhexeiidcnhsoevnoill4ylac1ho0cvealnooittnaeallthabenoddtyothrseee.rsCsrraeocineeklSewhrreasoppneed swHeiatesmniaiibteaepeermrvenissetishcen BFTeeestCroetatieterienoretenescwoFirlotlhmeltbrerercaoesrseoesleedef:lorsaiPmrBseiorphoiutsotatehnepaonastpaprpheaiioPnaetriioln,daeBfntosesr?evShsiaomTnplecshewill GaeoieryirsngiIentrhievtaaCtosinrodonuvcetofonfetchetrnoep.sstyasstiyudsyford.ebesweecilonlndcuancetieoadlnlwoinatnsiSnliableearEisroeoscvitrsmifisfcoiercshsooonmnydoasybie36. TRiot1cneasiytboiarene.duEtbieonrndeeinmpgaisrcerwooiwsl.cla(pbsieccerrmeeexcneesmriamewaditlilaonnbde,.tiEslmsvasetssciaistne.mpsio7esnsbTuoorftteaLnrisev.esr2,6forssmpeaiyrciebnno',dyfborrain. poCCrIaTlAiohtbse tihleigrbeiespnorneeciiorbgdiela dierasofwelthlTe.aosshaovA niyerP,haarw nsdatchoet.orfiinessignFeeSponrosttewdidsI ucbiengY etohreed Tr the River Taboratory:s Archives, Ber Fast, Himesota: B TpeurraienncetoliloranarbobfwitirleChsboiwed,uvasRoanltsetsftoonratPrhueeriicnSiaue,racsit.onLooufist,heMisseseoduyrito reduce oral EO>C NeComele feos hans O SohOPiM res, hp2 03739 - APPEFNoDmIoXco1wR.i(sCeornclpuxdpeedr)inent vou: (4 SOLES "887: Acute Degnal Toxicity Jangefinding Study 5. CSOrNovDsUoCnT.EDwB_Y:LSoafnenty iEvasloaltioDn hLaibmoriataorly, TEST ARTICLE: Riker Laboratories, Tne, SE. Paull MiDninveissoitoan PCROONPTORSOELDARSTTAIRCTLIEN:G/ COMPLETION DNTE OF STUDY TEST S>YSTEM AND SOURCE: NPeelw-FZreeaelza,ndIWnhc.i,teRoAglebrisn,o ARrakbabnistass SNeuxm:ber: ZIG ~ soy weil Range: 3; OWIECTIVE: METHOD: Tohfetohbejatcetsitvearotficltehisinstauldbyinwoilrlabbbietst.o apKpabrboixtismawteerethescalcuuctteoddeasrmatlhetotexsitc.ity Sanydstgeemnefroarlthaveaiirlasbeinlsiittyi.vity of response, historical data, ease of handling Trhaendoamnilmyalhso,usesdelienctesdtanfdraormdawilraer-gmeershcoclaogneysbyinhetaelmtpheraantdurweeiagnhdt,huwmiildlitybe bceontarsoslilgendedraoomnsusbweirtehdfeoacri:taagn,d wwhaitcehr woiflflerecdorraedsploinbditutmo.a cEaarcdh aafnfiimxaeldwitlol hthaeiouatnsdidtehesofonttheasctaicgiee. pTlhaecetdruonnk otfheesaucrhfaacneimoaf) wtihlelibnetacctliptpreidn aftreesionfgle andnootisamagaeldssequwoafiltSlel/ybIe[c)sh,aamtidSncitrsetreirz+ eed'LtChtehEe)totmxeais/ctxigat,rytiohcfolweetvheeart,tessuitfppaltrehtmeisecenltead,losdaaoggsaeaigteiloenvlaeellvselsd.o ATnhye atdedsittiaorntailcldeoswaiglel bleevaedlsmiwniilslterbeeddotcoumtehneteadniamnadlsfiinledthweitfhortmhirsecperiovteodcol. fPrloansttihcecsoproinasrplr.wilAlftbeor faidtmtiendigotnraetaicohnanofimathleantedstthaerttircalnek, wraapfpleedxiwbileth wSinlplervbeioursetuprlnaesdtictosthheeeitringcagwehsichforwiall24occholuurdeextphoesutraestpearritoidclea:fterTwhheicahnimal Tthiemeantihmealtsestwilalrtibceleobwsielrlvedbofroremopvheadrmafcrootmoxtihce dreeramcatlionssurbfoatche doufritnhge atnhiemaelxso. apfotseurrerepmoorviaold o(fimtmhoediatteostlyaprotuitcldeos(edaaidlmyinfiosrtr1a4tidoany,s ofnoollaownidngtwdoosheourasd)miannids wtirlatlioanl)sowbiethreaclolrdreeda.ctiTohnes abceuitneg mreecdoiradnedl.ethaIlnitdioasle a(nLdDSOf)inaolf btohedytewsetights airntitchleeRwiiklelr bLeaboaprpartooxriimeasteAdr.chivAeLsL,raStw.daPtaual,andMintnheesoftian.al report will be store 2 purina Rabbit Chow, Ralston Purina, St. Louis, Missouri 2 Gtheesticoonllaorf wrielslidubaelwotrenstfoarrtitchlee.duration of the study to reduce oral in- EAr), Va Ex LA biter A dAin= 03740 mois 4 ACUTE PERCUTANEOUS ABSORPTION TOYICITY STUDY - ALSTNO RABDITS with re-95 Swnary of maacticos Dose TTTHumber Affected Folloviinmgebeorme (afq) Sex sesction Weer oosed rasinistration 3.000 MPowWpesrisscntiitviictaymt 5/0 o=w 6 reaction noted amFomllmowiengrDmoseee Mainistzation o=y 7 TFionlelevoifngoabsotsne == 2 TTiimmee twheenn nzoaatnimaanlieailn tihnetdheosedogserogurpouepxhiebxihtiebditetdhetrheescrteiacotnion 238 Ja2 APPENDIX (Concluadcdr DFSTRNS No: HA QOF/Y GE . 1. Oo . Amendmentto Protbeol 10. c Staples Fhe pi gried Comp fi RS TSotudylDirdect A Date ryeect 3 Doe do He A im Study Directs EY is oA i Date 3: > Study Dire s/nDate : 4a code Abe sdodsAe ceptcamewill Ge Study Directo Date Tol "me Study Direce tor Tate --- "a Et Br-- mm ----------res-- pira EE 03742 APPENDIX 11 - Principal Participating Personnel Involved in the Study _-- Namo X. L. Ebbens, BS FFuunectilons Supervisor, Acute Toxicology K. D. O'MallHeyo, BS Dr. V. Pothapragada . G. c. pecore SAdEvYancDeldreTcotxoircolog9ist Commercial Chemicals Chemist Supervisor Animal Laboratory 03743 APPENDIX IIT 12. Composition Characteristics 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. 03744 13. APPENDIX Iv 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. 03745 tan anes vei b. Ro Ricker + 53-4 - REDFL.A GUrbeilffi+ch220--32520-28 2. reso V K. L. EBBENS - RIKER SAFETY EVALUATION LAB - 203-1 Fun W. C. McCORMICK - MEDICAL DEPT. - TOXICOLOGY SERVICES - 220-2E _--Suueet JSFUCKN-IE1N28A2,9B,SOFRC1P-9T180I2O9NanSdTUFDIeE-S8ON FC-143, FC-95, FC-99, FC-134, FC-135,7 3M mentioned compounds. Ptlheoadseermcaolnsitdoexricitthiys/skainnaaubtshoorrpitziaotnionstufdoiresyocuorndluacbtoerdatoonrytthoe release above > PchIfortaomevrplemioisumniniuondnntssado.rebfyreasertnTsoheaoosrcduonmsttpehhlresaueatmtmfeplddltuaehoteraanoa.dcnshaateWlnuimyadlislilciyeassslinsoaitnraadneriabeeclb'ayetsniieeinnstsgclauouibdfEssesFdoutirehLpdieitneisinoetntnrhuaeomnefnroesiupLangeomchrepotlm.etposlete adtcnhordenatwetaxnhatien.miyarlccoIodtnnacptrilsaeetteynioootcunonhccaselhvruoetusaligidonennsWneohrteacntoehnodctlehderanduirdpnergmeasyioscuneorisnnpFgtaehrpisiosstrnispmvlaeaetnsttyeoxrwiiJeliotlnnsgsybe.e.bsreHesossweperiveedr, Thank you for your patience in this matter. Selon 2 wo:kih coz746 - Internal Consporndenn W1bA. WVirnokkoenr ~- 223306--2288 he APPENDIX V (Concluded) COMMERCIAL CHEMICALS DIVISION ANALLAYBRTEPOIRTC14A6 _L__. WW. CG. MOCOMICK - 220-28-02 Fim V. POTHAPRAGADA AND V. BUNNELLE - 236-3A Swe RIKER SKIN ABSORPTION STUDY owe June 9, 1980 RR . i y Br uw 4 LeL,east Reference: Commercial Chemicals Division Analytical Request #5669 . Faonralylzaecdk.of time, only a selected set of serua samples as TOTAL F, ppm Compound DayFlemalesDuy28 DaylMalesDay 28 c-129 26.1 69.6 na 23.3 e136 02 18a w.8 239 c128 4h 26.5 1.6 10.5 Fo-98 26.4 93.1 219 %.3 re-135 69 20.8 2.3 6 #e-95 0.9 128.0 103 10.2 re-99 4523.15 uuLess 1792.a7 766s.6 bay-- 7. Day 16 Day28 Day7 MDaayl14esay 28 ve-143 10.1 12.1 3.5 5.4 08 Method af Awalynbas bO.xygF.enHaBgoemnb,/GEAnTael.elnBllqoucehenC;lo8n7,fe54l5t, 1a97n8). wate 70V.2. BA uBunnnnellie e V.wFe DP)Jootlhianpdreurgapdha PE bRyead aye arrbdd, SWeivnRietveeinervses 7' Gy : . 03747