Document 8RbM0Q7qzBnJz6J5bVgMRoo8B

HAZLETON LABORATORIES AMERICA INC. 9 2 0 0 LEESBURG Tu ONPIKE VIENNA VIRGINIA 2 2 1BO U S A RAT TERATOLOGY STUDY T-3352 FINAL REPORT Submitted to 3M Comoanv St. Paul, Minnesota March 21, 1984 (S) H A Z L E T O f M LABORATORIES AMERICA INC SJOCIIIWUK-J""""! v.6~~* -i 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 Findings Reported Inspector/Reviewer Protocol 6/15/83 6/15/83 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 HAZLETON LABORATORIES AMERICA. INC. 9 2 0 0 L E E S B U O G TU BNPIKE VIENNA VIRGINIA 2 2 1BO U S A 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: 't m LAWRENCE Tj^VlETZEL, Ph.D. Life Sciences Division Laboratory Supervision: Teratology: ____ GEORGE A. BURDOCK, Ph.D. Diplomate, American Board of Toxicology Life Sciences Division RUTH S. DURLOO, B.S. Life Sciences Division Study Coordinator: BARBARA R. COLPEAN, B.tf. , B.S. Life Sciences Division blm HAZLETON LABORATORIES AN/1ERICA. INC. 9 2 0 0 lE E SBU BG TUONPIKE VIENNA VIRGINIA 221 SO U S A TABLE OF CONTENTS SUMMARY INTRODUCTION CONTROL AND TEST MATERIALS TEST ANIMALS METHODS Mating Period Groups and Dosage Levels Compound Preparation and Administration Maternal Observations and Records Cesarean Sacrifice Visceral Examination of Fetuses Skeletal Examination of Fetuses Tissue Preservation Statistical Analyses Specimen, Raw Data, and Final Report Storage RESULTS - MATERNAL DATA Mortality and Clinical Observations Body Weights and Food Consumption Uterine Weights Gross Pathology RESULTS - CESAREAN DATA >_ Pregnancy Rates, Corpora Lutea, and Uterine Implantations Fetal Viability, Weight, and Sex Fetal Development TABLES Table 1 - Summary of Maternal Clinical Observations Table 2 - Mean Maternal Body Weights and Body Weight Changes Table 3 - Mean Maternal Food Consumption Table 4 - Mean Terminal Body Weights, Gravid Uterine Weights, and Terminal Body Weights Table 5 - Summary of Maternal Gross Pathology Findings Key to Tables 6-14 Table 6 - Summary of Mean Ovarian and Uterine Data Paae 1 3 3 4 5 5 5 6 7 7 11 12 12 12 13 13 14 14 14 14 16 17 18 19 20 21 22 U) 00 GO 00 HAZLETON LABORATORIES AMERICA. INC. 9200 lEESBU^G TURNPIKE VIENNA VIRGINIA221eo USA 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 Incidence of External Findings Per Litter Table 12 Incidence of 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 1 - Individual Clinical Signs Key to Appendices 2, 3, and 4 Appendix 2 - Individual and Mean Maternal Body Weights and Body Weight Changes Appendix Appendix Individual and Mean Food Consumption 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 - Individual Vi sceral Findings in Fetuses Appendix 8 - Individual Skeletal Findings in Fetuses Appendix 9 - References LABORATORIES AMERICA, INC. S P O N S O R : 3M Company M A T E R I A L : T-3352 SUBJECT: FINAL REPORT Rat Teratology Study Project No. 154-161 A T E : 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 CD* 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. HAZLETON LABORATORIES AMERICA. INC. 9 2 0 0 LEESBURG TURNPIKE VIENNA VlBClNIA 2 2 1 0 0 U S A 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. HAZLETON LABORATORIES AMERICA. INC. ~20C l E E S B u RG Tl/RNPi k E. VIENNA viPGifwiA 221 SO U S A 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 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. HAZLETON LABORATORIES AMERICA, INC. -4 154-161 TEST ANIMALS Two hundred fifty-nine (130 male and 129 female) sexually mature, cesarean-derived Sprague-Dawley Crl:CD (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 Chow 5001) and tap water (via an automatic watering system) were available ad libitum. The mean room temperature + the standard deviation was 73.6F + 1.68 and the mean relative humidity + the standard deviation was 59.4X + 3.44 during the study. A twelve-hour light/dark cycle was maintained. HAZLETON LABORATORIES AMERICA. INC. 9 2 0 0 l E S 8U B G t u s n PiKE VIENNA v iflC iM * 2 2 1 8 0 . 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 Dose3 mg/kg/day 1 25 0 2 25 1 3 25 10 4 25 30 3 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 1n a range finding study. The results from that study were reported separately. HAZLETON LABORATORIES AMERICA, INC. 92GC ^EESBURG TURNPIKE VIENNA ViOGiNiA 22 180 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 number of matings was confirmed.3 Compound Preparation 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 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. 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. HAZLETON LABORATORIES AM ERICA INC. 9 3 0 0 LEESBURG TURNPiXE V I E N N A V I R G I N I A S 3 1BO. 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 dally 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 HAZLETON LABORATORIES AMERICA. INC. 9 2 0 0 l EE SB U P G Tu r n p i k e Vie n n a v o G'Ma 2 2 10O U S A 8- - 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 evalua tion. 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 (Gem*) 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 skele tons 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. HAZLETON LABORATORIES AMERICA. INC. 9 2 0 0 l EE SB U R C t u r n p ik e viEhafstA v iP G '^ ia 2 2 18G U 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 log.^, square (X ), square root (X% ), reciprocal (1/X), angular (arcsine X )%, and rank, in that order. If rank transformation was ineffective in removing HAZLETON LABORATORIES AMERICA. INC. 9 2 0 0 l E6SBU**G T i j b n p k E V i e n n a vtftG**JA 22 i SO 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 log-|g transformation. B = Data analyzed following square (X2) transformation. C = Data analyzed following square root (X% ) transformation. D = Data analyzed following reciprocal (1/X) transformation. E = Data analyzed following angular (arcsine X44) trans formation. F = Data analyzed following rank transformation. Mean fetal body weights per litter were statistically analyzed 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.OX one-tailed probability level. Control vs. compound-treated group mean comparisons of the above data were evaluated at the 5.OX two-tailed probability level. HAZLETON LABORATORIES AMERICA. INC. g 2 Q C t E E S B u f i C t u b n p i k E V i e n n a v i OGn*a 2 2 1 0 0 u S - 11 - 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% level. 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 statis tically 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. HAZLETON LABORATORIES AMERICA. INC. 9 2 0 0 LEESBURG TuflNOKE Vi6NNA VIRGINIA 22 180 U S A - 12 - 154--161 RESULTS - MATERNAL DATA Mortality and Clinical Observations Individual clinical observations are presented in Appendix 1. A surwnary 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 significantly lower 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. HAZLETON LABORATORIES AMERICA. INC. 9 2 0 0 i E S B u G t u O n p i k E V i e n n a v i r g i n i a 22 i BO U 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. HAZLETON LABORATORIES AMERICA. INC. 9200 LEESBURG TuBNp,,<E viENfwA viOG^ia221BO USA - 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 Ltea, and Uterine Implantations Pregnancy rates, number of corpora ltea, 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 1 HAZLETON LABORATORIES AMERICA, INC. 9 20C LEESBURG TuNP"<E VIENNA v iP C in ia 2 2 1 0 0 U S A - 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. Table 1 Summary of Maternal Clinical Observations3 Rat Teratology Study of T-3352 154-161 Observation Group: Dose Level (mg/kg): Pretreatment______ Days 0-5 1234 0 1 10 30 Number of females examined Number of females appearing normal Number of females found dead or sacrificed prior to Day 20 23(2) 24(1) 24(1) 21(4) 23(2) 24(1) 24(1) 21(4) 000 0 Hunched Thin Languid Anorexia Soft feces Alopecia Rough halrcoat _______Treatment_______ Days 6-15 12 34 0 1 10 30 23(2) 24(1) 24(1) 21(4) 20(2) 21(1) 24(1) 17(2) 00 0 0 2(2) KD 1 11 23 _____ Posttreatment Days 16-20 1 2 34 0 1 10 30 23(2) 24(1) 24(1) 21(4) 19(2) 21(1) 21(1) 16(1) 0000 1(2) (3) (1) 4 3 3 5(1) (1) a Numerals Indicate the number of animals with that particular finding. () = Observations noted 1n nonpregnant females. Table 2 Mean Maternal Body Weights and Body Weight Changes Rat Teratology Study of T-3352 154-161 Body Welqht Mean Weight (g) Mean Change (g) Dav(s) 0 6 8 12 16 20 0-6 6-8 6-12 6--16^ 6-20 16-20 0-20 N: N: N: N: N: N: Group 1 0 mg/kg 230.77 23 260.93 23 264.78 23 282.82 23 308.71 23 365.16 23 30.17 3.85 21.89 47.78 104.23 56.44 134.39 Group 2 1 mg/kg 230.15 24 259.94 24 263.75 24 283.36 24 311.02 24 368.01 24 29.80 3.81 23.42 51 .08 108.08 57.00 137.03 Group 3 10 mg/kg 238.63 24 268.94 24 272.81 24 287.05 24 310.81 24 367.30 24 30.32 3.87 18.11 41 .87 98.35 56.49 128.67 Group 4 30 mg/kg 237.34 21 268.60 21 265.33 21 267.37 21 287.92 21 345.03 21 31 .25 -3.02s" -1 .22 19.33s" 76.44 57.11 107.69s" N: Indicates the sample size on which mean calculations were based. calculations. I Only pregnant females were used 1n mean Table 3 Mean Maternal Food Consumption (g) Rat Teratology Study of T-3352 Interval Days Group 1 0 mg/kg 0-6 131.76 N: 23 7-8f 37.98 N: 23 9-12 78.93 N: 23 13-16 84.49 N: 23 17-20 104.56 N: 23 7-16^ 201.40 N: 23 0-20f 437.72 N: 23 Group 2 1 mg/kg 129.11 24 38.37 24 80.75 24 85.40 23 103.76 24 202.70 23 435.50 23 Group 3 10 mg/kg 131.05 24 38.62 24 73.69 23 78.24 23 100.76 24 188.23 22 417.40 22 Group 4 30 mg/kg 130.34 20 36.60 21 71.21 16 68.45 13 96.47s" 20 173.64s" 12 399.16 11 N: Indicates the sample size on which the mean calculations were based. Only pregnant females were used 1n mean calculations. Invalid food consumption values were not Included 1n mean calculations. Group and Dose Level 1 0 mg/kg 2 1 mg/kg 3 10 mg/kg 4 30 mg/kg Table 4 Mean Terminal Body Weights, Gravid Uterine Weights, and Terminal Body Weights Minus Gravid Uterine Weights Rat Teratology Study of T-3352 Terminal Body Welqht 365.16 N: 23 368.01 N: 24 367.30 N: 24 345.03 N: 21 Gravid Uterine Welqht 69.52 23 73.62 23 67.51 24 66.47 20 Terminal Body Weight Minus Gravid Uterine Welqht 295.64 23 293.56 23 299.78 24 280.33s" 20 N: Indicates the sample size on which the mean calculations were based. Only pregnant females were used 1n mean calculations. Table 5 Summary of Maternal Gross Pathology Findings Rat Teratology Study of T-3352 ORGAN AND DESCRIPTION Group: Dose Level (mg/kg): 1 0 Number of animals examined Number with no gross pathology 23(2) 19(2) LUNG Dark red focal areas LIVER Irregular shape Lobes adhered to one another KIDNEY(S) Pelvis dilated OVARY(IES) Cystic Clear 4 CERVIX Contained yellowish-green viscous material UTERUS/UTERINE HORN Distended with clear fluid 2 1 24(1) 24(1) 3 10 24(1) 20(1) 1 1 1 1 1 1 154-161 4 30 21(4) 18(3) 3 (1) (1) ( ) = Finding present 1n nonpregnant females. - 21 - Key to Tables 6-14 154-161 Preanancv ratP (Dercent) - 1(0nu0m.ber of pregnant rats/number of rats inseminated) x Survival Rate (percent) - (number of rats surviving to Day 20/number of rats placed on study at initiation) x 100. Mean Implantation Efficiency (percent! - Group mean of ([implantations per litter/ corpora lutea per litter] x 100). Mean Incidence of Resorptions (percent)3 - Group mean of ([resorptions per litter/ implantations per 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 1itter/implantations per litter] x 100). Mean Incidence of External Variants (percent) - Group mean of ([number of fetuses per U t t e r with external variants/ number of fetuses per U t t e r 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 U t t e r 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. Table 6 Summary of Mean Ovarian and Uterine Data Rat Teratology Study of T-3352 154-161 Number of females Number of pregnant females Pregnancy rate (X) Number of females surviving to Day 20 Survival rate (X) Mean number of: Corpora lutea Implantations Early resorptions Late resorptions Total resorptions Indices calculated on a per Utter basis: Mean Implantation efficiency (X) Mean Incidence of early resorptions (X) Mean Incidence of late resorptions (X) Mean Incidence of total resorptions (X) Group: Dose Level (mg/kg): 1 0 234 1 10 30 25 25 25 25 23 24 24 21 92 96 96 84 25 25 25 25 100 100 100 100 16.1 13.5 0.9 0.0 0.9 16.2 14.5 1.2 0.0 1.2 15.6 14.2 1.3 0.1 1.5 16.2 14.0 1.0 0.0a 1.0 85.16 7.09 0.00 7.09 89.02 7.46 0.00 7.46 91 .78 9.97 0.88 10.85 86.76 7.32 0.34 7.66 a One late resorption was noted for female No. 27228, therefore, the actual mean was 0.04. Table 7 Summary of Mean U t t e r Data9 Rat Teratology Study of T-3352 Mean number of: Fetuses - dead - live Indices calculated on a per Utter basis: Mean Incidence of fetal mortality (X) Mean Incidence of fetal viability (X) Mean percent males (X) Live fetuses Mean body weight (g)b Males - unadjusted mean - covariance adjusted mean Females - unadjusted mean - covariance adjusted mean Group: Dose Level (mg/kg): 1 0 0.0 12.5 7..39 92..61 53..26 3.39 3.39 3.18 3.18 2 1 0.0 13.3 7.46 92.55 49.54 3.27 3.27 3.15 3.15 3 10 0.0 12.8 10..85 89..15 51 ,.24 3.21 3.21 3.05 3.05 4 30 0.0 13.0 7,.66 92 .35 51 .20 2.95 2.95S 2.80 2.80S Sex, percent males, and mean body weight data Include values for live fetuses only. b Statistical analysis performed on covariance adjusted means. Table 8 Summary of External Findings Rat Teratology Study of T-3352 154-161 Number of fetuses examined Number of fetuses within normal limits Number of fetuses with variants Number of fetuses with anomalies Number and type of variants Trunk - short Tall - underdeveloped Number and type of anomalies Palate - cleft Tail - undeveloped - no tail Group: Dose Level (mg/kg): 1 0 2 34 1 10 30 289 320 306 272 288 320 304 271 0 0 11 1 0 20 0 011 1 la 1 0 20 1 la 1 a Finding confirmed at skeletal evaluation. r-\e3* Table 9 Summary of Visceral Findings Rat Teratology Study of T-3352 Group: Dose Level (mg/kg): 1 0 23 1 10 Number of fetuses examined Number of fetuses within normal limits Number of fetuses with variants Number of fetuses with anomalies 104 116 112 89 106 107 14 10 3 20 2 Number and type of variants Brain - left ventricle dilated - dark material around brain Liver - dark areas on lobe - all lobes appeared dark - dark area 1n U v e r K1dney(s) - dilated renal pelvis Ureter(s) - distended Testes - small Skin - edema between skin and peritoneal wall 18 14 1 1 87 85 1 1 3 1 1 1 Number and type of anomalies K1dney(s) - fused Cryptorchlsm 20 2 1 21 154-161 4 30 98 96 2 0 2 1 1 0 Table 10 Summary of Skeletal Findings Rat Teratology Study of T-3352 Number of fetuses examined Number of fetuses within normal limits Number of fetuses with variants Number of fetuses with anomalies Group: Dose Level (mg/kg): Number and type of variants Lagging ossification Skull - Incomplete closure (<75%) - Interparietal ossification Incomplete - parletals ossification Irregular - supraocdpltal ossification Incomplete - supraocdpltal nonfused - hyoid ossification 1ncomplete/nonoss1fled R1b cage - sternebrae bipartite - sternebrae <3 ossified - ribs >13 pairs ossified - ribs <13 pairs ossified - ribs ossification Irregular Vertebral column - thoracic centra ossification Incomplete - thoracic centra nonfused - lumbar ossification 1ncomplete/nonoss1fled - lumbar arches fused - caudals <3 ossified - caudal vertebrae nonosslfled - sacral vertebrae nonosslfled Pelvic girdle - pubis ossification 1ncomplete/nonoss1fled - Ischium ossification Incomplete HlndUmbs - <4 ossified Bone alignment Ribs - fused - forked - malallgned thoracic centra and arches - angulated Sternebrae - checkered Vertebrae malallgned - thoracic 1 0 185 94 91 0 171 4 36 3 23 1 41 2 1 1 1 36 7 1 1 5 1 1 4 3 1 154-161 2 1 204 115 89 0 153 6 31 5 15 34 7 1 4 24 11 8 5 1 3 10 194 103 91 0 152 9 49 6 16 19 5 2 28 11 6 11 1 4 30 174 76 98 0 195 5 33 4 20 13 28 2 19 1 31 6 1 17 2 2 3 1 1 1 2 2 1 I rCTo> Table 11 Incidence of External Findings Per Litter Rat Teratology Study of T-3352 Number of litters examined Number of Utters within normal limits Number and percent of Utters with variants Number and percent of Utters with anomalies Number and percent with variants Trunk - short Tall - underdeveloped Number and type with anomalies Palate - cleft Tall - undeveloped - no tall Group: Dose Level (mg/kg): 1 0 23 22 0/0.00 1/4.35 1/4.35a 2 1 24 24 0/0.00 0/0.00 3 10 24 22 1/4.17 2/8.33 1/4.17 1/4.17 1/4.17 4 30 21 20 1/4.76 0/0.00 1/4.763 a Finding confirmed at skeletal evaluation. Table 12 Incidence of Visceral Findings Per Utter Rat Teratology Study of T-3352 154-161 Group: Dose Level (mg/kg): 1 0 Number of Utters examined Number of Utters within normal limits Number and percent of Utters with variants Number and percent of Utters with anomalies 23 12 10/43.48 2/8.70 Number and percent with variants Brain - left ventricle dilated - dark material around brain Liver - dark areas on lobe - all lobes appeared dark - dark area 1n U v er K1dney(s) - dilated renal pelvis Ureter(s) - distended Testes - small Skin - edema between skin and peritoneal wall 4/17.39 7/30.43 1/4.35 1/4.35 Number and percent with anomalies K1dney(s) - fused Cryptorchlsm 2/8.70 2 1 24 18 6/25.00 0/0.00 1/4.17 1/4.17 5/20.83 4/16.67 3 10 24 20 2/8.33 2/8.33 1/4.17 1/4.17 1/4.17 1/4.17 1/4.17 4 30 21 19 2/9.52 0/0.00 1/4.76 1/4.76 I ro CD Table 13 Incidence of Skeletal Findings Per Litter Rat Teratology Study of T-3352 154-161 Group : Dose Level (mg/kg) : 1 0 234 1 10 30 Number of Utters examined Number of Utters within normal limits Number and percent of Utters with variants Number and percent of Utters with anomalies 23 1 22/95.65 0/0.00 24 2 22/91.67 0/0.00 24 4 20/83.33 0/0.00 21 1 20/95.24 0/0.00 Number and percent with variants Lagging ossification Skull - Incomplete closure (<75%) - Interparietal ossification Incomplete - parletals ossification Irregular - supraocdpltal ossification Incomplete - supraocdpltal nonfused - hyoid ossification 1ncomplete/nonoss1fled R1b cage - sternebrae bipartite - sternebrae <3 ossified - ribs >13 pairs ossified - ribs <13 pairs ossified - ribs ossification Irregular Vertebral column - thoracic centra ossification Incomplete - thoracic centra nonfused - lumbar ossification 1ncomplete/nonoss1fled - lumbar arches fused - caudals <3 ossified - caudal vertebrae nonosslfled - sacral vertebrae nonosslfled Pelvic girdle - pubis ossification 1ncomplete/nonoss1fled - Ischium ossification Incomplete H1ndl1mbs - <4 ossified Bone alignment Ribs - fused - forked - malallgned thoracic centra and arches - angulated Sternebrae - checkered Vertebrae malallgned - thoracic 4/17.39 16/69.57 2/8.70 11/47.83 1/4.35 17/73.91 1/4.35 1/4.35 1/4.35 1/4.35 16/69.57 7/30.43 1/4.35 1/4.35 5/21.74 1/4.35 1/4.35 3/13.04 2/8.70 1/4.35 3/12.50 12/50.00 3/12.50 7/29.17 14/58.33 2/8.33 1/4.17 2/8.33 13/54.17 7/29.17 5/20.83 5/20.83 1/4.17 1/4.17 6/25.00 15/62.50 5/20.83 7/29.17 9/37.50 4/16.67 2/8.33 14/58.33 7/29.17 4/16.67 1/4.17 1/4.17 4/19.05 13/61.90 2/9.52 9/42.86 8/38.10 8/38.10 2/9.52 9/42.86 1/4.76 13/61 .90 6/28.57 1/4.76 10/47.62 2/9.52 2/9.52 3/14.29 1/4.76 1/4.76 1/4.76 1/4.17 2/9.52 1/4.76 Table 14 Mean Incidence of External, Visceral, and Skeletal Findings Per U t t e r Rat Teratology Study of T-3352 Group: Dose Level (mg/kg): 1 0 Mean values calculated on a per Utter basis: Number with variants Number with anomalies Incidence of variants (X) Incidence of anomalies (X) External 0.0 0.0 0.0 0.9 Mean values calculated on a per Utter basis: Number with variants Number with anomalies Incidence of variants (X) Incidence of anomalies (X) Visceral 0.6 0.1 13.3 2.0 Skeletal Mean values calculated on a per Utter basis: Number with variants Number with anomalies Incidence of variants (X) Incidence of anomalies (X) 4.0 0.0 47.5 0.0 2 1 0.0 0.0 0.0 0.0 0.4 0.0 8.9 0.0 3.7 0.0 44.9 0.0 3 10 0.0 0.1 0.4 2.1 0.1 0.1 2.1 1.9 3.8 0.0 45.4 0.0 4 30 0.0 0.0 0.3 0.0 0.1 0.0 1.9 0.0 4.7 0.0 54.3 0.0 31 - Appendix 1 Individual Clinical Signs3 Rat Teratology Study of T--3352 154-161 Maternal Number 27134 27136 27141 27152 27160 27172 27178 27179 27190 27201 27202 27205 27208 2721 1 27212 27213 2721 5 27221 27224 27225 27228 Group 1 1 1 1 2 2 2 2 3 3 3 4 4 4 4 4 4 4 4 4 4 Observation Alopecia Alopecia Alopecia Alopecia Alopecia Alopecia Alopecia Alopecia Alopecia Soft feces Alopecia Alopecia Alopecia Alopecia Alopecia Alopecia Alopecia Alopecia Alopecia Alopecia Alopecia Thin Soft feces Hunched Thin Anorexia Alopecia Rough haircoat Alopecia Alopecia Alopecia Alopecia Alopecia Hunched Thin Languid Alopecia Hunched Thin Hunched Bodv Area Abdomen Leg-fore-right Abdomen Legs-hind-both Leg-hind-left Legs-fore-both Leg-fore-left Legs-fore-both Paws-fore-both Paw-fore-right Paws-fore-both Paw-fore-left Paws-fore-both Leg-hind-left Leg-fore-left Paw-fore-left Abdomen Hips-both Hip-right Leg-hind-right Paw-fore-left Abdomen Abdomen Abdomen Chest Hips-both Paws-fore-both Qay(s) 17-20 16-20 9-20 13-15, 20 8-12, 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 3 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. k Invalid food consumption value not included in mean calculations. c Gravid uterine weight inadvertently not recorded. Maternal Humber 27130 27131 27132 27133 27134 27135 27136 27137 27138 27139 27140 27141 27142 27143 27144 27145 27146 27147 27148 27149 27150 27151 21152 27153 27154 N Mean S.O. Disposition P, 20-C HP. 20-C P. 20-C P. 20-C P. 20-C HP. 20-C P. 20-C P. 20-C P. 20-C P. 20 C P. 20-C P. 20 C P. 20-C P, 20-C P. 20-C P, 20-C P. 20 C P. 20-C P, 20 C P. 20-C P. 20-C P. 20-C P, 20-C P. 20-C P. 20-C Appendix 2 Individual and Mean Maternal Body Weights and Body Weight Changes" Rat Teratology Study of T-3352 Group 1 - 0 mg/kg 154-161 0 226.9 (246.5) 236.9 216.7 217.0 (221.4) 212.5 225.6 261.2 238.2 226.7 215.3 228.3 228.2 206.6 250.4 269.3 220.4 236.4 223.5 224.6 242.0 217.0 257.4 224.5 Body Weight (gl Pay of 6estatlon 6 8 12 246.4 (278.6) 254.7 246.4 254.8 (260.3) 241.4 248.6 300.5 274.6 263.3 245.4 248.9 260.1 238.6 289.3 294.4 247.1 268.5 254.6 259.3 284.0 234.6 287.6 258.3 248.1 (278.8) 258.8 253.8 260.2 (262.4) 247.5 251.5 298.4 276.0 265.6 248.1 248.2 264.9 237.4 296.0 297.9 255.1 277.0 257.2 260.0 291.8 241.0 293.0 262.4 269.7 (276.3) 278.8 274.7 286.8 (249.3) 268.5 271.0 322.9 300.6 275.3 264.8 271.3 279.6 262.8 318.3 311.2 278.2 295.9 278.0 273.9 297.2 250.1 297.3 278.0 16 283.7 (271.8) 299.8 297.9 304.8 (252.3) 291.8 297.2 341.3 327.5 290.4 291.9 302.9 284.8 286.9 349.6 336.4 303.1 331.6 313.1 298.8 336.5 280.3 342.4 307.7 20 340.6 (282.1) 368.0 363.5 375.2 (258.6) 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 23 230.77 16.219 23 260.93 18.872 23 264.78 19.049 23 282.82 18.256 23 308.71 21.529 23 365.16 25.625 0-6 17.5 (32.1) 17.8 29.7 37.8 (38.9) 28.9 23.0 39.3 36.4 36.6 30.1 20.6 31.9 32.0 38.9 25.1 26.7 32.1 31.1 34.7 42.0 17.6 30.2 33.8 23 30.17 7.188 6-8 1.7 (0.2) 4.1 7.4 5.4 (21) 6.1 2.9 -2.1 1.4 2.3 2.7 -0.7 4.8 -1.2 6.7 3.5 8.0 8.5 2.6 0.7 7.8 6.4 5.4 4.1 23 3.85 3.023 Body Weight Change (q) ________ Days__________ 6-12 6-16' 6-20 23.3 (23) 24.1 28.3 32.0 (11.0) 27.1 22.4 22.4 26.0 12.0 19.4 22.4 19.5 24.2 29.0 16.8 31.1 27.4 23.4 14.6 13.2 15.5 9.7 19.7 37.3 (-6.8) 45.1 51.5 50.0 (-8.0) 50.4 48.6 40.8 52.9 27.1 46.5 54.0 24.7 48.3 60.3 42.0 56.0 63.1 58.5 39.5 52.5 45.7 54.8 49.4 94.2 (3.5) 113.3 117.1 120.4 (1.7) 108.9 103.9 112.7 129.9 88.0 99.1 108.3 56.8 102.3 118.5 94.3 97.7 117.6 126.0 101 .0 95.3 91.4 102.1 98.4 23 21.89 6.131 23 47.78 9.472 23 104.23 15.393 16-20 56.9 (10.3) 68.2 65.6 70.4 (6.3) 58.5 55.3 71.9 77.0 60.9 52.6 54.3 32.1 54.0 58.2 52.3 41.7 54.5 67.5 61.5 42.8 45.7 47.3 49.0 23 56.44 10.770 0-20 111.7 (35.6) 131.1 146.8 158.2 (37.2) 137.8 126.9 152.0 166.3 124.6 129.2 128.9 88.7 134.3 157.4 119.4 124.4 149.7 157.1 135.7 137.3 109.0 132.3 132.2 23 134.39 18.029 Maternal Number 27155 27156 27157 27150 27159 27160 27161 27162 27163 27164 2)165 2)166 27167 27160 2)169 27170 27171 27172 27173 27174 27175 27176 2)177 27170 27179 N Mean S.O. Disposition P. 20-C P. 20-C P, 20-C NP, 20-C P. 20-C P. 20-C P. 20-C P. 20-C P, 20-C P. 20-C P. 20-C P, 20-C P, 20-C P, 20-C P, 20-C P, 20-C P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P, 20-C P, 20 C P. 20-C P, 20-C Appendix 2 - Continued Individual and Mean Maternal body Weights and Body Weight Changes8 Rat Teratology Study of 1-3352 Group 2 - 1 mg/kg 154-161 body Weight (q) Day of Gestation 0 6 8 12 16 20 220.7 232.6 235.3 (205.1) 204.5 224.7 226.6 229.4 230.4 203.0 223.0 245.2 219.6 225.5 247.2 262.6 249.7 221.5 226.0 215.3 219.2 216.2 246.9 254.7 226.7 254.9 265.8 262.9 (237.0) 244.5 262.9 252.2 260.4 270.9 236.2 254.5 272.0 253.7 255.8 271.2 293.7 270.9 246.2 253.4 245.0 252.2 250.4 270.3 263.2 247.3 258.6 270.6 269.4 (245.2) 239.6 269.8 258.9 266.5 271.2 235.3 259.2 273.1 258.4 251.5 273.6 291.0 209.1 250.2 254.4 255.1 256.6 250.4 277.7 297.1 252.6 280.7 300.3 288.4 (250.6) 259.4 287.0 277.4 289.4 283.6 255.5 280.1 291.5 279.5 269.8 295.4 312.9 305.1 271.0 275.0 275.6 266.6 272.5 297.1 314.8 271.2 305.1 325.9 304.5 (250.8) 284.9 308.6 301.5 312.7 327.0 279.8 300.9 315.9 318.4 301.2 320.9 338.9 337.5 301.9 296.9 307.7 287.9 298.4 326.6 354.1 307.2 360.2 389.3 352.5 (269.0) 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 24 230.15 15.038 24 259.94 13.721 24 263.75 15.304 24 283.36 15.476 24 311.02 17.772 24 360.01 21.094 0-6 26.2 33.2 27.6 (32.7) 40.0 38.2 25.6 31.0 32.5 33.2 30.7 26.8 34.1 30.3 24.0 31.1 29.2 24.7 27.4 29.7 33.0 34.2 23.4 28.5 20.6 24 29.80 4.638 6-8 3.7 4.8 6.5 (7.4) -4.7 6.9 6.7 6.1 0.3 -0.9 4.7 1.1 4.7 -4.3 2.3 -2.7 10.2 4.0 1.0 10.1 4.4 0.0 7.4 13.9 5.3 24 3.81 4.550 Oodv Weight Change (ql ________ Days__________ 6-12 6-16f 6-20 25.0 34.5 25.5 (120) 14.9 24.1 25.2 29.0 12.7 19.3 25.6 19.5 25.0 14.0 24.2 19.2 26.2 25.6 21.6 30.6 14.4 22.1 26.6 31.6 23.9 50.2 60.1 41 .6 (13.0) 40.4 45.7 49.3 52.3 56.1 43.6 46.4 43.9 64.7 45.4 49.7 45.2 50.6 55.7 43.5 62.7 35.7 40.0 56.3 70.9 59.9 105.3 123.5 09.6 (31.2) 102.5 103.5 113.6 120.0 116.5 102.4 107.8 97.9 119.3 100.3 120.5 93.4 115.8 105.8 108.5 112.6 63.8 109.9 98.8 135.7 126.8 24 23.42 5.649 24 51.08 8.705 24 108.08 14.482 16-20 55.1 63.4 48.0 (18.2) 62.1 57.8 64.3 67.7 60.4 58.8 61.4 54.0 54.6 54.9 70.8 48.2 57.2 50.1 65.0 49.9 20.1 61.9 42.5 64.8 66.9 0-20 131.5 156.7 117.2 (63.9) 142.5 121.7 139.2 151.0 149.0 135.6 130.5 124.7 153.4 130.6 144.5 124.3 145.0 130.5 135.9 142.3 96.0 144.1 122.2 164.2 147.4 24 57.00 9.398 24 137.03 14.702 I Co I u, , 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 2 7203 27204 N Mean S.D. Disposition P, 20-C P, 20-C P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P, 20-C P. 20-C P, 20-C P. 20-C P. 20-C P. 20-C NP. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P, 20-C P. 20-C P. 20-C P, 20-C P. 20-C Appendix 2 - Continued Individual and Mean Maternal Body Weights and Body Weight Changes* Rat Teratology Study of T-3352 Group 3 - 1 0 mg/kg ------------------Body Weight (g) _______ ;__________Day of Gestation 0 6 8 12 16 20 249.1 224.5 214.0 242.5 226.8 241.4 227.0 234.5 234.8 271.6 227.5 241.8 210.4 218.6 (238.7) 267.7 260.6 239.7 202.5 228.8 242.1 263.2 257.0 244.2 256.7 275.8 261.2 251.6 274.3 258.7 281.3 262.2 268.9 257.6 305.1 247.1 265.4 235.8 250.1 (254.8) 288.2 298.2 265.7 232.3 257.2 275.4 290.2 284.4 272.9 295.0 278.9 269.3 265.2 277.9 260.3 283.3 265.9 276.3 266.2 308.1 243.9 265.4 233.3 251.0 (252.8) 296.4 307.4 263.6 237.5 255.2 281.6 295.2 283.4 280.1 302.1 294.4 292.2 277.9 294.5 276.3 300.1 282.4 289.0 279.2 330.9 257.5 281.9 237.1 267.5 (256.9) 305.3 328.1 279.5 246.0 268.3 286.5 313.3 298.7 294.7 307.9 312.5 309.9 297.0 317.8 295.1 329.5 282.7 310.1 309.5 357.0 274.9 300.8 266.6 285.9 (253.9) 325.7 344.0 310.0 281 .9 285.7 322.5 338.5 333.9 329.9 338.0 365.7 373.6 353.7 372.6 358.3 388.9 334.9 372.5 362.9 414.2 332.3 355.0 322.8 341.3 (255.2) 376.5 405.9 370.1 336.1 345.4 386.6 398.0 399.6 390.3 357.9 24 238.63 18.304 24 268.94 18.955 24 272.81 20.507 24 287.05 22.576 24 310.81 23.830 24 367.30 24.797 0-6 26.7 36.7 37.6 31.8 31.9 39.9 35.2 34.4 22.8 33.5 19.6 23.6 25.4 31.5 (16.1) 20.5 37.6 26.0 29.8 28.4 33.3 27.0 27.4 28.7 38.3 24 30.32 5.759 68 3.1 8.1 13.6 3.6 1 .6 2.0 3.7 7.4 8.6 3.0 -3.2 0.0 -2.5 0.9 (-2.0) 8.2 9.2 -2.1 5.2 -2.0 6.2 5.0 -1.0 7.2 7.1 24 3.87 4.388 Body Weight Change (gl Days 6-12 6-16f 6-20 18.6 31 .0 26.3 20.2 17.6 18.8 20.2 20.1 21.6 25.8 10.4 16.5 1.3 17.4 (2-1) 17.1 29.9 13.8 13.7 11 .1 11.1 23.1 14.3 21.8 12.9 36.7 48.7 45.4 43.5 36.4 48.2 20.5 41.2 51.9 51.9 27.8 35.4 30.8 35.8 (0.9) 37.5 45.8 44.3 49.6 28.5 47.1 48.3 49.5 57.0 43.0 89.9 112.4 102.1 98.3 99.6 107.6 72.7 103.6 105.3 109.1 85.2 89.6 87.0 91.2 (0.4) 88.3 107.7 104.4 103.8 88.2 111.2 107.8 115.2 117.4 62.9 24 18.11 6.659 24 41.87 8.974 24 98.35 13.456 16-20 53.2 63.7 56.7 54.8 63.2 59.4 52.2 62.4 53.4 57.2 57.4 54.2 56.2 55.4 (13) 50.8 61.9 60.1 54.2 59.7 64.1 59.5 65.7 60.4 19.9 24 56.49 8.812 0-20 116.6 149.1 139.7 130.1 131.5 147.5 107.9 138.0 128.1 142.6 104.8 113.2 112.4 122.7 (16.5) 108.8 145.3 130.4 133.6 116.6 144.5 134.8 142.6 146.1 101.2 24 128.67 15.118 Maternal Number 2J205 27206 27207 27208 27209 27210 2721 1 2721 2 2721 3 2721 4 2721 5 2721 6 2721 7 2721 8 27219 27220 27221 27222 27223 27224 27225 27226 27227 27228 27229 N Mean S.D. Disposition P, 20-C P. 20-C P, 20-C NP, 20-C P. 20-C P. 20-C P. 20-C NP, 20-C P. 20-C NP. 20-C P, 20-C P, 20-C P, 20-C P, 20-C P. 20-C P, 20-C P, 20-C P, 20-C P. 20-C P, 20-C NP, 20-C P. 20-C P, 20-C P, 20-C P, 20-C Appendix 2 - Continued Individual and Mean Maternal Body Weights and Body Weight Changes8 Rat Teratology Study of T -3352 Group 4 - 3 0 mg/kg Body Weiqht (a) Day of Gestation 0 6 8 12 16 20 219.4 239.5 209.2 (217.4) 222.8 249.6 227.0 (260.9) 244.3 (219.8) 259.0 226.5 247.3 225.4 237.3 243.2 209.3 232.5 218.8 257.8 (229.0) 258.4 231.6 250.9 274.4 244.2 269.7 242.3 (231.3) 244.4 2B2.2 269.7 (312.6) 289.3 (255.4) 290.1 267.3 283.7 255.4 266.7 269.7 235.6 272.1 252.0 281.6 (262.2) 289.5 260.0 274.7 300.3 240.6 264.4 244.9 (233.9) 230.5 288.5 263.7 (300.3) 289.8 (256.2) 287.4 258.4 286.4 243.8 263.4 272.5 235.4 270.0 251.2 269.4 (242.0) 292.7 258.2 265.1 295.7 244.6 246.2 260.1 (229.9) 255.8 294.4 245.7 (272.0) 288.0 (259.0) 285.9 264.9 302.3 254.9 274.7 291.0 231 .3 263.6 244.4 230.7 (235.2) 301.0 265.1 266.0 304.2 263.6 254.8 278.9 (224.0) 278.3 306.1 269.0 (236.8) 317.4 (248.1) 308.0 280.1 325.8 281.3 287.4 312.8 253.0 274.4 258.8 295.9 (197.7) 329.7 291.5 262.5 317.1 316.7 330.3 344.1 (237.8) 349.4 364.3 312.6 (272.5) 379.3 (270.3) 362.7 341.7 386.5 343.5 336.3 364.6 297.6 300.2 309.8 374.0 (234.2) 386.3 346.8 326.1 372.9 21 237.34 17.470 21 268.60 17.970 21 265.33 19.666 21 267.37 23.236 21 287.92 24.033 21 345.03 27.680 0-6 24.8 30.2 33.1 (13.9) 21.6 32.6 42.7 (31.7) 45.0 (35.6) 31.1 40.8 36.4 30.0 29.4 26.5 26.3 39.6 33.2 23.8 (33.2) 31.1 28.4 23.8 25.9 21 31.25 6.528 Body Weight Change (q> ________ Days___________ 6-8 6-12 6-16f 6-20 16t20 -3.6 -0.3 2.6 (26) -13.9 6.3 -6.0 (-12-3) 0.5 (0.8) -2.7 -8.9 2.7 -11.6 -3.3 2.8 -0.2 -2.1 -0.8 -12.2 (-20.2) 3.2 -1.8 -9.6 -4.6 0.4 -23.5 17.8 (-14) 11.4 12.2 -24.0 (-40.6) -1.3 (3.6) -4.2 -2.4 18.6 -0.5 8.0 21.3 -4.3 -8.5 -7.6 -50.9 (-27.0) 11.5 5.1 -8.7 3.9 19.4 -14.9 36.6 (1.3) 33.9 23.9 -0.7 (-75.8) 28.1 (-7.3) 17.9 12.8 42.1 25.9 20.7 43.1 17.4 2.3 6.8 14.3 (-64.5) 40.2 31.5 -12.2 16.8 72.5 60.6 101 .8 (6.5) 105.0 82.1 42.9 (-40.1) 90.0 (H.9) 72.6 74.4 102.8 88.1 69.6 94.9 62.0 28.1 57.8 92.4 (-28.0) 96.8 86.8 51 .4 72.6 53.1 75.5 65.2 (13.8) 71.1 58.2 43.6 (35.7) 61.9 (22.2) 54.7 61 .6 60.7 62.2 48.9 51.8 44.6 25.8 51.0 78.1 (36.5) 56.6 55.3 63.6 55.8 21 -3.023- 5.589 21 -1.22 16.688 21 I9 .3 3 S- 16.454 21 76.44 20.754 21 57.11 11.499 0-20 97.3 90.8 134.9 (20.4) 126.6 114.7 85.6 (-8.4) 135.0 (50.5) 103.7 115.2 139.2 118.1 99.0 121.4 88.3 67.7 91.0 116.2 (5.2) 127.9 115.2 75.2 98.5 21 107.69S 20.177 i cun> i 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. 37 - 0-6 113.6 (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 23 131.76 17.761 Appendix 3 Individual and Mean Food Consumption3 Rat Teratology Study of T-3352 Group 1 - 0 mg/kg Food Consumption (q) Interval (Days of Gestation! 9-12 13-16 17-20 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 111113..76 106.3 100.9 101 .8 94.2 99.8 94.1 92.9 117.4 117.1 99.1 104.8 103.8 121 .1 105.7 23 37.98 4.988 23 78.93 10.880 23 84.49 8.071 23 104.56 9.290 179.8 (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 23 201.40 20.254 154-161 0-20F 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 23 437.72 38.302 38 - 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. 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 24 129.11 7.957 Appendix 3 - Continued Individual and Mean Food Consumption3 Rat Teratology Study of T-3352 Group 2 - 1 mg/kg ____________ Food Consumption fq) Interval (Days of Gestation) 7-8F 9-12 13-16 17-20 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 (161.3) 78.3 80.7 79.7 78.8 93.9 72.8 84.1 si.1 h (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 7-166 205.6 222.6 185.9 (272.3) 198.4 199.9 186.1 193.3 194.0 167.6 206.9 191.5 (269.4) 192.3 222.9 207.1 219.5 213.3 194.0 213.5 223.3 187.5 201 .8 226.6 208.6 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 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. 39 - 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 Consumption3 Rat Teratology Study of T-3352 Group 3 - 1 0 mg/kg 154-161 7-8f Food Consumption (q) Interval (Pays of Gestation! 9-12 13-16 17-20 7-16 0-20F 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 (103.0) 76.0 94.9 78.2 67.8 66.5 66.5 75.4 (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 (63.6) (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 (200.1) (263.5) 223.4 187.2 175.6 165.5 172.8 !92.2 (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 (384.8)J (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 - 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.O. 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) 148.7 132.3 123.3 (-r 20 130.34 14.541 Appendix 3 - Continued Individual and Mean Food Consumption2 Rat Teratology Study of T-3352 Group 4 - 3 0 mg/kg 7-6F Food Consumption (q) Interval (Days of Gestation) 9-12 13-16 17-20 7-76E 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 (106.6) (34.1) 80.5 (57.7) 68.4 60.5 81 .0 60.8 65.4 85.4 (81.5)b 85.0 (72.2) (220.0) (48.3) 79.6 (75.7)b 44.2 73.1 58.7 50.1 76.6 (52.2). (86.4) 74.7 (80.9) (2-2) (99.5) (58.4) 73.9 56.9 87.9 (84.1) 68.8 86.1 (72.6) (237.1) (73.7) (128.4) (3.7) 81 .0 72.8 32.8 69.5 83.0 97.3 95.2 (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 (121.4) 88.4 114.8 (62.2) 100.7 97.2 91.4 95.4 140.2 167.9 187.3 (146.9) (165.4) 197.5 (222.8) (55.5) (244.7) (148.1) 174.6 144.9 208.2 (173.4) 163.7 212.1 (182.2) (372.0) (183.5) (404.8) (79.4) 205.1 (184.1)` 100.9 181 .3 21 36.60 10.755 16 71.21 13.023 13 68.45 15.381 20 96.47^ 8.931 12 < 173.64' 32.816 cr cr ex x t 41 154-161 Appendix 4 Individual and Mean Terminal Body Weights, Gravid Uterine Weights, and Terminal Body Weights Minus Gravid Uterine Weights (g)a Rat Teratology Study of T-3352 Group 1 - 0 mg/kg Maternal Number Terminal Bodv Weiqht Gravid Uterine Weiqht Terminal Body Weight Minus Gravid Uterine Weiqht 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 - 154-161 Appendix 4 - Continued Individual and Mean Terminal Body Weights, Gravid Uterine Weights, and Terminal Body Weights Minus Gravid Uterine Weights (g)a Rat Teratology Study of T-3352 Group 2 - 1 mg/kg Maternal Number Terminal Bodv Weiqht Gravid Uterine Weiqht Terminal Body Weight Minus Gravid Uterine Weiqht 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 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 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 86.8 292.7 321 .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 - 154-161 Appendix 4 - Continued Individual and Mean Terminal Body Weights, Gravid Uterine Weights, and Terminal Body Weights Minus Gravid Uterine Weights (g)a Rat Teratology Study of T-3352 Group 3 - 1 0 mg/kg 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 Bodv Weiqht 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 Weiqht 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 Weiqht 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 - 154-161 Appendix 4 - Continued Individual and Mean Terminal Body Weights, Gravid Uterine Weights, and Terminal Body Weights Minus Gravid Uterine Weights (g)a Rat Teratology Study of T-3352 Group 4 - 3 0 mg/kg Maternal Numhpr Terminal Bodv Weiqht Gravid Uterine Weiqht Terminal Body Weight Minus Gravid Uterine Weiqht 27205 27206 27207 27208 27209 27210 27211 27212 27213 27214 2721 5 27216 27217 27218 27219 27220 27221 27222 27223 27224 27225 27226 27227 27228 27229 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 64.8 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 .2 251.9 270.4 269.6 276.3 307.1 282.4 307.8 289.7 263.7 307.5 272.4 267.9 296.6 238.1 275.6 292.6 314.4 271 .9 259.0 291 .7 N Mean S.D. 21 345.03 27.679 20 66.47 15.015 20 280.33s" 20.353 Maternal Number 21130 21131 21132 21133 21134 21135 21136 21131 21138 21139 21140 21141 21142 21143 21144 21145 21146 21147 21148 21149 27150 27151 27152 27153 27154 Total N Mean S.D. Ovarian Corpora Lutea 14 Not Pregnant 20 16 15 Not Pregnant 15 13 17 17 10 16 (13) 14 14 17 16 13 18 19 21 17 13 24 15 354 22 16.1 3.08 Uterine Implantations 14 16 15 15 15 13 15 16 9 13 (H) 4 13 15 15 10 14 16 15 14 13 12 15 297 22 13.5 2.79 Appendix 5 Individual and Mean Ovarian and Uterine Data Rat Teratology Study of T-3352 Group 1 - 0 mg/kg Implantation Early Early Late Efficiency (XI Resorptions Resorptions (X) Resorptions 100.0 1 7.1 0 80.0 1 6.3 93.8 1 6.7 100.0 1 6.7 0 0 0 100.0 100.0 88.2 94.1 90.0 81.3 (107.7) 28.6 92.9 88.2 93.8 76.9 77.8 84.2 71.4 82.4 100.0 50.0 100.0 0 .2 0 0 2 2 (1) 0 1 0 1 1 1 0 0 2 2 1 1 0.0 15.4 0.0 0.0 22.2 15.4 (7.1) 0.0 7.7 0.0 6.7 10.0 7.1 0.0 0.0 14.3 15.4 8.3 6.7 0 0 0 0 0 0 (0) 0 0 0 0 0 0 0 0 0 0 0 0 22 85.16 17.525 20 22 0.9 0.75 22 7.09 6.365 0 22 0.0 - Late Resorptions (X) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 (0.0) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 22 0.00 - Total Resorptions 1 1 1 1 0 2 0 0 2 2 (1) 0 1 0 1 1 1 0 0 2 2 1 1 20 22 0.9 0.75 154-161 Total Resorptions (X) 7.1 6.3 6.7 6.7 0.0 15.4 0.0 0.0 22.2 15.4 (7.1) 0.0 7.7 0.0 6.7 10.0 7.1 0.0 0.0 14.3 15.4 6.3 6.7 22 7.09 6.365 a Invalid data excluded fron mean calculations. Appendix 5 - Continued Individual and Mean Ovarian and Uterine Data Rat Teratology Study of T-3352 Group 2 - 1 mg/kg 154-160 Maternal Number 27155 2)156 2)15) 27158 2)159 2)160 2)161 2)162 2)163 2)164 2)165 2)166 2)167 2)168 2)169 2)170 2)171 2)172 2)173 2)1)4 2)175 2)1)6 2)177 2)1)8 2)1)9 Total N Mean S.D. Ovarian Corpora Lutea 16 16 14 Not Pregnant 18 1) 16 19 1) 18 1) 15 16 15 14 15 21 12 16 14 11 1) 15 17 22 388 24 16.2 2.46 Uterine Implantations 16 14 13 18 14 14 1) 16 16 14 14 15 15 14 14 16 12 15 12 3 16 14 16 19 34) 24 14.5 2.96 Implantation Efficiency 1X1 100.0 87.5 92.9 100.0 82.4 8).5 89.5 94.1 88.9 82.4 93.3 93.8 100.0 100.0 93.3 76.2 100.0 93.8 85.7 27.3 94.1 93.3 94.1 86.4 24 89.02 14.566 Early Resorptions 2 1 4 1 1 0 2 0 3 0 1 1 3 0 4 0 0 0 0 0 0 1 0 3 2) 24 1.2 1.37 Early Resorptions (X) 12.5 7.1 30.8 5.6 7.1 0.0 11.8 0.0 18.8 0.0 7.1 6.7 20.0 0.0 28.6 0.0 0.0 0.0 0.0 0.0 0.0 7.1 0.0 15.8 24 7.46 9.344 Late Resorptions 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 24 0.0 - late Resorptions (X) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 24 0.00 - Total Resorptions 2 1 4 1 1 0 2 0 3 0 1 1 3 0 4 0 0 0 0 0 0 1 0 3 2) 24 1.2 1.37 Tota 1 Resorptions (XI 12.5 7.1 30.6 5.6 7.1 0.0 11.8 0.0 18.8 0.0 7.1 6.7 20.0 0.0 28.6 0.0 0.0 0.0 0.0 0.0 0.0 7.1 0.0 15.8 24 7.46 9.344 Appendix 5 - Continued Individual and Mean Ovarian and Uterine Oata Rat Teratology Study of T-3352 Group 3 - 1 0 mg/kg 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 Total N Mean S.O. Ovarian Corpora Lutea 19 11 19 15 14 15 14 15 15 18 14 18 13 15 Not Pregnant 15 17 16 15 14 16 16 20 15 15 374 24 15.6 2.06 Uterine Implantations 15 10 13 14 14 13 13 15 14 14 14 15 12 13 15 15 16 15 14 16 16 18 15 12 341 24 14.2 1.64 Implantation Efficiency (X) 78.9 90.9 68.4 93.3 100.0 86.7 92.9 100.0 93.3 77.8 100.0 83.3 92.3 86.7 100.0 88.2 100.0 100.0 100.0 100.0 100.0 90.0 100.0 80.0 24 91.78 9.014 Early Resorptions 3 1 0 1 1 0 3 2 1 0 0 1 1 2 1 2 1 0 2 0 0 1 0 9 32 24 1.3 1.88 Early Resorptions (XI 20.0 10.0 0.0 7.1 7.1 0.0 23.1 13.3 7.1 0.0 0.0 6.7 8.3 15.4 6.7 13.3 6.3 0.0 14.3 0.0 0.0 5.6 0.0 75.0 24 9.97 15.392 Late Resorptions 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 0 1 0 0 0 0 0 0 0 3 24 0.1 0.34 Late Resorntlnn* fll 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 7.1 0.0 0.0 7.7 0.0 0.0 6.3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 24 0.88 2.385 Total 3 1 0 1 1 0 3 2 1 0 1 1 1 3 i 2 2 0 2 0 0 1 0 9 35 24 1.5 1.89 154 1GO Tots 1 20 0 10.0 00 7i 7] 0.0 23.1 13.3 7i 0.0 77 6.7 0.3 23 1 67 13.3 17 S 00 14 3 no 0.0 5.6 00 75.0 24 10.85 15.429 Appendix 5 - Continued Individual and Mean Ovarian and Uterine Oata Rat Teratology Study of T-3352 Group 4 - 3 0 mg/kg Haternal Number 27205 27206 27207 27208 27209 27210 2721 1 2721 2 2721 3 2721 4 27215 27216 21217 2721 B 2721 9 27220 27221 27222 27223 27224 27225 2)226 2)227 27228 27229 lota 1 N Hean S.O. Ovarian Corpora lutea 14 17 15 Not Pregnant 16 15 14 Not Pregnant 16 Not Pregnant 14 16 17 15 16 17 15 18 16 21 Not Pregnant 18 17 15 18 340 21 16.2 1.69 Uterine Implantations 14 16 15 16 15 5 15 14 16 17 15 14 14 12 4 13 18 15 15 14 17 294 21 14.0 3.45 Implantation Efficiency (XI 100.0 94.1 100.0 100.0 100.0 35.7 93.8 100.0 100.0 100.0 100.0 87.5 82.4 80.0 22.2 81.3 85.7 83.3 88.2 93.3 94.4 21 86.76 20.606 Early Resorptions 1 2 0 1 4 1 1 1 1 2 1 0 1 0 0 3 1 1 0 0 0 21 21 1.0 1.05 Early Resorptions (X) 7.1 12.5 0.0 6.3 26.7 20.0 6.7 7.1 6.3 11.8 6.7 0.0 7.1 0.0 0.0 23.1 5.6 6.7 0.0 0.0 0.0 21 7.32 7.790 Late Resorptions 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 21 0.0 0.22 Late Resorptions (XI 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 7.1 0.0 21 0.34 1.549 Total Resorptions 1 2 0 1 4 1 1 1 1 2 1 0 1 0 0 3 1 1 0 1 0 22 21 1.0 1.02 Total Resorptions (X) 7.1 12.5 0.0 6.3 26.7 20.0 6.7 7.1 6.3 11 .8 6.7 0.0 7.1 0.0 0.0 23.1 5.6 6.7 0.0 7.1 0.0 21 7.66 7.608 Appendix 6 Individual and Mean Litter Data3 Rat Teratology Study of T-3352 Group 1 - 0 mg/kg Maternal Number Total Resorptions Dead Number of Fetuses Fetal Loss (X)b Live M v e (X) Sc Hales 27130 27131 27132 27133 27134 27135 27136 27137 Z713B 27139 27140 27141 27142** 27143 27144 27145 27146 27147 27148 27149 27150 27151 27152 27153 27154 1 Not Pregnant 1 1 1 Not Pregnant 0 2 0 0 2 2 (1) 0 1 0 1 1 1 0 0 2 2 1 1 0 7.1 0 6.3 0 6.7 0 6.7 0 0.0 0 15.4 0 0.0 0 0.0 0 22.2 0 15.4 (0 ) (7.1) 0 0.0 0 7.7 0 0.0 1 13.3 0 10.0 0 7.1 0 0.0 0 0.0 0 14.3 0 15.4 0 8.3 0 6.7 13 15 14 14 15 11 15 16 7 11 (13) 4 12 15 13 9 13 16 15 12 11 11 14 92.9 93.8 93.3 93.3 100.0 84.6 100.0 100.0 77.8 84.6 (92.9) 100.0 92.3 100.0 86.7 90.0 92.9 100.0 100.0 85.7 84.6 91.7 93.3 6 7 5 10 7 7 8 9 4 4 7 3 6 9 7 7 6 8 5 7 5 4 10 Total N Unadjusted Mean Unadjusted S.O. Covariance Adjusted Mean Covariance Adjusted S.D. 20 22 0.9 0.75 1 22 0.0 0.21 22 7.39 6.500 276 22 12.5 2.99 22 92.61 6.501 151 23 6.6 1.93 a Sex, percent males, and mean weight data Include values for live fetuses only. * Percent fetal loss Includes resorptions as well as dead fetuses. c Statistical analysis performed on covariance adjusted means. ** Invalid data excluded from mean calculations. 154-161 Females 7 B 9 4 8 4 7 7 3 7 6 1 6 6 6 2 7 8 10 5 6 7 4 138 23 6.0 2.20 Percent Hales 46.2 46.7 35.7 71.4 46.7 63.6 53.3 56.3 57.1 36.4 53.8 75.0 50.0 60.0 53.8 77.8 46.2 50.0 33.3 58.3 45.5 36.4 71.4 23 53.26 12.576 c Mean Weight (at Hales females 3.5 3.0 3.5 3.3 3.6 3.6 3.3 3.2 3.0 3.1 3.4 3.2 3.6 3.5 3.3 3.3 3.8 3.5 3.1 2.9 3.2 3.1 3.6 2.3 3.4 3.2 3.3 3.1 3.1 2.9 3.3 3.1 3.5 3.3 3.2 2.9 3.3 3.0 3.8 3.6 3.7 3.7 3.1 3.1 3.3 3.3 23 3.39 0.226 3.39 .005 23 3.18 0.301 3.18 .005 Appendix 6 - Continued Individual and Mean litter Oataa Rat Teratology Study of T-3352 Group 2 - 1 mg/kg 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 lota 1 N Unadjusted Mean Unadjusted S.O. Adjusted Mean Covariance Adjusted S.O. Total Resorptions 2 1 4 Not Pregnant 1 1 0 2 0 3 0 1 1 3 0 4 0 0 0 0 0 0 1 0 3 27 24 1.2 1.37 Dead 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 24 0.0 - Number of fetuses Fetal Loss m t > Live Live (%) 12.5 14 87.5 7.1 13 92.9 30.8 9 69.2 5.6 7.1 0.0 11.8 0.0 18.8 0.0 7.1 6.7 20.0 0.0 28.6 0.0 0.0 0.0 0.0 0.0 0.0 7.1 0.0 15.8 17 94.4 13 92.9 14 10 0.0 15 88 .2 16 10 0.0 13 81.3 14 10 0.0 13 92.9 14 93.3 12 80.0 14 10 0.0 10 71.4 16 10 0.0 12 10 0.0 15 10 0.0 12 10 0.0 3 100.0 16 10 0.0 13 92.9 16 10 0.0 16 84.2 24 7.46 9.344 320 24 13.3 2.94 24 92.55 9.338 Hales 6 7 6 7 7 7 8 10 6 8 5 8 6 5 2 8 9 5 5 2 9 4 9 8 157 24 6. 2. a Sex, percent males, and mean weight data Include values for live fetuses only. " Percent fetal loss Includes resorptions as well as dead fetuses. c Statistical analysis performed on covariance adjusted means. males 8 6 3 10 6 7 7 6 7 6 8 6 6 9 8 8 3 10 7 1 7 9 7 8 163 24 6.8 2.13 Percent Males 42.9 53.8 66.7 41.2 53.8 50.0 53.3 62.5 46.2 57.1 38.5 57.1 50.0 35.7 20.0 50.0 75.0 33.3 41.7 66.7 56.3 30.8 56.3 50.0 24 49.54 12.596 ISA-161 Mean Weight (alc Males Females 2.9 3.2 3.1 3.0 3.5 3.1 3.2 3.3 3.4 3.3 3.4 3.2 3.3 2.9 3.3 3.1 3.4 3.2 3.4 3.2 3.4 3.1 3.2 3.1 3.5 3.2 3.5 3.4 3.0 2.9 3.3 3.4 3.5 3.6 3.5 3.4 2.9 2.9 2.9 3.0 3.2 2.9 3.2 3.2 3.5 3.3 3.0 2 . 8 24 3.27 0.210 3.27 .005 24 3.15 0.198 3.15 .005 Appendix 6 - Continued Individual and Mean Litter Data9 Rat Teratology Study of T-3352 Group 3 - 1 0 mg/kg Maternal Number 21100 27181 27182 27183 27184 27185 27186 27187 27188 27189 27190 27191 27192 27193 27194 27195 27196 27197 27198 27199 21200 27201 27202 27203 27204 Total N Unadjusted Mean Unadjusted S.D. Covariance Adjusted Mean Covariance Adjusted S.D. Total Resorptions 3 1 0 1 1 0 3 2 1 0 1 1 1 3 Not Pregnant 1 2 2 0 2 0 0 1 0 9 35 24 1.5 1.89 Oead 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 24 0.1 - Number of Fetuses Fetal Loss live U v e (%) 20.0 10.0 0.0 1.1 7.1 0.0 23.1 13.3 7.1 0.0 7.1 6.7 8.3 23.1 12 80.0 9 90.0 13 10 0 .0 13 92.9 13 92.9 13 10 0 .0 10 76.9 13 86.7 13 92.9 14 10 0 .0 13 92.9 14 93.3 11 91 .7 10 76.9 6.7 13.3 12.5 0.0 14.3 0.0 0.0 5.6 0.0 75.0 14 93.3 13 86.7 14 87.5 15 1 0 0 . 0 12 85.7 16 10 0 . 0 16 10 0 . 0 17 94.4 15 10 0 . 0 3 25.0 24 10.85 15.429 306 24 1 2 .8 2 .83 24 89.15 15.429 Hales 6 7 9 6 9 8 5 6 8 10 5 5 8 5 4 4 8 a 6 5 8 6 4 2 152 24 6. 1. 9 Sex, percent males, and mean weight data Include values for live fetuses only, b Percent fetal loss Includes resoprtlons as well as dead fetuses. c Statistical analysis performed on covariance adjusted means. Females 6 2 4 7 4 5 5 7 5 4 8 9 3 5 10 9 6 7 6 11 8 11 11 1 154 24 6.4 2.81 Percent Hales 50.0 77.8 69.2 46.2 69.2 61 .5 50.0 46.2 61.5 71.4 38.5 35.7 72.7 50.0 28.6 30.8 57.1 53.3 50.0 31 .3 50.0 35.3 26.7 66.7 24 51.24 15.255 154-161 Hean Weight (g)c Hales Females 3.1 3.1 3.2 2.9 3.1 2.9 3.3 3.1 3.3 3.3 3.3 3.0 3.1 2.9 3.2 3.0 3.0 3.0 3.0 2.9 3.3 3.1 2.8 2.8 3.3 3.1 3.0 2.9 3.2 3.0 3.0 2.9 3.4 3.3 3.1 2.9 3.1 2 .8 3.2 3.0 3.5 3.3 3.5 3.2 3.2 3.1 3.9 3.8 24 3.21 0.221 3.21 .005 24 3.05 0.21 3.05 .005 Appendix 6 - Continued Individual and Mean Litter Oataa Rat Teratology Study of T-3352 Group 4 - 3 0 mg/kg Maternal Number 21205 27206 27207 27200 27209 27210 2721 1 27212 2 721 3 27214 2721 5 2 721 6 2721 7 2721 0 27219 27220 27221 27222 27223 27224 27225 27226 27227 27220 27229 Total N Unadjusted Hean Unadjusted S.O. Covariance Adjusted Hean Covariance Adjusted S.O. Total Resorptions 1 2 0 Not Pregnant 1 4 1 Not Pregnant 1 Not Pregnant 1 1 2 1 0 1 0 0 3 1 Not Pregnant 1 0 1 0 22 21 1.0 1.02 Dead 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 21 0.0 - Number of Fetuses Fetal loss (%)b live Live (?1) 7.1 12.5 0.0 13 92 .9 14 07 .5 15 100 0 6.3 26.7 20.0 15 93 8 11 73 3 4 00 .0 6.7 14 93 .3 7.1 6.3 11.0 6.7 0.0 7.1 0.0 0.0 23.1 5.6 13 92 .9 15 93 .8 15 80 .2 14 93 .3 14 100 .0 13 92 .9 12 100 .0 4 100 .0 10 76 .9 17 94 .4 6.7 14 93 .3 0 . 0 15 100 .0 7.1 13 92 .9 0 . 0 17 100 .0 21 7.66 7.600 272 21 13. 0 3. 41 21 92 .35 7 .610 Sex Hales Females 67 77 87 07 47 31 68 76 5 10 87 86 68 67 75 22 46 98 10 4 11 4 58 89 138 21 6 .6 2 .25 134 21 64 2.10 Sex, percent males, and mean weight data Include values for live fetuses only. b Percent fetal loss Includes resorptions as well as dead fetuses. c Statistical analysis performed on covariance adjusted means. Percent Hales 2 sn o 53.3 S3 3 36 4 75.0 42.9 SI B 33 3 S3 3 S7 ] 4? Q 46 2 SR 3 50.0 40.0 52.9 71 .4 73 3 38 5 47.1 21 Si 20 11.412 Hean Weight (g|c Hales Females 2.8 2.8 2.4 2.2 3.1 2.9 3.0 2.9 3.2 3.1 3.0 2.7 2.9 2.8 3.3 3.2 3.0 2.8 3.0 2.8 3.1 3.2 2.7 2.7 3.3 3.0 2.9 2.7 3.1 2.9 2.7 2.5 2.5 2.6 3.3 3.0 2 . 0 2.7 3.0 2.7 2.0 2.6 21 2.95 0.246 2.95s- .005 21 2.80 0.235 2.80s - .005 Appendix 7 Individual Visceral Findings In Fetuses Hat Teratology Study of T -3352 Group 1 - 0 mg/kg 154-161 Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses having one or more visceral variants Percent of fetuses having one or more visceral variants (X) Identification letter(s) of fetuses with: Brain - left ventrical dilated - dark material around brain liver - dark areas on lobe - all lobes appeared dark - dark area 1n liver Kldney(s) - dilated renal pelvis Ureter(s) - distended Testes - small Skin - edema between skin and peritoneal wall Number of fetuses having one or more visceral anomalies Percent of fetuses having one or more visceral anomalles(X) Identification letter(s) of fetuses with: Kldney(s) - fused Cryptorchlsm 22 77 11 33 01 5 5 0 0.00 NP 0 0.00 22 77 11 33 23 5 4 1 20.00 5a 3 2 40.00 22 77 11 33 45 5 5 0 0.00 NP DM H OH 000 0.00 0.00 0.00 2 2 2 2 2 22 7 77 7777 11111 11 333 3444 6 7B90 12 5456345 53552 45 0 10 1100 O.l 25.00 0 . 0 0 16.67 33.33 0 . 0 0 0 . 0 0 P0 PD H 0 0 0 00 0 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NP - Not Pregnant. d Fetus K was noted to have an undeveloped tall during external examination. This finding was confirmed at skeletal examination. Appendix 7 - Continued Individual Visceral Findings In Fetuses Rat Teratology Study of T-3352 Group 1 - 0 mg/kg 154-161 Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses having one or more visceral variants Percent of fetuses having one or more visceral variants (X) Identification letter(s) of fetuses with: Brain - left ventrical dilated - dark material around brain Liver - dark areas on lobe - all lobes appeared dark - dark area In liver K 1dney(s) - dilated renal pelvis Ureter(s) - distended Testes - small Skin - edema between skin and peritoneal wall Number of fetuses having one or more visceral anomalies Percent of fetuses having one or more visceral anomalles(X) Identification letter(s) of fetuses with: Kldney(s) - fused Cryptorchlsm 2 7 1 A 3 2 2 0 0.00 2 7 1 4 4 4 4 0 0.00 22 77 11 44 56 5 5 0 0.00 5 4 1 20.00 22 77 11 44 78 3 3 0 0.00 5 1 4 80.00 2 2 22 7 777 11 11 4 5 55 90 12 6 6 0 0.00 5 4 1 20.00 4 3 1 25.00 4 3 1 25.00 2 7 1 5 3 4 3 0 0.00 2 7 1 5 4 5 5 0 0.00 0 0.00 0 0.00 N 0 0.00 0 0.00 ADGN 01 0.00 20.00 AK 3 0 0.00 0 0.00 00 1 0.00 0.00 25.00 0 0.00 0B i ctn* i Appendix 7 - Continued Individual Visceral Findings In Fetuses Rat Teratology Study oF 1-3352 Group 2 - 1 mg/kg 154-161 Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses having one or more visceral variants Percent of fetuses having one or more visceral variants (X) Identification letter(s) of fetuses with: Brain - left ventrical dilated - dark material around brain Liver - dark areas on lobe - all lobes appeared dark - dark area In liver K 1dney(s) - dilated renal pelvis Ureter(s) - distended Testes - small Skin - edema between skin and peritoneal wall Number of fetuses having one or more visceral anomalies Percent of fetuses having one or more visceral anomalles(X) Identification letter(s) of fetuses with: Ktdney(s) - fused Cryptorchlsm 22 77 11 55 56 5 4 1 20.00 5 4 1 20.00 lN LN 0 0.00 0 0.00 22 77 11 55 78 3 3 0 0.00 NP 0 0.00 2 7 1 5 9 6 6 0 0.00 2 7 1 6 0 5 5 0 0.00 2 7 1 6 1 5 5 0 0.00 2 7 1 6 2 5 5 0 0.00 22 77 11 66 34 6 6 0 0.00 5 3 2 40.00 2 7 1 6 5 5 5 0 0.00 2 7 1 6 6 5 5 0 0.00 2 7 1 6 7 5 5 0 0.00 K GK 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 NP = Not Pregnant. Appendix 7 - Continued Individual Visceral Findings In Fetuses Rat teratology Study of T-3352 Group 2 - 1 mg/kg 154-161 Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses having one or more visceral variants Percent of fetuses having one or more visceral variants (X) Identification letter(s) of fetuses with: Brain - left ventrical dilated - dark material around brain Liver - dark areas on lobe - all lobes appeared dark - dark area 1n liver Kldney(s) - dilated renal pelvis Ureter(s) - distended Testes - small Skin - edema between skin and peritoneal wall Number of fetuses having one or more visceral anomalies Percent of fetuses having one or more visceral anomalles(X) Identification letter(s) of fetuses with: Kldney(s) - fused Cryptorchlsm 2 7 1 6 8 4 2 2 50.00 IL 1 0 0.00 2 7 1 6 9 5 5 0 0.00 0 0.00 2 7 1 7 0 4 4 0 0.00 0 0.00 2 7 1 7 1 6 6 0 0.00 0 0.00 2 7 1 7 2 4 4 0 0.00 22 77 11 77 34 5 5 0 0.00 4 2 2 50.00 22 77 11 77 56 1 1 0 0.00 6 4 2 33.33 2 7 1 7 7 5 5 0 0.00 A 3 G3 00 0.00 0.00 00 0.00 0.00 0 0.00 0 0.00 2 7 1 7 8 6 6 0 0.00 2 7 1 7 9 6 6 0 0.00 00 0.00 0.00 I in CTl I Appendix 7 - Continued Individual Visceral Findings In Fetuses Rat Teratology Study of T -3352 Group 3 - 1 0 mg/kg 154-161 Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses having one or more visceral variants Percent of fetuses having one or more visceral variants (X) Identification letter(s) of fetuses with: Brain - left ventrical dilated - dark material around brain Liver - dark areas on lobe - all lobes appeared dark - dark area In liver Kldney(s) - dilated renal pelvis Ureterfs) - distended Testes - small Skin - edema between skin and peritoneal wall Number of fetuses having one or more visceral anomalies Percent of fetuses having one or more visceral anomalles(X) Identification letter(s) of fetuses with: Kldney(s) - fused Cryptorchlsm 2 7 1 B 0 4 4 0 0.00 2 7 1 B 1 3 3 0 0.00 2 7 1 B 2 5 5 0 0.00 2 7 1 8 3 5 5 0 0.00 2 7 1 8 4 5 5 0 0.00 2 7 1 8 5 5 5 0 0.00 2 7 1 8 6 4 4 0 0.00 2 7 1 8 7 5 5 0 0.00 2 7 1 8 8 5 5 o 0.00 2 7 1 8 9 K o 0.00 2 7 1 9 0 o 0.00 2 7 1 9 i 0 0.00 2 7 1 9 2 n 0.00 0000000000100 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 20.00 0.00 0.00 K a Fetus N was noted to have a cleft palate during external examination. Appendix 7 - Continued Individual Visceral Findings 1n Fetuses Rat Teratology Study of T-3352 Group 3 - 1 0 mg/kg Maternal Number: Number of.fetuses examined Number of fetuses within normal limits Number of fetuses having one or more visceral variants Percent of fetuses having one or more visceral variants (X) Identification letter(s) of fetuses with: Brain - left ventrical dilated - dark material around brain Liver - dark areas on lobe - all lobes appeared dark - dark area 1n liver Kldney(s) - dilated renal pelvis Ureter(s) - distended Testes - small Skin - edema between skin and peritoneal wall Number of fetuses having one or more visceral anomalies Percent of fetuses having one or more visceral anomalles(X) Identification letter(s) of fetuses with: Kldney(s) - fused Cryptorchlsm 2 7 1 9 3 4 4 0 0.00 0 0.00 2222222222 7 1 7 1 7 1 7 1 7 1 7 2 7 2 7 2 7 2 7 2 9 5 99 67 99 89 0 0 000 123 0 4 5 5 5 5 4* 6 6 6 5 1 5 0 0.00 5 0 0.00 5 0 0.00 5 0 0.00 354 012 0.00 16.67 33.33 65 1 000 0.00 0.00 0.00 H P P 0 0 0 0 10 0 00 0 0.00 0.00 0.00 0.00 25.00 0.00 0.00 0.00 0.00 0.00 B NP Not Pregnant. a Fetus B was noted to have no tall and a short trunk during external examination. Appendix 7 - Continued Individual Visceral Findings In Fetuses Rat Teratology Study of T-3352 Group 4 30 mg/kg 154-161 Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses having one or more visceral variants Percent of fetuses having one or more visceral variants (X) Identification letter(s) of fetuses with: Brain - left ventrical dilated - dark material around brain Liver - dark areas on lobe - all lobes appeared dark - dark area In liver Kldney(s) - dilated renal pelvis Ureter(s) - distended Testes - small Skin - edema between skin and peritoneal wall Number of fetuses having one or more visceral anomalies Percent of fetuses having one or more visceral anomalles(X) Identification letter(s) of fetuses with: Kldney(s) - fused Cryptorchlsm 2 7 2 0 5 5 5 0 0.00 222 777 222 0 00 6 78 5 5 0 0.00 5 4 1 20.00 NP 000 0.00 0.00 0.00 NP = Not Pregnant. 2 7 2 0 9 5 5 0 0.00 2 7 2 1 0 4 4 0 0.00 22 77 22 11 12 2 2 0 0.00 NP 000 0.00 0 .0 0 0.00 22 77 22 11 34 5 5 0 0.00 NP 0 0.00 2 7 2 1 5 5 5 0 0.00 2 7 2 1 6 5 5 0 0.00 2 7 2 1 7 5 5 0 OJ 0 00 0.00 0.00 0.00 Appendix 7 - Continued Individual Visceral Findings In Fetuses Rat Teratology Study of T-3352 Group A - 30 mg/kg Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses having one or more visceral variants Percent of fetuses having one or more visceral variants (X) Identification letter(s) of fetuses with: Brain - left ventrical dilated - dark material around brain Liver - dark areas on lobe - all lobes appeared dark - dark area 1n liver Kldney(s) - dilated renal pelvis Ureter(s) - distended Testes - small Skin - edema between skin and peritoneal wall Number of fetuses having one or more visceral anomalies Percent of fetuses having one or more visceral anomal1es(X) Identification letter(s) of fetuses with: Kldney(s) - fused Cryptorchlsm 2 7 2 1 __ 6 5 5 0 0.00 0 0.00 2 7 2 1 9 5a 5 0 0.00 0 0.00 2 7 2 2 0 5 5 0 0.00 0 0.00 2 7 2 2 1 A A 0 0.00 0 0.00 2 7 2 2 2 2 2 0 0.00 0 0.00 2 7 2 2 3 A A 0 0.00 0 0.00 22 77 22 22 A5 6 6 0 0.00 NP 0 0.00 2 7 2 2 6 5 5 0 0.00 22 77 22 22 7B 5 5 0 0.00 5 A 1 20.00 2 7 2 2 9 6 6 0 0.00 N 0 0.00 0 0.00 0 0.00 0 0.00 NP * Not Pregnant. a Fetus L was noted to have an underdeveloped tall during external examination This finding was confirmed at skeletal examination. i c0ri 1 Appendix 8 Individual Skeletal Findings In Fetuses3 Rat Teratology Study of T-3352 Group 1 - 0 mg/kg 154-161 Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses having one or more skeletal variants Percent of fetuses having one or more skeletal variants (X) Identification letter(s) of fetuses with: tagging Ossification Skull - Incomplete closure (<75%) - Interparietal ossification Incomplete - parletals ossification irregular - supraoccIpltal ossification Incomplete - supraoccIpltal nonfused - hyoid ossification Incomplete/nonosslfled Rib cage - sternebrae bipartite - sternebrae <3 ossified - ribs >13 pairs ossified - ribs <13 pairs ossified - ribs ossification Irregular Vertebral column - thoracic centra ossification Incomplete - thoracic centra nonfused - lumbar ossification Incomplete/nonosslfled - lumbar arches fused - caudals <3 ossified - caudal vertebrae nonosslfled - sacral vertebrae nonosslfled Pelvic Girdle - pubis ossification Incomplete/ nonosslfled - Ischium ossification Incomplete Hlndltmbs - <4 ossified Bone Alignment Ribs - fused - forked - malallgned thoracic centra and arches - angulated Sternebrae - checkered Vertebrae malallgned - thoracic NP - Not Pregnant. a There were no skeletal anomalies noted In any fetuses. 22 77 11 33 01 8 2 6 75.00 NP 22 77 11 33 23 10 7 3 30.00 9 7 2 22.22 2 7 1 3 A 9 6 3 33.33 2 7 1 3 5 El u El I E BCGL IJl B H K K K K K 222 22 22 77777 77 1 l1 11 11 33 334 44 6 7B 90 12 10 1 9 90.00 7 6 1 14.29 10 6 4 40.00 10 7 3 30.00 4 2 2 50.00 7 3 4 57.14 8 2 6 75.00 I BE IKN0 I INO E EFMIKL NO ILO G 0 KO C 0 BN LO 0 KN 0 C 0 B CE IM CE IH EIM CEM CJ CEI B M EM El C El C Appendix 8 - Continued Individual Skeletal Findings In Fetuses* Rat Teratology Study of T-3352 Group 1 - 0 mg/kg Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses having one or more skeletal variants Percent of fetuses having one or more skeletal variants (X) Identification letter(s) of fetuses with: lagging Ossification Skull - Incomplete closure (<75%) - Interparietal ossification Incomplete - parletals ossification Irregular - supraocclpltal ossification Incomplete - supraocclpltal nonfused - hyoid ossification Incomplete/nonosslfled Rib cage - sternebrae bipartite - sternebrae <3 ossified - ribs >13 pairs ossified - ribs <13 pairs ossified - ribs ossification Irregular Vertebral column - thoracic centra ossification Incomplete - thoracic centra nonfused - lumbar ossification Incomplete/nonosslfled - lumbar arches fused - caudals <3 ossified - caudal vertebrae nonosslfled - sacral vertebrae nonosslfled Pelvic Girdle - pubis ossification Incomplete/ nonosslfled - Ischium ossification Incomplete Hlndllmbs - <4 ossified Bone Alignment Ribs - fused - forked - malallgned thoracic centra and arches - angulated Sternebrae - checkered Vertebrae malallgned - thoracic a There were no skeletal anomalies noted In any fetus. 22 222 77777 11111 44444i 3 4 5 6 7 1 2 2 0 0.00 8 7 1 12.50 10 2 8 80.00 8 2 6 75.00 6 4 2 33.33 8 5 3 37 2 2222 2 7 7777 7 1 1111 1 4 5555 5 90 1 23 4 10 4 6 60.00 10 5 5 50.00 8 5 3 37.50 7 1 6 85.71 7 2 5 71.43 9 6 3 33.33 EHLNO EHL HILO 0 FI F C CF F BF CINO BF C BF HI H E CHI FGM E II 8 HIN H l I, l GIJ LIJ l CFIJ FJH FHll BE FJ H B i oIXs) I Appendix 8 - Continued Individual Skeletal Findings in Fetuses3 Rat Teratology Study of T-3352 Group 2 - 1 mg/kg Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses having one or moreskeletal variants Percent of fetuses having one or more skeletal variants (X) Identification letter(s) of fetuses with: lagging Ossification Skull - Incomplete closure (<75%) - interparietal ossification incomplete - parietals ossification Irregular - supraoccipital ossification Incomplete - supraoccipital nonfused - hyoid ossification incomplete/nonosslfled Ribcage - sternebrae bipartite - sternebrae <3 ossified - ribs >13 pairs ossified - ribs <13 pairs ossified - ribs ossification Irregular Vertebral column - thoracic centra ossification incomplete - thoracic centra nonfused - lumbar ossification Incomplete/nonosslfled - lumbar arches fused - caudals <3 ossified - caudal vertebrae nonossifled - sacral vertebrae nonossifled Pelvic Girdle - pubis ossification incomplete/ nonossifled - Ischium ossification Incomplete Hlndllmbs - <4 ossified Bone Alignment Ribs - fused - forked - malaligned thoracic centra and arches - angulated Sternebrae - checkered Vertebrae malaligned - thoracic NP Not Pregnant. a There were no skeletal anomalies noted in any fetus. 22 2 2 7777 11 1 1 5 555 __5 6 7 8 9 0 9 100.00 8 6 2 25.00 6 1 5 83.33 NP KH BFHJKM NP B M JKH B DJKHP E K K G K COL K 8 H 22 22 2 77 77 7 11111 56 66 6 90 123 11 4 7 63.64 8 6 2 25.00 9 7 2 22.22 10 5 5 50.00 10 2 8 80.00 22 22 77 7 7 11 11 66 6 6 45 6 7 8 8 0 0.00 9 8 1 11.11 8 7 1 12.50 9 3 6 66.67 C1K0 BCFIR IP Cl l El BCEIKL l CG CJ RC G HO J 10 I EGI CO Appendix 0 - Continued Individual Skeletal Findings In Fetuses Rat Teratology Study of T-3352 Group 2 - 1 mg/kg Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses having one or more skeletal variants Percent of fetuses having one or more skeletal variants (X) Identification letter(s) of fetuses with: taggtnq Ossification Skull - Incomplete closure (<75%) - Interparietal ossification incomplete - parletals ossification Irregular - supraocdpltal ossification Incomplete - supraocdpltal nonfused - hyoid ossification Incomplete/nonosslfled Rib cage - sternebrae bipartite - sternebrae <3 ossified - ribs >13 pairs ossified - ribs <13 pairs ossified - ribs ossification Irregular Vertebral column - thoracic centra ossification Incomplete - thoracic centra nonfused - lumbar ossification Incomplete/nonosslfled - lumbar arches fused - caudals <3 ossified - caudal vertebrae nonosstfled - sacral vertebrae nonosstfled Pelvic Girdle - pubis ossification Incomplete/ nonosstfled - Ischium ossification Incomplete Hlndltmbs - <4 ossified Bone Alignment R<bs - fused - forked - malallgned thoracic centra and arches - angulated Sternebrae - checkered Vertebrae malallgned - thoracic a There were no skeletal anomalies noted In any fetus. 222 22 2222 T77 77 7777 1 11 11 1 1 1 1 6 6 7 77 7 7 77 890 12 34 56 8 6 2 25.00 9 5 4 44.44 6 4 2 33.33 10 8 2 20.00 B 5 3 37.50 10 5 5 50.00 B 1 7 87.50 2 10 03 27 10 0.00 70.00 22 2 777 111 777 78 9 8 B 0 0.00 10 4 6 60.00 10 9 1 10.00 BN BFN BFN G OH H D EL EFI EN0 CE E EFL BC KL FKL El NO EIL C KL CN CEHIK IN CHO EF BC 0 CL EL BC C F CFHIN 0 ECl C i cn i Appendix 8 - Continued Individual Skeletal Findings In Fetuses8 Rat Teratology Study oF T-3352 Group 3 - 1 0 mg/kg Maternal Number: Humber of fetuses examined Number of fetuses within normal limits Humber of fetuses having one or more skeletal variants Percent of fetuses having one or more skeletal variants (X) Identification letter(s) of fetuses with: iaqglnq Ossification Skull - Incomplete closure (<75%) - Interparietal ossification Incomplete - partetals ossification Irregular - supraoccIpttal ossification Incomplete - supraocclpltal nonfused - hyoid ossification Incomplete/nonosslfled Rib cage - sternebrae bipartite - sternebrae <3 ossified - ribs >13 pairs ossified - ribs <13 pairs ossified - ribs ossification Irregular Vertebral column - thoracic centra ossification Incomplete - thoracic centra nonfused - lumbar ossification Incomplete/nonosslfled - lumbar arches fused - caudals <3 osslfled - caudal vertebrae nonosslfled - sacral vertebrae nonosslfled Pelvic Girdle - pubis ossification Incomplete/ nonosslfled - Ischium ossification Incomplete Hlndllmbs - <4 ossified Bone Alignment Ribs - fused - forked - malallgned thoracic centra and arches - angulated Sternebrae - checkered Vertebrae malallgned - thoracic a There were no skeletal anomalies noted In any fetus. 222222 22 2 777777 77 7 111111 11 1 888888 88 8 0 1 2 34 5 6 7 0 8 2 6 75.00 6 3 3 50.00 8 5 3 37.50 8 3 5 62.50 8 7 1 12.50 8 5 3 37.50 68 02 66 10 0 .0 0 75.00 8 3 5 62.50 22 2 77 7 1 1 .1 89 9 90 1 9 9 0 0.00 8 3 5 62.50 9 1 8 88.89 2 7 1 9 2 7 7 0 0.00 NO HO BG Cf L 1 CE BB 8 CHIl C BC BCIH BH BCF CK CFILM C fHO DFG1JL MO FGIJMO Jl C It L DIKE FN FG IK C I H I CK IJ Appendix 8 - Continued Individual Skeletal Findings In Fetuses Rat Teratology Study of T-3352 Group 3 - 1 0 mg/kg Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses having one or more skeletal variants Percent of fetuses having one or more skeletal variants (X) Identification letter(s) of fetuses with: lagging Ossification Skull - incomplete closure (<75X) - Interparietal ossification Incomplete - parletals ossification Irregular - supraoccIpltal ossification Incomplete - supraocclpltal nonfused - hyoid ossification Incomplete/nonosslfled Rib cage - sternebrae bipartite - sternebrae <3 ossified - ribs >13 pairs ossified - ribs <13 pairs ossified - ribs ossification Irregular Vertebral column - thoracic centra ossification Incomplete - thoracic centra nonfused - lumbar ossification Incomplete/nonosslfled - lumbar arches fused - caudals <3 ossified - caudal vertebrae nonosslfled - sacral vertebrae nonosslfled Pelvic Girdle - pubis ossification Incomplete/ nonosslfled - Ischium oss1fIcatIon Incomplete Htndllmbs - <4 ossified Bone Alignment Ribs - fused - forked - malallgned thoracic centra and arches - angulated Sternebrae - checkered Vertebrae malallgned - thoracic NP Not Pregnant. There were no skeletal anomalies noted In any fetus. 22 77 11 99 34 6 4 2 33.33 NP F F t 2 7 1 9 5 9 4 5 55.56 222 22 222 777 77 7 77 111 12 222 999 90 0 00 678 90 123 8 8 0 0.00 9 7 2 22.22 10 3 7 70.00 8 4 4 50.00 10 4 6 60.00 10 7 3 30.00 11 4 7 63.64 10 6 4 40.00 2 7 2 0 4 2 2 0 0.00 0 C0G0 0 G NO BFINO 0 CH CF K CEK I K CK IN CFK C CFHIKN CFKO C CF L CO F COFM EF IN B 0 C CK 0 H 0 1 CT* CT* 1 Appendix 8 - Continued Individual Skeletal Findings in Fetuses* Rat Teratology Study of T-3352 Group 4 - 3 0 mg/kg Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses having one or more skeletal variants Percent of fetuses having one or more skeletal variants (X) Identification letter(s) of fetuses with: lagging Ossification Skull - Incomplete closure (<75X) - Interparietal ossification Incomplete - parletals ossification Irregular - supraocclpltal ossification Incomplete - supraocclpltal nonfused - hyoid ossification Incomplete/nonosslfled Rib cage - sternebrae bipartite - sternebrae <3 ossified - ribs >13 pairs ossified - ribs <13 pairs ossified - ribs ossification Irregular Vertebral column - thoracic centra ossification Incomplete - thoracic centra nonfused - lumbar ossification Incomplete/nonosslfled - lumbar arches fused - caudals <3 ossified - caudal vertebrae nonosslfled - sacral vertebrae nonosslfled Pelvic Girdle - pubis ossification Incomplete/ nonosslfled - Ischium ossification Incomplete Hlndllmbs - <4 ossified Bone Alignment Ribs - fused - forked - malaltgned thoracic centra and arches - angulated Sternebrae - checkered Vertebrae malallgned - thoracic NP - Not Pregnant. * There were no skeletal anomalies noted In any fetus. 2222 7777 2222 00 00 56 78 8 2 6 75.00 9 1 8 88.89 10 4 6 60.00 NP P II GIP INO FI I GLP L FP K 0 CGI JIN P GIJP I FGJ CF IIP FL 0 PK CGLP P P H G G FI 22 77 22 01 90 10 6 4 40.00 7 3 4 57.14 22 77 22 11 12 2 2 0 0.00 NP J IJO J JIO JO F I J J 22 77 22 11 34 9 7 2 22.22 NP J 8 2 22 7 77 2 22 1 11 567 8 0 8 100.00 10 2 8 80.00 10 5 5 50.00 J BCFGIJ LH F IL EFNQ F CM N P F 8F F Hl Appendix B - Continued Individual Skeletal Findings In Fetuses Rat Teratology Study oF T-3352 Group 4 - 3 0 mg/kg Maternal Number: Number oF Fetuses examined Number of fetuses within normal limits Number of fetuses having one or more skeletal variants Percent of fetuses having one or more skeletal variants (X) Identification letter(s) of fetuses with: lagging Ossification Skull - Incomplete closure (<75%) - Interparietal ossification Incomplete - parletals ossification Irregular - supraoccIpltal ossification Incomplete - supraoccIpltal nonfused - hyoid ossification Incomplete/nonosstfled Rib cage - sternebrae bipartite - sternebrae <3 ossified - ribs >13 pairs ossified - ribs <13 pairs ossified - ribs ossification Irregular Vertebral column - thoracic centra ossification Incomplete - thoracic centra nonfused - lumbar ossification tncomplete/nonosslfled - lumbar arches fused - caudals <3 ossified - caudal vertebrae nonosslfled - sacral vertebrae nonosslfled Pelvic Girdle - pubis ossification Incomplete/ nonosslfled - Ischium ossification Incomplete Hlndllmbs - <4 ossified Bone Alignment Ribs - fused - forked - malallgned thoracic centra and arches - angulated Sternebrae - checkered Vertebrae malallgned - thoracic NP Not Pregnant. There were no skeletal anomalies noted In any fetus. 2 7 2 1 __0 9 8 1 11.11 22 2222 7 7 77 77 2 2 2222 122 222 90 1234 9 5 4 44.44 B 4 4 50.00 B 7 1 12.50 2 1 1 50.00 6 1 5 83.33 11 0 11 100. o 2 7 2 2 5 NP IK 0K IK L CIH C0FJ CK CEIKIP CK BCEKL 01 NP J EHLR E H B J CIKIR L l EFl E E l L 222 2 7777 2222 2222 6 78 9 9 5 4 44.44 10 7 3 30.00 B 1 7 87.50 11 5 6 54.5' BEHI EFK K B N l H1N HKN BCF1 CM N BCEFHI N L BF HQ N N 1 - 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. Suppl.. 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., "Transformations: 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 k 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, Contributions to Probability and Statistics. Stanford University Press, Palo Alto, 1960. - 70 - Appendix 9 - Continued References Rat Teratology Study of T-3352 STATISTICAL METHOOS/LABORATORY PROCEDURES 154-161 Miller, R. G., Jr., Simultaneous Statistical Inference. McGraw-Hill, New York, 1966, Ch. 6.1. Staples, R. E., "Detection 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. "Embryological Considerations in Teratology." 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 Experimental Design. 2nd Ed., McGraw-Hill, N.Y., Ch. 10, 1971.