Document KJboqjVGGpNKOGBE68q5zjjew

A d SiG - o G G O N-Et FOSE alcohol Teratology - 000375 HAZLETON LABORATORIES AMERICA. INC- 9 2 0 0 L E E S B U R G TURNPIK E. VIENNA. VIRGINIA 2 2 1 BO. U S A I RAT TERATOLOGY STUDY T-3352 FINAL REPORT Et v- l-*' Submitted to 3M Comoany St. Paul, Minnesota March 21, 1984 0003~6 (ffi HAZLETON LABORATORIES AMERICA. INC 9 2 0 0 U EICijOC * vigNis 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: Inspecti ons/Revi ew 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 00037 Vi) HAZLETON LA B O R A TO R IES AM ERICA, INC. 9 2 0 0 l E E S B U B G T U R N P KE VIENNA VIRGINIA S 3 i 8 0 . 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: LAWRENCE T.^WETZEL, Ph.O. Life Sciences Division Laboratory Supervision: Teratology: GEORGE A. BURDOCK, Ph.D. Diplomate, American Board of Toxicology Life Sciences Division /c L a /__X_________._/I^ o RUTH S. DURLOO, B.S. Life Sciences Division Study Coordinator: BARBARA R. COLPEAN, B.A\, B.S. Life Sciences Division blm 000378 HAZLETON LA B O R A TO R IES AM ERICA, INC. 9 2 0 0 L E E 5 0 U R G TURNPIKE VIENNA. VIRGINIA 2 2 1 0 0 . 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 U5(X)0000-4-JO'OlUlUl 1 3 3 4 11 12 12 12 13 13 14 14 14 14 16 17 18 19 20 21 22 000379 0 HAZLETON L A B O R A T O R IES A M ERICA , INC. 9 2 0 0 l E E S G U B G T U P N P i K E V I E N N A . VIRG INIA 32 1 6 0 . U S A TABLE OF CONTENTS - CONTINUED Page 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 FindingsPer Litter Table 12 - Incidence of Visceral FindingsPer Litter Table 13 - Incidence of Skeletal FindingsPer Litter Table 14 - Mean Incidence of External, Visceral, and Skeletal Findings Per Litter 23 24 25 26 27 28 29 30 APPENDICES Appendix 1 - Individual Clinical Signs 31 Key to Appendices 2, 3, and 4 32 Appendix 2 - Individual and Mean Maternal Body Weights and Body Weight Changes 33 Appendix 3 - Individual and Mean Food Consumption 37 Appendix 4 - Individual and Mean Terminal Body Weights,Gravid Uterine Weights, and Terminal Body Weights Minus Gravid Uterine Weights 41 Appendix 5 - Individual and Mean Ovarian and Uterine Data 45 Appendix 6 - Individual and Mean Litter Data 49 Appendix 7 - Individual Visceral Findings in Fetuses 53 Appendix 8 - Individual Skeletal Findings in Fetuses 61 Appendix 9 - References 69 HAZLETON 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 D 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. m m sszL HAZLETON L A B O R A TO R IES AM ERICA. INC. 9 2 0 0 L E E S B U R G TURNPIKE VIENNA. VIRGINIA 2 2 1 8 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. 000382 HAZLETON LA B O R A TO R IES AM ERICA. INC. 9 2 0 G L E E S B U R G TU RNPIK E- VIENNA VIRGINIA 3 S 1 BO. 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. 000383  HAZLETON V * L A B O R A TO R IES A M E R IC A INC. 9 3 0 0 L E E S B U R G TURNPIKE. VIENNA. VIRGINIA 3 3 1 BO. U S A 4- - 154-161 TEST ANIMALS Two hundred fifty-nine (130 male and 129 female) sexually mature, cesarean-derived Sprague-Oawley 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 stainless- steel 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 59.4% + 3.44 during the study. A twelve-hour light/dark cycle was maintained. 000384 HAZLETON L A B O R A TO R IES AM ERICA. INC. 9 2 0 0 L E E SB U R G TURNPIKE. VIENNA. VIRGINIA 2 2 1 9 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 Based on individual animal body weights at each weighing interval during the dosing period. Animals were dosed on Days 6 through 15 of presumed gestation. Dose levels were selected based upon Information obtained in a range finding study. The results from that study were reported separately. ^ HAZLETON L A B O R A T O R IES A M E R IC A INC. 9 2 0 C - E E S B U H G TURNPIKE. VIENNA. VIRGINIA 2 S 18 0 . 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*1 and any remaining compound 1n 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. 3 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. 000386 HAZLETON L A B O R A T O R IES AM ERICA, INC. 9 2 0 0 L E E S B U R G TURNPIKE. VIENNA. VIRGINIA 2 2 1 8 0 . 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 00038V HAZLETON LA B O R A TO R IES AM ERICA. INC. 9 2 0 0 L E E SB U R G TURNPIKE. VIENNA. VIRGINIA 2 2 1 BO. 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. 000388 HAZLETON L A B O R A T O R IES A M ERICA . INC. 9 2 0 0 LE E SB U R G TURNPIKE. VIENNA, VIRGINIA S S I S O 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 (AN0VA) (Winer, 1971). If the variance proved to be hetero geneous, a series of transformations was performed until variance homo geneity was achieved. These transformations were log1 0 , square (X2), square root (X*), reciprocal (1/X), angular (arcsine X% ), and rank, in that order. If rank transformation was Ineffective in removing 0003*9 LABO RATO RIES A M E R IC A INC. 9 2 0 0 L E E S B U R G T U R n P iKE. VIENNA. v i G ' N i A 2 2 1 BO. 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-jo transformation. B = Data analyzed following square (X^) transformation, C * Data analyzed following square root (X% ) transformation. D = Data analyzed following reciprocal (1/X) transformation. E = Data analyzed following angular (arcsine X*) 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 5.0% one-tailed probability level. Control vs. compound-treated group mean comparisons of the above data were evaluated at the 5.0% two-tailed probability level. 000390 HAZLETON L A B O R A TO R IES AM ERICA, INC. S S O O L E E S B U R G TURNPIKE. VIENNA, VIRGINIA S S ' 8 0 U S A - 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. 000391 HAZLETOfX LA B O R A TO R IES AM ERICA. INC. 9200 L E E S B U R G TUBNPIKE VIENNA. VIRGINIA22180. U S A - 12 - 154-161 RESULTS - MATERNAL DATA Mortality and Clinical Observations Individual clinical observations are presented in Appendix 1. A summary of clinical observations is presented in Table 1. No animals were found dead or sacrificed In extremis during the study. Clinical observations were considered incidental. These observations included hunched and/or thin appearance, languid behavior, anorexia, soft feces, alopecia, and rough haircoat. Body Weights and Food Consumption Individual and mean body weights and body weight changes are presented in Appendix 2 and Table 2, respectively. Individual and mean food consumption values are presented in Appendix 3 and Table 3, respectively. Evaluation of the body weight changes revealed a significant decrease in body weight gain during treatment (Days 6-15) for the Group 4 females, resulting in a 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. 000392 HAZLETON LA B O R A T O R IES A M E R IC A INC. 9 3 0 0 L E E S B U R G t u r n p i k e VIENNA. VIRGINIA 2 8 1 9 0 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. 000393 HAZLETON L A B O R A TO R IES A M ERICA. INC. 9 2 0 0 L E E S B U R G TURNPIKE VIENNA VIRGINIA SS 1 9 0 . U S A - 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 L A B O R A TO R IES AM ERICA. INC. 9 2 0 0 l E S 8 U G Tu n p i k 6. VIENNA v ir g in ia i eo 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 tall. 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. 000395 Table 1 Summary of Maternal Clinical Observations3 Rat Teratology Study of T-3352 154-161 Observation Group: Dose Level (mq/kq): Pretreatment Oavs 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) 0000 Hunched Thin Languid Anorexia Soft feces Alopecia Rough halrcoat Treatment Davs 6-15 1234 0 1 10 30 23(2) 24(1) 24(1) 21(4) 20(2) 21(1) 24(1) 17(2) 0000 2(2) KD 1 1 32 1 3 Posttreatment Davs 16-20 12 34 0 1 10 30 23(2) 24(1) 24(1) 21(4) 19(2) 21(1) 2 K D 16(1) 0 0 00 1(2) (3) (1) 4 3 3 5(1) (1) a Numerals indicate the number of animals with that particular finding. () - Observations noted in nonpregnant females. Table 2 Mean Maternal Body Weights and Body Weight Changes Rat Teratology Study of T-3352 154-161 Body Welaht Mean Weight (g) Mean Change (g) Day(s) 0 6 8 12 16 20 0-6 6-8 6-12 6-1 6f 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 calculations. sample size on which mean calculations were based. Only pregnant females were used 1n mean I 000397 Table 3 Mean Haternal Food Consumption (g) Rat Teratology Study of T-3352 Interval Oays 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 7-16B 104.56 N: 23 201.40 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 22 154-161 Group 4 30 mg/kg 130.34 20 36.60 21 71.21 16 68.45 13 96.47s20 173.64s12 399.16 11 N: Indicates the sample size on which the mean calculations were based. Only pregnant females were used calculations. Invalid food consumption values were not Included In mean calculations. 86E000 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 154-161 Terminal Bodv Welqht 365.16 N: 23 368.01 N: 24 367.30 N: 24 345.03 N: 21 Gravid Uterine Weloht 69.52 23 73.62 23 67.51 24 66.47 20 Terminal Body Weight Minus Gravid Uterine Weight 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. 66C00O 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. 000400 - 21 - Key to Tables 6-14 154-161 Pregnancy rate (percent) - (number of pregnant rats/number of rats inseminated) x 100. Survival Rate (percent) - (number of rats surviving to Day 20/number of rats placed on study at initiation) x 100. Mean Implantation Efficiency (percent) - Group mean of ([implantations per litter/ corpora lutea per litter] x 100). Hean Incidence of Resorptions (percent)3 - Group mean of ([resorptions per litter/ implantations per litter] x 100). Hean Incidence of Fetal Mortality (percent) - Group mean of ([dead and resorbing fetuses per litter/ implantations per litter] x 100). Mean Incidence of Fetal Viability (percent) - Group mean of ([live fetuses per litter/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 litter examined externally] x 100). Mean Incidence of External Anomalies (percent) - Group mean of ([number of fetuses per litter with external anomalies/ number of fetuses per U t t e r examined externally] x 100). Hean 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 (oercentl - Group mean of ([number of fetuses per litter with skeletal variants/ number of fetuses per litter examined skeletally] x 100). Mean Incidence of Skeletal Anomalies (percent) - Group mean of ([number of fetuses per litter with skeletal anomalies/ number of fetuses per U t t e r examined skeletally] x 100). a Values calculated separately for early, late, and total resorptions. 000401 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 litter 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. 000402 Table 7 Summary of Mean Utter Oataa Rat Teratology Study of T-3352 154-161 Mean number of: Fetuses - dead - live Indices calculated on a per Ut te r basis: Mean Incidence of fetal mortality (%) Mean Incidence of fetal viability (%) Mean percent males (X) U v e fetuses Mean body weight (g)b Hales - 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 3.18 234 1 10 30 0.0 13.3 0.0 12.8 0.0 13.0 7.46 92.55 49.54 10.85 89.15 51.24 7.66 92.35 51.20 3.27 3.27 3.15 3.15 3.21 3.21 3.05 3.05 2.95 2 .9 5 S 2.80 2.80S a Sex, percent males, and mean body weight data Include values for live fetuses only, b Statistical analysis performed on covariance adjusted means. COVOOO 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 Tall - undeveloped - no tall Group: Dose Level (mg/kg): 1 0 234 1 10 30 289 320 306 272 288 320 304 271 0 011 1 0 20 0 011 1 ia 1 020 1 1 1 a Finding confirmed at skeletal evaluation. r4s*a O o o o 000405 Table 9 Summary of Visceral Findings Rat Teratology Study of T-3352 Group: Dose Level (mg/kg): 1 0 23 1 1 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 Kldney(s) - fused Cryptorchlsm 20 2 1 21 154-161 4 30 98 96 2 0 2 1 1 0 000406 Table 10 Summary of Skeletal Findings Rat Teratology Study of T-3352 Group: Dose Level (mg/kg): 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 Lagging ossification Skull - Incomplete closure (<75X) - Interparietal ossification Incomplete - parletals ossification Irregular - supraocdpltal ossification Incomplete - supraocdpltal nonfused - hyoid ossification 1ncomplete/nonoss1f1ed 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 23 1 10 204 194 115 103 89 91 00 153 152 69 31 49 56 15 16 34 19 75 1 42 24 28 11 11 86 5 1 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 Table 11 Incidence of External Findings Per Utter Rat Teratology Study of T-3352 154-161 Number of litters examined Number of Utters within normal limits Number and percent of Utters with variants Number and percent of litters with anomalies Number and percent with variants Trunk - short Tall - underdeveloped Number and type with anomalies Palate - cleft Tall - undeveloped - no tall Group: Oose 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 1/4.76 I ro a Finding confirmed at skeletal evaluation. O o o o Table 12 Incidence of Visceral Findings Per Litter Rat Teratology Study of T-3352 154-161 Group: Dose Level (mg/kg): 1___ 0 Number of Utters examined Number of litters within normal limits Number and percent of litters 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 Kldney(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 Kldney(s) - fused Cryptorchism 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 rOoO OyO Table 13 Incidence of Skeletal Findings Per Utter 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 - h y d d 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 1ncomplete/nonoss1f1ed - Ischium ossification Incomplete H1ndl1mbs - <4 ossified Bone alignment Ribs - fused - forked - malaUgned thoracic centra and arches - angulated Sternebrae - checkered Vertebrae malaUgned - 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 feOlrOJ 000410 Table 14 Mean Incidence of External, Visceral, and Skeletal Findings Per Utter Rat Teratology Study of T-3352 Group: Dose Level (mg/kg): External Mean values calculated on a per Utter basis: Number with variants Number with anomalies Incidence of variants (X) Incidence of anomalies (X) Mean values calculated on a per litter basis: Number with variants Number with anomalies Incidence of variants (X) Incidence of anomalies (X) Visceral Skeletal Mean values calculated on a per Ut te r basis: Number with variants Number with anomalies Incidence of variants (X) Incidence of anomalies (X) 1 0 0.0 0.0 0.0 0.9 0.6 0.1 13.3 2.0 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 0.0 154-161 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 Group Observation 27134 27136 27141 27152 27160 27172 27178 27179 27190 27201 27202 27205 27208 27211 27212 27213 27215 27221 27224 27225 27228 1 Alopecia Alopecia 1 Alopecia Alopecia Alopecia 1 Alopecia Alopecia 1 Alopecia Alopecia 2 Soft feces 2 Alopecia 2 Alopecia Alopecia 2 Alopecia 3 Alopecia 3 Alopecia 3 Alopecia 4 Alopecia Alopecia Alopecia Alopecia 4 Thin 4 Soft feces 4 Hunched Thin Anorexia Alopecia Rough haircoat 4 Alopecia 4 Alopecia 4 Alopecia Alopecia Alopecia 4 Hunched Thin Languid Alopecia 4 Hunched Thin 4 Hunched 3 All animals not included in this tabl 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 Damisi 17-20 16-20 9-20 13-15, 8-12, 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, 1810 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 appeared normal throughout the study. 000411 - 32 - Key to Appendices 2, 3, and 4 154-161 P * Pregnant NP Not Pregnant C Cesarean Section Performed (preceded by day of gestation) () = Data excluded from mean calculation. Explanation of Footnotes a Only data from pregnant animals surviving to Day 20 cesarean section were used in mean calculations. b Invalid food consumption value not included in mean calculations. Gravid uterine weight inadvertently not recorded. 000412 M atern al Number 21130 27131 27132 27133 27134 27135 27136 27137 27I3B 27139 27140 27141 27142 27143 27144 27145 27146 27147 27148 27149 27150 27151 27152 27153 27154 N Mean S.O. D isposition P, 20-C NP. 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 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 In d iv id u a l and Mean M aternal Body Weights and Body W eight Changes3 Rat T erato log y Study of T-3352 Group 1 - 0 mg/kg ________________Body W eight ( o l _________________ Day o f 6estat1on 0 6 8 12 16 20 228.9 (246.5) 236.9 216.7 217.0 (221.4) 212.5 225.6 261.2 238.2 226.7 215.3 228.3 228.2 206.6 250.4 269.3 220.4 236.4 223.5 224.6 242.0 217.0 257.4 224.5 246.4 (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) 268.5 271.0 322.9 300.6 275.3 264.8 271.3 279.6 262.8 318.3 311.2 278.2 295.9 278.0 273.9 297.2 250.1 297.3 278.0 283.7 (271.8) 299.8 297.9 304.8 (252.3) 291.8 297.2 341.3 327.5 290.4 291.9 302.9 284.8 286.9 349.6 336.4 303.1 331.6 313.1 298.8 336.5 280.3 342.4 307.7 340.6 (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 (3 2 .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 (2.1) 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 W eight Change f o l ________ Pays__________ 6-12 6-16F 6-20 23.3 (2.3) 24.1 28.3 32.0 (-1 1 .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 (35) 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 10.770 154-161 0-20 111.7 (3 5 .6 ) 131.1 146.8 158.2 (3 7 .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 o o o h* CJ M atern al Number 27155 27156 27157 27158 27159 27160 27161 27162 27163 27164 27165 27166 27167 27168 27169 27170 27171 27172 27173 27174 27175 27176 27177 27178 27179 N Mean S.O. D isposition 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 P. 20-C P. 20-C Appendix 2 - Continued In d iv id u a l and Mean M aternal Body W eights and Body W eight Changes* Rat T era to lo g y Study o f T-3352 Group 2 - 1 mg/kg 0 228.7 232.6 235.3 (205.1) 204.5 224.7 226.6 229.4 238.4 203.0 223.8 245.2 219.6 225.5 247.2 262.8 249.7 221.5 226.0 215.3 219.2 216.2 246.9 254.7 226.7 6 254.9 265.8 262.9 (237.8) 244.5 262.9 252.2 260.4 270.9 236.2 254.5 272.0 253.7 255.8 271.2 293.7 278.9 246.2 253.4 245.0 252.2 250.4 270.3 283.2 247.3 Body Weight LaL IfiJL 8 12 258.6 270.6 269.4 (245.2) 239.8 269.8 258.9 266.5 271.2 235.3 259.2 273.1 258.4 251.5 273.6 291.0 289.1 250.2 254.4 255.1 256.6 250.4 277.7 297.1 252.6 280.7 300.3 288.4 (250.6) 259.4 287.0 277.4 289.4 283.6 255.5 280.1 291.5 279.5 269.8 295.4 312.9 305.1 271.8 275.0 275.6 266.6 272.5 297.1 314.8 271.2 16 305.1 325.9 304.5 (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 20 360.2 389.3 352.5 (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 24 368.01 21.094 _ 0-6 26.2 33.2 27.6 (3 2 .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 2280..56 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 4.558 Body W eight Change f o l ___________ Days__________ 6-12 6- 16f 6-20 25.8 34.5 25.5 ( 12. 8) 14.9 24.1 25.2 29.0 12.7 19.3 25.6 19.5 25.8 14.0 24.2 19.2 26.2 25.6 21.6 30.6 14.4 22.1 26.8 31.6 23.9 50.2 60.1 41.6 (1 3 .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 58.6 55.7 43.5 62.7 35.7 48.0 56.3 70.9 59.9 105.3 123.5 89.6 (3 1 .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 14.482 154-161 16-20 55.1 63.4 48.0 (IB.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 28.1 61.9 42.5 64.8 66.9 0-20 131.5 156.7 117.2 (6 3 .9 ) 142.5 121.7 139.2 151.0 149.0 135.6 138.5 124.7 153.4 130.6 144.5 124.3 145.0 130.5 135.9 142.3 96.8 144.1 122.2 164.2 147.4 24 57.00 9.398 24 137.03 14.702 I 4* O o o ,,. . M aternal Humber 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 N Mean S.O. D isposition 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 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 Appendix 2 - Continued In d iv id u a l and Mean M aternal Body Weights and Body W eight Changes^ Rat T era to lo g y Study o f T-3352 Group 3 - 1 0 mg/kg _______________ 06 Body W eight (a ) Day o f G e sta tio n 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) 305.3 328.1 279.5 246.0 268.3 286.5 313.3 298.7 294.7 307.9 312.5 309.9 297.0 311.8 295.1 329.5 282.7 310.1 309.5 357.0 274.9 300.8 266.6 285.9 (253.9) 325.7 344.0 310.0 281.9 285.7 322.5 338.5 333.9 329.9 338.0 365.7 3 J3. b 353.7 372.6 35Q.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 6-8 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 (-20) 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 W eight Change f o l ________ Days__________ 6-12 6--16" 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 (21) 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 (1 .3 ) 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 0-20 116.6 149.1 139.1 130.1 131.5 147.5 107.9 138.0 128.1 142.6 104.8 113.2 112.4 122.7 (1 6 .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 i icno i o o o 1 27205 27206 27207 27208 27209 27210 27211 27212 27213 27214 27215 27216 27217 27218 27219 27220 27221 27222 27223 27224 27225 27226 27227 27228 27229 N Mean S.O. D isposition P, 20-C P. 20-C P, 20-C HP, 20-C P. 20-C P, 20-C P. 20-C MP. 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 MP, 20-C P, 20-C P. 20-C P. 20-C P. 20-C Appendix 2 - Continued In d iv id u a l and Mean M aternal Body W eights and Body W eight Changes9 Rat T erato log y Study o f T-3352 Group 4 - 3 0 mg/kg Body W eight ( a l Pay o f G e sta tio n 0 6 8 12 16 20 219.4 239.5 209.2 (217.4) 222.8 249.6 227.0 (280.9) 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) 244.4 282.2 269.7 (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 (317) 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 W eight Change f a i ________ Pays__________ 6-8 6-12 6-16^ 6-20 16-20 -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 (-2 0 .2 ) 3.2 -1.8 -9.6 -4.6 0.4 -23.5 17.8 (-14) 11.4 12.2 -2 4 .0 (-4 0 .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 (-2 7 .0 ) 71.5 5.1 -8.7 3.9 19.4 -14.9 36.6 (-7 .3 ) 33.9 23.9 -0.7 (-7 5 .8 ) 28.1 (-7 .3 ) 17.9 12.B 42.1 25.9 20.7 43.1 17.4 2.3 6.8 14.3 (-6 4 .5 ) 40.2 31.5 -12.2 16.8 72.5 60.6 101.8 (6 .5 ) 105.0 82.1 42.9 (-4 0 .1 ) 90.0 (1 4 .9 ) 72.6 74.4 102.8 88.1 69.6 94.9 62.0 28.1 57.8 92.4 (-2 8 .0 ) 96.8 86.8 51.4 72.6 53.1 75.5 65.2 (1 3 .8 ) 71.1 58.2 43.6 (3 5 .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 (3 6 .5 ) 56.6 55.3 63.6 55.8 21 -3.023- 5.589 21 -1.22 16.688 21 19.33316.454 21 76.44 20.754 21 57.11 11.499 0-20 97.3 90.8 134.9 (2 0 .4 ) 126.6 114.7 85.6 (-8 .4 ) 135.0 (5 0 .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 1 0 7 . 69S 20.177 O O O 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 - Appendix 3 Individual and Mean Food Consumption3 Rat Teratology Study of T-3352 Group 1 - 0 mg/kg 154-161 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 _____________ Food Consumption (g) Interval fDavs of Gestation) 7-SF 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 94.5 119.1 113.7 111.6 106.3 100.9 101.8 94.2 99.8 94.1 92.9 117.4 117.1 99.1 104.8 103.8 121.1 105.7 23 37.98 4.988 23 78.93 10.880 23 84.49 8.071 23 104.56 9.290 7-16 179.8 (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 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 000417 27155 27156 27157 27158 27159 27160 27161 27162 27163 27164 27165 27166 27167 27168 27169 27170 27171 27172 27173 27174 27175 27176 27177 27178 27179 N Mean S.D. 38 - Appendix 3 - Continued Individual and Mean Food Consumption3 Rat Teratology Study of T-3352 Group 2 - 1 mg/kg 154-161 0-6 126.8 134.4 113.4 (125.4) 123.5 129.6 123.5 123.5 127.3 117.4 131 .6 145.9 124.9 126.2 136.7 139.4 132.4 131.3 124.7 115.4 138.0 125.2 137.6 136.5 133.5 7-8F Food Consumption (g) Interval fOavs of Gestation) 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 81.1 (108.5)d 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 7-16B 0-20F 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) 192.3 222.9 207.1 219.5 213.3 194.0 213.5 223.3 187.5 201.8 226.6 208.6 428.7 467.5 404.4 (489.0) 418.3 424.4 407.3 419.5 427.8 383.0 439.9 434.1 (504.1) 428.2 476.0 448.4 456.2 442.3 425.5 435.6 471 .4 415.7 434.7 478.0 449.6 24 129.11 7.957 24 38.37 4.222 24 80.75 12.279 23 85.40 6.301 24 103.76 6.289 24 202.70 14.943 24 435.50 23.804 000418 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 - Appendix 3 - Continued Individual and Mean Food Consumption Rat Teratology Study of T-3352 Group 3 - 1 0 mg/kg 154-161 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 _____________ Food Consumption (g)________________________ Interval fDavs of Gestation) 7-8F 9-12 13-16 17-20 7-U8 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) 223.4 187.2 175.6 165.5 172.8 192.2 (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 (338941.-8\)b (501.8) 481 .0 416.2 384.1 389.1 400.7 429.4 (575.4) 439.1 505.4 24 131.05 13.235 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 0004^-9 27205 27206 27207 27208 27209 27210 27211 27212 27213 27214 27215 27216 27217 27218 27219 27220 27221 27222 27223 27224 27225 27226 27227 27228 27229 N Mean S.O. - 40 - Appendix 3 - Continued Individual and Mean Food Consumption3 Rat Teratology Study of T-3352 Group 4 - 3 0 mg/kg 154-161 ___________ Food Consumption ( q ) _____________________ _______ Interval (Days of Gestation)_____________________ 7-8F 9-12 13-16 17-20 7-16B 0-2QF 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. 3D (-) 20 130. 34 14. 541 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 b (81.5) 85.0 h (72.2)? (220.0) (48.3) 79.6 (75.7) 44.2 73.1 58.7 50.1 76.6 (52.2)b (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 (85 *82)b 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 (121 46 )b 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) 100.9 181.3 348.1 388.3 402.6 . (339.5) (355.5) 445.4 (464.8) (261.3). (503.9) (318.6) 406.2 364.9 448.0 . (395.1) 370.9 446.3 . (373.7) (648.8) (401.9) (649.1) (272.7) 454.5 (413.6) 315.6 (276.7) 21 36.60 10.755 16 71.21 13.023 13 68.45 15.381 20 c_ 96 .475 17123.64 S- 11 399.16 8 .931 32.816 46.421 ? 000420 - 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 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 Terminal Bodv Weiqht 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 Gravid Uterine Weight 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 Terminal Body Weight Minus Gravid Uterine Weight 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 000421 - 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 27155 27156 27157 27158 27159 27160 27161 27162 27163 27164 27165 27166 27167 27168 27169 27170c 27171 27172 27173 27174 27175 27176 27177 27178 27179 Terminal Bodv Weiqht 360.2 389.3 352.5 Not Pregnant 347.0 366.4 365.8 380.4 387.4 338.6 362.3 369.9 373.0 356.1 391 .7 387.1 394.7 352.0 361.9 357.6 316.0 360.3 369.1 418.9 374.1 Gravid Uterine Weiqht 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 80.6 68.9 88.1 86.8 Terminal Body Weight Minus Gravid Uterine Weiqht 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 00042 - 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 Terminal Bodv Weight Gravid Uterine Weight Terminal Body Weight Minus Gravid Uterine Weight 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 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 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 20.4 301.2 319.3 287.2 302.2 288.7 317.9 282.5 302.7 296.4 339.8 261.8 285.9 267.0 284.3 303.7 342.8 292.9 254.7 286.4 305.1 314.2 308.8 311 .8 337.5 N Mean S.O. 24 367.30 24.797 24 67.51 13.989 24 299.78 22.724 00042-3 - 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 Number 27205 27206 27207 27208 27209 27210 27211 27212 27213 27214 27215 27216 27217 27218 27219 27220 27221 27222 27223c 27224 27225 27226 27227 27228 27229 Terminal Bodv Weiqht 316.7 330.3 344.1 Not Pregnant 349.4 364.3 312.6 Not Pregnant 379.3 Not Pregnant 362.7 341.7 386.5 343.5 336.3 364.6 297.6 300.2 309.8 374.0 Not Pregnant 386.3 346.8 326.1 372.9 Gravid Uterine Weiqht 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 Terminal Body Weight Minus Gravid Uterine Weiqht 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 20 280.33$" 20.353 000424 Maternal Number 27130 27131 27132 27133 27134 27135 27136 27137 27138 27139 27140 27141 27142* 27143 27144 27145 27146 27147 27148 27149 27150 27151 27152 27153 27154 Total N Mean S.O. Ovarian Coroora 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 U terine Im plantations 14 16 15 15 15 13 15 16 9 13 (14) 4 13 15 15 10 14 16 15 14 13 12 15 297 22 13.5 2.79 In d iv id u a l and Mean O varian and U te rin e Data Rat T e ra to lo g y Study o f T-3352 Group 1 - 0 mg/kg Im plantation E ffic ie n c y IX) 100.0 80.0 93.8 100.0 100.0 100.0 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 E a rly R e s o rp tio n s 1 1 1 1 0 .2 0 0 2 2 (1) 0 1 0 1 1 1 0 0 2 2 1 1 E a rly Resorptions (XI 7.1 6.3 6.7 6.7 0.0 15.4 0.0 0.0 22.2 15.4 on 0.0 7.7 0.0 6.7 10.0 7.1 0.0 0.0 14.3 15.4 8.3 6.7 Late R e s o rp tio n s 0 0 0 0 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 - T o ta l Resorottons 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 T o ta l R esorp tions 1X1 7.1 6.3 6.7 6.7 0.0 15.4 0.0 0.0 22.2 15.4 - (.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 22 7.09 6.365 3 In v a lid data excluded from mean c a lc u la tio n s . 1 c-tnk t Appendix 5 - Continued In d iv id u a l and Mean O varian and U te rin e Data Rat T era to lo g y Study o f T-3352 Group 2 - 1 mg/kg M aternal Number 21155 21156 2715 J 2715# 27159 27160 27161 27162 27163 27164 27165 27166 27167 2716# 27169 27170 27171 27172 27173 27174 27175 27176 27177 27178 27179 T o ta l N Mean S.D. Ovarian Corpora Lutea 16 16 14 Not Pregnant 18 17 16 19 17 18 17 15 16 15 14 15 21 12 16 14 11 17 15 17 22 388 24 16.2 2.46 U te rin e Im plantations 16 14 13 18 14 14 17 16 16 14 14 15 15 14 14 16 12 15 12 3 16 14 16 19 347 24 14.5 2.96 Im plantation E ffic ie n c y (XI 100.0 87.5 92.9 100.0 82.4 87.5 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 E a rly R e s o rp tio n s 2 1 4 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 E a rly Resorptions (XI 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 R e s o rp tio n s 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 - la te 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 - T o ta l 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 27 24 1.2 1.37 T o ta l 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 o o o 10 a Appendix 5 - Continued In d iv id u a l and Mean O varian and U te rin e Data Rat T erato log y Study o f T-3352 Group 3 - 1 0 mg/kg 154-160 M aternal Number Ovarian Comoro Lutea 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 19 11 19 15 14 15 14 15 15 18 14 18 13 15 Not Pregnant 15 17 16 15 14 16 16 20 IS 15 Total N Mean S.O. 374 24 15.6 2.06 U te rin e Im plantations 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 Im plantation E a rly e f f ic ie n c y 1X1 R esorptions 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 3 1 0 1 1 0 3 2 1 0 0 1 1 2 100.0 88.2 100.0 100.0 100.0 100.0 100.0 90.0 100.0 80.0 1 2 1 0 2 0 0 1 0 9 24 91.78 9.014 32 24 1.3 1.88 E a rly Resorptions (X) 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 R e s o rp tio n s 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 Resorptions (X) 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 Resorptions 3 1 0 1 1 0 3 2 1 0 1 1 1 3 1 2 2 0 2 0 0 1 0 9 35 24 1.5 1.89 T o ta l Resorptions (X) 20.0 10.0 0.0 7.1 7.1 0.0 23.1 13.3 7.1 0.0 7.1 6.7 8.3 23.1 6.7 13.3 12.5 0.0 14.3 0 .0 0.0 5.6 0.0 75.0 24 10.85 15.429 Appendix 5 - Continued In d iv id u a l and Mean O varian and U te rin e Data Rat T erato log y Study o f T-3352 Group 4 - 3 0 mg/kg 154-160 M atern al Number Ovarian Corpora Ltea 27205 27206 27207 27208 27209 27210 27211 27212 27213 27214 27215 27216 27217 27218 27219 27220 27221 27222 27223 27224 27225 27226 27227 27228 27229 14 17 15 Not Pregnant 16 IS 14 Not Pregnant 16 Not Pregnant 14 16 17 15 16 17 15 18 16 21 Not Pregnant 18 17 15 18 lo ta l N Mean S.O. 340 21 16.2 1.69 U te rin e Im plantations 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 Im plantation E ffic ie n c y (X) 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 E arly 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 E a rly 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 R e s o rp tio n s 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 (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 7.1 0.0 21 0.34 1.549 T o ta l R e s o rp tio n s 1 2 0 1 4 1 1 1 1 2 l 0 1 0 0 3 1 1 0 1 0 22 21 1.0 1.02 T o ta l 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 i 00 I 00 Appendix 6 In d iv id u a l and Mean L i t t e r Data3 Rat T erato log y Study of T-3352 Group 1 - 0 mg/kg M atern al Number 27130 27131 27132 27133 27134 27135 27136 27137 27138 27139 27140 27141 27142d 27143 27144 27145 27146 27147 27148 27149 27150 27151 27152 27153 27154 T o ta l R e s o rp tio n s 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 Dead 0 0 0 0 0 0 0 0 0 0 (0) 0 0 0 1 0 0 0 0 0 0 0 0 Number o f Fetuses F e ta l Loss m b Live Live (X) 7.1 13 92.9 6 .3 15 93.8 6.7 14 93.3 6.7 14 93.3 0.0 15.4 0.0 0.0 22.2 15.4 (7.1) 0.0 7.7 0.0 13.3 10.0 7.1 0.0 0.0 14.3 15.4 8.3 6.7 15 11 15 16 7 11 (13) 4 12 15 13 9 13 16 15 12 11 11 14 100.0 84.6 100.0 100.0 77.8 84.6 (9 2 .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 S Males 6 7 5 10 7 7 8 9 4 4 7 3 6 9 7 7 6 8 5 7 5 4 10 T o ta l 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 3 Sex, percent males, and mean w e igh t data In clu d e values f o r li v e b Percent f e t a l lo ss In clu d e s re s o rp tio n s as w e ll as dead fe tu s e s . c S t a t is t ic a l a n a ly s is performed on cova ria nce a d ju s te d means, d In v a lid data excluded from mean c a lc u la tio n s . fetuses o n ly , 62*600 154-161 [ Females 7 B 9 4 8 4 7 7 3 7 6 1 6 6 6 2 7 B 10 5 6 7 4 138 23 6.0 2.20 Percent Nales 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 Mean Weight ( g ) C Nales 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 .00! Appendix 6 - Continued In d iv id u a l and Mean l i t t e r Data3 Rat te ra to lo g y Study of T-3352 Group 2 - 1 mg/kg M atern al 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 lo ta l N Unadjusted Mean Unadjusted S.D. Covariance A djusted Mean Covariance A djusted S.O. T o ta l 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 Bead 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 o f Fetuses F e ta l lo s s (%)> l i v e l l v t (X) 12.5 14 81.5 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 14 100.0 15 88.2 16 100.0 13 81.3 14 100.0 13 92.9 14 93.3 12 80.0 14 100.0 10 71.4 16 100.0 12 100.0 15 100.0 12 100.0 3 100.0 16 100.0 13 92.9 16 100.0 16 84.2 24 7.46 9.344 320 24 13.3 2.94 24 92.55 9.338 Males 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. 2.1 3 Sex, percent m ales, and mean w e ig h t data In clu d e values f o r li v e fe tu s e s o n ly . " Percent f e t a l loss Inclu de s re s o rp tio n s as w e ll as dead fe tu s e s . c S t a t is t ic a l a n a ly s is performed on cova ria nce a d ju ste d means. 000430 154-161 { Females 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 Hales 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 Mean W elaht la ic Hales 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 In d iv id u a l and Hean L i t t e r Data3 Rat T eratology Study o f T-3352 Group 3 - 1 0 mg/kg Maternal Number T o ta l R e s o rp tio n s Dead Number of Fetuses F e ta l Loss f * lb Live L ive {*1 S Males 21180 21181 27182 27183 27184 27185 27186 27187 27188 27189 27190 27197 27192 27193 27194 27195 27196 27197 27198 27199 27200 27201 27202 27203 27204 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 0 20.0 0 10.0 0 0.0 0 7.7 0 7.1 0 0.0 0 23.1 0 13.3 0 7.1 0 0.0 0 7.1 0 6.7 0 8.3 0 23.1 0 6.7 0 13.3 0 12.5 0 0.0 0 14.3 0 0.0 0 0.0 0 5.6 0 0.0 0 75.0 12 9 13 13 13 13 10 13 13 14 13 14 11 10 80.0 90.0 100.0 92.9 92.9 100.0 76.9 86.7 92.9 700.0 92.9 93.3 91.7 76.9 14 93.3 13 86.7 14 87.5 15 100.0 12 85.7 16 100.0 16 100.0 17 94.4 15 100.0 3 25.0 6 7 9 6 9 8 5 6 8 10 5 5 8 5 4 4 8 8 6 5 8 6 4 2 Total N Unadjusted Mean Unadjusted S.O. Covariance A djusted Mean Covariance Adjusted S.O. 35 24 1.5 1.89 0 24 0.0 24 10.85 15.429 306 24 12.8 2.83 24 89.15 15.429 152 24 6.3 1.97 a Sex, pe rcen t m ales, and mean w e ig h t data In clu d e values f o r li v e fe tu se s o n ly , b Percent f e t a l lo ss Includes re s o p rtto n s as w e ll as dead fe tu s e s . c S t a t is t ic a l a n a ly s is performed on covariance a d ju ste d means. 154-161 ; 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 Males 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 Mean H e tq ht (a )c Males 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 0.217 3.05 .005 1 in i--* i Appendix 6 - Continued In d iv id u a l and Mean L i t t e r Data3 Rat T erato log y Study o f T-3352 Group 4 - 3 0 mg/kg M atern al Number 21205 27206 27207 27208 27209 27210 27211 27212 27213 27214 27215 27216 27217 27218 27219 27220 27221 27222 27223 27224 27225 27226 27227 27228 27229 T o ta l N Unadjusted Mean Unadjusted S.D. Covariance A djusted Mean Covariance Adjusted S.D. T o ta l R e s o rp tio n s 1 2 0 Not Pregnant 1 4 1 Not Pregnant 1 Not Pregnant l 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 o f Fetuses F e ta l Loss ( X lb Live L iv e (XI 7.1 12.5 0.0 13 92.9 14 B7.5 15 100.0 6.3 26.7 20.0 15 93.8 11 73.3 4 80.0 6.7 14 93.3 7.1 6.3 11.8 6.7 0.0 7.1 0.0 0.0 23.1 5.6 13 92.9 15 93.8 15 88.2 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 7.608 272 21 13.0 3.41 21 92.35 7.610 S Males 6 7 8 8 4 3 6 7 5 8 8 6 6 7 2 4 9 10 11 5 8 138 21 6.6 2.25 3 Sex, pe rcen t males, and mean w e igh t data In clu d e values f o r li v e fe tu s e s o n ly , b Percent f e t a l lo ss in clu d e s re s o rp tio n s as w e ll as dead fe tu s e s . c S t a t is t ic a l a n a ly s is perform ed on covariance a d ju ste d means. 000432 154-161 ex fem ales 7 7 7 7 7 1 8 6 10 7 6 8 7 5 2 6 8 4 4 8 9 134 21 6.4 2.18 Percent Hales 46.2 50.0 53.3 53.3 36.4 75.0 42.9 53.8 33.3 53.3 57.1 42.9 46.2 58.3 50.0 40.0 52.9 71.4 73.3 38.5 47.1 21 51.20 11.412 Mean W eight la)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 2.8 2.7 3.0 2.7 2.8 2.6 21 2.95 0.246 2.95S- .005 21 2.1 o.; 2.80S- .005 tn IV) Appendix 7 In d iv id u a l V isce ra l Findings In Fetuses Rat T eratology Study o f T-3352 Group 1 - 0 mg/kg 154-161 M a te rn a l Number: Number o f fe tu se s examined Number o f fetuse s w ith in normal lim it s Number o f fe tu se s having one o r more v is c e ra l v a ria n ts Percent o f fe tu se s having one o r more v is c e r a l v a ria n ts (X) Id e n tific a tio n le tte r(s ) of fetuses w ith : B rain - le f t v e n tric a l d ila te d - dark m a te ria l around b ra in L iv e r - dark areas on lobe - a l l lobes appeared dark - dark area In liv e r Kldney(s) - d ila te d renal p e lv is U re te r(s) - distended Testes - small Skin - edema between s k in and p e rito n e a l w a ll Humber o f fe tu se s having one o r more v is c e ra l anomalies Percent o f fe tu se s having one o r more v is c e r a l anom alles(Jt) Id e n tific a tio n le tte r(s ) of fetuses w ith : Kldney(s) - fused C ry p to rc h is m 22 77 11 33 01 5 5 0 0.00 NP 0 0.00 2222 7777 1111 3333 234 5 5 4 1 20.00 5a 3 2 40.00 5 5 0 0.00 NP DM H OH 000 0.00 0.00 0.00 222222 2 7777777 11 1 111 1 333 3444 67a 90 12 5 5 0 0.00 4 3 1 25.00 5 5 0 0.00 6 5 1 16.67 3 2 1 33.33 4 4 0 0.00 5 5 0 0.00 P0 P0 0000000 0.00 0.00 0.00 0.00 0.00 0 .0 0 0.00 NP * Not Pregnant. a Fetus K was noted to have an undeveloped t a l l d u rin g e x te rn a l e xa m in a tio n . This f in d in g was con firm ed a t s k e le ta l e xa m in a tio n . Appendix 7 - Continued In d iv id u a l V is c e ra l Findings In Fetuses Rat T erato log y Study o f T-3352 Group 1 - 0 mg/kg 154-161 M atern al Number: Number o f fe tu se s examined Number o f fetuse s w ith in normal lim it s Number o f fetuse s having one o r more v is c e ra l v a ria n ts Percent o f fe tu se s having one o r more v is c e ra l v a ria n ts (X) Id e n tific a tio n le tte r(s ) of fetuses w ith : B rain - le f t v e n tric a l d ila te d - dark m a te ria l around b ra in L iv e r - dark areas on lobe - a l l lobes appeared dark - dark area In liv e r Kldney(s) - d ila te d renal p e lv is U re te r(s) - distended Testes - small Skin - edema between s k in and p e rito n e a l w a ll Number o f fe tu se s having one o r more v is c e ra l anomalies Percent o f fetuse s having one o r more v is c e ra l anom alles(X) Id e n tific a tio n le tte r(s ) of fetuses w ith : Kldney(s) - fused C ry p to rc h ls m 2 7 1 4 __3 2 2 0 0.00 0 0.00 2 7 1 4 4 4 4 0 0.00 0 0.00 22 77 11 44 56 5 5 0 0.00 5 4 1 20.00 N 00 0.00 0.00 22 77 11 44 7B 3 3 0 0.00 5 1 4 80.00 ADGN 01 0.00 20.00 0 2222 77 77 11 11 4555 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 AK J 00001 0.00 0.00 0.00 0.00 25.00 8 2 7 1 5 4 5 5 0 0.00 0 0.00 c-Fn* i o o f* CO Appendix 7 - Continued In d iv id u a l V isce ra l Findings In Fetuses Rat Teratology Study o f T-3352 Group 2 - 1 mg/kg 154-lbl M atern al Number: Number o f fetuse s examined Number o f fe tu se s w ith in normal lim it s Number o f fetuse s having one o r more v is c e ra l v a ria n ts Percent o f fetuse s having one o r more v is c e ra l v a ria n ts (X) Id e n tific a tio n le tte r(s ) o f fetuses w ith : Brain - le ft v e n tric a l d ila te d - dark m a te ria l around b ra in L iv e r - dark areas on lobe - a l l lobes appeared dark - dark area In liv e r Kldney(s) - d ila te d renal p e lv is U re te r(s) - distended Testes - small Skin - edema between s k in and p e rito n e a l w a ll Number o f fe tu se s having one o r more v is c e ra l anomalies Percent o f fe tu se s having one o r more v is c e ra l anom alles(X) Identification letter(s) of fetuses with: Kldney(s) - fused Cryptorchlsm 2222 7 77 7 1111 S5 S5 56 7 8 5 4 1 20.00 5 4 1 20.00 3 3 0 0.00 NP lH LN 0 00 0.00 0.00 0.00 2 7 1 S 9 6 6 0 0.00 2 7 1 6 0 5 S 0 0.00 2 7 1 6 1 5 5 0 0.00 2 7 1 6 2 S 5 0 0.00 22 77 11 66 34 6 6 0 0.00 5 3 2 40.00 2 7 1 6 5 S S 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 000 000000 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NP = Not Pregnant. Appendix 7 - Continued In d iv id u a l V isce ra l Findings In Fetuses Rat T eratology Study o f T-3352 Group 2 - 1 mg/kg M atern al Number: Number o f fe tu se s examined Number o f fe tu se s w ith in normal li m it s Number o f fe tu s e s having one o r more v is c e ra l v a ria n ts Percent o f fetuse s having one o r more v is c e ra l v a ria n ts (X) Id e n tific a tio n le tte r(s ) of fetuses w ith : Brain - le f t v e n tric a l d ila te d - dark m a te ria l around b ra in l i v e r - dark areas on lobe - a l l lobes appeared dark - dark area In U v e r Mdney(s) - d ila te d renal p e lvis U re te r(s) - distended Testes - small Skin - edema between s k in and p e rito n e a l w a ll Number o f fetuse s having one o r more v is c e ra l anomalies Percent o f fe tu se s having one o r more v is c e ra l anom alles(X) Identification letter(s) of fetuses with: Kldney(s) - fused Cryptorchtsm 2 7 1 6 a 4 2 2 50.00 2 7 1 6 9 5 5 0 0.00 2 7 1 7 0 4 4 0 0.00 2 7 1 7 1 6 6 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 2 7 1 7 8 6 6 0 0.00 2 7 1 7 9 6 6 0 0.00 A J II 1 0 0 00 00 00 0000 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 Appendix 7 - Continued In d iv id u a l V isce ra l Findings In Fetuses Rat T erato log y Study o f T-3352 Group 3 - 1 0 mg/kg 154-161 M atern al Number: Number o f fe tu se s examined Number o f fe tu se s w ith in normal lim it s Number o f fe tu s e s having one o r more v is c e ra l v a ria n ts Percent o f fe tu se s having one o r more v is c e ra l v a ria n ts (X) Id e n tific a tio n le tte r(s ) of fetuses w ith : Brain - le f t v e n tric a l d ila te d - dark m a te ria l around b ra in L iv e r - dark areas on lobe - a l l lobes appeared dark - dark area In liv e r Kldney(s) - d ila te d renal p e lv is U re te r(s) - distended Testes - small Skin - edema between s k in and p e rito n e a l w a ll Humber o f fe tu se s having one o r more v is c e ra l anomalies Percent o f fe tu se s having one o r more v is c e r a l anom alles(X) Id e n tific a tio n le tte r(s ) of fetuses w ith : Kldney(s) - fused C ry p to rc h ls m 2 7 1 8 0 4 4 0 0.00 2 7 1 a 1 3 3 0 0.00 2 7 1 8 2 5 5 0 0.00 2 7 1 B 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 0 0.00 2 7 1 8 9 5 5. 0 0.00 2 7 1 9 0 5 4 0 0.00 2 7 1 9 1 5 5 0 0.00 2 7 1 9 2 4 4 0 0.00 00000 00 00 0 100 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 c l e f t p a la te d u rin g e x te rn a l exa m in ation . Appendix 7 - Continued In d iv id u a l V isce ra l Findings In Fetuses Rat T eratology Study o f T-3352 Group 3 - 10 mg/kg M atern al Number: Number o f. fe tu s e s examined Number o f fe tu s e s w ith in normal lim it s Number o f fe tu se s having one o r more v is c e ra l v a ria n ts Percent o f fe tu se s having one o r more v is c e r a l v a ria n ts (%) Id e n tific a tio n le tte r(s ) of fetuses w ith : Brain - le f t v e n tric a l d ila te d - dark m a te ria l around b ra in L iv e r - dark areas on lobe - a l l lobes appeared dark - dark area In U v e r Kldney(s) - d ila te d renal p e lv is U re te r(s) - distended Testes - small Skin - edema between s k in and p e rito n e a l w a ll Number o f fe tu se s having one o r more v is c e ra l anomalies Percent o f fe tu se s having one o r more v is c e ra l anomalies(%) Id e n tific a tio n le tte r(s ) of fetuses w ith : Kldney(s) - fused C ry p to rc h ls m 22 77 11 99 34 4 4 0 0.00 NP 0 0.00 2 7 1 9 5 5 5 0 0.00 2 7 1 9 6 5 5 0 0.00 2 7 1 9 7 5 5 0 0.00 2 7 1 9 8 5 5 0 0.00 222 777 122 900 901 4a 3 0 0.00 6 5 1 16.67 6 4 2 33.33 2 7 2 0 2 6 6 0 0.00 2 7 2 0 3 5 5 0 0.00 2 7 2 0 4 1 1 0 0.00 N P 00 00 1000 00 0.00 0.00 0.00 0.00 25.00 0.00 0.00 0.00 0.00 0.00 B NP * Not P regnant. a Fetus B was noted to have no t a l l and a s h o rt tru n k d u rin g e x te rn a l e xa m in a tio n . Appendix 1 - Continued In d iv id u a l V isce ra l Findings In Fetuses Rat T erato log y Study o f T-3352 6roup 4 - 3 0 mg/kg 154-161 N a te rn a l Number: Number o f fetuse s examined Number o f fe tu se s w ith in normal lim it s Number of fe tu se s having one o r more v is c e ra l v a ria n ts Percent o f fe tu se s having one o r more v is c e ra l v a ria n ts (X) Id e n tific a tio n le tte r(s ) of fetuses w ith : Brain - le f t v e n tric a l d ila te d - dark m a te ria l around b ra in L iv e r - dark areas on lobe - a l l lobes appeared dark - dark area in liv e r Kldney(s) - d ila te d renal p e lv is U re te r(s) - distended Testes - small Skin - edema between s k in and p e rito n e a l w a ll Number o f fe tu se s having one o r more v is c e r a l anomalies Percent o f fe tu se s having one o r more v is c e ra l anom alles(X) Identification letter(s) of fetuses with: Kldney(s) - fused Cryptorchtsm 2 T 2 0 5 5 5 0 0.00 222 777 222 000 678 5 5 0 0.00 5 4 1 20.00 NP 0 000 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 00 0 0.00 0.00 0.00 22 77 22 11 34 5 5 0 0.00 NP 0 0.00 222 777 222 111 567 5 5 0 0.00 5 5 0 0.00 5 5 0 0.00 000 0.00 0.00 0.00 Appendix 7 - Continued In d iv id u a l V is c e ra l Findings In Fetuses Rat T e ra to lo g y Study o f T-3352 Group A - 30 mg/kg M a te rn a l Number: Number of fe tu se s examined Number o f fe tu se s w ith in normal lim it s Number o f fe tu se s having one o r more v is c e ra l v a ria n ts Percent o f fe tu se s having one o r more v is c e ra l v a ria n ts {%) Id e n tific a tio n le tte r(s ) of fetuses w ith : Brain - le f t v e n tric a l d ila te d - dark m a te ria l around b ra in L iv e r - dark areas on lobe - a l l lobes appeared dark - dark area In liv e r Kldney(s) - d ila te d renal p e lv is U re te r(s) - distended Testes - small Skin - edema between s k in and p e rito n e a l w a ll Number o f fe tu se s having one o r more v is c e ra l anomalies Percent o f fetuse s having one o r more v is c e ra l anom alles(X) Id e n tific a tio n le tte r(s ) of fetuses w ith : Ktdney(s) - fused C ry p to rc h is m 2 7 2 1 8 5 5 0 0.00 2 7 2 1 9 5a 5 0 0.00 2 7 2 2 0 S 5 0 0.00 2 7 2 2 1 4 4 0 0.00 2 7 2 2 2 2 2 0 0.00 2 7 2 2 3 4 4 0 0.00 22 77 22 22 45 6 6 0 0.00 NP 0 000000 0.00 0.00 0.00 0.00 0.00 0.00 0.00 2 7 2 2 6 5 5 0 0.00 22 77 22 22 78 5 5 0 0.00 m 5 4 1 20.00 2 7 2 2 9 6 6 0 0.00 N 000 0 0.00 0.00 0.00 0.00 NP - Not Pregnant. a Fetus L was noted to have an underdeveloped t a l l d u rin g e x te rn a l e xa m in a tio n . This fin d in g was confirm ed a t s k e le ta l e xa m in ation . T H ^ oo Appendix 8 In d iv id u a l S keletal Findings In Fetuses3 Rat Teratology Study o f T-3352 Group 1 - 0 mg/kg 154-161 M atern al Number: Number o f fetuses examined Number o f fe tu se s w ith in normal lim it s Number o f fetuse s having one o r more s k e le ta l v a ria n ts Percent o f fe tu se s having one o r more s k e le ta l v a ria n ts (X) id e n tific a tio n le tte r(s ) of fetuses w ith : Lagging O s s ific a tio n S k u ll - incom plete c lo su re (<T5X) - In te rp a rie ta l o s s ific a tio n Incomplete - pa rle ta ls o s s ific a tio n Irre g u la r - s u p ra o c c lp lta l o s s ific a tio n Incomplete - s u p ra o c c lp lta l nonfused - hyoid o s s ific a tio n Incom plete/nonosslfled Rib cage - sternebrae b i p a r t it e - sternebrae <3 o s s ifie d - r ib s >13 p a irs o s s ifie d - r ib s <13 p a irs o s s ifie d - rib s o s s ific a tio n Irre g u la r V e rte b ra l column - th o ra c ic ce n tra o s s if ic a t io n Incom plete - th o ra c ic centra nonfused - lumbar o s s ific a tio n Inco m p le te /n on osslfle d - lumbar arches fused - caudals <3 o s s ifie d - caudal vertebrae nonosslffed - sacral vertebrae nonosstfted P elvic G ird le - pubis o s s ific a tio n Incom plete/ n o n o s s tfle d - Ischium o s s ific a tio n Incomplete H lndllm bs - <4 o s s ifie d Bone Alignm ent Ribs - fused - forked - m alallgned th o ra c ic ce n tra and arches - angulated Sternebrae - checkered Vertebrae m alallgned - th o ra cic NP * Hot Pregnant. 3 There w e r e no skeletal anomalies noted In a n y fetuses. 22 77 11 33 01 B 2 6 75.00 NP 22 77 11 33 23 10 7 3 30.00 9 7 2 22.22 22 77 11 33 45 9 HP 6 3 33..33 2222222 77 7 77 7 7 111111 1 33 3 34 4 4 678 90 1 2 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 El IJ B El I E CF BCGL IJL B H 1 BEIUNO 1 INO E EFHIKL NO ILO G 0 KO C 0 BN LO 0 KN 0 CEIM CEN CEIM CJ EIN CEI B M EM Cl El cr> *- i Appendix 8 - Continued In d iv id u a l S ke le ta l Findings in Fetuses3 Rat T erato log y Study o f T-3352 Group 1 - 0 mg/kg 154-161 M aternal Number: Number o f fetuse s examined Number o f fetuse s w ith in normal lim it s Number o f fe tu se s having one o r more s k e le ta l v a ria n ts Percent o f fe tu se s having one o r more s k e le ta l v a ria n ts (%) Id e n tific a tio n le tte r(s ) of fetuses w ith : Laaolnn O s s ific a tio n S k u ll - Incomplete clo sure (<75*) - In te rp a rie ta l o s s ific a tio n Incomplete - p a rle ta ls o s s ific a tio n Irre g u la r - s u p ra o c d p lta l o s s ific a tio n Incomplete - s u p ra o c d p lta l nonfused - hyoid o s s ific a tio n Incom plete/nonosslfled Rib cage - sternebrae b ip a r t i t e - sternebrae <3 o s s ifie d - r ib s >13 p a irs o s s ifie d - r ib s <13 p a irs o s s ifie d - rib s o s s ific a tio n irre g u la r V e rte b ra l column - th o ra c ic ce n tra o s s if ic a t io n Incom plete - th o ra c ic centra nonfused - lumbar o s s ific a tio n Inco m plete/nonosslfled - lumbar arches fused - caudals <3 o s s ifie d - caudal vertebrae nonossified - sacral vertebrae nonossified P elvic G ird le - pubis o s s ific a tio n Incom plete/ n o n o s s ifie d - Ischium o s s ific a tio n Incomplete HindiIm bs - <4 o s s ifie d Bone Alignment Ribs - fused - forked - m alallgned th o ra c ic c e n tra and arches - angulated Sternebrae - checkered Vertebrae m alallgned - tho ra cic a There we re no skeletal anomalies noted 1n any fetus. 22222222 2222 77777777 7777 111 111 1 1 1 111 44444445 5555 34567890 1234 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 37.50 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 33.3 N EHLNO EHL F F BF I C CF F L GIJ CINO LI 3 H HILO 0 BF C BF HI H L CFIJ FJH E CHI FGN E II 8HIN H FH1L BE FJ L l1 H B 00044 Appendix B - Continued In d iv id u a l S keletal Findings In Fetuses3 Rat T eratology Study o f T-3352 Group 2 - 1 mg/kg 154-161 M atern al Number: Number o f fe tu se s examined Humber of fe tu se s w ith in normal lim it s Number o f fe tu se s having one o r more s k e le ta l v a ria n ts Percent o f fe tu se s having one o r more s k e le ta l v a ria n ts (X) Id e n tific a tio n le tte r(s ) of fetuses w ith : laqqfnq O s s ific a tio n S k u ll - Incomplete clo sure (<75X) - In te rp a rie ta l o s s ific a tio n Incomplete - pa rle ta ls o s s ific a tio n Irre g u la r - s u p ra o c c lp lta l o s s ific a tio n Incomplete - su p ra o c c lp lta l nonfused - hyoid o s s ific a tio n Incom plete/nonosslfled Rtbcage - sternebrae b ip a r tite - sterne bra e <3 o s s ifie d - r ib s >13 p a irs o s s ifie d - r ib s <13 p a irs o s s ifie d - rib s o s s ific a tio n Irre g u la r V e rte b ra l column - th o ra c ic ce n tra o s s ific a t io n Incom plete - th o ra c ic centra nonfused - lumbar o s s ific a tio n Inco m p le te /n on osslfle d - lumbar arches fused - caudaIs <3 o s s ifie d - caudal vertebrae nonosslfled - sacral vertebrae nonosslfled P elvic G ird le - pubis o s s ific a tio n Incom plete/ n o n o s s lfle d - Ischium o s s ific a tio n Incomplete HindiIm bs - <4 o s s ifie d Bone Alignment Ribs - fused - forked - m alallgned th o ra c ic c e n tra and arches - angula.ted Sternebrae - checkered Vertebrae m alallgned - th o ra cic NP * Not Pregnant. 3 There we re no skeletal an omalies noted In an y fetus. 2222 7777 1l 11 5555 56 7B 9 0 9 100.00 8 6 2 25.00 6 1 5 83.33 NP KM BFHJKM NP B M JKH B DJKMP E K K G K COL K B H 22222 77777 11111 56666 90 123 11 4 7 63.64 B 6 2 25.00 9 7 2 22.22 10 5 5 50.00 10 2 8 80.00 2222 777 7 111 1 66 6 6 456 7 B 8 0 0.00 9 8 1 11.11 a 7 1 12.50 9 3 6 66.67 CIKO BCFIR IP Cl L Cl BCEIKl L CG CJ RC G HO J IQ I I CGI CO C-MNK Appendix B - Continued In d iv id u a l S keletal Findings In Fetuses3 Rat Teratology Study o f T-3352 Group 2 - 1 mg/kg 154-161 M a te rn a l Number: Number o f fe tu se s examined Number o f fe tu se s w ith in normal lim it s Number o f fe tu se s having one o r more s k e le ta l v a ria n ts Percent o f fe tu se s having one o r more s k e le ta l v a ria n ts (X) Id e n tific a tio n le tte r(s ) o f fetuses w ith : Laqalna O s s ific a tio n S k u ll - Incomplete c lo su re (<75X) - In te rp a rie ta l o s s ific a tio n Incomplete - p a rle ta ls o s s ific a tio n Irre g u la r - s u p ra o c c lp lta l o s s ific a tio n Incomplete - su p ra o c c lp lta l nonfused - hyoid o s s ific a tio n Incom plete/nonosstfled Rib cage - sternebrae b i p a r t i t e - sternebrae <3 o s s ifie d - r ib s >13 p a irs o s s ifie d - r ib s <13 p a irs o s s ifie d - rib s o s s ific a tio n Irre g u la r V e rte b ra l column - th o ra c ic cen tra o s s ific a tio n Incomplete - th o ra c ic centra nonfused - lumbar o s s ific a tio n In co m p le te /n on osslfle d - lumbar arches fused - caudals <3 o s s ifie d - caudal vertebrae nonosslfled - sacral vertebrae nonosslfled P elvic G ird le - pubis o s s ific a tio n Incom plete/ n o n o s s lfle d - Ischium o s s ific a tio n Incomplete H lndllm bs - <4 o s s ifie d Bone Alignm ent Ribs - fused - forked - m alallgned th o ra c ic ce n tra and arches - angulated Sternebrae - checkered Vertebrae m alallgned - th o ra c ic 222 22 2 22 2 777 777 77 7 111111111 667 77 777 7 89 0 1234 5 6 B 6 2 25.00 9 5 4 44.44 6 4 2 33.33 10 B 2 20.00 8 5 3 37.50 10 5 5 50.00 8 1 7 87.50 2 10 03 27 100.00 70.00 222 777 11 1 777 78 9 B B 0 0.00 10 4 6 60.00 10 9 1 10.00 BN BFN BFN G OH H 0 EL EFI EN0 CE E EFL BC KL FKL Et NO EIL C KL CN CEHIK IN CH0 EF BC 0 Cl EL BC C F CFHIN 0 ECL C a There we re no skeletal an om al ie s noted In a n y fetus. b^OO Appendix 8 - Continued In d iv id u a l S keletal Findings In Fetuses3 Rat T e ra to lo g y Study o f T-3352 Group 3 - 1 0 mg/kg 154-161 M a te rn a l Number: Humber o f fe tu se s examined Humber o f fetuse s w ith in normal lim it s Humber o f fe tu se s having one o r more s k e le ta l v a ria n ts Percent o f fetuse s having one o r more s k e le ta l v a ria n ts (X) Id e n tific a tio n le tte r(s ) of fetuses w ith : laqqtno O s s ific a tio n S k u ll - Incomplete clo su re (<75X) - In te rp a rie ta l o s s ific a tio n Incomplete - p a rle ta ls o s s ific a tio n Irre g u la r - s u p ra o c c lp lta l o s s ific a tio n Incomplete - su p ra o c c lp lta l nonfused - hyoid o s s ific a tio n Incom plete/nonosslfled Rib cage - sterne bra e b i p a r t i t e - sternebrae <3 o s s ifie d - r ib s >13 p a irs o s s ifie d - r ib s <13 p a irs o s s ifie d - rib s o s s ific a tio n Irre g u la r V e rte b ra l column - th o ra c ic cen tra o s s ific a tio n Incomplete - th o ra c ic centra nonfused - lumbar o s s if ic a t io n In c o m p le te /n o n o s s lfle d - lumbar arches fused - caudals <3 o s s ifie d - caudal vertebrae nonosslfled - sacral vertebrae nonosslfled P elvic 61rdle - pubis o s s ific a tio n Incom plete/ n o n o s s lfle d - Ischium o s s ific a tio n Incomplete HindiIm bs - <4 o s s ifie d Rone Alignm ent Ribs - fused - forked - m a lallgn ed th o ra c ic c e n tra and arches - angulated Sternebrae - checkered Vertebrae m alallgned - th o ra cic 3 There w e r e no skeletal an omalies noted In any fetus. 22222222 2 77777777 7 1 11111 11 1 888888 8B8 0 1234 56 7 8 8 2 6 75.00 6 3 3 50.00 B 5 3 37.50 8 3 5 62.50 8 7 1 12.50 8 5 3 37.50 68 02 66 100.00 75.00 8 3 5 62.50 222 77 7 1 1 .1 899 90 1 9 9 0 0.00 8 3 5 62.50 9 1 8 B8.B9 2 7 1 9 2 7 7 0 0.00 NO HO 86 CF L I CE B 8B 3 J l BGJ C It FG CHIL BC BCIM BH BCF C CK l D1KL FN IK C I 1 EK CFILM C FMO DF61JL MO FGIJMO N IJ Appendix 8 - Continued In d iv id u a l S keletal Findings In Fetuses9 Rat T erato log y Study o f T-3352 Group 3 - 1 0 mg/kg 154-161 M atern al Number: Number o f fe tu se s examined Number o f fe tu se s w ith in normal lim it s Number o f fetuse s having one o r tore s k e le ta l v a ria n ts Percent o f fe tu se s having one o r more s k e le ta l v a ria n ts (X) Id e n tific a tio n le tte r(s ) of fetuses w ith : tagging O s s ific a tio n S k u ll - Incomplete clo su re (<75X) - In te rp a rie ta l o s s ific a tio n Incomplete - p a rle ta ls o s s ific a tio n Irre g u la r - s u p ra o c c tp lta l o s s ific a tio n Incomplete - s u p ra o c c lp lta l nonfused - hyoid o s s ific a tio n Incom plete/nonosslfled Rib cage - sternebrae b ip a r t i t e - sternebrae <3 o s s ifie d - r ib s >13 p a irs o s s ifie d - r ib s <13 p a irs o s s ifie d - rib s o s s ific a tio n Irre g u la r V e rte b ra l column - th o ra c ic ce n tra o s s ific a t io n Incomplete - th o ra c ic centra nonfused - lumbar o s s ific a tio n Inco m p le te /n o n o sslfle d - lumbar arches fused - caudals <3 o s s ifie d - caudal vertebrae nonosslfled - sacral vertebrae nonosslfled P elvic G ird le - pubis o s s ific a tio n Incom plete/ n o n o s s lfle d - Ischium o s s ific a tio n Incomplete H indllm bs - <4 o s s ifie d Bone Alignm ent Ribs - fused - forked - m alaligned th o ra c ic ce n tra and arches - angulated Sternebrae - checkered Vertebrae m alaligned - th o ra cic N P = N o t P r e g n a n t . 9 There were no skeletal anomalies noted In any fetus. 22 77 11 99 34 6 4 2 33.33 NP 2 22 2 22 2 222 7777777 777 1 11 1 12 2 222 9999900 000 5 6 7B9 0 1 23 4 9 4 5 55.56 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 2 0 0.00 0 COGO 0 G F F NO BFINO 0 CH CF K cue 1 K CK IN CFK C CFHIKN CFKO C CF L CO E CDFN EFIN 8 0 C CK D M 0 f^fr O 000447 Appendix B - Continued In d iv id u a l S k e le ta l F ind in gs 1n Fetuses8 Rat T erato log y Study o f T-3352 Group 4 - 3 0 mg/kg 154-161 M atern al Number: Number o f fe tu se s examined Number o f fe tu se s w ith in normal li m it s Number o f fe tu se s having one o r more s k e le ta l v a ria n ts Percent of fetuse s having one o r more s k e le ta l v a ria n ts (X) Id e n tific a tio n le tte r(s ) of fetuses w ith : Lagging O s s ific a tio n S k u ll - Incomplete clo su re (<75X) - In te rp a rie ta l o s s ific a tio n Incomplete - pa rle ta ls o s s ific a tio n Irre g u la r - s u p ra o c c lp lta l o s s ific a tio n Incomplete - su p ra o c c lp lta l nonfused - hyoid o s s ific a tio n 1ncomplete/nonoss1f1ed Rib cage - sternebrae b i p a r t it e - sternebrae <3 o s s ifie d - r ib s >13 p a irs o s s ifie d - r ib s <13 p a irs o s s ifie d - rib s o s s ific a tio n Irre g u la r V e rte b ra l column - th o ra c ic ce n tra o s s if ic a t io n Incomplete - th o ra c ic cen tra nonfused - lumbar o s s if ic a t io n In e o m p le te /n o n o s s lfle d - lumbar arches fused - caudals <3 o s s ifie d - caudal vertebrae nonosslfled - sacral vertebrae nonosslfled P elvic G irdle - pubis o s s ific a tio n Incom plete/ n o n o s s lfle d - Ischium o s s ific a tio n Incomplete Hlndllm bs - <4 o s s ifie d Bone Allonment Ribs - fused - forked - m alallgned th o ra c ic ce n tra and arches - angulated Sternebrae - checkered Vertebrae m alallgned - th o ra cic HP Hot Pregnant. 8 There were no skeletal anomalies noted In any fetus. 2222 7777 2222 0000 5678 8 2 6 75.00 9 1 6 88.89 10 4 6 60.00 NP P IL GLP LNO FI I 6LP L FP K D CGIJLN P GIJP l FGJ CFILP FL 0 PK C6LP H 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 JLO JO F 1 J 22 77 22 11 34 9 7 2 22.22 NP J 8 222 777 222 111 56 7 8 0 8 100.00 10 2 8 80.00 10 5 5 50.0 J BCFGIJ IN F IL CFNQ F CM N P F BF F i i 000448 Appendix B - Continued In d iv id u a l S keletal Findings In Fetuses8 Rat T e ra to lo g y Study oF T-3352 Group 4 - 3 0 mg/kg 154-161 M a te rn a l Number: Number o f fe tu se s examined Number o f fe tu se s w ith in normal lim it s Number o f fe tu se s having one o r more s k e le ta l v a ria n ts Percent o f fetuse s having one o r more s k e le ta l v a ria n ts (X) Id e n tific a tio n le tte r(s ) of fetuses w ith : tanging O s s ific a tio n S k u ll - Incomplete clo su re (<75X) - In te rp a rie ta l o s s ific a tio n Incomplete - pa rle ta ls o s s ific a tio n Irre g u la r - s u p ra o c c lp lta l o s s ific a tio n Incomplete - s u p ra o c c lp lta l nonfused - hyoid o s s ific a tio n Incom plete/nonosslfled Rib cage - sternebrae b i p a r t it e - sternebrae <3 o s s ifie d - r ib s >13 p a irs o s s ifie d - r ib s <13 p a irs o s s ifie d - rib s o s s ific a tio n Irre g u la r V e rte b ra l column - th o ra c ic ce n tra o s s ific a tio n Incomplete - th o ra c ic cen tra nonfused - lumbar o s s ific a tio n Inco m p le te /n on osslfle d - lumbar arches fused - caudals <3 o s s ifie d - caudal vertebrae nonosslfled - sacral vertebrae nonosslfled P elvic G ird le - pubis o s s ific a tio n Incom plete/ n o n o s s lfle d - Ischium o s s ific a tio n Incomplete H lndlim bs - <4 o s s ifie d Bone Alignm ent ~Rlbs - fused - forked - m alalfgned th o ra c ic ce n tra and arches - angulated Sternebrae - checkered Vertebrae m alaltgned - th o ra c ic NP * Not Pregnant. a There we re no skeletal an omalies noted In any fetus. 22 2 2 2 2 2 2 77 7 7 7 7 7 7 222 222 22 1 1222222 8 90 12345 9 8 1 11.11 9 5 4 44.44 8 4 4 50.00 8 7 1 12.50 2 1 1 50.00 6 1 5 83.33 11 NP 0 11 100.00 EK E 0K EK L CLN COFJ CK CEIKLP CK BCEKl DI NP 3 EHLR E H 8 J CIKLR L l EFl E E l L 222 2 7 77 7 2 22 2 2222 6 789 9 5 4 44.44 10 7 3 30.00 8 1 7 87.50 11 5 6 54.! BEHI EFK K 8 N l HIN HKN 8CF1 CH N BCEFHI N l 8F NQ N N i cn 00 i - 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. Roval Statist. Soc. Su p d I.. 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, 6. 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." 3. Am. Stat. Assoc.. 50:1096-1121, 1955. Dunnett, C. W., "New Tables for Multiple Comparisons with a Control." Biometrics. 20:482-491, 1964. Fisher, R. A., Statistical Methods for Research Workers. Oliver & Boyd, Edinburgh, 1950. Fleiss, J. L., Statistical Methods for Rates and Proportions. 2nd Ed., Wiley, New York, Ch. 9, 1981. Games, P. A., and Howell, J. F., "Pairwise Multiple Comparison Procedures with Unequal N's and/or Variances: A Monte Carlo Studv." 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. 000449 - 70 - Appendix 9 - Continued References Rat Teratology Study of T-3352 STATISTICAL METHOOS/LABORATORY PROCEDURES 154-161 Hiller, 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. 1., "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. 0004S0