Document 99NOnEdgJnp3BbBD2VegMpze5

Attachments to Letter to C. Auer dated May 4, 2000 AR226-0! 73 Perfluoroctane Sulfonate Studies Teratology Pilot Teratology Study in Rats, T-3551 Final Report, May 13, 1983, 3M Reference T3551.12 04207 @ HAZLETON LAB0RATORIES AMERICA, INC. Yay 13, 1983 ToWxiilcloialnogCi.stMcCormick, 111 TM2e2od0xi-ic2caollo3gMDyepCSaeernrttvneirecnets/3H St. Paul, Minnesota 55101 AFRECREIORNN mm \ ( Mar 16 1953 CL Leos Dear Bil: 150-158, PiElnoctlosReadt TareeratfooluorgycoSpiteusdyofwitthhe1-f3i5n1al." reHpiotrht cfoopryProofjetchtisNo. Tetter, I an forwarding one copy of the report to Marshall Johnson. If you have any coments or questions, please contact ne. Best regards. Sincerely, LETnic:lsomsure cor E. Marshall Johnson LStaawfRfencSEcie7.ntisEtTZEL, Ph.D. Departnent of Toxicology PHONE (703) 883 5400. TELEX 099436 (HAZLABS VINA) CABLE azLaBs wasnoc COA 208 @HAZLETONusomuronessencanc PILOT TERATOLOGY STUDY IN RATS rss ED . FINAL REPORT Submitted to 3M Company t. Paul, Minnesota May 13, 1983 04209 @HAZLETON usomronesauencane. SUBJECT: Pilot Teratology Study in Rats Project No. 154-158 We, the undersigned, hereby declare that the work was performed under our supervision, according to the procedures herein described. . Study Director: Staff Scientist Department of Toxicology Laboratory Supervision: Cadfod Department of Toxicology Teratology: shhh Department of Toxicology [ Mutee: Group Leader Scientific Resources Department tlh 04210 @ HAZLETONuaomrones svercn c. TABLE OF CONTENTS Page SUMMARY 1 TROOUCTION 3 CONTROL AND TEST MATERIALS 3 TEST ANIMALS 4 Groups and Dosage Levels 5 METHODS Mating Period 4 4 Compound Preparation and Administration Maternal Observations and Records 5 6 Cesarean Sacrifice and Tissue Preservation Statistical Analyses 7 8 Specimen, Raw Data, and Final Report Storage 9 RESULTS - MATERNAL DATA Clinical Signs 10 10 Mortality 10 Body Weights 10 Food Consumption 1 Gross Pathology 1 Uterine Weights un RESULTS - CESAREAN DATA 12 Pregnancy Rates, Corpora Lutea, Uterine Implantations, and Implantation Efficiency 12 Fetal Viability, Weight, and Sex 12 Fetal Development 12 TABLES Table 1 - Clinical Observations During Gestation 14 Table 2 - Mean Maternal Body Weights and Body Weight Change 15 TTTaaabbbllleee 43 -- MMSeeuaamnnarTFyoeordnoifnCaoGtnrossuSemapdtyPiaoWtnehioglVhoatglsyu,esFiGnrdaviindgsUterine Weights, 1i6; and Terminal Body Weights Minus Gravid Uterine Weights 18 TKaebyleto5Ta+blSeum6ary of Ovarian, Uterine, and Litter Data 19 Table 7 - Mean Incidence Values for Visceral and Skeletal Findings 21 Key to Table 8 23 Table 8 - MpeearnLiItntceirdence of Visceral and Skeletal Findings 2 04211 @HAZLETONusonsronessence TABLE OF CONTENTS - CONTINUED Page APPENDICES Key to Appendix 1 25 Appendix 1 - Individual and Mean Maternal Body Weights 26 Appendix 2 - Individual and Mean Food Consumption Values 28 Appendix 3 - Individual Terminal Body Weights, Gravid Uterine Weights, and Terminal Body Weights Minus Gravid Appendix 4 - Uterine Weights Individual and Mean Ovarian, Uterine, and Litter 31 Data 34 Appendix 5 - Individual and Mean Live Fetal Data 3% Appendix 6 - Individual Visceral Findings for Each Litter 8 Appendix 7 - Individual Skeletal Findings for Each Litter 39 Appendix 8 - References a2 04212 @ HAZLETON LABORATORIES AMERICA, INC. SPONSOR: 3 Company ATE: Hay 13, 1563 Project Wo. 160-138 SUBJECT: FINAL REPORT Pilot Teratology Study in Rats SUMMARY 7-3351, suspended in corn oil at concentrations intended to deliver 1, 5, 10, or 20 mg/kg/day (Groups 2, 3, 4, and 5, respectively), was administered by oral intubation to four groups of mated female Sprague-Dawley SO rats on gestation Days 6 through 15. A fifth group ventcle only. (Group 1) of mated females served as the control group and received the No Group 5 females survived to cesarean section on gestation Day 20. Treatment-related clinical observations in Groups 4 and 5 included hunched and conwilsions thin appearance of the as well as prostration animals. In and anorexia addition, were noted tremors and in Group aminals. tod weight sain of the dems during gestation was less in Groups 3, 4, and 5 compared to control, with a significant reduction in weight gain occurring in Groups 4 and 5. A significant decrease in food consumption occurred in Groups ulcerated areas on the glandular 4 and and/or 5. Apparent treatment-related nenglandular stomach mucosa were found during necropsy of Grow fenales. 004213 @HAZLETON wusonrones serch re. SS raTumn Anawa SEAA 2. 154-158 Analysis of individual and mean uterine data demonstrated no effect of T-3351 on fetal mortality or fetal viability. Mean fetal weight was comparable for either sex in all groups. External, visceral, and skeletal abnormalities were generally similar for all groups. One Group 3 fetus was found to have a small eye upon external examination. Another Group 3 fetus had fused hind limbs and anal atresia. Skeletal examination confirmed the external limb anomaly. c04214 @HAZLETON aonsronessveronnc. Er ee Sa. 154-158 INTRODUCTION This study was designed to determine the maternal and embryo/ fetal toxicity of T-3551 when administered by gavage to pregnant rats during the period of fetal organogenesis for the purpose of setting dosage levels for an expanded teratology study. The rats were placed in breeding on January 11, 1983, and cesarean sections were completed on February 3, 1983. This report presents the methods and results from this study. CONTROL AND TEST MATERIALS The vehicle and control material, Duke's Corn 011 (C. F. Sauer stored at room temperature. Co., Richmond, Virginia), Lot 80235, was received on May 28, 1982 and was The test material, T-3351, a white powder, was received from the sponsor on January 5, 1983, and was stored at room temperature. The test material was assumed to be 100% active compound. Information on methods of synthesis and stability, as well as data on composition or other characteristics which define the test material, are on file with the sponsor. 04215 @HAZLaE onroT nesaO veroN nnc. Ea -4- 154-158 TEST ANIMALS Sexually mature, cesarean-derived Sprague-Dawley Cr1:o(SD)ER rats were chosen for this study because they are sensitive to a number of agents which are known to be embryotoxic and/or teratogenic. Rats have historically been used in safety evaluation studies of this type and are required by the regulatory agencies. Thirty-six male and thirty-six female thirteen-week 01d rats were received from Charles River Breeding Laboratories, Kingston, New York, on December 22, 1982. The rats were held in quarantine for two weeks, during which time a health status examination was performed by a staff veterinarian. The rats were housed one male and one female per cage during breeding. Following confirmation of mating, the females were housed individually in elevated wire-mesh cages with food (Purina Rodent Laboratory Chow 5001) and tap water available ad libitum. The females were uniquely identified by ear tag after mating was confirmed. Tempera- tures in the study room ranged from 71 to 76% with a relative humidity between 37 and 65%. METHODS Mating Period During the mating period, one female was paired with one male until mating was confirmed or until two weeks had elapsed. Daily vaginal examinations of each female were performed to detect the presence and 04216 E@ HAZLETONueo omros nes merc ne. 150-158 rR viability of sperm or the presence of a copulatory plug. The day of observation of sperm or copulatory plug was designated as "Day 0% of gestation. Groups and Dosage Levels Upon confirmation of mating, each female was assigned to one of the following groups. Group. 1 2 3 4 5 . Dose. mg/kg/day 0 1 5 10 20 . Number of Females 6 6 7 7 7 2 Based on individual animal body weights at each weighing interval during the dosing period. The females were placed in the dose groups one at a time beginning with the high-dose group and continuing sequentially through the control group until all mated females were assigned to a group. All males were sacrificed via carbon dioxide asphyxiation and discarded without necropsy once a sufficient number of matings were confirmed. Compound preparation and Adninistration Suspensions of the test material in the corn oil vehicle were prepared on weight per value basis. The required amount of compound 04217 @HAZLETONwaonronesmera re. . EE 154-158 6- for each level was weighed on an electronic Arbor 126 balance and transferred to a 7 ml homogenizer. Approximately 5 ml of corn oil was added and the test material was ground into a fine suspension with a teflon pestle. This suspension was transferred to a beaker and any remaining compound in the homogenizer was rinsed into the beaker. Additional corn 0il was added to the suspension to produce the desired concentration and the suspension was mixed on a stirrer for approximately ten minutes. Prepared suspensions were mixed with a magnetic stirrer during dosing. Females were given the appropriate dosing suspension or vehicle by oral intubation on a daily basis beginning on Day 6 and continuing through Day 15 of gestation. The test material was administered orally because of the relative ease and accuracy of dosing. Fresh dosing suspensions were prepared weekly and stored under refrigeration (approximately 41F). Samples of each test mixture as well as the vehicle were sent to the sponsor for analysis. Maternal Observations and Records All animals were examined twice daily for mortality and mori- bundity (from day of receipt through study termination) and once daily for clinical signs of toxicity and pharmacologic effects (throughout 6.8, 12, 16, and 20 of gestation. gestation). Body weights and food consumption were recorded on Days 0, 04218 @HAZLETONusomronesaescanc. RannTom anaSa -1- 154-158 Cesarean Sacrifice and Tissue Preservation A gross necropsy was performed on all animals (found deads, moribund sacrifices, and terminal sacrifices). The uterus and ovaries from found dead animals and animals sacrificed because of moribundity were removed and examined for the number of implantation sites and corpora lutea, respectively. Prior to gestation Day 20, surviving females were assigned random numbers and all personnel performing cesarean sections and/or external, visceral, or skeletal examinations of the fetuses were unaware of the dose level from which the animals were derived. On Day 20 stoxide asphciation. of gestation, all surviving females were weighed and sacrificed by carbon The uterus from each female was weighed and examined for the number and placement of uterine implantation sites, number of live and dead fetuses, The uterus of early and each animal late was resorbing reveighed fetuses, after the and any abnormalities. contents vere renoved. The ovaries were examined for the number of corpora lutea. Each live fetus was sexed, weighed, and examined for external abnormalities. Findings were recorded. Segtaning at the ovarian end of the right uterine horn, the first six fetuses, regardless of sex, were selected for further evaluation. After the external examination was completed, the first fetus was identified with a tag and fixed in Bouin's solution for soft tissue evaluation (Wilson, et al., 1965). The next two fetuses were eviscerated, tagged, and processed for skeletal examination using a 04219 @HAZLETONwsomsrones serca nc. ETE SES -8- 154-158 technique modified from that reported by 1964). This sequence was repeated until been selected. Staples (Staples and Schnell, a maximum of six fetuses had Statistical Analyses Mean maternal body weight gains (Days 6-16 and 0-20), total food consumption, gravid uterine weight, terminal body weight minus gravid uterine weight, resorption incidence, percent males, and fetal viability were analyzed in the following order. Levene's test for homogeneity of variances (Levene, 1960; Draper and Hunter, 1969) was performed and if the variances proved to be homogeneous, the data were analyzed by one-way Classification analysis of variance (ANOVA) (Winer, 1971). If the variances proved to be heterogeneous, a series of transformations was performed until variance homogeneity was achieved. These transformations. were: logy, square (3), square root (X%), reciprocal (1X), angular (arcsine X%), and rank, in that order. If rank transformation was ineffective in removing variance heterogeneity, ANOVA of ranked data was completed. If ANOVA of untransformed or transformed data was significant, Dunnett's t-test (Dunnett, 1955 and 1964) was used for control vs. compound-treated group mean comparisons. If ANOVA was not significant, the analysis was complete. Mean number of fetuses with visceral variants per litter and skeletal variants per litter were analyzed by Fisher's exact test for proportions (Fisher, 1950). 04220 @HAZLETONusonsrones vemosne TT Lge 154-158 In addition to the above data, analysis of covariance (ANCOVA) (Winer, 1971) was used to analyze mean fetal weights. The litter was used as the experimental unit. Levene's tests and ANOVA were evaluated at the 5.0% one-tailed probability level. Control vs. compound-treated group mean comparisons were evaluated at the 5.0% two-tailed probability level. | Statistical references are appended to this report, and statisti- cally significant differences, as indicated by the aforementioned tests, are designated throughout this report by the term "significant and/or as follows: $+ = Significantly higher than the control value. S- = Significantly lower than the control value. Specimen, Raw Data, and Final Report Storage ANI specinens, raw data, and the final report are stored in the archives of Hazleton Laboratories America, Inc. 04221 @HAZLETON uisoruronesmeneame. EE a 154-158 S10 RESULTS - MATERNAL DATA Clinical Signs Summary clinical signs are presented in Table 1. Treatment-related clinical observations were noted in the Groups 4 and 5 animals during the trestaent and postireataent phases. These Included inched and thin appearance and rough hafrcoat Tn both groups, and tremors, convulsions, prostration, and anorexia in the Group 5 females. ertatity Al Group 5 females were found dead or sacrificed in a moribund condition prior to cesarean section on Day 20 of gestation. All other animals survived to Day 20 of gestation. Body teiants Individual and mean body weights and body weight changes are presented in Appendix 1. Mean weight values and body weight changes are presented in Table 2. Lover mean body veight values vere ted in the treated groups. Decreased body weight gain during gestation was noted in Groups 3, 4, and 5, of with significant deaths in Group decreases noted 5, body weight in Groups 4 and 5. change values could ot(Due to be the number determined for Days 0-20.) 04222 @HAZLETON usomronessenca ne: ES RRRRURS TORR AA RGASEW UA Su- 154-158 Food Consumption Individual and mean food consumption values are presented in Appendix 2. Mean food consumption values are presented in Table 3. Decreased food consumption was noted in all treated groups in a dose-related fashion. Significantly lower total food consumption values (Days 0-20) were noted in Groups 3 and 4. (Due to the number of deaths in Group 5, total food consumption values could not be determined.) Gross pathology Summary gross pathology findings are presented in Table 4. Treatnent.related findings were noted in the Group rats and included ulcerated-like areas on the glandular or nonglandular stomach mucosa. Uterine weights Individual and mean uterine weights are presented in Appendix 3. Summary uterine weights are presented in Table 5. The terminal body weights minus the gravid uterine weights were lower in the treated groups when compared to the control group; however, no statistical differences were noted. The gravid uterine weights were comparable between the control and treated groups. 04223 @HHAAZZLLEETTOONNLABoORnArToORnIeEsSmAMeERnIeCA.vIeNC. S1- 150-158 RESULTS - CESAREAN DATA Individual and mean ovarian, uterine, and litter data are presented in Appendix 4. Individual and mean live fetal data are presented in Appendix 5. Summary ovarian, uterine, and litter data are presented in Table 6. F pregnancyr faRatteess,,e CCoorrppoorry aa Lutes,Lite, Uterine lmplantations, and Implantation pregnancy rates were 100 percent for Grows 2, 3, and 5; 83 percent for Grow 1, and 8 percent for Grow 4. The mean number of corpora lutea and uterine implantation were comparable for all groups. The implantation efficiency for the control growp was low; however, this may be attributed to two animals which had implantation efficiencies of 38.8 and 35.7 percent. Fetal Viability, Weight, and Sex The mean incidence of resorptions was similar for Grows 1-4. The mean incidence of fetal viability was comparable between the control grow and Groups 2, 3, and 4, as were mean fetal weights and the percent males per litter. Fetal Development Individual visceral findings are presented in Appendix 6 indivi dual skeletal findings are presented in Appendix 7. Mean incidence values 04224 @HAZLsE omoT ne sO encsNwe. SS Rn Tom van An SaAn S1- 154-158 for visceral and skeletal findings are presented in Table 7 (based on number of fetuses) and Table 8 (based on number of litters). External anomalies were noted in two Group 3 fetuses at cesarean section. These included a small right eye in one fetus, and short and : thickened tail, no external genital/anal opening and hind legs which were fetuses appeared normal. joined from the pelvis to the feet in the other fetus. All remaining There was no apparent treatment-related increase in the incidence of visceral or skeletal variants or anomalies. Incompletely descended testes vere noted fn two Group 4 fatuses. Skeletal anomalies noted in one Group 3 fetus included a small pubis, fused ischia, and cojoined hind limbs. This fetus was the one for which the tail and hind limb external abnormalities were noted. 04R25 er Ee 1 Taste 1 Ai te oFIs A a a PLob Pk 28: Mean Maternal ody WeiT ghts aT ndBody veeigght onChange 150-158 Paar atotosy Say of T3461 To Rots GDronoeuLpevnedl E E soy eigE R ht Sm R ad va etoht e n Changen om1 ng WSeDn Lnean mC6ody 2T0e%d 0B.d2e WwBldZls WHEis 6daHke 22.0.000 th2ong NShn. 2C6o5ls LlTow 2Weoe 2l6.o08o 2e9.m8s Wmeas 5s.o0w 11.5.925 sa3 ng MSeB.n 2lLoLss moMw 2e9m 2so WSAi R leas07So n15m.2 om4 g MSeha.n 2258A.705 25l4e.3i3s 25G4.805 26f2.1o5 26z6e.0d8 33e3e.7n5 z3i% 105w.0a0 . wag5 hg MSeDa.n 22M8o.2w9 24l5i.0s6 23s8.o70e 2026.a73m 0 175.08 -C 64x.5:0% :- . 38 883 om es 0 re fBro m-- mm oLwowMFoRam aOmAL aAmS aUpR aUmR To en mm we ws wx ow Loom my we we ue aw ECo Eme Ema we ue wa aw ws SS 1 ere oat5ictmpaen we wae wwete, 28gg8 Tae 4 158-158 PilotSuTmearraytoGlroogsysSPtautdhyoolfog1y-F3l5a5dinIgns.Rats nm a0 oESCRIPTION bose level (aGfkm): Td T2 F3 WA A NNaabbeerr ooff aanniiamaallss weixtahninnoedgross Testons ssss 71 11 21 soUSninocogotrhatgelda-nidkuelaarremauscodsaark foct on glandular mucosa 31 Ulcaratad- ike areas on mnglandular mucosa 1 siRedmdischarge 1 HeaErnslarged atria weHarss on median lobe adhered to diaphrage 1 4S 1 oSmap ll pote 1 a32 3@ Mean Terntna) Body WelghtTsa,bleGra5vid Uterine Hetoht,s and 158-158 TermigPailloBtodTyerVatollongy WStwudey SofravTi-3g55a1rfinnRatMseigs GDorsoeu'pLeavnedl BToedryatWneallt UteriGnreaveialht MinuTserGatrnaavlidoUdtyeriWneelgNhettght o1mg HSein. 35355..378% 22.520 29S2.e5 t2ag HSeibn. ug2.2430 78..0597 2S1.097 sm3okg HeSiDn. 3106..53006 i2ni8nis 27160.:1290 ween MSeoa.n 32.67.2571 1n23m02 25189.397 L. wm5ng HSeOn -: :- .: 38 Q3s S19 Key to Table 6 154-158 e Brequancy Rath e_(percent) o=iT(antuinpoenr) of p1r5e07gnant fenales/mnber of females B Survia vFEaTl Rr ate a(pert cent) G=et(enaumobrercoofufaetmiaolne)s xsu1r0v0i,ving to Day 20/nunber of Mean_eITnpcloarnpotraatioTnuteEaffpiceirenecytBTiter] (e pexrcen) t) 10).= Group mean of ([resorptions per Mean Incidence ofnReesaorrpteiornsr(s percen.t) = Group mean of ((resorptions per Mean Incidence of eFertalraVitabailitpy he(rperecen)t) o=o)Group mean of ( [live 04231 Sumary of Ovarian,TaDbelrein6e, and Litter Data 150188 THe Terstorogy Study of T-3551 In Rats be level yGarolg: O1T T 2 3W4 we5 PaNrabemgebnrranocofyf frfeaemtmaeallee(ss3)wprietghnamnatting confiraed 85$ w 5 w77 8; ow;7 Wrinkner of females surviving to Day 20 wow w 7 w5 5 NeCTmomrpprtoaarmtabaotTioootfen:ss 1W52 em185 w18y7 o1w6s3 ow100\ fFeettarupstioCnsehaed 0o54e5 3o82s8 aafdooe 3T0%a9 8:To . InHNdeeiicinens roecpsalolnrctputlaiatotineodnioncneifdfaeincpceier.enc(1y3i)tt(e0r0 bass: nwol mB2e eTao mTan : : LiMNeaeaanTneti{unrnceeitsdaebnnccee ooff feettaal vmioarbtiahliittyy ((86)) %S8o w0d6 sooo sGnod : eaWnieb"ody 2weiCigomhvatagrui(sa3tn)ecde adjusted iaeo iaom oams nam el PerceFnetmamlaelses2 Ciomvaadriiuasntceed adjusted edsyeoeoIw3Efm 0 s3ms osmIl RC: 2 The ovaries of two animals ere too autolyzed to cant corpora len. . 32 Data alyzed following rank transformation. 88 154-158 eon SF mo=pomAtEecumIs FBBErrEETcis sts Musber and nL percent of fetuses having one or wwoos wwer wwmowener ygyeaonroo pvwee8rr Uwymin wwneeess veo wos wee om Bo [ or i-- oo I SE--A 2 rftp- erseT: enEsssi, 238g pea EE re wow vvveiIars jamms das pyvvueeersnn wmveaEiero wom pweoso yomees gwumoesemiesse ouG0UhisiaRe Wen IncFidietnoceTVeaatlTooatbolfsoey 7SVt-iuCsyacnoaft]iTns3an6d51SeitnetRatlsFindings bose owt GGrao: 31 Rib case Vertetest cHshtiEenrrnreeSrqhtbaoiraplutyrteiatsnestiriaed mconmipele oVysessse ings -Tlohbar raen M(rireenigitfiliaeedoesified y7oe3Ss8s Pelvic girdle C-ifiiccahhuiimnmtnwsacopm3eetteerelay axsifies 0[1/3E58E0 ibis momsshi ad #738 soFnuseadttrgimbeosen,tmatecakteirgended thoracic cantra snd aches Gyusss nsFoohr deSin)trion mGYiostn Nbrre SndHpeErcenat nofnfeetuses having one or woo Nbr nd percent of fetuses with: oFnEeRatTtgEmRnSt snd cafotned hind 11a bts smal) woo T2F po9oe0os0 ohoioshs w0o0h0I 0w/o0s0 Souhoeenss oaeess 000 000 15015 43 . omgooonoo naInaNedEs 0He5in0l obhaioseo ooobXoo AHa]a0o Ga0o% goreos. oUoEo wyoahr # u3Sm8es beEodso vas 000 wis wee 3288 5 -3Key to Table 8 154-158 FMeean Incidence of Visceral Anomalies (eptte)rcent) r=onGrso"up dmeoamn eodf (v[insucmebrearlloyf per litter] x 100). Meana Incidenceeaorf nVisscpeerTeal T VariC antsEa (percer nt) k=eeGnroaupmmmeaon owfiso(naumnberpeorf Titter] x 100). MeanFIencidenceoofpSkeeletral Anomaleieresume (perceonFt) r=eGrtouup rmenaneodf (S(rneurmeberru1foyf per Titter] x 100). MTeiatnterI)ncxide1n0c0e). of Skeee leeteal VaEraiTantas a(prerceent) r= eGrotupemneatn Sofe(hnuamnbserpoofr 04235 Hen Tctdence of Viscera)TsandtSe8keletal Findings per Litter 150158 Fit Terstotoay Shuty of T3851 In ats tose evel oorm :1 E 2 F3 Ta visceral onabtamarofl51 efStaertasesehxsmiicnhoerwdartports ttn ass se 16 02 03 03 0a Inmceeitdreincocef oofffatvweamrssitawniitetshssas fes 0oGho 6g6lEas atoEee aioeold Scetetar NNeomTWboneidryeanrotfesofs1oifctfateevtvrcaseartsiesaxtwnaeitmdstihonnedvrpenrtsVitter basis NToemeern5s7 offetuwsmeastwiitehs ammalfes 5576 Aaes dofns aadi daSs %2 wao oaGo oi WoeR 823 88 Lo -25- Key to Appendix 1 154-158 P = Pregnant NP = Not Pregnant C = Cesarean Delivery, Preceded by Day of Gestation FD = Found Dead, Preceded by Day of Gestation MS = Moribund Sacrifice, Preceded by Day of Gestation 04237 EH wee wBomEm wEeE B oeoR OmR iORE = H BWBooommmo EEe oGOOMEEE = Bom oe -=BaB8ms.OonnMmym oni13imE3Ee3 vad mr _-- A oy er SR cSo pele ae m en, ges = Y mW WE RRWD YWP E mR p mHe E OED ROED H BD BOBI ROm H OB S0m BH TWO anOvWm OWE OBA OWE NE WR E BOONM ER DOOBB EOOORNBC EE OOBB OYEOOBB OOOBBEE B8HOEH mOOOWEm g E eon goret S BOBS BE NEW HsBBwoaeayhOOBEmwmTmeeh mE O0O0HnW EOmawnBznd RmOmnWEyenM mBO= wBseEBE&a#uOs0nW w8wEWisBmls 130 i eg ho sp 8288 oo i EEN mee SSp ere iyee grosgm mOeMmB JOEEE g BoS E aBnOBan EOhB SOhmOo N m8 we mm "Be x my my 3 any we 5.1 ze TERAans UoHu OWE oun OER M8 2B ome ME OM OE OBOE wm ut aB 8oo w% Enmiimsm On FEiEs rRis E aOwBeaL BmO#E5eR0 EH OiXxB B FmBx3 ojMmre #aJaoer s " w Thou AE BW kd eyep wt et ad 0 re 2 A 0uta analyved folloving rast transformation. rt 32882 arn WE shia Smber 2 FE con1-0wm EX CEE EE Group 2 - 1 ma/kg. 5h i ' ve mm ows we uy nm ws 33g383 Inghvidua) A4o3p4enHdeixn 2o-dCoCnotnisnmuepdtion Values 1950-158 Plo Teratology Study of T-3251 In Rats. Food Consumption (oad comTaopttalioFono(d ) MaNtT uemrbnearl TE engw em n -- SrAs Group 3- 5ma/ky a2mm12s 2af2sd lalss3dd 11U8s2 uw19oz.0 o22as8n a839s93 22008738 30755 6RB2s7 d13e7e 130 ulaos les i1s0s leg a22 oe wpraox 2s Eg 3 183 Me 2 #a 308 . H5o5n a2g3es leeamrs 16L.e60w 1L.6621288 927.388m5 2: Grow 4 - 10 mg/kg 220057788 279 1w8s4 d7 11.504 ass m1g62o8 li1us2ss6 a2av38e 833.5728 222007778600 WaAi3o o1da8er3ss uwssee ieyese a1adsa m3S6e78s8 265 Bo ago se wi as m3 M5ean a20606 1L6e%s 1543s6 0s0ee 2310 36s5.h0o05" 3hS ]bBY Individus) AsonpdenMdeiaxn 2Fo-odCoCnotnisnuumepdtion Values 158-158 Pilot Teratology Study of T-3351 In Rats Maternal re Fondconsg umption e (anja ) ConTsoitmaplFtiooond usbero . e 2 Gr5-o20umgp/kg 320076650 1553 1a817 1132 o-z -i -: 2200788678 aa220 1l12es4s z3SasB 00os2a ::: :s: S27609 Bdoa a1513 eiss oods :: :: . Hsooa.n w2am wZnw adwns oOwo 8v P28 88 Mautmebrenra.l 003%87 2f20o3r0a9 HSeom 222000573.8 220776 ie M5e0a.n 82 2 & Individua] Terminal Body WAeplpoehntdsi.x G3ravid Uterine Weights, and 150-158 TerminPailloStaTyerlatooflotgsy MSitnuudsy rofayTi-d355U1terfnineRathseights odyTeeraitgrhatl (a) 31SHo28t 40reguant mml8se 358.r36s Greaviigdhtute(ro)ine Group 1+ 0 mg/kg 22.'9s jawna 22..5202 MinuTserGartanavlidBUotdeyrWineelgHhettoht 229:.25 a2So0tes 20s2l.e5i : Grow 2 - 1 markg 5i393.8e.06 E2x7.]7 2218203.1800 Fa2d 3 w&9s3 225umas1 u2aa 78..0597 2w81a.r9s pprrote) wawnsee wwaea ppeot iwwnedya amieet yuown 23235 2 nit sermonEoErt TermPin BoTdy MeLlonts 2: SMinlus tGT riavnidsUrr1n Veettptss , a sae . wpln E2F30od a8E1d m5o:9 BiBmnsseehat nasy mBrh eAtErts wom 1- nBsasaat 2aaFi widne om 4 b1ini0sdmg awwita wjE n ntToE mo sE os tre miwfets ms3il meth i f&mEdsH mwls nayh Mautsetrenral 2020076868 ms200e1786s79 wm Appendix 3 - Continued 198-158 Indivi"dTuesr)miPnTiaellromtSianTdayelrWaBetaiodglyhotgHsyelMSoithnutudssy, GoSfrraav1vi-id3d5UU1tteeririninnReeatMWseelioghhttss, and BodyTeeraiignhatl (o) :-: ::: : Greaviigdhtuter(0i) ne. Group 5 - 20 majky :-: :2; : MinuTserGmrianvaildUBtodeyriNneelghbtetght 2:. z:: : 22 8=@ gy mtr re ce a ers iy of 1351 Ta ats MBeE oewle owleee DmeOseDs wwioeylte-ommSmEeNwnG EEpesoCs edmeie wile Boop ws eo: row om [I it wom wood [I I EEttm ET | #od i FI. #0F # &. LE i w 08 nw [ mot Wo Th ses Boom mm mBo on 2i s [i g d sFoFm w 8 m 2B2 0o5o 85 uin HnHsE ood1 qi#o00F 8ifF 80#88 Aixi motow ou o Wooo o wHoom Bm ome wm n2s 23 A -- 2825 wEaY oowee avlemi g mi o i3 Bo mee, moth MW wong gE TE he Phot Teratalogy Study of 1-3%51 1a Rats mSeEe wrwoyirsJeEweG EEmeEss wwne se ngood 2gf3 3fF B HOE W ne . ss wes me porn esi BB Won tw wo i | ; 233 883 wa JRE Pi aBa bi1 aad 333 " iY : i o=e 1i i Pe4 o2n) otoa B 2a=B0a diii: iiii w=n I2n 52) ots oemecosttb mit, 345 5% lStionoF LSTe ett Botse me oo t= mty 2SwI8o "3 ith Ey wn 2 Luana EEE it E#1d ii P[y2 Eia) i2 ne sms 2&81B 1 H1ii3t aith iah iw= EE EEE H8u i By ii 8: iasw Hane 1iiiit ia imn wiE t E TR wm Maternal Or ER e ENPercenatme moE ue m mw el (em) m #wm i ii #8g ooHou 3i #0 : au 3 mo Boothasm0 wm om om m8Bo8B E mEmEemEl 34 ;] 0 EE 232825 I, T JR "Piet Terstotogs Suds oTf3051 1 Auks he I Erm woFFe oes 1 4fF 31d 1d 11d1d1d Peed ny Tes origsaweeoes 888 i : B poe on boone mwa. ET SE wE efEE EEE E EERd E d EE ae LL FB EEE OTTO OTot EE Tia et 00 0: 00 00 00 00 00 00 wo 00 00 20 00 w TEEETTTT oo ee es ve ee eu 25a3 i Sind a as as 0s as as os eo oo so oo oo oo tn eT "Pek Tarsotoas Sudy o1f 361 in Ruts ee J --_---- . TalsfeSr sett CBE REE esSEE os . 9, re ; a - pe dik SEBeckers mn Felco tau avgcn amreskeletal g53-3 & ow ow os ow o: rPrrotr | PF. i : 1 i 48548 om os wm on wm on or 0 [bEEsE : ee ior 0000 qs SEE ot Tartare Suu of 1-3915m ks gong eed fEodE8E8 EE ora FEEEEEEEREE | EEEE EAG1r R0EHRr ITtaEe sr LLae mLr eL m0o0n0e mL fab nr oa montotn SE EE m : EER. T co '> er gESEE . , : , 58 worRmEs mfiEs ins Ca : Ln B : ' mie 2 23& #5 [e-- Eaat ESh ary pTsL SE Fe ie J m EPo E rPo E bdr: i : etc FE : . i exe tom 3 TE4Eed TEE . ty rR so 0 0 1 0 0 es 0 0 0 0 ErRa Ecn . :. -32 884 Rs Let 3 -a2- Rroepefpneedrniedxinxces8 Plot Teratology Study of T-3551 in Rats STATISTICAL METHODS/LABORATORY PROCEDURES . 154-158 : ABagrrtilceutltt,ureM. aSnd.', W:137-170, 1937. A"pSpolmieedExaBmipolleosgy.o"f StJa.tisRtoiycaall MSettahtoidsst. ofSoRce.seaSrucphpli.n RDervaipesri,ted.N". RT.e,chnaanmdetrHiucnst,er1,1:2W3.-40G,.,`196*9T.ransformations: Some Examples TDruenantemtetn,tsC.witW.h, a "CAontMruollt.i"pleJ.CaAmnp.arSitsaotn. PArsoscoec.d,ure50:f1o0r96C-o1m1p2a1r,in1g955S.everal BDiuammmeettrti,csC,. 2W0.:,462"-N4e9w1,Ta1b9l6e4s. for Multiple Comparisons with a Control." wGiatmhes,`UPn.equAa.l, aNn'ds Hoawnedl/lo,r Statist., 1:113-125, 1976. J."VaFr.i,anc"ePsa:irwiAse MMounltteiplCearCloompaSrtiusdoyn."ProcJe.durEeds. EFidsihnebru,rghR,. 1A9.5,0.Statistical Methods for Research Workers, Oliver & Boyd, CLoenvternie,butHi.o,ns"RotbousPtroTbeasbitlsitfyor aEnqdualSittaytisotficVsa,riaSntcaensf,o"rdinUnIi.veOrlskiitny edPirteesds,, FaleATto, TOB0.-- oo Statens iSntaptlhees, KRO.H-EA.liaznadrinScRhendell, MV.ethLo.,d "fRoerfinFeemteanltsBoinne.R"apidStCalienarTiencghnToelcohgnyi,c 39:61-63, 1964. 2 TWielcshonni,duesJ., TGr.e Uannidv. WoafrkCahniyc,agoJ.P,resesd,itCohrisc.aga,2 Te1r0a6t51 o,logpy0 o:e PT rinciH ples ,a0nd HWeibnrera,n-HIB.T1,J.,RYS,tCathiastica3l10,PTriOnciploeso in Eexppeerriiameenntteall DDeesstiagnn, 2nd Ed., 04254