Document Eqzv9DnyQzbDnYLJEn7rXB3YL

HAZL=CN LAS09;ATORIES AMERICA. 9200 L.EESBLJRC TURNPIKE VIENNA INC. VIRGINIA 221 BO U S A RAT TERATOLOGY STUDY T-3352 FINAL REPORT Submittedto 3M Comoany St.Pau-1M,innesota March 21, 1984 EHAZLE'CC:NLABORATOAMRERII@E-,SAI.NC ..CC IE 56@-C OFFICE OF QUALITY ASSURANCE Project Title: Rat Teratology Study Project No.: 154-161 Quality Assurance inspections of the study and review of the final report of the above referenced project were conducted according to the standard operating procedures of the Office of Quality Assurance and according to the general requirements of the Good Laboratory Practice regulations that were issued on December 22, 1978, by the Food and Drug Administration for compliance on and after June 20, 1979. Findings from the inspections and final report review were reported to management and to the study director on the following dates: Inspections/Review Protocol 6/15/83 Findings Reported 6/15/83 Inspec tor/Revi ewer E. Burroughs Inspection 8/3-5/83 8/5/83 E. Burroughs Report Review 2/11,12,14,15/84 2/24/84 P. Miller dWe*--K Snyd:Lsf Di@recftfor . "f Office of Quality Assurance HAZL=CDN LABC--)RAT(:)RIES ANAERICA. 9200 LEESBURG TURNPIKE VIENNA INC:. VIRGINIA 221 BC U SA SUBJECT: Rat Teratology Study Project No. 154-161 We, the undersigned, hereby declare that the work was performed under our supervision, according to the procedures herein described. Study Director: -o@a@ LAWRENCE T.NETZEL, Ph.D. Life Sciences Division Laboratory Supervision: Teratology: GEOR& A. BURDOCK, Ph.D. Dipi,om-ate,American Board of Toxicology Life Sciences Division RUTH S. DURLOO, B.S. Life Sciences Division Study Coordinator: BARBARA R. COLPEAN, -Life Sciences Division B.S. blm 19 HAZL=CN LABORATORIES ANAERICA. INC. 9200 @-EESOURG TURNPIKE VIENNA V#RC;INI2A2180 U S A TABLE OF CONTENTS Paqe SUMMARY 1 INTRODUCTION 3 CONTROL AND TEST MATERIALS 3 TEST ANIMALS 4 METHODS 5 Mating Period 5 Groups and Dosage Levels 5 Compound Preparation and Administration 6 Maternal Observations and Records 7 Cesarean Sacrifice 7 Visceral Examination of Fetuses 8 Skeletal Examination of Fetuses 8 Tissue Preservation 8 Statistical Analyses 9 Specimen, Raw Data, and Final Report Storage 11 RESULTS - MATERNAL DATA 12 Mortality and Clinical Observations 12 Body Weights and Food Consumption 12 Uterine Weights 13 Gross Pathology 13 RESULTS - CESAREAN DATA 14 Pregnancy Rates, Corpora Lutea, and Uterine Implantations 14 Fetal Viability, Weight, and Sex 14 Fetal Development 14 TABLES Table I - Summary of Maternal Clinical Observations 16 Table 2 - Mean Maternal Body Weights and Body Weight Changes 17 Table 3 - Mean Maternal Food Consumption 18 Table 4 - Mean Terminal Body Weights, Gravid Uterine Weights, and Terminal Body Weights 19 Table 5 - Summary of Maternal Gross Pathology Findings 20 Key to Tables 6-14 21 Table 6 - Summary of Mean Ovarian and Uterine Data 22 (EHAZL=CN LABORATORIES At,4ERICA. INC. 9200 LFESBuRr@ TLJRNPIKE VIENNA VIRGINIA22 180 U S A TABLE OF CONTENTS - CONTINUED TABLES - CONTINUED Table 7 - Summary of Mean Litter Data Table 8 - Summary of External Findings Table 9 - Summary of Visceral Findings Table 10 - Summary of Skeletal Findings Table 11 - Incidenceof External Findings Per Litter Table 12 - Incidenceof Visceral Findings Per Litter Table 13 - Incidence of Skeletal Findings Per Litter Table 14 - Mean Incidence of External, Visceral, and Skeletal Findings Per Litter APPENDICES Appendix I - IndividualClinicalSigns Key to Appendices 2, 3, and 4 Appendix 2 - Individual and Mean Maternal Body Weights and Body Weight Changes Appendix 3 - Individual and Mean Food Consumption Appendix 4 - Individual and Mean Terminal Body Weights, Gravid Uterine Weights, and Terminal Body Weights Minus Gravid Uterine Weights Appendix 5 - Individual and Mean Ovarian and Uterine Data Appendix 6 - Individual and Mean Litter Data Appendix 7 - IndividualVisceral Findings in Fetuses Appendix 8 - IndividualSkeletal Findings in Fetuses Appendix 9 - References Pacie 23 24 25 26 27 28 29 30 31 32 33 37 41 45 49 53 61 69 HAZLENC(MN LABORATORIES AMERICA, INC. SFDCNsoR: 3M Company NAATERIAL: T-3352 SUBJEC7-: FINAL REPORT Rat Teratology Study Project No. 154-161 DA7E: March 21, 1984 SUMMARY T-3352, suspended in corn oil at concentrations intended to deliver 1, 10, or 30 mg/kg/day (Groups 2, 3, and 4, respectively) was administered by oral intubation to mated female Sprague-Dawley derived CDO rats on presumed gestation Days 6-15. A fourth group (Group 1) of mated females served as the control group and received the vehicle only. During treatment with T-3352, significantly lower than control food consumption values and body weight gains were noted for Group 4 females. Loss of body weight occurred in Group 4 females during Days 6 to 12 of gestation. Mean gravid uterine weights were comparable for all groups, whereas the mean terminal body weight minus the gravid uterine weight was significantly less than control in the Group 4 animals. Most cesarean data measured appeared unchanged following treatment with T-3352. Statistically, male and female fetuses derived from Group 4 dams weighed significantly less than control fetuses. Although not significant, there was an increase in the incidence of skeletal variants in fetuses obtained from Group 4 dams. EHAZL=C)N LABORATORIES AMERICA. 9200 L.EESSURG TURNPIKE VIENNA INC. VIRGINIA 221 SC USA 2 154-161 The data from this study show that T-3352 is not teratogenic in rats at doses as high as 30 mg/kg of body weight, although that dose produced deleterious effects in the dams. HAZL=CN LABORATORIES AMERICA, @20C; @FESBURC; TURNPIKE VIENNA ff@JC. VIRGINIA 22 1 ec u sA 3 154-161 INTRODUCTION This study was designed to evaluate the embryo/fetal toxicity and teratogenic potential of T-3352 when administered by oral gavage to pregnant rats during the period of fetal organogenesis. On July 18, 1983, breeding of the rats was begun, and cesarean sections were completed on August 11, 1983. The study was conducted according to a protocol designed to satisfy existing guidelines of the Food and Drug Administration as well as Good Laboratory Practice Regulations. This report presents and discusses the methods and results from the study. CONTROL AND TEST MATERIALS The vehicle and control material, Duke's's Corn Oil (Lot No. 80275), a slightly viscous, yellow liquid, was received from the C. F. Sauer Co., Richmond, Virginia, and was stored at room temperature. The test material, T-3352, large chunks of off-white compound, 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 the methods of synthesis, stability, as well as data on composition, or other characteristics which define the test material, are on file with the sponsor. (OHAZL=CN LAE30RAT(--)RIES AMERICA, 92C)C LEESBURG TURNPIKE VIENNA INC. VIRGINIA 221 BO u S A 4 154-161 TEST ANIMALS Two hundred fifty-nine (130 male and 129 female) sexually mature, cesarean-derived Sprague-Dawley Crl:CDO (SD)BR rats were received from Charles River Breeding Laboratories, Inc., Kingston, New York, on June 29, 1983. The rat was selected for use in this study because historically this species has been used in teratology studies and is required by appropriate regulatory agencies. The animals were housed individually in elevated stainless-steel cages and acclimated to laboratory conditions for approximately three weeks prior to initiation of the study. During this time, one female rat was euthanatized due to an unthrifty appearance and one female was found dead. Following an examination by a staff veterinarian for health status, 120 rats/sex were placed in breeding on July 18, 1983, and the remaining 7 rats/sex were placed in breeding one day later due to caging limitations. The rats were housed one male and one female per cage during breeding. Following confirmation of mating, the females were uniquely identified by ear tags and individually housed in elevated stainlesssteel cages. Food (Purina Rodent Laboratory ChowO 5001) and tap water (via an automatic watering system) were available ad libitum. The mean room temperature + the standard deviation was 73.6*F + 1.68 and the mean relative humidity + the standard deviation was 59.4% + 3.44 during the study. A twelve-hour light/dark cycle was maintained. (OHAZL=CN LABORATORIES AN4ERICA. 920C LFESBLJRC; TUQNPOKE VIENNA INC. VIRGINIA ZZ 180. U S A 5 154-161 METHODS Mating Period During the mating period, one female was paired with one male until mating was confirmed or until two weeks had elapsed. A sufficient number of mated females, during the course of this study, were obtained after four days of cohabitation and mating was discontinued. Daily vaginal examinations of each female were performed to detect the presence and 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 by use of a table of random numbers (Cochran and Cox, 1957). Group Number of Females a Dose mg/kg/day 1 25 0 2 25 1 3 25 10 4 25 30 a Based on individual animal body weights at each weighing interval during the dosing period. Animals were dosed on Days 6 through 15 of presumed gestation. Dose levels were selected based upon information obtained in a range finding study. The results from that study were reported separately. (OHAZL=CN LAE30RATC)RIES AMERICA, 920C -EESBURG TURNPIKE VIENNA INC. VIRGINIA 22 1 80, U S A 6 154-161 All males and all remaining females were sacrificed via carbon dioxide asphyxiation and discarded without necropsy once a sufficient a number of matings was confirmed. Compound PreDaration and Administration Suspensions of the test material in the corn oil vehicle were prepared on a weight per volume basis. The compound was first ground in a mortar and pestle into a workable powder. The required amount of compound for each level was then weighed on an electronic Arbor 126 balance and transferred to a 7 ml tissue grinder. Approximately 3 ml of corn oil was added and the test material was ground into a fine b suspension. This suspension was transferred to a precalibrated beaker and any remaining compound in the tissue grinder was rinsed into the beaker. Additional corn oil was added to the suspension to produce the desired concentration and the suspension was mixed on a magnetic stirrer. 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 presumed gestation. The dose administered to each female was based on the most recently recorded individual body weight. The test material was administered orally because of the relative ease and accuracy of dosing. a One female was euthanized following mating confirmation due to alopecia. b Due to the amount of compound required to prepare Group 4 suspensions, the compound was divided into four tissue grinders and subsequently transferred to one precalibrated beaker. (OHAZL=CN LABORATORIES AMEMCA@ 9200 LEESBURG TURRVPIKE VIENNA INC:. VIRGINIA 221 80@ U S A 7 154-161 Fresh suspensions of the test substance for dosing were prepared weekly. Samples of each test mixture as well as the vehicle were sent to the sponsor for analysis. A 10 gram sample of compound and a 30 ml sample of corn oil were taken on August 4, 1983, and stored at room temperature. Maternal Observations and Records All animals were observed twice daily for mortality and moribun- dity (from day of receipt through animal sacrifice). The females were also examined once daily for clinical signs of toxicity and pharmacologic effects (throughout gestation). Individual body weights were recorded at initiation and on Days 6, 8, 12, 16, and 20 of gestation. Food consumption during gestation was determined on Days 6, 8, 12, 16, and 20. Sacrifice at Time of Cesarean Sectioning A gross necropsy was performed on all females. Prior to terminal sacrifice and cesarean section on Day 20 of gestation, all females were assigned random numbers so that 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 of gestation, all females were weighed and sacrificed by carbon dioxide asphyxiation. The uterus from each female was excised, weighed, and examined for the number and*placement of implantation sites, number of live and dead fetuses, number of early and late resorbing HAZL=C)N LABORATOF=IIES AN4ERICA. INC. 9200 LEESBURG TL)RNPIKE VIENNA VIRGINIA22190 USA 154-161 fetuses, and any abnormalities. The ovaries were examined for the number of corpora lutea. Each female was examined grossly for any abnormalities. Each fetus was sexed, weighed, examined externally, and tagged for identification. Beginning at the ovarian end of the left uterine horn and continuing past the cervix into the right uterine horn, the first available fetus was fixed in Bouin's solution for visceral evaluation. The next two fetuses were processed for skeletal evaluation. This process was repeated until all available fetuses were selected for evaluation. Dead fetuses were discarded without examination. Visceral Examination of Fetuses Approximately one-third of all live fetuses from each litter were fixed in Bouin's solution and sectioned by the Wilson Technique for assessing soft tissue development (Wilson, 1965). During examination of the fetuses' viscera, particular attention was paid to examination of the eyes, palate, and brain. Stainless-steel razor blades (Geme) were used for sectioning procedures. Skeletal Examination of Fetuses The remaining fetuses were eviscerated and placed in 95% ethyl alcohol. After proper fixation, dehydration, and maceration, the skeletons were stained in 1% KOH, with an alizarin red solution and cleared in glycerol (modified Staples and Schnell, 1964). This evaluation included examination of the skull, long bones, vertebral column, rib cage, extremities, and pectoral and pelvic girdles. Bone alignment and degree of ossification were assessed. HAZL=(=N LASORATORIES ANAE;:UCA. "C. 920C @F-ESBUMC; TURNPIKE V.R=NNA VIRGINIA 2218C L@ S A 9 154-161 Tissue Preservation The following are the procedures for preservation of the various tissues: (1) The uterus and ovaries of each animal were preserved in 10% neutral buffered formalin; (2) The fetuses examined by Wilson's technique were placed in tissue capsules, preserved in 95% ethyl alcohol, and sealed in plastic bags after sectioning; (3) Fetuses stained for skeletal examination were preserved in plastic bags containing a glycerol:ethyl alcohol (1:1) solution with several crystals of thymol to retard bacterial and mold growth. Statistical Analyses Maternal body weight changes (Days 6-8, 6-16, 16-20, and 0-20), total food consumption (Days 7-8, 7-16, 17-20, and 0-20), gravid uterine weight, and terminal body weight minus gravid uterine weight data of the control group were compared statistically against the data of the compound-treated groups of the same sex. Analyses of the above data were performed in the following order: Levene's test for homogeneity of variance (Levene, 1960; Draper and Hunter, 1969) was performed and if the variances proved to be homo- geneous, the data were analyzed by one-way classification analysis of variance (ANOVA) (Winer, 1971). If the variance proved to be hetero- geneous, a series of transformations was performed until variance homo- 2 geneity was achieved. These transformations were log10, square (X ), % % square root (X ), reciprocal (1/X), angular (arcsine X ). and rank, in that order. If rank transformation was ineffective in removing EHAZL=CN LABC)RATC:)RIES AMERICA. 9200 LEESBLiRr, TLJRN@IKE VIENNA INC. VIRGINIA 221 60 U S A - 10 - 154-161 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. Data transformations are designated throughout this report as follows: A = Data analyzed following loglo transformation. B = Data analyzed following square (X2) transformation. C = Data analyzed following square root (X4) transformation. D = Data analyzed following reciprocal (I/X) transformation. E = Data analyzed following angular (arcsine X formation. trans- F = Data analyzed following rank transformation. Mean fetal body weights per litter were statisticallyanalyzed as follows: Bartlett's test for homogeneity of variances (Bartlett, 1937) was -performed by one-way classification of covariance (ANCOVA) (Winer, 1971). If ANCOVA was significant, control vs. treatment group comparisons were analyzed using the Games and Howell Modification of the Tukey-Kramer honestly significant difference test (Games and Howell, 1976). Tests for homogeneity of variances, ANOVA, and ANCOVA were evaluated at the 5.0% one-tailed probability level. Control vs. compound-treated group mean comparisons of the above data were evaluated at the 5.0% two-tailedprobability level. HAZLETC)N LABORATORIES AMERICA. S200 LF-ESBURG TURNRIKE VIE@NA INC. VIQC;It@'A 22 1 BCI I S A 154-161 In addition to the above data, fetal viability was analyzed by nonparametric one-way ANOVA (Kruskal and Wallis, 1952, 1953; Miller, 1966). The litter was used as the experimental unit. The number of fetuses exhibiting skeletal variants of the rib cage and bone alignment and the total number of fetuses affected by skeletal variants were analyzed using the Cochran-Armitage test for linear trend in proportions (Cochran, 1954; Armitage, 1955; Fleiss, 1981) and Fisher's "exact" test (Fisher, 1950). If a significant trend was noted, the results of Fisher's "exact" test were evaluated at the one-tailed, 5% level. If a significant trend was not observed, or if there was a significant trend with severe departure from it, the results of Fisher's "exact" test were evaluated at the two-tailed, 5% leve l . When using these statistical tests on indices, the actual proportions prior to conversion to percentages were the data that were analyzed. Statistical references are appended to this report, and statistically significant differences, as indicated by the aforementioned tests, are designated throughout this report by the term "significant" and/or as follows: S+ = Significantly higher than the control value. S- = Significantly lower than the control value. Specimen, Raw Data, and Final Report Storage All specimens, raw data, and the final report are stored in the archives of Hazleton Laboratories America, Inc. HAZL=CDN LABORATC)RIES AMR=RICA, 9200 LEESBL.)RG TLJRN@IKE Vir:NNA INC:. VIRC;INIA 22 180 U SA - 12 154-161 RESULTS - MATERNAL DATA mortality and Clinical Observations Individual clinical observations are presented in Appendix I A summary of clinical observations is presented in Table 1. No animals were found dead or sacrificed in extremis during the study. Clinical observations were considered incidental. These observations included hunched and/or thin appearance, languid behavior, anorexia, soft feces, alopecia, and rough haircoat. Body Weights and Food Consumption Individual and mean body weights and body weight changes are presented in Appendix 2 and Table 2, respectively. Individual and mean food consumption values are presented in Appendix 3 and Table 3, respectively. Evaluation of the body weight changes revealed a significant decrease in body weight gain during treatment (Days 6-15) for the Group 4 females, resulting in a significantlylower overall body weight gain during gestation. Group 3 females also gained less weight than control females during gestation, although that finding was not statistically significant. Body weight gains during the nontreatment phases (Days 0-6 and 16-20) were comparable between the control and compound-treated groups. EHAZL=CN L-AE30RATC)RIES AMERICA. 9200 LEESBLJRG TUF4NPIKE VIENNA INC. VIRGINIA 221 BO LJ S A - 13 - 154-161 A decrease in overall mean food consumption was noted in the Group 4 females after Day 9 of gestation. Mean total food consumption values for Group 4 were significantly lower than control for Days 7-16 and 17-20. Slightly lower mean food consumption values were noted for Groups 3 and 4 over Days 13-16 and 0-20 and for Group 3 over Days 7-16. All other food consumption values were comparable to control. Uterine Weights Individual and mean terminal body weights, gravid uterine weights, and terminal body weights minus gravid uterine weights are presented in Appendix 4 and Table 4, respectively. Gravid uterine weights were comparable between the control and treated groups. Terminal body weights were decreased and terminal body weights minus gravid uterine weights were significantly decreased in the Group 4 females when compared to control. Gross Pathology A summary of maternal gross pathology findings is presented in Table 5. Gross pathology findings noted at necropsy were considered incidental.. (OHAZL=CN LAE30RATORIES AMERICA, 9200 LEESBURG TL)RNI-IKE VIENNA INC. VIRGINIA 22, BC U SA - 14 154-161 RESULTS - DATA OBTAINED AT CESAREAN SECTIONING Individual and mean ovarian and uterine data are presented in Appendix 5. Individual and mean litter data are presented in Appendix 6. Individual visceral and skeletal findings in fetuses are presented in Appendices 7 and 8, respectively. Summary ovarian and uterine data are presented in Table 6. Summary litter data are presented in Table 7. Summaries of the external, visceral, and skeletal findings are presented in Tables 8 through 14. Pregnancy Rates, Corpora Lutea, and Uterine Implantations Pregnancy rates, number of corpora lutea, and implantation efficiencies were comparable for all groups. Fetal Viability, Weight, and Sex The mean incidences of early, late, and total resorptions, fetal loss, and the number of dead fetuses were comparable between the control and treated groups. The mean fetal weights of the Group 4 males and females were significantly lower than their respective controls. The percent of male fetuses was 49.54%, 51.24%, and 51.20% for Groups 2, 3, and 4. respectively, and 53.26% for the control group. Fetal Development The percents of external and visceral variants and anomalies in fetuses were comparable between the control and treated groups. Gross external examination of fetuses at cesarean section revealed one Group I HAZL=(=N LABORATORIES AN.OERICA, 920C LEESBLJRG TUQNPIKE VIENNA INC. VIRGINIA 22 180 USA 15 - 154-161 fetus with an undeveloped tail, one Group 3 fetus with a short trunk and no tail, one Group 3 fetus with a cleft palate, and one Group 4 fetus with an underdeveloped tail. Cryptorchism was noted in two Group 1 fetuses and in one Group 3 fetus examined viscerally by Wilson's sectioning. One fetus from Group 3 was noted to have fused kidneys. No other visceral anomalies were observed. Visceral variants consisted mainly of dilated renal pelves and distended ureters in Groups 1 and 2 fetuses. No skeletal anomalies were observed. Comparing the number of fetuses with skeletal variants (treated groups versus control) showed that the number of fetuses affected by skeletal variants was not significantly different than control for any group. However, the number of bone alignment and rib cage variants in fetuses derived from Group 4 dams, animals in which toxicity was observed, was significantly higher than control fetuses. qr CD en ;z .o CD Ln -bi cu cu I cn ko CD rq > lu " C:. cli cn CD en 16 cn m cn to > LM L. cn cu rn IV Ll M m to rs- cu 41 to ra CD (D en 0 E 4-1 CD tz 4) %A L- > 4-1 to C%j cu L- CD ew C%i C%i cli CD cm E S- S- o0 a CD cu r_ L- X C6 0 4-J CD LA LM 0 cu cu (D E cu 4.b- %a_ 0 w (U @o .0 LA EEELA .0 = =) = ol = = = 4-1 ra 0 w Smu 7; (D (Um Li C" L. 41 m cm C04-0= c0 0 < V) = CL ra 4-1 tA E LM a) to C6 c cu 0 E 4-) 4-A to LA = 41 to > LA E 0u x - 17 Ln -tr CD en m Ln M q-rer tm E cn LM ko qr r- u'% CD cv ew ew cn cn cn Ln CD co r- Ln M rM M M -tr%o LA a tm mE 0 c@ qr %oC,4 r- m m CIQ qcr CD c@ C%J 60 cli m c@ -crC7, Ln C%J L-C> C%i cv E CD 4) cu tm tm C%i -@ U-) w C.) cm tm E 1011 Ln CD mr m" cv -W cro -W LM csi m %o C%i C%i C%i c%i CO cc CD M r_ CD mm-womoq m r c@ I-Ir c@ C.; L@; @ c@ C%J %a cli C%i Ln CD Ln C,5 C6 CV) >1 CD 0 0 tm r c CC) r- r- Ln C71cc C,5 -1*1m -c; CO CO r -crM (D &A m c@ c., U4 m c@ M- r-: m >I E m C%i %o co C%i CD %o r-i m .rrCD LM en .0 ra C%i cli C-7 4--) (D a) LA Ln 4.J 0 4.J UC%i %o CD CD CD C,4 CIJ co tz CD rli C)I 10 10I 10I %DI IDI I E C) c;l 4-J cy C" 3c m > 06 E m 4A L; C" 4-1 C C) &A d) 4-A 18 m LA cli C-)C%j C%i LA CD cr) E i- CD Cl)C%i cn n cli r- C,4 C%i r@ C%i C'W Ln C-) C-) C%i C"J -cr CV u r cn L..) C%i C%i en C%i Ln co C%i CD c-, co C,4 C4 qt CD C%i CD c@ c-, CD ev C,4 CD Ln m m csi co C-) al ON CD C%i Ln r.:c., c., c-, c-, r-:m m m ew r- C%i co cli c@o C%i C:)CNJ C-5 C%i cli r > tn -1" LL. C%i U- CD C%i C%i CU tA a d) to > 06 E m LA 3: LA 0 ea > to LA d) to r_ m V 19 m r= 4-J :)4 3c 3: 0 r_ w CD CD C 4-J m C%i 4m tm cv C%i 3c > S- cn C%i (a LMLn .4-c1n vi=Cm enI clu clw to .4-J Ln cm > CD 1.0C,4 cu qcrCD cu LA r_ 4) 4-J 4 c W 4-J L'i 0 tu @-i to -0 cc 0 tv tv S- L- L^ cu CD = I-- a 4-J m tm to to 4) E 4-J cr C-) 4-1 to- CD cn r_ CL) L@ C., c@ Ir %o cli %D C%i cli Cli > C-1 cn m cc 0 d) .0 cu a> m tm t7) tm cm be tm C%i t7) C-) al a$ E r= C) 4-1 4-J M am Lj Ic cn Ln cn cn 20 en ol r- U- " Ln >@m O)M cn a% CL.., :3 C" 0 -Ike L. @, cm tm E 11 > Ln 4A &A 4-) tm ra tu cu to >1 S- Ln to to E LA 0 u CA 0 C-.) CL go x (A 4) LM o tA L. tv E 4-J 0 3: cu =1 .0.0 EE to 4A cu tv m CD to 0 W 4-) CL m= cu "0 tA 4) wi "D V) vi >. > w (D tA 0) CZ >s -cc L.) C-) @l0 IA 39 0 cu to 4--o rC) 9= w 4-J L&J - wi a) cu cm 41 &A ra E a (U 4-J (U LCL t7) r_ LA- 21 - Key to Tables 6-14 154-161 Pregnancy rate (percent) - (number of pregnant rats/number of rats inseminated) x 100. Survival Rate (percent) - (number of rats surviving to Day 20/number of rats placed on study at initiation) x 100. Mean Implantation Efficiency (percenta - Group mean of ([implantations per litter/ corpora lutea per litter] x 100). Mean Incidence of Resorptions (percent)a - Group mean of ([resorptions per litter/ implantationsper litter] x 100). Mean Incidence of Fetal Mortality (percent) - Group mean of ([dead and resorbing fetuses per litter/ implantations per litter] x 100). Mean Incidence of Fetal Viability (percent) - Group mean of ([live fetuses per litter/implantationsper litter] x 100). Mean Incidence of External Variants (percent) - Group mean of ([number of fetuses per litter with external variants/ number of fetuses per litter examined externally] x 100). Mean Incidence of External Anomalies (percent) Group mean of ([number of fetuses per litter with external anomalies/ number of fetuses per litter examined externally) x 100). Mean Incidence of Visceral Variants (percent) Group mean of ([number of fetuses per litter with visceral variants/ number of fetuses per litter examined viscerally] x 100). Mean Incidence of Visceral Anomalies (percent) Group mean of ([number of fetuses per litter with visceral anomalies/ number of fetuses per litter examined viscerally] x 100). Mean Incidence of Skeletal Variants (percent) Group mean of ([number of fetuses per litter with skeletal variants/ number of fetuses per litter examined skeletally] x 100). Mean Incidence of Skeletal Anomalies (percent) Group mean of ([number of fetuses per litter with skeletal anomalies/ number of fetuses per litter examined skeletally] x 100). a Values calculated separately for early, late, and total resorptions. 22 - cn cv m0 cn Lm %r %D Ln cr@cv CD Ln -tr-.0LM c@ cn CD Lmen " LM 0 m ev0 C,@ cl ul Ln Mr C@ U@ C@ C'@ 0 m CD CD C) co CO r,- M ul 0! C9 09 C@% CD CD cri " %o CD 1.0 C@ a: 9 I'@ cn r- CD rGo CD tA 0% CD m 79 9 CD Ln rl-0 r@: co E 0) C%l Ln C.) en I -0 0 >1 M 4V-)J m > Cr-D 0 0 0 -IC 1- *11 CD tm > 'o-k C) m 1^ LA &A C- r- 0 ipt 4-1 .2 4-@ 4-J @.j 4-1 C6 0 CA a) > E> 4.J c W ro - CU 4, m tm E w 4J to E 4) (D 4-4 m S- , 0 eo S- L- d) w .0 = eE to L- > c .c0u tm > E I= V) tA LA r_ LM c r_ 0 0- M04-J-4-@ (D r- 06 4a CL 04-4 0 L. CL i- =) - 0 S- 0 I- @ 4j LA 0 LA a) m a) LA Q) .0 M 4-J L. 4) L. E $- = L- '= 0 to @ft a, - r- 06@ m L- 1= 4-J 4-) c0 ra C-) a) x cc to 0 w -i I.- CD ai to 4.j 4.J ra m 0 CD 00 0 0 04-@ 4-J d) (D 4) MMUWU 4j r- r- rr_ a) (D d) m to C6 L) ti Q tA 4) c c r_ c u m m to m - CD a) W 4) ox x x x c cC%ci; C%i C%i 0 a) E 0 tA m 3: 41 CL LM a) 4-4 to a go 23 cn 99 %%oo Lenn 0 C) en 9 c@ cn CY% 61) C! 09 LM Ln -W C9 7 c@ a' tn 9 C7 LM lw LM uli I'@ r- C%i cn cn qr cc en 4-1 cn Lw 4-1 LM m @o rq CD CD cli cn cn Ln CL = 0 -IC S- c- Ln Ln Ln Ln 99 m cn cn en r- Ln Ln Cv CV cn a% co co M cn m cn cn cn to Lra d) I-- "C di to > W .0 LA E 4) IA = 4-1 4) LLcu 2c I- 4-4 4-1 to to E> 06 to go 41 4-@ W d) C, 4- 4- 4- 44- 00 w m 41 go w E U U ,, r- r- 4) 4) uC C W fa m cc W 4) 0) ra 0) (U E cu 4-A LA L^ E E ra d) u 4.4 r_ t,! L-1 c,2 = S- "-.)L. m = (a 02 to > m > - a 0 r- 0 d) u u 3: LA W -Ift vi = CA =0 4) 41 .0 to m 4) (D d) LA- > 2c -i tA tA >E go 4.J d) mu a to 4-A 01 10 0 cu r- E E- (D m L4,; LA --^ mm EC fa 41 r- @ d) M (i u L- (D 4-1 CL o 4-@ xm tu 4-A V) V) 24 Ln cv en f"--cv " @ I- CV 'cCOn@ cn - CD CD CD CD m cn CD m CcOo C) C:l to IA Ln C" cn rn -0 r_ U- 0 Colo a= L- 4-1 cu cu Ln LD m x >1 to w cm 00 4-) >1 to vi E CC 4-J to CC 0- E L. 0 to r_ > ev E CC 4-J 4-J 4-J X a) L^ %A tA &A 4) (D (U w 1^ IA 4A = :3 = 4-A 41 4-@ cu cu w w LA CA w 4-1 a m iv tv 06 > 0 > 4.6- w 0 cu 4u 41 m $- >% 0 a) 41 = "0 r_ to cu OL a, 41- 06 W >@@ 4.@ u (U > (U 4j 000 0 W tI 4-@ m a) m cu U 9A 4-; (U E 0 tm a Ee s e :3 = = = = = = 2c 25 cn cn lm cn cvr- m c@'i en %o CD 0 -W CD Ln Ln CP cn r_ cn cn CD 4-1 (D to 0 -01ivi-I:r co CD C:)M cm be cn > cu rq0-t- f--Ln CO C%i cv to 3: to cu r_ ra > to X Vi (A tA (A (L)CD a) 4) CA vi ul tn == == +i +i +i +i 4) 4) a) 4) cc 0 0 i- L. S- 4) a) d) w .0.0.0.0 E e r= r= 4-J '0 L. 0 L. > M r_ IC cl i- I- Li ra 0 0. r- w to-- to > L- I- t^ 4J W M 0 M +J W r_ 41 (L)CL) CL) to 4-1 4-1 0 W M L- .0 L-- (A cu > r=-eo 0 to--- .0 4) 10 = - 06 4-4 U -V Do-,%6- L- L4-J 4) to ea m to EE LA IA &A W 4) CL)(U 4-1 c w be V) E (k) &A %OL >t I Lm 4-1 u Q) 4-A r_ CL ai "0 :)4 .0 26 - -cr4.0co CD Ln Ln cn -W m co" ON --%D- r- CV C%J cn C%j C%j CD r- m -C- c-) C%i cn ON %o %a Cri Ln Ln Cc Clki CD Ln C" CD cn U") %o Ln Ln Cl) -cr-- 'cr CV) -tr Cw C%J C,4 @m cn LA- 0 (U 4-J LI 0 0 *i m S- ea 4) E= 4-1 Ln fa C:o alcn -W %o cn M CV @ cn -W m -trM (U cu LA CL E cu > L-1 cu E IA tA CL) M4.j- cu w w 4-1 4@ w cu CL 4-1 CD 0. E m CA (U GJ 4-J :: :: cu w 4-J - (U Cl vi tn@ E CA &n CL 0 (D IM i) (U r_ cu L- 0 0 L- - m - - -i.-EA Ln -W M 0 rl- M C U W W 4--;U- Vw LA a - - -- = - 4.J 0 4- .4.J 4- S- 0 W-MOCCMO S- Ll% u LA 0 0 tA m 4A . C) 1010 cu cu (U - - L. +j 44.- k&. L. C - W 0 u 0 LA C 0 0 0u --- LA LA 4-) U 00 r- w u0 u 4A u0 U S- Cu (D r- r- r- JA - -C OU.- (D w to to c Ln i- L- 0 4A - to 0 4-J U 4-J 4-J tO L- L- w L- V a) 4) - - m > > u- 1A I^ -0 L- %A w u ito to to L- (i m L- w o@ E IA (A 4-1.0 V 0E a L- 0 4-1 M ea to aEE = CL) cu ea c a w M W ==%-== = = M M M km aa > m tv U M LA A-) 4-J MM - 4-J 4-J W W 4A - - 4-J L- C-3 M %A .0 u cu 1--0 w 4) M 4a 4-04-J X@-- cp 3: 3: 3 tA 4^ vi (U IV cu CD LA 1^ 1^ 1^ = == = 4-J 4-J 4-A 4-@ cu 4) w 4w 4- 4- 400 0 L- $- L- L. (1)cu cu d) .0 40 m .0 E EE E zc ;c M 0 4-1 0-- >-WL--UQOCC 4- @ to m u 44. m m 06 4-@ 0 0 U E S- W M o (U S- u @.J r.L- r- a m :IftIA M tA 4-1 1^ 0 V) (U (U A V 0 c u o L- L- LA cA %A E 0 4) (U .0 = = 0 M '0 4-D4-J- - - L- @ LA L'iS- S- L. 0 CL 0 = >$ 4^ = 0) tm m Lt7).U (U tm V) .0 to E .0 S- - 4) 0 Cu 'cr tM 4-) U CC cu v *0 @ M 4J= W@@ IM w Um = E iA L. @ tr 4W = 0 to c to 4) 0) a M- r= m L- m E CD .0 a cu (U CU w cn :2. 27 CV) m CD ev cv QT qr C%J @ C:) CD , ,9 9 c%i" CD C@ CD CD fa C:) LO Ul) .-i C%i 0 cn m Ln cn cv &- cn CD' w cn C@l CA cm W- 0 tm E V) re tm cu > a) 4-1 0 x +i to L- %A IV 0 Op.- CA (D fa E 4-J tO r- > fa a > 4.J 4.J cu - LA 3: 3: 4-- to c cm fa tA CM fa 4-) L. S- - 4w cu S- 4-J 4-J tv m w r= cu m to 4.4u- CL to x- 0 (D 3: .@-i 0 - 4-J W w 0. tA %A > c- I- w 4-J C- CU w u 4-1 10 ca.W- IV @- 4-1 4a $- L. i- L. w >m 4-J 4-1 w 4w w 0 cu W 4-J CL 06 = 10 10 0 im to go to , S- to CU w w CU IV = w@ .0.0.0 m .0 .0 m E E E E r= E La- 28 Ln cv I"!Ci -ccvrC"D Ic-o c1-o@ lw -W q@,r cv 9 C9 119 qr co vCVi0 -T-T CD%0 -mr S.w j) 4-1 co C:, CD m cv cn cy,m 'n Lm Ci I'@Cl!r! = -W cn cv qr fl- V) >1 (U 0 Lj- 0 4.J CD tm E w w 4-4 LA LA CD 4-J E *J vi %A r- -1-J 4,J E M .6j X (D .@-i41 Ln tA s- s- 4J 4-3 S- L4-A 4-) CU C) 00 CU 0 .0.0 to m L. S- d) w m .0 LA LM CU to r_ = CU CL L. ea > > -a cu CU cu - - C 06 L- 4.J W CC 0 0, r_ (D - Z @ U, M @ = = (U s- (U r_ (D 4-) W M tA M 4-J W 3 4-1 a 4.4 w w w 4-1) 4-@ W L- tA cu 4-J U NC L- $- to ID @ m S- (U > = - E U to m L- I r= r= M -- IA cu 'n CA I cu ::ftI- LA 4) (D (U r_ .6-1 @-i M) &A L. m cn ra E 4-) 4-1 4) c CA S- (U I EA CL-- 4A w m ::ft0 CU 4-J I- a = E le w 29 - Ln 4 C%i LM t7i cu 0 4-1 0 I-CU u vONi cn ecnn CCDD cn -rwcrqr c@ c@ rq t-- CV CD r4 cn %o C., w; CD rw im O-N %a cro-tr cenc cmo m*@.rwr4 q%r.%a cv cn cv cri *c1c11m1 cv c@n,1%o, - " " m @ @ @ @ rq ul m CUDl r%o- eenn L,4c@ _: M c11@%. toLn Ln r- (Y% qr r4 CUDl 0CD CLDn - en en ecnn c@ c@ c@ 0; Ln m Ln @% Cw cn r- ecnn rcL@O cn* 1--W1 r- W) cv r- -ir cn cn rco rv "I - Ln vi Ln Ln Ln Ln Ln r- m Ln Ul% -e Ln U*) Ln m Ln r-- m C" C" en en m Ln V m m r--m m r-- qr %o Ul) m cu cu CD tA tA LA LA ol cu Q- cu cu IA 4-1 - Cl CU 0 LA tA 0 w &A LA E E LA %A t^ 0.0 0 E LA w 0 tA u &A U 4.J LA a 0 W W C r- C r- 0 C- IA- to to -E LA L- 0 tu c cp r_ 4) L. 0 - "D "0 0) m +j = %- CU (U 0 - to M =- L. - = = w w m L- LA 4.j 4-) E G) @ @ L- 4.J 4.J - &A tA go >m Ln @-i 0W 4- 4- W 0 W W 4--b U r= r- M W 4-) -= .4.J ra V - Ln %A tA U 4-b 4.J&A &A &A %A V %A 4.J q4.- &A > > 1.6- tA 3: 3 4-@ M &A c L- &A U tA E &A %A to tA - 0 CA tA .6.J W W L- I- M M M &A - LA --- &A M M M CA 0E u L- to 4-J 0 4-1 41 4-1 0) 4.J 4-) E M 4-J u- 4- X 00 4-b 41 IM L. 0 4) 4J 4-J 4.J 4.J (U W OL CL 0 cm w > 0 M 0 4.J 4J @ M - 4J 4.J 4-1 0 44- L- M M %A cu 4) mm- 4-)- cA (D @ M.0 - - LA I I i^ (D d) A V 0 4A C C 0 L- L- LA LA %A E 4-j CL 06 4-J 0 4.J to r= L- 4) M = U 0 W@ " 0 d) a) .0 .0 .0 M "C 4-@4-A- - - L- - Ln %A 0 (D L) 4-) L- 06 = 0 u to = = CL tA &A a) &A m CL &A I I I I I f ai U U 0- .0 Li (U %A LA c Ln 0 4-1 fa v M - 1 4-1 a) -W m C LA go E 4) tA (D C 10 d) 0) .0 E = E to to L- 00 m to to c .0 L- .14 S- L- I- L- t7) (n a) cu d) 4) 0) m .0 .0 E EEE .0 iv E tz .0 4-1 0) 30 - cn CD Q CD CD CD CD 0 C@ -crCD Ln CD CD 0 CD C7! CD 0 C9 9 q@ 9 en CD ul@ CD LM C@ r@ C@ CD 0 CD c:o C=)CD m 0 m CD "I CD vi 4-J M (D m tn 0 4-J CD cn ra (D tm Q0 eu 4-J x 0 m a) cl 9 CD CD 0 CD CD C:p CD cn C'@J qr C:o f,- C) cu w cu u I- .6-@ X w LO vi > m 4 d) CL 0 LA LA tA C) "D CA W d) 4.J- 4-J C @ M M cc m to E E0 =I-Otvr- w to r_ > m >m m U.-U- u cc 4J 4-J tA @ @ 0) CL) 3: 39 Li L- L. W CL) to (D 4) "C > r ig P5 co x LA m 4 m -,apt Vt 0 LA 0 %A a) 4.J to M to to m E -E OS-OWC w to = > m - > to m = = %- u 0 4-3 +1 &A - CU (D m cu (D "D > r to CL) x LA to 4 m - lpt 4A &A CL) CD 4-@ 4-A - a 4-J C - to M m m co >m >M m = = %- u 4..) 4-1 tA @ - Li u to d) 4) > r= E Li(i cc mc d) x - 31 Appendix I IndividualClinical Signsa Rat Teratology Study of T-3352 154-161 Maternal Number Group observation Body Area Day(s) 27134 27136 27141 27152 27160 27172 27178 27179 27190 27201 27202 27205 27208 27211 27212 27213 27215 27221 27224 27225 27228 1 Alopecia Alopecia 1 Alopecia Alopecia Abdomen Leg-fore-right Abdomen Legs-hind-both Alopecia Leg-hind-left 1 Alopecia Alopecia Legs-fore-both Leg-fore-left 1 Alopecia Alopecia 2 Soft feces 2 Alopecia 2 Alopecia Alopecia Legs-fore-both Paws-fore-both Paw-fore-right Paws-fore-both Paw-fore-left 2 Alopecia 3 Alopecia 3 Alopecia 3 Alopecia 4 Alopecia Alopecia Paws-fore-both Leg-hind-left Leg-fore-left Paw-fore-left Abdomen Hips-both Alopecia Hip-right Alopecia 4 Thin Leg-hind-right 4 Soft feces 4 Hunched Thin Anorexia Alopecia Paw-fore-left Rough haircoat 4 Alopecia 4 Alopecia 4 Alopecia Abdomen Abdomen Abdomen Alopecia Chest Alopecia 4 Hunched Hips-both Thin Languid Alopecia 4 Hunched Paws-fore-both Thin 4 Hunched 17-20 16-20 9-20 13-15, 20 B-12, 16-19 15-19 12-14 9-20 6-8 7 11-18 15-17 18-19 18-20 20 20 18-19 13-20 16-20 13-15 18-20 16, 18-19 10 13-20 16-19 16 20 16-19 15-20 20 9-20 14-18 12-20 11-17 12-15 11-12 16-18 14-20 14-18 13 a All animals not included in this table appeared normal throughout the study. 32 - Key to Appendices 2. 3. and 4 154-161 P = Pregnant NP = Not Pregnant C = Cesarean Section Performed (preceded by day of gestation) = Data excluded from mean calculation. Explanation of Footnotes a Only data from pregnant animals surviving to Day 20 cesarean section were used in mean calculations. b Invalid food calculations. consumption value not included in mean c Gravid uterine weight inadvertentlynot recorded. 33 m M;zw cr=@ mo m cn 'a'c@ 0*M: cft* c@ Ln =,O w ;zln w; c; I'@ a@ CD CP m 1w: 4n @.Du-@@nm m -rw w P.- m = m r@ c@4 c@ U; -@c@c@ c@ - - -- -- - - - - - in gknwwt M C%; %D %D w w r, r,-rcc CD hm CD lei cr@ cm a. CD 0 m m m u% m c@ ' * o C! w w, 17 co - In C! CD 1! 11! 0! 0! c@ C! mw r .4 _: c@ ey @D cc 0! m-c" m c@ v- M m .. . . .. . . . .. .. . . . . .. c@ cl; cn*c@ cc*m' n* w* m -mm cm mmm=m "Mmm r@ vmmmm CD, o m r@ w CcDn m en en Q, 'K - 0 fo @ c lo LIVlo cc m o=Q o en elln c%0l1 a, cD@co-.o r en cn en c@ w: .1; w c:@cow fn r, C)'o@ -D cm @o %o - m m @ m e) cn m m In ey lo en ;@co a, cc m c. c, u, -r a, a, %0 qr .. .. . . . . . .. .. . . . .. .. .. . . . rn;::a, - -w m a, a, c@,wi - @ - CD a, a- c. r o c";; :: coo o 0 e. CD,w co r m c@, @w en m m Cc mo en ;;cc In 0 at %o en cc en 'a co m c,@tv a, a, c@ - m 0 c@ w- CD- co = m w kn ,no lo wmm" a, cv ew ev 2@ o- c',w CD a,-CD, mc:, m C>CDW w lo m a, o@ In Ln CoD a, w m ro, co c" w ".a 2- w w;zw low%I'Dmw m 7"! c@ c" wm c@ .r -w In %a -w -w wD -w w A2 e.) cc cn lro 1-n@ co en CD @ c%i eQ cy ew e) ev tv cy rw c%lcNj ""m . . . . eyevcv a, c9 tn cy o ry cn @;zo. =:;@In %o ty ew cz w; tn c@'D w e) ". wn @o CD =,w c; a; M' 11;r; 1; c@ P@ C:,Nn @D e) ey en cv c@ c@ c@ c@ c@ c@ c@ c@ c@ c@ c; c@ c@ . . . . . . . . . ew c@ c@ c@ c@ cy c: c: c: c: c: c@:c: a: a: c: c: 0: c: c: c: c: c: a: a: a: a: a: &7 a7 a7 ey m cvmw 34 7 Li d, m c:l U-1a, C! @o cc CC,Y CD wm 0w C" 0 m 0, cmwl w m r a In%D@o=Oicon11&w'nWI, r InW,@o r A .0 tv ul 0 m Ul.0 Znn w w wer wi m o@ e, CD 0 C, 12 C, cc w w In %0 m m w - w CD COr W; c@ c@ C4 c@ 0 #a C%i-.0 G@W M m 10 C:, 10 W M U, m cm m CD CIOOr@ cc cc ri ew m a. M.0 4n W cv M W %0 .0W ey cnm -W qr rrw; w; CO cc M mM W C:l-W a..m. a@ W! ,; .0, CD*CD-qr* r, c@ W* C; 0: CD' en u, e,w -0 r_M, a, a lull ci I LM a,rQ --.2 . r0 w C6 w w %o CD ul -MCD, r,c@' m fn m C"CQ 0-1w- C"-m- "M w C, cv C" V, - 0; @ 'conmm W w%;o 'MMo wM 10 M a@ mm"m0m,m0m U-,: C> CD C> 10 r,: cr q@ m c@c QD' w, C, C! cv co C., CY C:, meC=n, " qr a; C@D I'@ -w cm" mm c@ c@ 47; rz 4m - . c', - c, 0 r c%j co cc m . . .z .m .m .cp.%ul." .m .m.@ .w.u,.,o. . .C; cm m oo wo':c,2,-, :t;v;r@,;; - , CD %o w ,o qr clj m wm v: Lt; @u@ cn w a@ CD, - -w c-4 clj C:l 4m .0 r m e, m c%l en OD ew c.;64 c@ . . . . u,.w u,,n C> m -w c%l qr In CD1 @.0 e) ul @o qr w c:l CD clw %o ew CD ' e@ w; 4 @ a; cc)* Wcl m m u0l C:o rQ c%lcw m cj w m wD ev cljev c%iew ew z tv ew ej u, c@ m tv c" m u; a; " "m " csj ev cmc c%o en ev cu L3 c..) c; c@ c@ c@ c@ @, C6.:6 C6 c@ c; C6 c@ ev cv c%aew c%j m cw cv rq cw C6 c@ c@ C6 m ev ev m ev ev @o E 2c In @O n Cc Cp% 0 Cm en kn w*@@D .0 a o a @o M0 N en w In o Cc M - -- - - -- - lec; 35 - 7 09 '@,0: co C; t@ -0:W: 10.0 C, q@ w; c; c@ -W.0 0 10 In .0 In wi .0 wi ww .0 ww wi tn ww W$ Ln _Inc@' o C.20,@n 0t'n .0 in W %D an "I Cm" cy %o 10 1.@m COO, Con, c@ C! el In In W, cm - _: 6 4 m m W CP wm c@ I.: a: r; M w " w ol w; I.:t@ U, e, u@ I": w 1. CCOP c@ c@ -: g m r w -Wm r w In enen r w w w w w ulw 0! -W Cc cc a, -mm - - - - m m a, C! 11! 19 C@ C@ r M IW C" r_ 71 %"aC":-'- C-0OM C"D-M um'0- @-0 c-@@-:*M;c-@ tr@. -W - 0. W.0 a, en Cc e,c, m ccen e,a r@ 6 co, o@,ri@ c@ .0*u@ qr C,qr m.0 en -w0 rm_ 7 t7. E 04 LI D-1 x C"t" -.2 = 0 C06L 10 cc -: - ,@C! a: c@ -@ 7 - - - - - - I ,o @D - - - C" @ w r@ @; C7; e@ -: c@ co cc m m M M MM M MM m 7 C"2, m ev C. en ew C" qr C:, cv m , A!r! c@ a! 'r! c r C! 0! 1! W! 0! r! 0! 70' mm w m ewy -r em- WU,,C"4 In o W, CD .0 'a m CN40 - -W - cqr CD @n - m m - mwmmmm ul " m en en M M m cn C-1 En en C-) m 0! C! c@ e! W! 9 0! c@ @@ 0! 0! C@ 0! 17 "7 0! Cl!9 ewol"0 cy- vi04rvo CIVco@D;- 476@n-qrcc:)i.l0ou0 lveinCwW,-rWow W,MWM eMloM'Mco m cu en mm tn m m CD cc . C9 c2 M cu La 34C' r@ 0! 7 r! c@ c@ W! c@ - 7 c@ W! c@ e! W a 0 C%i01 cn CD In m a,'wD c'ac %a m r, w "I'c C, rm ev CK) ew m m M im 0; 64 1-: CD:, r; WO kn '-D 'D @O e@ w; r@ wa m W.0 4n ".D W c@ m .:u,-: u4 r@ c@c@ Ln a, 0 @o m @ CK)CP-OD CD 0 CD OD ul ey'CD ac "C E. f. ! qr c.,0 z m.. r4 c %4 . " w @ Ln w, Q '.D ".o c%ic.) w cc G@ew ow - fn " w c. -v 47@ .. . . .. .. . . .I . . ul CD qr cct,o c471o &n c%l @o m In w, %o m rw ev ew ev CD -w tv cn a, w! C! W! C@ 7 9 w! a! CO I'@r@ r c9 17 r@ C@ r@ r@ 4p, . o! %a en qr 0 .0r! qr cc Ljw le IjLe L@Le17, 1-@ w W w Ij? c:c:c:c:c:c:c:c:0:a:a:c:c:c:a:a7a:c:c:a:c:a: a:a:c: o 4) E C) m m @ km to ccoo C:@ cz) cc co cc co cc) c@ mw o cac, cl,cD c@jf@ ev c-Im e@ m tv r@ mw m = C) m r@ c L^ 36 c:,@ m ccC" . . . . . . . . . . . .C@ e@ I'@ 1= m C" C" ew en C=W CY 1. 4n -%07 r; w; W; In mul ul ul V! .0 ul w m w ccoc .0 m .0 C,@o ow Cc o .0 - ft -.0 WW W a@z@-@ C 4n a@ m m ul 4D Li cr= M D m a, 0! C9 . m,= cc M" I . . .. . . . . .. . . . .. . CD en WM W V) qr en cn en -W 3C -0 0 cc a, a, W, 09 0 en I'@ C@ C@ w CD m tn @o C" c@ c@ co @ C; tv I I I wi a, CD C. cc Cw I zc cn t c@ c; c,; 7 ey ;@@D 10 ;za W" W4 mmc@"Do"" w U, M 10 ft M CPI CY r. .110 ev cn Li w CD :c LI >, cv = >1 0 C"@ r 41 ai 10 10 m 0 61 m C9 W e! 11!r C) w - ey,i @w. m w en w e! ;z. - . - . W";, mm @- M.0 @D 'm g;w m mm c .. . . . . @ C" w -W 0 0 @D 0 - m A 4w " 'fno "MMM@@ mmm C9 c@ 9 c@ c@ c@ c@ 07 0! c:@ '! a@ 0! W" mm C-4 C%# cu ey 0! C910: r %0001 WI-V 9 9 C@ C@ I" 4v! C%ACDC"@ -W w m C., 6"ow Go CD cc, >0 11!IW 0! 0! W, W! p@ el C9 Cl, 'o -C w en 0m .. . .. . m CO c@ @.0 -W ev 1.@ w cn w e@ cp*-c@ M* 47, @D m ,Do m en m 'D m %o -rn M:;@ cci@D ;Zen @o u, m 4w C%jC.)In CC)OD C" w ev ev ev ew t@" m . . . . r, CD C:, CID . %,@ ul r cn en C" en -10 m CD C'Da - C@ co C., CD r c; c@ 0 c@ w w f7)@j w ww w w W Li W 0: c: 0: c: a: c: c: c: 0: 0: c: c: iz:0: c: Q: c: c: 0: 0: 0: 0: 0: c: a: ;c ca rw I- .0 4o E 91 @o @ 0 0 0 CCO, ICMD U, 'a , cc)gs, tv ev ew ey m CY - 37 - Maternal Number 27130 27131 27132 27133 27134 27135 27136 27137 27138 27139 27140 27141 27142 27143 27144 27145 27146 27147 27148 27149 27150 27151 27152 27153 27154 N Mean S.D. Appendix 3 Individual and Mean Food Consumptiona Rat Teratology Study of T-3352 Group 1 - 0 mg/kg 154-161 Food Consumption (g) Interval (Days of Gestation) 0-6 7-8 F 9-12 13-16 17-20 7-16 B 0-20 F 113.6 (142.4) 112.0 125.7 123.8 (122.3) 111.2 131.9 136.9 128.4 164.3 120.0 119.1 186.4 108.8 151.1 137.5 121.8 130.7 135.7 125.6 139.0 126.9 142.8 137.3 32.5 (31.7) 31.7 37.1 38.8 (34.6) 32.0 31.2 42.9 39.5 40.9 34.4 28.7 41.8 29.9 47.6 40.3 36.3 40.0 41.8 38.9 42.8 41.1 41.8 41.6 70.6 (58.5) 72.2 75.0 79.9 (53.5) 70.0 65.8 87.4 81.9 69.9 77.0 66.0 87.1 71.8 99.2 75.5 76.0 111.1 92.5 81.5 79.8 71.4 72.0 81.8 76.7 (60.0) 79.9 83.4 82.8 (57.6) 74.8 74.6 95.8 88.5 75.3 87.3 84.7 82.8 76.7 94.1 79.6 79.5 88.4 100.3 73.3 87.4 87.5 101.6 88.2 95.1 (74.0) 106.1 103.5 113.6 (67.5) 88.7 94.5 119.1 113.7 111.6 106.3 100.9 101.8 94.2 99.8 94.1 92.9 117.4 117.1 99.1 104.8 103.8 121.1 105.7 179.8 (150.2) 183.8 195.5 201.5 (145.7) 176.8 171.6 226.1 209.9 186.1 198.7 179.4 211.7 178.4 240.9 195.4 191.8 239.5 234.6 193.7 210.0 200.0 215.4 211.6 388.5 (366.6) 401.9 424.7 438.9 (335.5) 376.7 398.0 482.1 452.0 462.0 425.0 399.4 499.9 381.4 491.8 427.0 406.5 487.6 487.4 418.4 453.8 430.7 479.3 454.6 23 131.76 17.761 23 37.98 4.988 23 78.93 10.880 23 84.49 8.071 23 104.56 9.290 23 201.40 20-254 23 437.72 38.302 - 38 - Maternal Number 27155 27156 27157 27158 27159 27160 27161 27162 27163 27164 27165 27166 27167 27168 27169 27170 27171 27172 27173 27174 27175 27176 27177 27178 27179 N Mean S.D. Appendix 3 - Continued Individual and Mean Food Consumptiona Rat Teratology Study of T-3352 Group 2 - 1 mg/kg 154-161 0-6 126.8 134.4 113.4 (125.4) 123.5 129.6 123.5 123.5 127.3 117.4 131.6 145.9 124.9 126.2 136.7 139.4 132.4 131.3 124.7 115.4 138.0 125.2 137.6 136.5 133.5 F 7-8 Food Consumption (g) Interval (Days of Gestation) 9-12 13-16 17-20 B 7-16 F 0-20 37.6 42.9 32.3 (35.4) 38.6 40.1 34.4 35.9 36.0 30.4 40.2 35.1 32.6 36.7 39.7 41.6 42.8 42.7 35.9 39.8 46.6 37.9 38.3 47.0 35.8 83.0 87.0 73.0 (75.6) 81.5 79.1 72.0 78.6 64.1 64.4 82.6 75.3 128.3 67.2 87.6 76.8 88.0 81.0 77.1 84.2 83.3 73.2 79.6 87.1 84.1 85.0 92.7 80.6 b (161.3) 78.3 80.7 79.7 78.8 93.9 72.8 84.1 81.1 b (108.5) 88.4 95.6 88.7 88.7 89.6 81.0 89.5 93.4 76.4 83.9 92.5 88.7 96.3 110.5 105.1 (91.3) 96.4 94.9 97.7 102.7 106.5 98.0 101.4 96.7 109.8 109.7 116.4 101.9 104.3 97.7 106.8 106.7 110.1 103.0 95.3 114.9 107.5 205.6 222.6 185.9 b (272.3) 198.4 199.9 186.1 193.3 194.0 167.6 206.9 191.5 (269.4)b 192.3 222.9 207.1 219.5 213.3 194.0 213.5 223.3 187.5 201.8 226.6 208.6 428.7 467.5 404.4 b (489.0) 418.3 424.4 407.3 419.5 427.8 383.0 439.9 434.1 (504.1)b 428.2 476.0 448.4 456.2 442.3 425.5 435.6 471.4 415.7 434.7 478.0 449.6 24 129.11 7.957 24 38.37 4.222 24 80.75 12.279 23 85.40 6.301 24 103.76 6.289 24 202.70 14.943 24 435.50 23.804 - 39 - Maternal Number 27180 27181 27182 27183 27184 27185 27186 27187 27188 27189 27190 27191 27192 27193 27194 27195 27096 27097 27098 27099 27100 27101 27102 27103 27104 N Mean S.D. 0-6 133.2 137.5 130.6 132.7 124.0 144.7 124.2 121.1 128.1 134.0 109.1 129.6 110.6 119.3 (114.5) 131.0 149.4 133.3 115.3 124.1 132.2 130.5 170.5 130.6 149.6 24 131.05 13.235 Appendix 3 - Continued Individual and Mean Food Consumptiona Rat Teratology Study of T-3352 Group 3 - 10 mg/kg 154-161 F 7-8 Food Consumption (g) Interval (Days of Gestation) 9-12 13-16 17-20 7-16 B F 0-20 37.7 38.3 45.9 37.9 34.9 42.3 39.0 36.7 42.1 39.4 27.3 36.5 31.0 29.4 (33.5) 39.8 44.7 33.6 33.1 33.5 36.2 40.7 55.4 40.0 51.4 73.5 79.2 77.2 71.8 61.9 76.0 69.3 71.8 77.4 82.0 69.1 75.4 52.4 73.4 b (103.0) 76.0 94.9 78.2 67.8 66.5 66.5 75.4 b (127.7) 79.4 79.7 76.8 78.5 66.1 71.0 87.8 88.7 59.9 69.4 80.0 88.4 67.0 78.1 76.2 71.7 b (63.6)b (147.7) 83.8 75.4 74.7 65.5 70.1 76.1 108.9 84.0 101.5 92.5 106.0 82.5 92.3 104.7 103.2 99.9 98.5 98.2 108.6 93.7 94.0 99.3 97.3 (70.2) 107.3 108.2 95.7 93.2 99.5 95.7 106.7 112.9 105.1 123.2 188.0 196.0 189.2 180.7 184.6 207.0 168.2 177.9 199.5 209.8 163.4 190.0 159.6 174.5 b (200.1)b (263.5) 223.4 187.2 175.6 165.5 172.8 192.2 b (292.0) 203.4 232.6 413.7 439.5 402.3 405.7 413.3 454.9 392.3 397.5 425.8 452.4 366.2 413.6 369.5 391.1 b (384.8)b (501.8) 481.0 416.2 384.1 389.1 400.7 429.4 (575.4) 439.1 505.4 24 38.62 6.431 23 73.69 8.143 23 78.24 11.473 24 100.76 8.389 22 188.23 18.997 22 417.40 34.384 - 40 - Maternal Number- 27205 27206 27207 27208 27209 27210 27211 27212 27213 27214 27215 27216 27217 27218 27219 27220 27221 27222 27223 27224 27225 27226 27227 27228 27229 N Mean S.D. - 0-6 124.9 123.1 120.3 (106-8) 92.9 140.9 143.0 (139.0) 157.3 (107.8) 135.5 128.8 130.8 122.9 122.6 130.6 113.9 155.4 130.0 129.5 (131.1) 148.7 132.3 123.g 20 130.34 14.541 Appendix 3 - Continued Individual and Mean Food Consumptiona Rat Teratology Study of T-3352 Group 4 - 30 mg/kg 154-161 F 7-8 Food Consumption (g) Interval (Da-vsof Gestation) 9-12 13-16 17-20 B 7-16 F 0-20 30.9 31.6 34.2 (29.0) 18.5 41.0 35.3 (19.2) 64.7 (32.0) 32.3 27.5 39.3 28.5 29.5 40.6 28.1 49.9 37.6 56.4 (27.4) 44.5 35.6 23.9 38.7 50.6 86.2 76.3 (65.7) 60.5 81.8 b (106.6) (34.1) 80.5 (57.7) 68.4 60.5 81.0 60.8 65.4 85.4 b (81.5) 85.0 b (72.2)b (220-0) (48.3) 79.6 b (75.7) 44.2 73.1 58.7 50.1 76.6 (52.2) (86.4)b 74.7 b (80.9) (2.2) b (99.5) (58.4) 73.9 56.9 87.9 b (84.1) 68.8 86.1 b (72.6)b (237.1) (73.7)b (128.4)b (3.7) 81.0 72.8 32.8 69.5 83.0 97.3 95.2 b (85.8) 97.2 107.0 99.0 (66.8) 101.9 (62.7) 96.1 91.2 109.0 98.8 84.6 103.6 77.6 b (121.4) 88.4 114.8 (62.2) 100.7 97.2 91.4 95.4 140.2 167.9 187.3 (146.9) b (165.4) 197.5 b (222.8) (55.5) b (244.7) (148.1) 174.6 144.9 208.2 (173.4)b 163.7 212.1 b (182.2)b (372.0) b (183.5) (404.8)b (79.4) 205.1 b (184.1) 100.9 181.3 348.1 388.3 402.6 b (339.5)b (355-5) 445.4 (464.8)b (261-3) b (503.9) (318-6) 406.2 364.9 448.0 b (395.1) 370.9 446.3 b (373.7 (648.8))b (401.9)b b (649.1) (272.7) 454.5 b (413.6) 315.6 b (276.7) 21 36.60 10.755 16 71.21 13.023 13 68.45 15.381 20 96.47 s- 8.931 12 173.64 s- 32.816 11 399.16 46.421 - 41 - Appendix 4 Individual and Mean Terminal Body Weights, Gravid Uterine Weights, and Terminal Body Weights Minus Gravid Uterine Weights Rat Teratology Study of T-3352 Group 1 - 0 mg/kg 154-161 (g)a Maternal Number Terminal Body Weight Gravid Uterine Weight Terminal Body Weight Minus Gravid Uterine Weight 27130 27131 27132 27133 27134 27135 27136 27137 27138 27139 27140 27141 27142 27143 27144 27145 27146 27147 27148 27149 27150 27151 27152 27153 27154 340.6 Not Pregnant 368.0 363.5 375.2 Not Pregnant 350.3 352.5 413.2 404.5 351.3 344.5 357.2 316.9 340.9 407.8 388.7 344.8 386.1 380.6 360.3 379.3 326.0 389.7 356.7 68.8 85.5 79.9 74.0 74.4 63.0 79.1 89.3 46.9 60.1 67.2 26.4 68.5 81.4 70.7 54.9 71.5 88.9 80.0 65.9 64.3 60.3 77.9 271.8 282.5 283.6 301.2 275.9 289.5 334.1 315.2 304.4 284.4 290.0 290.5 272.4 326.4 318.0 289.9 314.6 291.7 280.3 313.4 261'.7 329.4 278.8 N Mean S.D. 23 365.16 25.625 23 69.52 14.207 23 295.64 20.212 - 42 - Appendix 4 - Continued Individual and Mean Terminal Body Weights, Gravid Uterine Weights, and Terminal Body Weights Minus Gravid Uterine Weights Rat Teratology Study of T-3352 Group 2 - 1 mg/kg 154-161 (g)a Maternal Number 27155 27156 27157 27158 27159 27160 27161 27162 27163 27164 27165 27166 27167 27168 27169 27170c 27171 27172 27173 27174 27175 27176 27177 27178 27179 Terminal Body Weight 360.2 389.3 352.5 Not Pregnant 347.0 366.4 365.8 380.4 387.4 338.6 362.3 369.9 373.0 356.1 391.7 387.1 394.7 352.0 361.9 357.6 316.0 360.3 369.1 418.9 374.1 Gravid Uterine Weight 67.5 67.5 48.6 90.3 75.7 77.8 81.0 84.8 72.4 80.0 70.6 77.8 65.8 83.5 - 91.8 66.7 88.8 61.1 17.0 80.8 68.9 88.1 86.8 Terminal Body Weight Minus Gravid Uterine Weight 292.7 321.8 303.9 256.7 290.7 288.0 299.4 302.6 266.2 282.3 299.3 295.2 290.3 308.2 - 302.9 285.3 273.1 296.5 299.0 279.5 300.2 330.8 287.3 N Mean S.D. 24 368.01 21.094 23 73.62 16.288 23 293.56 16.285 - 43 - Appendix 4 - Continued Individual and Mean Terminal Body Weights, Gravid Uterine Weights, and Terminal Body Weights Minus Gravid Uterine Weights Rat Teratology Study of T-3352 Group 3 - 10 mg/kg 154-161 (g)a Maternal Number 27180 27181 27182 27183 27184 27185 27186 27187 27188 27189 27190 27191 27192 27193 27194 27195 27196 27197 27198 27199 27200 27201 27202 27203 27204 Terminal Body Weight 365.7 373.6 353.7 372.6 358.3 388.9 334.9 372.5 362.9 414.2 332.3 355.0 322.8 341.3 Not Pregnant 376.5 405.9 370.1 336.1 345.4 386.6 398.0 399.6 390.3 357.9 Gravid Uterine Weight 64.5 54.3 66.5 70.4 69.6 71.0 52.4 69.8 66.5 74.4 70.5 69.1 55.8 57.0 72.8 63.1 77.2 81.4 59.0 81.5 83.8 90.8 78.5 20.4 Terminal Body Weight Minus Gravid Uterine Weight 301.2 319.3 287.2 302.2 288.7 317.9 282.5 302.7 296.4 339.8 261.8 285.9 267.0 284.3 303.7 342.8 292.9 254.7 286.4 305.1 314.2 308.8 311.8 337.5 N Mean S.D. 24 367.30 24.797 24 67.51 13.989 24 299.78 22.724 - 44 - Appendix 4 - Continued Individual and Mean Terminal Body Weights, Gravid Uterine Weights, and Terminal Body Weights Minus Gravid Uterine Weights Rat Teratology Study of T-3352 Group 4 - 30 mg/kg 154-161 (g)a Maternal Number 27205 27206 27207 27208 27209 27210 27211 27212 27213 27214 27215 27216 27217 27218 27219 27220 27221 27222 27223c 27224 27225 27226 27227 27228 27229 Terminal Body Weight 316.7 330.3 344.1 Not Pregnant 349.4 364.3 312.6 Not Pregnant 379.3 Not Pregnant 362.7 341.7 386.5 343.5 336.3 364.6 297.6 300.2 309.8 374.0 Not Pregnant 386.3 346.8 326.1 372.9 Gravid Uterine Weight 64.B 59.9 74.5 73.1 57.2 30.2 71.5 73.0 78.0 79.0 71.1 68.4 68.0 59.5 24.6 81.4 71.9 74.9 67.1 81.2 Terminal Body Weight Minus Gravid Uterine Weight 251.9 270.4 269.6 276.3 307.1 282.4 307.8 289.7 263.7 307.5 272.4 267.9 296.6 238.1 275.6 292.6 314.4 271.9 259.0 291.7 N Mean S.D. 21 345.03 27-679 20 66.47 15.015 20 280.33S- 20.353 45 7 MCI 0 . =oc.:,. . . . . . . . . . . . . . . . . . . . . m L- Q coo CD two I ft X- 0 :; " 4@ = 4u @-I a r ol zm @o tn--: @ @o'@0' c:iw; CL, w; I.:Q' I.:CD' d; C-J 0' c; w; cc*%0' tv m CD le o: r_ m0 iOW. a CD tn C@ Q0 r_ 0a c@o@c@ 40 M a, C', co co m @o tv CD (Do m CPI OD CD @D vi tn W! ew OD 6M M 6'1 -0 a@ M M 6n &M CD W @D In -W M M 6@ -- - - - - -- - - - M 47, 10 c #a ve 6> CD W C) -0 u@ tL. C, en - - -- - - 41 0 -W m cc 4p% CD Q tn CW w r; %M C'. x 0= w cv 41 @c:, 46 qren 0 00 Q U, qr a@ W- C;c@c;cC;.Q=.C.) .C;Q=Q=CD C; . . . CD=CD ,C,A QOCD =C:,C)QCD=CDQCDCDC:,=OCDCD=CDCOO= -1.01 01 Ou L') CD >* c C" CQ 0 Q@!= CD CD 0 cn rn rQ -M -r_ @D CL 0! 9 lo:r r C@ W: 11! C9 9 9 7 c@ 9 C9 I'@ r! r, C" w m cC,:lm m C" a, m m C" 0 m @ 0 cr, w 0, C" C" cc kl! cc wm --- wlrw-loow WWI ---------------- w w @p 14-@OCY, ---- U, cr C" 10 1>0 W Li wm c@ cm 47 01- m C, L- ey -M"0"00=-Cm qr CD "I CV u's cc U, Ir en ew 41 C; C; Q CD CD 0 C:" CD* cc cc CCO, r 0 CD 0M C:l CD Q CD 0 4= CD 0 0 C, Le) ul xr tn M 06 w 4C1L 1 "Ia- cm 0 CD C) m L- m en CD CD @o m 0 en C) M m 0 C) @o %a CD -4 CD CD CD -a- cil tv CD CD 40 CD o@ C%IW t" C%i m 0! C@ 0! 7 C9 9 r! 7 C@ M 9 9 9 C@ 9 9 9 9 cc m CD .0 m 0 emn "cm @wo C0D z a 0 = C) 0 = 0 C) m cz Cc)m C,4 - a, C2 M CD c@ 47' 12 5-2 CD m w -W en C" %n w w -W In - - - -- - -- -- - -- - Ln @ No w %o QD m - - - - - -- - - - C%o en r Li 10 4v a) @.C!C2 T crCD -m@ =G=== 48 0 1- cwC. a 10 DCD OOM%cMv 0 C, C@ -rQ= -.r- O.C.D=C; 0. 0C;==.=.==06000 00-0 r,C-tW"n go 010- 41 cm L0.) Ln r_ CD c@ 0cv m c@ C=! c@ c:@ '- c@ C! c@ CL w LM C=C:D@ C" Cm:@ CC)@CoCD@!- 0m9 CD cn a, =c22@!www". m mwcmcw0,., '010 -0 ;z %cooCD kn 110 10 le I- 10 01.1! cw":!0114 mz cm 14 Iewno z .0 z@0 rQ C" qrU,'D w 0, "El OW 01 12 2 :Ll 49 - 7 r C, 2c wz m m i"cnfnm m entnm m m cnm e@ c" 0 e! 17 C! m c@ c@ c@ C! cux rm- In m cv - - -- -- - -- - -- 'a co C) a w L,5 mo em -.o m u, u, w m C! a m @o CD & o >1 CL c"-C .2 c@ cg 7 7 0 @o 0 CD W.0 ;Z= m c, Q m 0 .0 tn m @mm .71 c" tn wl a: c@ c@ 1: a: r@ * r@ f@ cc c@- C@ m m CD en C5 m at cn m c@'co cc c" ol - - - - -en @-o - - - - - - C! C@ e@ CD C> m w m 0 0 c:l 0 0 C:.0 CD 0 m 0- 0 00 Q Q cn Q en @n ew CD cv CD 0 c I., 'Goo w - - - w (D ew c:)CD 6. cL o z =c:. cD - - - cD - w w, cp,o 'om m kn @D 4u c%,"" cD c%i0 m cy c%j 3t wL a m4, c E Iwo Iv L, E E 'o 41 -wo 1w* c! = vi 4w, Go lo w-c 41 @ w c@ 'co mv cL. &-A cj mo wqo 50 C@ C! r!fnW: r -Wr knw M 0!M 1*@ C" en w tnCD m C9 C! 7 U! E@ r 17 c@ c@ 0 kn M %o W C:lW 0 r C" cc @o en @D @o w %a m @o a CP%m m m c w m @o cv m en eIn o cD cxl a cc c. c" w E m C! w c@ c@ c9 m 0 C)0 0 C)Q C) c:-0 0 0 CD CD 0 CD c:l0 Q c:@(D 0 cDoC) C! ev m -w 'owc'o C) cv Q en 0 en CD r (Z 0 C:,0 CD Q C:-m r7 cL. oE 4u o =- v 39 > cL L. 0 w w Ea c tj co cr,0 m r v4 @D CD cy, 0 tv el x cm z LI@ 4w do = w a CL c w a, 6 2c 2 '= >c ' >o lo a. Im 51 I" tn C" m m m en en -w en 0 en wo, o@ ,o %on en tn ,n ew a CV Ln C, cm x r C"rn CD CL w w r c@ n r. ap c.. n.motnul WWI w wm @o ul c .0 -W 0! M qr .0- rw WMRC"CRC 0! -mcn@!OIC7101- c@! 0' 'D CD tn 0 Q -V 0 w; cn ul CY Cc C9 C9 m 00 W" C@ C@ C@ C@ "I CD om M cc C@ 7 C! C@ 11! C@ Q0@0 CDOCDO=004=c:looc:loo OCDOOOOCDOOO C:..Po I M cl. 0 ap Q 0 0 C:oM Ir!C9 ulr cn rc 3: t- 0 wwwwwo - om 6m 0-9 - mmmmcpcp, clo0g -m" V0WMW @ m 00 Ln 61 4 *, 0: 52 cw c m,ol .7 . C! CQ enm en .. . .. . . en. cw ev eQr;m ow r,m m e. M CD I'mw u@ 0: C! $--Z Iwo Mff; rmn ',11 C1W!) 0"! C"@ r! qC"rl@C%W@O &n &n lw 0I"n: 0! U, e,m qr a, vi m IV w-wwol w -W m @c 4n m m @o a w cl, 0 cc-0, CD 10 c 6- CL cr r 1= CO M C! M C@ Cc C@ C! C@ "I t, C@ a! C@ CD m en 0 m e@encomcd R.CDO low m CD C. CD M 0, co v@ , m 0, 0, 0, m @D C" 0, 0' IW uz 41 C, CD .0100 10 c=!-7 c@ %o .0'CD - = CD M' C! 7 c@ ;z Q CD Q 9=1 0 CD 0 0 Q 0 CDCDC=CD0 Q 0 CD 0 CD CD CD CD ;z CD I 00 0. cz 0 co UOI%002; Cc,,0012 VW-C) -CDC" lr_u - 0)- CD C@;z CL 0 0 2c En E -o - 06 cc Ln w w r, qr 61,a w a, -n m v m to 53 tm w 1.5 = -o E x r_ = :; :: r cr M CV fn en co 0 cn C-D c@p 0 0 u, CD 0 fn LM CD CD cn m m ul r CD CD CD CD 0 C@ m CD 0 C@ x v co 0 4v CD 0 CD a CD CD c:- 0 CD x m> > 3c lo > E E : E 4, m Or.cc a 0 CL 0 'o w v> -; r- m r_ c 0 a 41 0 CcLL 6. w m -,oo > lo oco lw- 4) be 4u 0 1 c7, dL 6 cL,b, LLj cj 54 a, 0 r_ x Lo cv kn in 0 C) CD ev LM cu In CV en imn -r cc Q C> .0 CD CD C! = cc C:@ on r CD Ln40 CD CD tv cv CD CD 6. 0) 2.0 E 3c x CD cc C! ag CC@D dc C@ 0 CD Q Lo - CD C! Q co 4= C) CD 41 to 16V cr c Gi -c.0 fe 7; 92. 4w s- .0 ol Im w - 41 ow 6.-- cL 6 00,m-v= CL E 41 r_ L-.o IV a, 4; v E m to le M L. L. -C 4w 4) GP ai > lit Z 9 C. c A w 10 iw 40 .0 v E L. CL 10 CL a- (U kc L-i cm >, x cm m C. C@ 0 CD 9 An 6n CD C:. 0 CSO .n en m CD 0 0 Lm ul$ = 0 0 CD 0 Ln 6n CD 0 0 @c CD 0 cc cn m cz 0 In -w - CD CD 55 C! CD 4= C@ be 4= c:l 00 cz 0 CD 0 CD CD Q c:- CD C@ lo 1:16 Ile- ol w 1- 0 4, c en c olo L- .2 4L1. w.1 - -w = - c, cm 4I1, c .5 2- ou 7Z:i- c'oL-5 -eai'o a) 7c; =2m- a) C-.Kw-.u m -Ice -ow v o LL, ,A W I- 6 6. C w G, w 41 c c 4C, -06 z &A - V 4) cc _j w Ad u c @ 36" h LI@ 6. 4) 19 Ld zm @ :E 41 = 12. r_ 56 - CV %o %0 CD 0 C:l ev Lm 0 CD Iv cm v5 cL c:lCD C@ .r cv CD cv cn An c=! C=@ -o Im c:l0 C@ CD ev @o cn CD C! C:,0 CD cv m ev w.o CD C! CD 0 0 c:l c:l CD 0 c:-0 c:l C! CD c:l CD (D l-1o 3c c 4u 4u 31 o E 10- 0 @w o 1cw r_ x w o 41 -loo to C,10 41 41 coLr_ L.low L- L- LO- tr en r_ > lo 4, -10 41 ww jm E E Lw ==w Z L. = L. 4) ' 4) cu en r_ a, cn oE, cnm cL i-cz = ow -a .v r CD U-@ in cu @ - at CM .n w CD ev @ - cc cm Ln - co m C! In LM m CD 6n tn CD 0 - co .0 CD 9 CD 0 4= - co tn rq - CD w In CD cc en CD 9 In In CD CD cc In C) CD cc 9 m0 cc CD lo CD W.0 57 C@ C)C) ad CD 9 0 CD CD 9 0 CD CD CD 0 CD 9 C) CD CD C! 0 CD CD 0 39 4, C6 4u L- ol L- w 4u c ac ,u c cn r cL w lo o-o 41, :4.I1z 4, 40 r_ r- c c o' cm c lo > w cu & 4-1 c c) L. L- E EE Lt.) aj m 14-10.. ke w Ln or awl r c c', id u cv CY fn tn tn cv cv ern, CD 0 en r_ ol 0 vi mfn 1.0 w en CD ol co CD CD CD CD c@,@o CD CD C:, CV 'e, In @n CD c:o I r4 f- cr, cnl iQ) .0 58 - CD 00 In cv do CD 0 0 CD CD C) CD C! 41 cr cil E0c waa -0c Lo- CL 0 A .1 W m 0 m:; m 4@ %I ai w 0 -E r= r= M -J 4.1 .Wl 0-0 19 0, 2r fa CY p- em 'o C@ V%C) 0 C! Ln 4n ev m C@ - @ CD CD CY CY C! CV M -w CDC CD 4u .. . InInC>cz CD m x ICL CY C%tC) @c Ln In .0 cu E fts 59 CD 0 lm C! CD CD CDC) CD C) IV ec CL E W.0 4D ,M, @; r 00 r_ 0 tm CZ w .1 1 CL 0.0 W 0 CIO I-.2 ..@ m Go 41.0 CL 4c) 4D ai 0 E m 0 a -0-0- v 'A 4) -W -W -Co VM I -IM LW CL. 961 w go o-'V) E I- op w CL. 9L CL z 7 cn r_ JU x - ..E C, CL CD OL -Cc a c3c C%lp- cv VY cm C! C, cw cc cw ri m m wi In c:l c:l wi -Z ,a @o cz 0 C-4 C%i C%i qr cli cu ev clw C-W CD 0 C:) qr w m CD n CD CD ra r- C%i cm CD to C@ %n vi Q 0 Cli M C! U-1 CD C:) wt m 60 C! CD.c:i CD C:! C:.c:- E 41 CD C! tm C! CD CD C! C) CD C@ 10 CD E x CD 4D qo 31 m L. w cl L- 0 .0 6. W M qo L- 0 4m C >m W 4u oco L. L. L. .OE L- 0.0 0.0 WI- 4>1, I- .2 - t" 'o W W.0 C2, W 4u > 41 6..= 1-2 r mE 0 4u ML. co -1 IV W.W 0- LI) 4u IV .0 w E I- wc r- - v NC 'W" tn m Go ar k cc" @oC@! 61 ME 3r cc CD go agw CD bg C" CD ol Mw z C%i r cm %c m gn I ey fn c%; ol .U co r4 CY x r_ en - Ln cn- ev tn fn 40 CC) .0 vi cx be W. bd be bg I-) m W.U Go 2 G, CD OL r_ 41 G) c L' CL 0'0 0 I 2 00cr_o 4; (D 4U 4, a r- w CC0 6. 6 GO w V 41 1 0 41 10 XW 1=0 ww0 EEE Cc w c@. C, 0 .W0.077 4w 6. L- L- 06 0 C6 -A I I I I I I u IM 0. 41 Ad 4D v oice 0 4n 2- CL 62 co _j .j cc An kn In 0 Lj w CD w cn C! qr .0 0 lo -w cc m qr CC - - - con qr co cc el m 3c en In 0 co r, lo tm v@)0 OD m x cL ew p- qw 'r I C) ev cc)0 - cc _j _j 41 V) 06 (D -c clo cD xz L- jg c C, Ln L. -. ! cr, 4w a c o 3t 6, cw j oo o v, cL c E r -1 41 rL E lo I cL 0c cn 4m . - c IQ, lo"o tp m m ffl m c lo L @.w= v L" V 0 06 4- W U o tn.!: um v m m m m c c - s- m 'a w v =cL cL 06 a o = = >1 I I I I I LIj cn I- 'm @! 4u 9= a c 41 u c v t" cp & v- o 31 coclcr. v, 63 C. 0, M%o %a CD go Cc= 0 0 "CO 0 &nkm 4n 6w CL c c@, Ln ow fu en o lp m In cc Lj cc C7. en -In m Lj r_ w co cnm rv cL w c%o I=o cc)@D m u4 el C@ m cp,CD cc cg) be cL z x bc cl. cc x x zx C I.u CL 0 41 uw 4,v co C) lo cw ca c w cc 0m 41 9 91010 00 0c 41 c CX 6. 1 do m cc lp 41 16 ww "v oo c w om w. w c, c, mLc c@ cL m C 6, I-1.@'0 n fe to w vmm-oo==mfc 4u cL- fo 0 c Ac wv v w @.E m 4@0 .5 lo 126 .4Q1.clp 41 411 E ER cu WAVo 41 4-1:.12:e o@@ @ L- L@-I ir Im, I v iu to a 'Lo r_ o w cw r caa=- 'do, 4u u fo cr 40 4,L-l c do wdo cL orw o- 4) z L4,. @ wo h 64 (2qr @o CD P-1 co CID0 CD to rn w LI) co x a, cv tn "Q c@ 0 ey tn tn In cc @ @ I.: en CD ev en CW m @o co ty, 6@ r 'wr 0 C! W.0 r. W, cc Li -.i w_jci ui 0 z "i Ld co to co go ww z: z rr 7Z 00 00 7; OL 0 0E w 39 0c 0 0 c 1. 0 a 00 4.1 am a 0 CO MM 41 W -W 0 V 41 a, L- 6 to fo m m m m m 0 0.06- o- -0 0 m CL- .0.0 0 WC ar_l CL ww :9! :92 o 6. @ -0 I- CL a 0 cc m w E .0 00 I- L. 4c Ee tmbg M!"I 10 w w cz el lu 4u a, !11 W 4u w m ILO OM, 431, 401 Lo. All 4=1 4@ w - 65 - w w0 5"C tn cxo - C7. - 0.2 Ex c ? 10 M- cm CO CC cm ev eav W Li CD M co0, C" a% cow cornn m bg ev co cccv10In Cc .0 .0= .00 wdowzx CcWl W,n e" en Go r Cc cc en ccrn In C. cc CQ 1 co U-Wen C! .0 en en 0 CD W, CD 00 bc x bg 0 06 CL 0 E- L- 0 0 .4w, cm 0 10 CEL '4*b c c0 cc E=-E > X:= M> =M wt -0 "10 -2- LW* E= 4=1 L41 6@, L@- .0 41 W zc 0 0 10 0 ou m v sp w c@.06 110-m el 9.1 w 0 L, M.-c-1 :. -t 1; -- A2 L- E E E 0= mm wm a 0 '!.t CL zz 0 0 .1 owl a, 10 06 w L. 4D 4u u 4d M, V 0 L. -0 1 0 10 41 c ,w 41 41 EE 41 41 01= 66 - 7 C.- cv0 r ewewQ CD cv - ev 0 en 0 C! @o -W 0 C) ra cv ey C:. en0 en ey c%iC) 9 CD C, C%l C3" cc qr -W 0 km 0 M cp% cc C@ CNCD z Id 1.) be kc he Ng I"ile w U. 0 z cc 0 Cd cc u- le CD C@ ol 'a cc CZ)c:l0 CO Ln 6.CD a, 1=0 m CY m xz CD 00 CL 0 1-0 w 14-1 41 r0 >> v w 4u 4w 4d z IV 06 im C6 0 4u 0r m mI- m 161I,'ll ju-Iv- L- 6- 1.0 L- m V 4>1 % M.0 AV0 41 w =.o Q=w 10 Lfa 41 110. L. =1 41 z Cm w to -0 3- 7 E O:CK gri.0 40 z vi 2. cu Zm C. ul InIn ew CY co Q cu CW tn cc CD cc c@ 67 c:r w co ew cw rQ tv cv In en - - - CDco ev cv Q C! cn Ln 1 be be 2c -1 co >1 C" qr ew 0.0 C9 CD G, to LV 1L0i a. Lo C0,.11, 1@0 CL w ev U% ew @D .4 W.0 CL E c E L- 0 0 4u r- c. r 0 0 w w c 0C.5 10 41 4m, L- 6. 10 w OW 41 10 10 10 -= = - OMMA 00 0 0 @-- CL v Cm 40 w v .0 E L. ai CL. c -9.jz w Cn 4.U W.0 CL iZ6= do m L- L. ==2:. - I I I III I = -- AV0 CL to v CD "Mul ix Z. 9L .4" wr Ap_ w Ad to IM 4L, cE 'o, r " c0 cm 41 0 cr cc[ I.,,. 0. Z to 68 C-i- clitv em W! z z = z z z CD C-4 - Z! mi Li Li C) C! bg bd C%i- ev C%i C%i - ow C. fn CD C:) C? m 6-1 m cc un CD cr bg -a ad. w bg A. ci Li Li ww z C 'Er 0-0-0 CD Ln cc x dD CL oCLl 110-0I- C6 w ev C%ip- ell w w w CD cn @.r w -W C" CO b.C bg r_ L. 41 @ a, W.0 > 4D W 0 ip a .5.! w 3t2 wA im 4, 4u 4) 06 0m u c w cr 0 fe OEL 4, tn a 40 W L4-,a W &v M OC r- 10 0 .5L en @o v -0 wm w 4u CL M- =0 :::z CL- =.O AV0 fa W W 6. 6 - OL E 0 0 41 w m C- C %%a 7:; L 4; w 40 en 6 m -0 :: v 0) w- w oz 'Z 0 EE E -0 Z -t C, 1 1r v IU w Qi w 4,1 a = @O.C.0 .0 E EE m 42. z z z Ia,- w 41 IV a 41 w LO..,1 .W 4a1 wr 4.1 4. "4-1-- ki to r vw mr 0 CL. v GL.P L. 4u w vi :iw 0. zm 69 - Appendix 9 References Rat Teratology Study of T-3352 STATISTICAL METHODS/LABORATORY PROCEDURES 154-161 Armitage, P., "Tests for Linear Trends in Proportions and Frequencies." Biometrics, 11:375-385, 1955. Bartlett, M. S., "Some Examples of Statistical Methods of Research in Agriculture and Applied Biology." J. Royal Statist. Soc. Supnl-., IV:137-170, 1937. Cochran, W. G., "Some Methods of Strengthening the Common Chi-Square Tests." Biometrics, 10:417-451, 1954. Cochran, W. G., and Cox, G. M., Experimental Designs, 2nd Ed., John Wiley and Sons, Inc., New York, 1957. Draper, N. R., and Hunter, W. G., mtransformations: Some Examples Revisited." Technometrics, 11:23-40, 1969. Dunnett, C. W., "A Multiple Comparison Procedure for Comparing Several Treatments with a Control." J. Am. Stat. Assoc., 50:1096-1121, 1955. Dunnett, C. W., "New Tables for Multiple Comparisons with a Control." Biometrics, 20:482-491, 1964. Fisher, R. A., Statistical Methods for Research Workers, Oliver & Boyd, Edinburgh, 1950. Fleiss, J. L., Statistical Methods for Rates and Proportions. 2nd Ed., Wiley, New York, Ch. 9, 1981. Games, P. A., and Howell, J. F., "Pairwise Multiple Comparison Procedures with Unequal N's and/or Variances: A Monte Carlo Study." J. Ed. Statist., 1:113-125, 1976. Kruskal, W. H. and Wallis, W. A., "Use of Ranks in One-Criterion Variance Analysis." J. Am. Stat. Assoc., 47:583-621,1952. Kruskal, W. H. and Wallis, W. A., "Errata to Use of Ranks in One-Criterion Variance Analysis." J. Am. Stat. Assoc., 48:907-911, 1953. Levene, H., "Robust Tests for Equality of Variances," in I. Olkin edited, Contributionsto Probabilityand Statistics, Stanford University Press, Palo Alto, 1960. - 70 - Appendix 9 - Continued References Rat Teratology Study of T-3352 STATISTICAL METHODS/LABORATORY PROCEDURES 154-161 Miller, R. G., Jr., Simultaneous Statistical Inference, McGraw-Hill, New York, 1966, Ch. 6.1. Staples, R. E., udetection of Visceral Alterations in Mammalian Fetuses." Teratology, 9(3):A-37,1974. Staples, R. E. and Schnell, V. L., "Refinements in Rapid Clearing Technic in the KOH-Alizarin Red S Method for Fetal Bone." Stain Technology, 39:61-63, 1964. Wilson, J. G. "EmbryologicalConsiderations in Teratology.n Ch. 10. In Teratology: Principles and Techniques. Ed. J. G. Wilson and J. Warkany. The Univ. of Chicago Press, Chicago, 1965. Winer, B. J., Statistical Principles in Experimental Design, 2nd Ed., McGraw-Hill, N.Y., Chs. 3-9, 1971. Winer, B. J., Statistical Principles in ExperimentalDesign, 2nd Ed., McGraw-Hill, N.Y., Ch. 10, 1971.