Document kE6zpNQvk38wMdpJDeDmmy4y

AR R26 _ 0659 N-Et FOSE alcohol Teratology - [ a @ HAZLETONusonsronesavencane. PILOT RAT TERATOLOGY STUDY T-3362 FINAL REPORT Submitted to 3M Company St. Paul, Minnesota May 11, 1983 000325 @HAzLETON, SUBJECT: Pilot Rat Teratology Study Project No. 154-159 We, the undersigned, hereby declare that the work was performed Pluss. Ganlfc Rodent Toxicology I Department of Toxicology Ld filles Research Associate Department of Toxicology ReaeagdHeaen Scientific Resources Department C0326 (@ HAZLETONusonsrones enc ne. TABLE OF CONTENTS f-- INTRODUCTION. CONTROL AND TEST MATERIALS veTErTSvToonrAsNsIMApLeSriod Groups anrdacDoesragaeioLnevealnsd Administration EE Maternal OTobesrerrtviaitaionmsdaTnedstRuencorpdrsaservation Eel Aa 1 Fiat Report. storage RESULTS - MATERNAL DATA Clinical Signs J Mortality Body Weights Food Consumption race 1 3 3 4`$ Co 5 6$ 10 10 i10 10 1m EFered) E Deveopr ennt e sex 38 RESULTS - CESAREAN DATA 12 Pregnancy Rates, Corpora Lutea, Uterine Implantations, and Implantation Efficiency 12 Te TABLES Table d1 T- aanCliniceatlerObnsaervtaotyionvset eaDuring GesBteastioRnataht Change 115% TTaobtlee 3 - MoemanaFroodorCtonrsounmptbiaotnnotVaalguyesFindings 417 Table 5 - Mean er oo Va Terminal Body ed Wise av veerine ions" Weights, Gravid Uterine Weights, and 20 Ao Key to ry Table 6 of ovarian, Uterine, and Litter Data %21 ea heat Table 7 - Mean Key to Table 8 InTncciiidtdeeennccee VofaluVeisscefroarl ViasdcerSakleleatnadl SkFeilnedtianlgsFindings 23 25 000327 @HAZLsE omoT ne mOencN anc, pace TABLE OF CONTENTS (CONTINUED) ILS Soc het ones Wines roeid ering welomts 34 APPENDICES Key to Appendix 1 27 Appendix 1 - Individual and Mean Maternal Body Weights and Weight Changes 28 Appendix 2 - Individual and Mean Daily and Total Food Consumption 31 Appendix 3 - Individual Body Weights, Gravid Uterine Weights, and Appendix 4 - Individual and Mean Ovarian, Uterine, and Litter Data 37 Appendix 5 - Individual and Mean Live Fetal Data 40 Appendix 6 - Individual Visceral Findings for Each Litter 43 Appendix 7 - Individual Skeletal Findings for Each Litter a4 Appendix 8 - References 4% 000328 @ HAZLETON LABORATORIES AMERICA, INC. SPONSOR: 3 Canpany MATERIAL: 1.3352 DATE: May 11, 1983 Progect Wo. 154-159 SUBJECT: FINAL REPORT Pilot Rat Teratology Study sunny T-3352, suspended in corn oil at concentrations intended to deliver 1, 10, 37.5, or 75 mg/kg/day (Groups 2, 3, 4, and 5, respectively), was administered by oral intubation to four groups of mated female Sprague-Dawley S-D rats on gestation Days 6 through 15. A Fifth group (Group 1) of mated females served as the control and received the vehicle only. Apparent compound-related deaths occurred in seven of seven Group 5 and three of seven Group 4 females on or before Day 17 of station. Clinical observations in Groups 4 and 5 included hunched, thin appearance, languid behavior, and apparent anorexia. Body weight gain during treatment was less in Group 3, 4, and 5 females compared to control values obtained during that tine. The terminal body welght minus the gravid uterine weight was decreased in Group 4 females compared to control. A mmber of gross pathology Findings at necropsy ov sacrifice were noted in Groups 4 and 5 and these included incidences of liver, adrenal, lung, and/or gastrointestinal tract effects. ~nez29 @HAZLETONusossrones merca nc Lz. 154-159 Evaluation of mewn fetal weight dats indicated that fetal weights of both sexes decreased with incressing dose level. A significant decrease in mean fetal weight occurred in Group 4 males and females, although data for only two litters were available for that group. Cleft palate was found in two of six Group 4 fetuses (one fetus in each litter) examined by Wilson's technique. Incompletely descended testes vere mted in one fetus from each Grow 4 litter evaluated for visceral defects. Incidences of skeletal variants were similar for all groups. 00033 @HP AZLs ETONi ueomro onessn eca ne ors Sa. INTRODUCTION This study was designed to determine the maternal and embryo/ fetal toxicity of T-3352 when administered by gavage to pregnant rats during the period of fetal organogenesis for the purpose of setting dose levels for an expanded teratology study. The rats were placed in breeding on January 17, 1983, and cesarean sections were completed on February 18, 1983. this study. This report presents the methods and results from CONTROL AND TEST MATERIALS The vehicle and control material, Ouke's Corn 01 (C. F. Sauer Co., Richmond, Virginia), lot 80235, was received on January 24, 1983, and was stored at room temperature. The test material, T-3352, an off-white solid, was received fron 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. 000331 @HLiAs ZLETONuisomronsmerica ne sess -a- TEST aun Sexually mature cesarean-derived Sprague-Dawley Cr1:C0 (SD)BR 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 requlatory agencies. Thirty-six thelve to fourteen-veek old male rats and thirty-six eight to ten-week old female rats were received from Charles River Breeding Laboratories, Kingston, few York, on becemser 22, 1982. The rats were held in quarantine for three and one-half weeks, during which tine a health status examination was serforned by a staff veterinarian. The rats were housed one male and one female per cage during breading. 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 70 to 78F with a relative humidity setueen 44 and 69%. werHons Hating period During the mating period, one female was paired with one male until mating was confirmed or until two weeks had elapsed. Daily vaginal 000327 @HPAZO LES TOS NueE omronesmeric ne sess 5. examinations of each female were performed to detect the presence and Visbility of sperm or the presence of a copulatory plug. The day of abservation of spern or copulatory plug was designated as Day O of gestation. Groups and Dosage Levels Upon confirmation of mating, each female was assigned to one of the folloring groups. Grow RDoTseE. Number of Fenales 1 6 2 1 & 3 10 7 4s 7s37.5 77 2 Bduarsiendg otnhe idnodsiivnigdupaelrioadn.imal body weights at each weighing interval Giher matings. were confirmed. Gecause this anina's dose level would 5 An additonal Group 2 female was confirmed to have mated on a day when no have been known at cesarean sacrifice, she was removed from the study. Te fensles were placed into the dose grows 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 nusber of matings were con traed. 000323 @HHAZALEZ TONLssoEommoonT nee:mOencN anc _ ee Compound reparation and Administration Suspensions of the test material in the corn ofl vehicle were prepared on a weight per volume basis. The required amount of compound for levels 2, 3, or 4 was weighed into a homogenizer on an electronic Arbor 126 balance. Compound for Group 5 was weighed on powder paper on an a1 Arbor 126 balance and of corm ofl was added rinsed into a and the test Waring material blender. Approximately 4 was growd into a fine suspension. This suspension was rinsed from the homogenizer or the blender nto 8 beaker and additional corn ofl as added to produce the desired concentration. The suspension was mixed an a stirrer for approximately fifteen minutes. Prepared suspensions were mixed with 3 asgnetic stirrer doing dosing. Pansies were given the appropriate dosing suspension or vehicle by oral intubation on a dafly basis begining on Day 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. Materna) Observations and Records A11 anfmals ere examined teice daily for mortality ind mori- bundity (from day of receipt through study termination) and once daily for clinical signs of toxicity and pharmacologic effects (throughout 000334 @HHAAZZLLEETTOONN.uesoommroonnees:mencanc, _-- Sr. gestation). Body weights and food consumption were recorded on Days 0, 6. 8, 12, 16, and 20 of gestation. Cesareen Sacrifice and Tissue preservation A gross necropsy was performed on all animals (found deads, moribund sacrifices, and terminal sacrifices). The uterus and ovaries from vere found dead animals and animals removed and examined for the sacrificed mmber of because of moribundity implantation sites and corpora Tutes, respectively. Prior to gestation Day 2, surviving femles were assigned random numbers and all persomel 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 of gestation, all surviving females were weighed and sacrificed by carbon dioxide asphyxiation. The uterus from each female was weighed and examined for the minber nd glaenent of uterine plantation sites, mmber of live and deat fetuses, arly and late vesorbing fetuses, and any abnormalities. The viarus of each antnal wis roweighed after fhe Contents were removed: The ovaries were examined for the number of corpora lutea. Each Tive foun wn senah, wight, wd waned for edema seomaiities. Findings were recorded. Beginning at the ovarian end of the right uterine horn, the first six fetuses, requrdless of sex, were selected for further J-- 000335 @HAZLETONusomrones mena ne. F---- _8- 154-159 third, and fiftn fetuses were identified with a tag and fixed in Bouin's solution for soft tissue evaluation (Wilson, et al, 1965). The second, fourth, and sixth fetuses were eviscerated, tagged, and processed for skeletal examination using a technique modified from that reported by Staples (Staples and Schnell, 1964). 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 (x2), square root (X%), reciprocal (1/X), angular (arcsine X%), and rank, in that order. If rank transformation was ineffective in removing variance heterogeneity, ANOVA of ranked data was comleted. If MOVA 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. 000336 HAZLETONusontrones merc ne. F-------- ee 154-159 In addition to the shove data, analysis of covariance (ACOA) (Winer, 1971) was used to analyze mean fetal weights. The litter was used as the experimental unit. Levene's tests and MOVA 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 falas: Sv = Significantly higher than the control vaTue. S- = Significantly lower than the control value. Specimen, Ro Date, and Final Report Storage AIT specimens, rau data, and the final report are stored in the archives of Hazleton Laboratorfes America, Inc. 000337 @HAZLETONusomrones secame. Fremm---------- S10- 154-159 RESULTS - MATERNAL DATA Clinica) Signs Summary clinical signs are presented in Table 1. Treatment-related clinical observations were noted in the Groups 4 a6 5 animals during treatment and in Group & animals postirestaent. No Grou 5 rats survived the treatment phase. Clinical signs for Groups 4 and 5 aninals included hunched and thin appearance, languid behavior, urine stains, and bloody crusted eyes, eyelids, nose, mouth, legs, pans. or genitals. Anorexia, ataxia, dyspnea, rough coat and pale appearance were also noted for several Group 4 or 5 rats. One Group 4 rat aborted thirteen fetuses on Day 20 prior to sacrifice. Alopecia was noted for some rats in each dose group and the control group. vortatity All Group 5 females were found dead on or before Day 16 of gestation and three Group females vere found dead an or before Day 17 of gestation. AI) other aninals survived to cesarean sacrifice on Day 20. Bodyveignts. 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. During gestation, lower than control mean body weight values vere noted in Grou 5 begiming on Day 8 and in Group 4 beginning on Day 12. Decreased body weight gain during gestation was noted in Groups 3 wu338 @HAZLETONusomuronesmenosne. F----_------ Su- 154-159 and 4. The decrease in the Group 4 animals was significantly different than the control value. Because of high mortality, Group 5 data were not included in statistical evaluation. Food Consumption Individual and mean food consumtion values are presented in Appendix 2. Mean food consumption values are presented in Table 3. Stightly decreased food consumption values were noted for Grows 4 and 5 compared to control on and after Day of gestation. Mean total food consumption values for Groups 2, 3, and 4 were statistically comparable to control. Total food consumption for Grow 5 wes not determined because of mortality. Gross Pathology Sumary gross pathology findings are presented in Table 4. No gross lesions were noted at necropsy for animals fron the control group or dose Grows 2 and 3. Findings noted for Group 4 animals were discolored Tiver, kidney, and adrenals; enlarged adrenals; dilated renal blood vessels, and red vaginal discharge. Findings noted for Group 5 animals were reddened and/or distended lungs, enlarged and/or friable Iver, enlarged adrenals, discolored and/or thin glandular gastric mucosa, fluid in stomach or intestines, and red vagina discharge. Uterine weignts Individual and mean uterine weights are presented in Appendix 3. Summary uterine weights are presented in Table 5. 000339 @H2AZsLELTOdNusorones menos ne Lsetss Si Wean termina? body weights were comparable for Grows 1, 2, and 3, but the mean terminal body weight of the Group 4 females was decreased compared to control animal weights. There vas an approximate 9% decrease in the mean gravid uterine weights of the Group 2, 3, and 4 animals com- pared to the control mean weight. For Group 2, this may be attributable to one dan with eight early resorbing fetuses. Terminal body weight minus gravid uterine weights were comparable for Groups 1, 2, and 3, but that weight vas decreased in the Group 4 animals compared to the control wise. RESULTS - CESAREAN OATA Individual and mean ovarian, uterine, and litter data are presented in Appendix 4. Individual and mean live fetal data are presented in Appendix 5. Sumary ovarian, uterine, and litter data are presented in Taste 5. Preananciy aRates, Corpora Luten, Uterine Imlantations, and Im-- plantation Pregnancy rates vere 100 percent for Groups 1, 2, and 3, and 85.7 percent for Grows 4 and 5. The mean number of corpora lutea and the mean number of uterine implantations were comparable for all groups as were mean implantation efficiencies. 000340 @Hp AZLETS ONveomrones avenioane sess 1 Feta Viability, Weight, and Sex Mean. resorption incidences were higher for Groups 2 and 4 than for the control group, but these differences were not statistically Significant. The increased incidence in Group 2 may be attributable to one dam with efght resorbing fetuses. Mean incidence of fetal viability and percent males were comparable for Groups 1-4. Mean live fetal weights of both sexes decreased with increasing dose level with Grow 4 values significantly lover than control. Feta Development Individual visceral findings are presented in Appendix 6; indivi- cual skeletal findings are presented In Appendix 7. Mean incidence values for visceral and skeletal findings are presented in Table 7 (based on number of fetuses) and Table 8 (based on number of litters). Gross external examination of fetuses at cesarean section revealed one abnormal fetus from a Group 3 dam. This fetus had no tail and appeared to have no thoracic or lumbar vertebrac. However, no skeletal evaluation was done on this fetus so that finding could not be verified. Skeletal examination of the selected fetuses revealed that the Incidence of skeletal variants was comparable for the control group and treated grows. No skeletal anomalies vere noted. The incidence of visceral variants was markedly higher for Grow 4 when compared to the coozal (@ HHAAZZLELTEOTNOuNssoomosnruroonneess:awemca ne: re Cue control group (50 percent vs. 5.56 percent). However, only two Group 4 litters were available for evaluation comared to six of the control group. Variants noted were dilated renal pelves (Group 2), dilated ureters (Groups 1 and 4), and incompletely descended testes (Group 4). Cleft palate was found in tuo of six Group 4 fetuses examined by Wilson sectioning. That anomaly was noted in one fetus from each of the tuo Mitters from which the fetuses selected for visceral examination were derived. Wo other visceral anomalies were observed. 000342 J" Sg, Sg Sigg, SR Seigl jfone a WM isinEAL, L tt Nest: Sr) ir | 222 23% .7 ow 4 , Lo , a om " Mean MaPtielronta)RaBtodTyerWaetiTogalhobtgsly2eaSntduByodoyf H1e-i3gh5t2 Change GDroosuepLaenvdel O1mg Tn2ghg Wm3ghe ssm`gke Beg5ky R sody Vetgnt Ew de(grams) NSieD.m 2e ss 6`s8we LeDos 25vi e2s 0e0ms 6sesae MSeDm 2g0o.0s 2200205s 22220m LeMm WdNam Wswie 5 NSeDm W 2107 .00M Lleid 7 216.7s3 7 0Ma.m 7 MTLiSs 7 9l9.e67k 7 NSWeD.m 2I0.s25s Loese aT0se MleEew s 2eems " ASLeOem 2 WseDm. 2smemo 2D0o.0m (-- 6 sas 0p68ao- ` 5 -Z & Statistical group comparisons performed on rank-transfarmed dota. 2 28_- 154159 p S Body p p setght pe Chano gc e e(sq) p0a.5n0 8 w7s16 6 "2s0se iz0 es 6 a10n.317 7 m7 en!5 7: 3a50i.6s8e5 15 670.705 0.2 -5 i 5 Mean Food CToanbsluemp3tion Values 184-159 PHIot Rat Teratology Study of 1.3352 Grow and Dose Level Food Consumption (gn/de) Day of Gestation Total Food Consumption) JETT tears Et om1 g NSeOm W lLmm 6 1L9.e2s 6 ol@es ` 1L9.o9w 6 wbaes 01.72537 ET2 E Neo W M5X2U 1L9.T2 005 2 `O0Y %s sSa81s0 Wag3hg MSWeDm 07Law wg7 eas l 27 saud7 o 2o7 ae 3007.s1i7e s; WS0a) ghg WSWOm. l2eMms 25Som l8`o1ss s16n5 1135a2 ais3saols Tas5ks esom. W 20T.e03m 6 sZ.ee 5 a8l.5e5s 0-C :. .: 2 Statistical group comparisons performed on rank-transformed data. a2 Simro GrosTsablPeo4los ining 150.159 Fie Rt Terstotosy Say of -35e wan wo oescaerion tose Lew) (yGeonw: D1 T2 W3 WE4s NWuamkbeerr Woifthrat2s egxrsomsoeTdestons So 6 r7 o dds umSeeidssdetnecndes 2{ uTEeelrila e Frise constatency 3 an 1 5. riGeSroreoesdnieshsses - atiates 11 ! ArmEoeemse :i am stCCooonnttnaaiinneedd bdlaarckreFdlFdluid Glimaniar meota reddned 1In hhnha focal wrens 3ii h 0 Norpregnant fem. 8882 a PSiutamyfooTfaTbeGlrreaots4os-loPgCuyotnoSttitangyueydoFfin1d-in3g2s 151-159 @oM m0 sarpTIOn eeveGeop:1 T2 TB3 W4m sA EFsittTaedswith dark fluid mtertal 1 omtiacted ' eReid/bleodydischaro dark red flutd se . 2 $8a 3 NeiTamiSlotoy Utwanedrse rntAes a 0 ho Trey Se of i gfoanhremeds iTeviinn weGlskde s waer Smie5s%a we oL l eEi MoEws n:3o% mtai e tetmi mW+sE a8+n mBtao was n n4 wTmai afixm mUne 23 wwCeoweUni5 wa ? ai?Eu w0}ns wison wU im C: i:. .:; Stine! sro copartions forse on riktrustaned dt. g .LBg8 -2- Key to Table 6 154-159 Pregnancy Rate (percent) = (number of pregnant rats/number of rats mated) x 10. SurFvaitsvapllaRcaetdeon(psetrucdeynt)) x1=00(n.umber of rats surviving to Day 20/number of Mean per InpTliatntetra/tcioornpoErfafiTcuiteeancpyer percent) litter] x = Group 100). mean of ([ implantations Mean R`eersor/pitmpiloanntaItniocnisdepnecre (percent) = Group Titter] x 100). mean of ([resorptions per Mean Incidence `etuses per of Fetal Mortality Titter/implantations per (percent) litter ] x - Group 100). mean of ([dead Mean Incidence etuses per of Fetol Viability Titter/implantations per (percent) litter] = Group x 100). mean of ([ live 000349 | SmTHot tnTa,es te ote 119 toe Leet aoay; I12 3 wsas F iEEdT Lrp ooeDieee-- s soon Wc n sw weooeW 3ref1p r ds wig espsanberta: wow ea wo es me wr tr Jfreie Tw a BbBoooouhssoonm omoomo&w owdDb y heer ppr lalinae scp i -- on ii waFTohsE nrp unma ah Sh moneg owan 2% heAomp boEdA ytRan ,a) Cae am am as g rreoucteos]~S mScoviarfmanece e adjusted . 3dmE .4no0 E3a.387 dW o2Fw7 m2dm.E7e5 - B BgE *1unm wt?E aroun 2 conte wat CcontTend toSaie eted onS0ldoysi,n 10 hher atlirosrwree ccontrasd. Nesn nctdeFnicieotVaAaluesTerfaotrToalVbiolsgecye7rSatludyanodfS1ke-l3e3t5al Findings 151159 bose lewl (aGgrao)w:: I_1 TT2 W3 WE. Visceral NNaombeer ooff ffoettuusseess weixtahtinnedormal 1iaits ki1 iMn 2a 5i NManmrbbeeri/rpseprecrecnetntofoffefteutseusseshatvihng:one or sore visceral ss uss 0 umm DOciioltmaaptteelddetrreaeltynerdepss)ettansded tests(es) s00s iss o 000 Iummo ne "Nomubetri/peerscent of fetuses having one or sore visceral o 0 0 mn : WmTbieerr/tpepricsetnet of fetuses with: o o oman Scetetal NMMumabbbeer pooeffrcffeeentttuusseeossf wfeiexttohunistnensendhoarvailngmointsor sore skeletal 1: yu` afo is MnobaTeagrnginpgercGaesnltcotfifoetnuses th: Ba wen ws smn CET sTiiapnretosenTrceprrpsetacalosousorsseisfiif(citacetasitsoinotnhtnInnc7ca5op8pl)ieettee YwSAaRMz aIapmNisEe mGumsys a3d00a wn Zh~ oSHiotptradaoocsciirpofintiaacalaittniiooennsoTnfciocmapteitosn = parte Trgulanty ossified Es0sh il5v s ado0 a 0o vem re se Hen IncidFenicfeeVRaalTesaorefoart7-oVirscyceorSanlhtcaindofskTe3l0e5t5al Findings 150159 toe tel (wroa:s 01 TF2 T5B WE. sceletal (Gntined) bNeReorTrhipeeomesfrrcfceeeetonunssitevrsiiofcenxtgafineotinnuneseedsorrsiunee skeletal va nts un s CVR ertebeat CcERhEinSerreBiraparrcyteiotcnoesmreen osiftcation vsos sAmA ww wes e -CthaoerespiCoeentrea aenetsnirtes vVassose uso6w m dAdmsmobdeee S oneoin egenrts Mvshs usoe us 08 : Kner ercen having one r sore seletel sma les oo # S25 Key to Table 8 154-159 MeanSEuIsnecsidweitnhce oafnoVmiaslcieersalpeArngmaTtiitetesr/m(upsebrecrentof) per Titter] x 100). Meaent_uisnecsdewnitche ovfarViiasnctesraplerVariTainttesr/nu(npbeercrento)f per litter] x 100). Meapner Ilnictitdeern]cexof100S)k.eletalarAnomarliees s(tperc)ent) Meapner ITnictitdeern]cex of100S)k.eletal VarianTtes Rab(peerrcent) f=etGursoeusp fetGursoeusp T= Greoup f=etGursoeusp emxeaamninoefd (v[insucseberrallofy emxeaamninoefd (|vuismcbeerralloyf imeamn oof (S[rnuemhbeerratoyf emxeaamninoefd (sLtnuemrbeerralloyf 000353 Hen nctdePnicke oTferVtssctaornay)pSnaoiy)Seolfa1ta-n04F2inidninkgsspr Litter 150159 toe te (aoiam: 1 F2 T3 was Visceral Examination nmPebbrceaerrntooffa Kimber of TTtiiAettLerEere:ss ewEwix8ita8thmhinaTeworsemtaastaioosfsafteTteeustseoss (6) s i so 50r 00 "m24e Percent of Titers ttnve mt. Fotos (6) we we 0 woo HeWroenitvsaaerlnucess coffaavtlasrciawuintctlhsnv)tirepoodrtsVitter basis: Kober of fetuses with womalis i wSrw toSwH 008 a19Rm% 3 Intenso smesties (5 0 8 a8 Skeletal Eaniation NNFRoibtrerecnefooffairttHtiNttiettereresssethxstahthmninamesasrlmoaasTefteetebuursreess () :soss0 soos 00 1 d2 52 Percent o ker sith variant feves (0) Wo Bn ime 100m HeWTaoncdeiedresone ber of ofafeltcuvasalerasitaensdtisthon(r3)a iprnitt fetuses ithMoma les basis: Boe z aolhe wLRkyEYaanm 3 ations of sailor (5 088 3 S27 Individual aKnedyMetaonAMpapteenrdniaxl 1Body Weights Pilot Rat Teratology Study of T-3352 154-159 NPP == PNortegnparnetgnant FCD == FCeosuanrdeadneadsec(tpiroencedpeedrfobrymedday (opfrecgeedsetdatiboynday of gestation) A = Aborted pups (preceded by day of gestation) & Body weight on day of death. b Statistical group comparison performed on rank-transformed data. Note: Banoddystwaetiigshttiscalinevpaalrueanttihoens.es are excluded from mean calculations 000355 | -- sme ase pceeastemnieetiesgpeespseee [ - -- wom sme mom rmmom mom uw om wo Boommm im me OoOBwm O8O&W OBOfOEREog OoEBm BOB # HHB o8m say HBBooommM oOmE Ob yBOE EE gOEiEEEgsE EN W E 8# # 8 oE>e 2gg8 8 | OiR ee friot aptF meeE memmR pteegsrie-- ow P--r--o rien | E EWEoooEmmm =ooBmmE LoBNHOoLREEEABEEH OBEOHEEEEBOHEBOSOEM F8B#H ow0H = hOBpOTy A RH WH WL BL Wh wom me moma @ me ww WiH r OoRw ArMaER BMdeSeoROoDmMaODOBEmLDe EoOdhEo mBBENh oa a acHyn ooo.cnnn ?8 = OWS WA WR WA OW we of g82s 3 BE sm FS o MHWooom mmwsR EoTRhiREm tt wpnteFgIa ELTEgroecur m EBBELbs eOoEWa mEaomE To= moaRnY E GB G ow88 iBlg: OE - hi . &gggg 3 Into nd entOoooprnesJ2toay!TFSa Ecommon [ Herenarn nent ce arson(au) Te foz Teta Font oc mmptin Grom 1 0s aHhHeeosss B 6BB s oO o hmo W o1ou3s m Bomner Bmoonom agfpissst Haaae [eA on os Wom w4a | uwMean Th 18.28 19.2 19O.9M2E ON 19.9 UR 26.13 Bi 90.23 . Hsaaaaatys BBBwreioORnowSBsi OmRrGIroup 2 mOm- Br1 mog/kg.noomm fy o@ioae aHeals WBOeRlD Om BS kMoMBe yobms wTeh wSnh wOeBE aUwm wNnE om2ls ' p5puesd) wSisa 5 Statistical ro comprtsons erfamsd on rnk rstaned ats g88 3 Tita)Pents RoopuTieeto2 n-wdohTnoyetasoronTdHEGoSnsmption [ rtearny e root conmptie zn Tw CThotarrot ot cot nsmption fa5ro E vWieo Ra0 1B8Gsrrouop 3k-weo10 mg/kg2nss fa whoo Broom he 22o03s0 pit FSfaess e wwae RoBoaho3 OofnmRd EORB kSs Eanf wSaii .} "Mean Ta 1.20 NH 10.8 19.04 MU mn 24.26 58s 394.17 . afe Grom 4- 31.5 ars 2 1a 3sr Bwaedaes sie ied 3 fms d1L.bd0 safieasn es wWB PhoioE dGnrhe NoG3a%hd Em Gle e iem eh dh inG0ahods euwn Whwe nUaRm Bwni KaeBs iBsRa Baet L MT:T mbes 8 Tn B--ene--s r--s E--TO--fron--men--ha--te--n 334 statistical evaluation, 3 divinP) ans AopTeoeunt-aedCtoTnotytianuoeronTdECEonsmption Tiss Shtaebrenr' e food ce onsmon n TarEw Tota root consption iase arom 5-75 gr WBsED102 1p 0s p reed am onis i pao Bo he mmeatyl fH10Ri5.)s0 safi+e4 aWdlblenoaGo0tgd)hshaaGyhp f Rpfemaim Steudes ltleilid JfweHi Bik . Heuww nTnee Sohwe 0as 8 OTE: bers In parentheses ie sxcluted from em caleslation nd statistical ssalation. gg8 3g Indu dy WelghtJso,peGnrdaivid3 Uterine etopts, and 150.159 TerminalPiBlootdyRaetiTgernatoHliogny GSeraiydofter1.3n3e52bents hHautnetrenar) soyTeHremiignhatl Greavitdtute(r3)ine Hines TeGrraaivntaal UotdeyroHeleonlton(9) Group 1-0 mag : fa21i06t06s S173w.2 irn0si3 Aes oh 05 wwfots23 Bis afiast eHoo i3 ffotxy , Hbecn 06i.52 pnex whzin ? Group 2 - 1 mg/g sa2ti0ss i2ox6.s]4 300.74 figs Susie @3 3a000l'.s0 203 Aaagys 0i5 anis 7Siaz Hpecnt 07 .5 fwne 5p.0x / Indtutdunt BodyoNpeteonns,3GravctodntUitnereidne Weights, and 150.159 Ternina)PilsootyRWaetigThetrsatKoliongsy SGrtaovdiydotf 1e-i3en35erints Maatmebrenral odyTeerntinaal (0 Graavitdtvt a) Grou 3- 10 mag frs2ai6ey0 Jw59ws.3 Pa7os affierrs]] m70 e 3550 Jojsx]] in fr we i H5em 00..557 aonm Group 4- 37.5 narky f22r166]297 F3o50u.n5d dead ay 15 ao (iets) Rorted pis 0ay 20 sfzioeyn F7Foo5uunnsdd ddeeaagd DDaayy 1167 8 en (251.8) Mot pregnant Heson a56r.6m50 1a9203 MinusTGerramviidnUtoedryinNeevleglngtnt (g) aa2i.es0 a2551.0 Sniaz u. m16n.3% : ms 1 w9e 3a WIE: Wmbers tn parentheses re excluded from sen calculation nd statistical elution. a2 HNoatebrenral a216e38 az2ie6esm 2z1i6e3 Individun sodyfVoeplegnhdtisx,3Gr-avCoindtiUntueerdine eights, nd 150-159 Teraina)PilsootyRWaetigThetrsatHoilooogsy GStruodvyidoUfteTr3i3n6e2deiints BndyTeerimgihnt) (4) Greaviigdhtute(rg)ine Grow 5 - 75 masky FFoouwndd ddeeaadd DDaayy 1164 FFFooouwnnddd dddeeeaaaddd DDDaaayyy 111345, dot pregnant FFoouunndd ddeeaadd DDuyy 1153 MinusTGerraatvniadlUtfeardiynWeeeigihgtht (5) . 8 | 233 8a2 RI BE os wBoosr tng te SE mest - fe EEE uivnSEN EOE aie adie 0= } Lolo % 5 & FT oae m 2 a 3 5 ot % } P Ii} Be 22 J TE pie we ORE eEeeesen BECUE edlio weiol Bae i i 8ww ]3 o3e I3 3i i3 aHl = ow wa sewroraw ot ow 3 #0] Bester aoe u at 7 ne "Ye nw "w . "ee . ] 828 82 EY wBoooob Bibomo i ng gr es - le EE eneenJE ECON adie wie yEd. wByELL. i n Ei BEarEi u 8888 sn Intend Lv rts aus aatmebrenral =oa f al ror f Tomales on pMeariceenrt eng BE EEE EEE yee Gd E ee id gor 1 8 a : i a i i i : =8:g33 aterm Ee a Pir ein Peracieent SRE em[) Eee] a i " mn 1) 1 B Bo fn n .Wenon i fpean in, ws 26 w :: 25 w Hh tH th ih Es i s2:3 [ wwnm E OEE mM m Epeaors eoem e B iB E EEE E mw es l em 8 838 3 aman rn - Tr"TT TTY TT En 88 ed a4 dh Eimer. 1 3 1 LL PE | el fe me she 0 50 BN 08 00 60 00 Bn 00 00 00 wo Sites ate ' ' PLT fie Mewoeorsore vcard 80 60 00 00 a0 08 wo oo 00 00 so oe weg Emme. 1 JES vila 00 r2 g F --TE L 0 044 444 1 FLL a0 00 00 we oo oo +0+4a 23gBg te same sen ii Id nn we CLo od Te - wet bd0801 P0114 Ene, 1 Lg | aERgy eeEE RE p ! ed bi } : { :; : i3 ' | tic 1. . | mei EERE EE EEE EY PH g82g By . gn SE LL - _ mT eT dET i ddefedr En RSE an : an Ann to BRR, rEg ii Che pod 8 | TE pm : ` ' Eigen LLL LLL 2228 a  a- RAepfpeernednicxes8 Pilot Rat Teratology Study of T-3352 STATISTICAL METHODS/LABRATORY PROCEDRES 154-159 ABgarritcleutltt,ureM. aSn.d, A"pSpolmieedExaBmipolleosgy.o"f StJa.tisRtoiycaall MSettahtoidsst. ofSoRce.seaSrucphpl.i,n 137-183, 1937. ROreavpiesri,tedN"., RT.echanndomeWt.riGc.s,Hu1n1t:e2r3-4(01.969), "Transformations: Same Examples TDruenantemtetn,tsC.witWh., a "CAontMruollt.i"pleJ.CoAmnp.arSitsaotn. APsrsoocce.d,ure50:f1o0r96C-o1m1p2a1r,in1g955S.everal Dunnett, C. W., "New Tables for Multiple Camparisons with a Control." Biometrics, 20:482-491, 1964. wGiatmhes,UnPe.quAa.l, aWn'ds Hoawnedl/lo,r J.VarFi.,anc"ePsa:irwiAse MMounltteiplCearCloompaSrtiusdoyn."ProcJe.durEed.s statist., 1:113-125, 1976. FlT CLeoovnetnrei,buTetHsi.,,ono s"RotbousPtroTbeasbm itlsitfyor aaEnqdduao SlStittaatyitsoatfitcVs,a,riaSntcaensf,o"rdinUnIi.veOrlskiitny edPiretsesd., iSntaptlhees, 'RK.GH-EA.liaznadrinScRhendell, MV.ethLo.,d "fRoerfinFeemteanltsBoinne.R"apidStCalienarTiencghnToelcohgnyi,c 39:61-63, 1964. WTielcshonni,quesJ., TGh.e Uannidv. WoafrkCanniyc,agoJ.P,resesd,iCtohrisc.ago,Te1r0a8t%o,lZ ogpyp: E PrincI iplesTand MWeibnrearn,-Hi8.i1,J.,RosStatisChtaeica$lI,PTriHncTiples ineExe perit mental Design, 2nd Ed., 000374