Document zoYQkr5OLx6OMOQr6Zp5nkgG6

v .f *_vV * -3 r >V. ( ^ h a z l e t o n LABORATORIES AMERICA, INC. -3a82 n0 n0 w. CC*>Ui*o>n0 ?n Ui*flNfufliiKtfIl, V\siHtfNNiN. A viMQ>MA 9 8 1 8 0 . U -S .A . RAT TERATOLOGY STUDY T-3351 FINAL REPORT Submitted to 3M Comoanv St. PauLMiuneseta December 19, 1983 000532 (g) H A Z L E T O N LABORATORIES AMERICA. INC. a o a U l i l l U B Q T U B N . 0 I K 1.vviiin| ^na.vnaiNi* aa^o.u.a.A. OFFICE OF QUALITY ASSURANCE Project Title: Rat Teratology Study Project Mo.: 154-160 Quality Assurance inspections of the study and review of the final report of the above referenced project were conducted according to the standard operating procedures of the Office of Quality Assurance and according to the general requirements of the Good Laboratory Practice regulations that were issued on December 22, 1978, by the Food and Drug Administration for compliance on and after June 20, 1979. Findings from the inspections and final report review were' reported to management and to the study director on the following dates: Inspections/Review Findings Reported Inspector/Reviewer Protocol 6/15/83 Study 7/6,8,11,12/83 Final report 12/6-9/83 6/15/83 7/15/83 12/16/83 E. Burroughs E. Burroughs P. Runge Uta*' V Office of Qualft Assurance 000533 HAZLETON LABORATORIES AMERICA. INC. a a o o i i i s i u c t l s n P 'k i . v n n * . v i q in ia aa^ao. u a.A SUBJECT: Rat Teratology Study Project No. 154-160 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 Staff Scientist Department of Toxicology Laboratory Supervision: GEORGE A. BURDOCK, Ph.O. Rodent Toxicology I Department of Toxicology Teratology: t RUTH S. DURL00, B.S. Research Associate Department of Toxicology Report Preparation: B.S. Technical Writer Scientific Resources Department tls 000534 * w* s- ^Si~r H A Z L E T O N LABORATORIES AMERICA. INC. 9aoo .e csa u n o v ii n n a v a q in ia aaa.u..A. TABLE OF CONTENTS SUMMARY INTRODUCTION CONTROL ANO TEST MATERIALS TEST ANIMALS METHOOS 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 OATA Mortality and Clinical Observations Body Weights and Food Consumption Uterine Weights Gross Pathology RESULTS - CESAREAN OATA 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 Minus GravidUterine Weights Table 5 - Summary of Maternal Gross Pathology Findings Key to Tables 6 - 14 Table 6 - Summary of Mean Ovarian and Uterine Data Page 1 3 3 4 5 5 5 6 6 7 8 8 8 9 11 12 12 12 13 13 14 14 14 15 17 18 19 20 21 23 25 000535 HAZLETON LABORATORIES AMERICA, INC. a o o w c s s i l o q t u h n P ' < i .v i * n n 4 V i r g i n i a a a ^ s o . u .*.a . TABLE OF CONTENTS - CONTINUED Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 - Summary of Mean U t t e r Data - Summary of External Findings - Summary of Visceral Findings - Summary of Skeletal Findings - Incidence of External Findings Per Litter - Incidence of Visceral Findings Per Litter - Incidence of Skeletal Findings Per Litter - Mean Incidence of External, Visceral, and Skeletal Findings Per Litter APPENOICES Appendix 1 - Individual Clinical Signs key to Appendices 2, 3, and 4 Appendix 2 -Individual and Mean Maternal Body Weights and Body Weight Changes Appendix 3 -Individual and Mean Food Consumption Appendix 4 -Individual and Mean Terminal Body Weights, Gravid Uterine Weights, and Terminal Body Weights Minus Gravid uterine Weights Appendix 5 -Individual and Mean Ovarian and Uterine Data Appendix 6 -Individual and Mean Litter Data Appendix 7 -Individual Visceral Findings in Fetuses Appendix 8 -Individual Skeletal Findings in Fetuses Appendix 9 -References Page 26 27 28 29 30 31 32 33 34 38 39 43 47 51 55 59 67 75 000536 HAZLETON LABORATORIES AMERICA, INC. 92 00 LEESBURG TURNPIKE, VIENNA. VIRGINIA 32100. U.S.A. s p o n s o r : 3M company D A T E : December 19, 1983 M A T E R IA L : T-3351 S U B JE C T: F IN A L REPORT Rat Teratology Study Project No. 154-160 SUMMARY T-3351, suspended In corn oil at concentrations Intended to deliver 1, 5, or 10 mg/kg/day (Groups 2, 3, and 4, respectively), was administered by oral Intubation to mated female Sprague-Dawley CO 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. Two Group 4 females died. Treatment-related clinical observations noted 1n Groups 3 and 4 Included thinness, hunched appearances, rough halrcoats, alopecia, and anorexia. Food consumed by Groups 3 and 4 animals was significantly less than control both during' treatment and throughout gestation. Compared to control body weight gains, significantly less body weight was .gained by Groups 3 and 4 females throughout gestation. Actual loss of body weight occurred in Groups 3 and 4 animals once treatment had been initiated. Terminal body weight minus gravid uterine weight was also significantly decreased In 000537. H A Z L E T O N LABORATORIES AMERICA. INC. 9 2 0 0 L f I S a u R G 'u B N O 'K I v f NNA V'AQiNiA 2 2 1 0 0 u S* - 2- 154-160 Groups 3 and 4. Treatment-related gross pathology in Group 4 animals included incidences of gastrointestinal tract effects. Statistical analysis revealed a positive treatment-related trend in fetal loss, attributable primarily to an increased incidence of late resorbing fetuses and dead fetuses in litters from Group 4 dams. Mean male and female fetal body weights were significantly decreased in fetuses Groups 3 and 4 litters. Significant increases in external and visceral anomalies occurred 1n fetuses from Group 4 dams and included subcutaneous edema, cleft palate, and cryptorchism. Anomalies were observed primarily in fetuses from Group 4 dams exhibiting signs of severe maternal toxicity, i.e., decreased food consumption and weight loss. Fetal toxicity manifested as increased numbers of late resorbing fetuses and dead fetuses, decreased fetal body weights, and delays in skeletal system ossification occurred in litters derived from that group as wel1. The specificity and frequency of these results Indicate that administration of T-3351 to pregnant rats during Days 6-15 of gestation at a dose of 10 mg/kg results in maternal toxicity, fetotoxlcity and an increased incidence of external and visceral anomalies and skeletal variants. T-3351 did not appear to be teratogenic in rats at dose levels less than or equal to 5 mg/kg. 000538 f<3fc @ H A Z t e t O I \ LABORATORIES AMERICA, INC. * a o o .wit s>au>naaa tu n ^ k ai , uv^iaifnuiLn a v a o in ia a a i o ,u .M . -3- 154-1 60 INTRODUCTION This study was designed to evaluate the embryo/fetal toxicity and teratogenic potential of T-3351 when administered by oral gavage to pregnant rats during the period of fetal organogenesis. The rats were placed in breeding on Dune 27, 1983, and cesarean sections were completed on Duly 26, 1983. The study was conducted according to a protocol de signed 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-3351, a white powder, was received from the sponsor on Danuary 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. 000539 @ H A Z L E T Q N lLABORATORIES AMERICA. INC 9 3 0 0 w d S l u a c ri^aistP iK . vmoiNi aa^so. u.s * -4- 154-160 TEST ANIMALS Two hundred sixty (one hundred thirty/sex) sexually mature, cesarean-derived Sprague-Dawley CrlrCD* (SD)BR rats were received from Charles River Breeding Laboratories, Inc., Kingston, New York, on June 8, 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, two male rats were euthanized due to an unthrifty appearance. Following an examination by a staff veterinarian for health status, one hundred twenty eight rats/sex were placed in breeding. The rats were housed one male and one female per cage during breeding. Following confirmation of mating, the females were uniquely identified by ear tags and individually housed In elevated stainlesssteel cages. Food (Purina Rodent Laboratory Chow* 5001) and tap water (via an automatic watering system) were available ad libitum. The mean room temperature the standard deviation was 72.9F + 1.36 and the mean relative humidity the standard deviation was 69.IX 3.16 during the study. A twelve-hour light/dark cycle was maintained. 000540 H A Z L E T O N LABORATORIES AMERICA. INC. 9 3 0 0 LC 6ltU *> 0 r v iIN N A . vtRQiNtA 3 3 ^ 8 0 . U.8 A -5- 154-160 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 nine days of cohabitation and mating was discontinued. Daily vag inal 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 wa$ 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 5 4 25 10 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. All males and all remaining females were sacrificed via carbon dioxide asphyxiation and discarded without necropsy once a sufficient number of matings were confirmed. 000541 * t* .4 ? 'jg- ,A " HAZLETON LABORATORIES AMERICA, INC. e ao o t iis a u O Q t u b n # i k i , v i n n a , v >o i n a a a i o . u .. a . - 6- 154-160 Compound Preparation and Administration Suspensions of the test material in the corn oil vehicle were prepared on a weight per volume basis. The required amount of compound for each level was weighed on an electronic Arbor 126 balance and trans ferred to a 7 ml tissue grinder. Approximately 3 ml of corn oil was added and the test material was ground Into a fine suspension. This suspension was transferred to a precalibrated beaker and any remaining compound in the tissue grinder was rinsed Into the beaker. Additional corn oil was added to the suspension to produce the desired concentration and the suspension was mixed on a magnetic stirrer. Prepared suspensions were mixed with a magnetic stirrer during dosing. Females were given the appropriate dosing suspension or vehicle by oral intubation on a dally 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. Fresh dosing suspensions were prepared weekly and stored under refrigeration (approximately 40F). Samples of each test mixture as well as the vehicle were sent to the sponsor for analysis. Maternal Observations and Records All animals were examined twice daily for mortality and moribun- dity (from day of receipt through animal sacrifice) and once daily for clinical signs of toxicity and pharmacologic effects (throughout gesta tion). Individual body weights were recorded at-initiation and on Days 0 0 0 * ^ 4 ? ') 900 L U J I V LABORATORIES AMERICA. INC. f u ^ N i 'K I , V 'IN N . VIMQIMIA 9 9 * 9 0 . U.9 * -7 - 154-160 6, 8, 12, 16, and 20 of presumed gestation. Food consumption during gestation was determined on Days 6, 8, 12, 16, and 20. Cesarean Sacrifice A gross necropsy was performed on all females found dead or terminally sacrificed. The uterus and ovaries from found dead females were removed and examined for the number of implantation sites and corpora lutea. Prior to terminal sacrifice and cesarean section on Day 20 of gestation, all surviving females were assigned random numbers so that all personnel performing cesarean sections and/or subsequent external, visceral, or skeletal examinations of the fetuses were unaware of the dose level from which the animals were derived. On Day 20 of gestation, all surviving females were weighed and sacrificed by carbon dioxide asphyxiation. The uterus from each female was excised, weighed, and examined for the number and placement of uterine Implantation sites, number of live and dead fetuses, number of early and late resorbing fetuses, and any abnormalities. The uterus was not reweighed after the contents were removed. 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 1n Bouln's solution for visceral evalua tion. The next two fetuses were processed for skeletal evaluation. This 000543 HAZLETON LABORATORIES AMERICA. INC. 9WOO b .C l U * 0 V 'IN N V>QINIA 8910Q. W * . 8- - 154-160 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 was fixed in 8ou1n's solution and sectioned by the Wilson Technique for assessing soft tissuedevelopment (Wilson and Warkany, 1965). During visceral examination of the fetuses, particular attention was paid to examination of the eyes, palate, and brain. Stainless-steel razor blades were used for sectioning procedures. Skeletal Examination of Fetuses The remaining fetuses were eviscerated and placed in 95% ethyl alcohol. After proper fixation and dehydration, the skeletons were macerated and stained in 1% KOH with an alizarin red solution, and cleared 1n 30% glycerol(modified Staples and Schnell, 1964). This eval uation 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. 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 1n 95% ethyl alcohol and sealed in plastic bags after sectioning; (3) Fetuses stained for skeletal 000S44 ( ^ ) H A Z L E L O f M lLaAbBiORATORIES AMERICA, INC. 9 0 0 b l l l u 0 ^ U n N fliK I, V lIN N A VliiQiN** a a i o , u.,a . -9 - 154-160 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 1f the variances proved to be homo geneous, the data were analyzed by one-way classification analysis of variance (ANOVA) (Winer, 1971). If the variance proved to be hetero geneous, a series of transformations was performed until variance homo- 2 geneity was achieved. These transformations were 1og^Q, square (X ), square root (X 1 / 2), reciprocal(1/X), angular (arcsine X 1 /2 ), and rank, in thatorder. If rank transformation was ineffective 1n removing variance heterogeneity, ANOVA of ranked data was completed. If ANOVA of untransformed or transformed data was significant, Dunnett's t-test (Dunnett, 1955 and 1964) was used for control vs. compound-treated group mean comparisons. If ANOVA was not significant, the analysis was complete. Data transformations are designated throughout this report as presented on the following page. 000545 (g) H A Z L E T O N LABORATORIES AMERICA, INC. a9 9A 0n0 w. eeb Sn aO.u,O Ga yr ^.amN O ' m . wvi'tlrwl bAK *. v i0 G i n A 99100. u S A - 10 - 154-160 A = Data analyzed following log-jo transformation. B = Data analyzed following square (X2) transformation. C = Data analyzed following square root (X1/2) transformation. 0 = Data analyzed following reciprocal (1/X) transformation. E = Data analyzed following angular (arcsine X1/2) transformation. F = Data analyzed following rank transformation. Mean fetal body weights per litter were statistically analyzed as follows: Bartlett's test for homogeneity of variances (Bartlett, 1937) was performed by one-way classification of covariance (ANCOVA) (Winer, 1971). If ANCOVA was significant, control vs. treatment group comparisons were analyzed using the Games and Howell modification of the Tukey-Kramer honestly significant difference test (Games and Howell, 1976). Tests for homogeneity of variances, ANOVA, and ANCOVA were evaluated at the 5.OX one-tailed probability level. Control vs. compound-treated group mean comparisons of the above data were evaluated at the 5.OX two-tailed probability level. In addition to the above data, percent fetal viability, percent fetal loss (dead and resorbing fetuses), percent early, late, and totalresorptions, and the number of dead fetuses were analyzed by nonparametric one-way ANOVA (Kruskal and Wallis, 1952, 1953; Miller, 1966) and the Terpstra-Jonckheere test for trend (Terpstra, 1952; Jonckheere, 1954). The litter was used as.the experimental unit. The teratology data listed on the next page were analyzed using the 00054G LABORATORIES AMERICA. INC. giaoa cei*u**Q t u a n p ik i. v iin n a .viaqimi a aa^ao . u * * - Il 154-160 Cochran-Armitage test for linear trend in proportions (Cochran, 1954; Armitage, 1955; Fleiss, 1981) and Fisher's "exact" test (Fisher, 1950). Visceral Anomalies Skeletal Variants Subcutaneous edema Cleft palate Cryptorchlsm Number of Utters affected Number of fetuses affected Skull Pectoral girdle R1b cage Vertebral column Pelvic girdle Limbs Bone alignment Number of litters affected Number of fetuses affected 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. 000547 A 'a ' I ^ H A Z L E T O N LABORATORIES AMERICA. INC. M 0 0 i.l> a u "0 V I |N^N A . VlOQllVi'A a a ^ e o . U S - 12 - *< 154-160 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. Two Group 4 females were found dead on Day 17 prior to cesarean section on Day 20 of gestation. No other animals were found dead or sacrificed in. extremis during the study. Treatment-related clinical observations were noted in several of the Groups 3 and 4 animals during the treatment and posttreatment phases. These observations included hunched and thin appearances, anorexia, bloody discharge from vagina, urine stains, alopecia, rough halrcoat and bloody crust. 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. Statistical analysis revealed a significantly lower than control mean body weight gain 1n the Groups 3 and 4 females for Days 6-8, 6-16, and 0-20 of presumed gestation. These findings were considered to be treatment related since, compared to the treatment .phase, there was a proportionally greater than control increase 1n mean body weight gain in the treated females during the posttreatment phase (Days 16-20). 000548 HAZLETON LABORATORIES AMERICA, INC. 9 9 0 0 L l t l t u A a T L P N O i < | , v < | N N A . v * * O U S M * 3 9 *1 9 0 .U 9 *. - 13 - 154-160 Mean total food consumption was significantly lower in the Group 4 females during Days 17-20. Significant decreases 1n mean food consumption were also noted 1n the Groups 3 and 4 females during Days 7-16 and 0-20 of presumed gestation when compared to control, concomitant with the decrease 1n body weight gain during the same Intervals. Uterine Weights Individual and mean terminal body weights, gravid uterine weights, and terminal body weights minus gravid uterine weights are presented 1n Appendix 4 and Table 4, respectively. The mean gravid uterine weight of the Group 4 females was sig nificantly lower than control. The mean terminal body weights minus the gravid uterine weights were lower in the treated groups when compared to the control group, with significant decreases noted in the Groups 3 and 4 females. Gross Pathology A summary of maternal gross pathology findings 1s presented in Table 5. An increased incidence of stomach lesions was noted 1n the Group 4 animals. Remaining gross pathology findings were considered incidental. 000549 HAZLETON LABORATORIES AMERICA, INC. 9 3 0 0 u i e s S u A G T u f l N B i K B , V ' C N N A V ' O Q ' N I A 3 3 'A G . U-3 .A. - 14 - 154-160 RESULTS - CESAREAN DATA Individual and mean ovarian and uterine data are presented in Appendix 5. Individual and mean U t t e r 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 incidence of early resorptions was comparable between the control and treated groups. Nonparametric analyses of the mean Incidence of late resorptions, total resorptions, number of dead fetuses, and fetal loss did not indicate statistical significance. However, there was a significant linear trend towards an increased incidence in these data with respect to control. The primary trend component was contributed by the high-dose group. The mean fetal weights of the Groups 3 and 4 males and females were significantly lower than their respective controls. The percent of male fetuses was 52.29%, 54.24%, and 60.38% for Groups 2, 3, and 4, respectively, and 44.01% for the control group. 000550 HAZLETON LABORATORIES AMERICA. INC. ao o u t t a o v j ^ o t u b n .< i v i i n n a . v '* o n i a a 9 < o . u .0 .a - 15 - 154-160 Fetal Development Statistically significant findings 1n the teratology data are presented in the following chart: Statistically Significant Teratology Data Teratology Observation Group: Visceral anomalies Subcutaneous edema Cleft palate Cryptorchism Number of litters affected Number of fetuses affected Skeletal variants Skull Pectoral girdle Rib cage Vertebral column Pelvic girdle Limbs Bone alignment Number of litters affected Number of fetuses affected 234 S+ S* s+ s+ s+ S+ s-s+ S+- s+ s+ S- s+ s+ s+ s+ Trend S s S s s s s s s s s s s s Departure from Trend S S NS NS S S S S S S s NS NS S S Significant NS Not significant 000551 HAZLETON LABORATORIES AMERICA, INC. 0 3 0 0 W t U * 0 T y B N i i K I , V I I N N A . V l A O ' M ' A 3 3 1 0 0 .U.0 .A. - 16 - 154-160 Significant treatment-related increases in the incidences of visceral anomalies and skeletal variants were noted in the Group 4 fetuses. The number of Group 4 Utters containing anomalous fetuses was also significantly increased compared to control. External and visceral anomalies observed Included cleft palate, subcutaneous edema, and cryptorchlsm. Those anomalies occurred primarily in fetuses derived from litters whose mean male or female pup body weights were significantly below those of the corresponding control litters. Dams producing affected litters had significantly decreased food consumption throughout treatment and decreased body weight gain or actual body weight loss during gestation. Numerous clinical signs of toxicity were also present in these animals. 000552 Table 1 Summary of Maternal Clinical Observations3 Rat Teratology Study of T--3351 Observation ' Group: Oose Level (mg/kg): Pretreatment Days 0--5 1234 0 1 5 10 Treatment Days 6-15 123 015 4 10 Number of females examined Number of females appearing normal Number of females found dead or sacrificed prior to Day 20 25 25 25 25 25 25 25 25 0000 25 25 25 25 21 21 16 11 0000 Hunched Thin Anorexia Ataxia Sensitive to touch Soft feces Bloody discharge from vagina Urine stains Alopecia Rough halrcoat Bloody crust Small eye Swollen neck \ 27 117 1 1 1 1 3359 66 1 1 aNumerals Indicate the number of animals with that particular finding. 154-160 Posttreatment Days 16-20 1234 0 1 5 10 25 25 25 25 21 20 17 5 v 0002 2 16 2 15 X a y- 1 11 j ' 1 1 : l-T? 3 1 15 L f: 3 5 4 12 $ 1 2 13 1 16 f.r 1 v-r 00055 CO I* Table 2 Mean Maternal Body Weights and Body Weight Changes Rat Teratology Study of T--3351 154-160 Body Weight Mean Weight (g) Mean Change (g) Dayill 0 N: 6 N: 8 N: 12 N: 16 N: 20 N: 0-6 6-8 , 6-12 6-16F 6-20 16-20f 0-20f Group 1 0 mg/kg 270.08 24 298.47 24 301.39 24 318.31 24 338.53 24 395.41 24 28.38 2.93 19.84 40.06 96.95 56.88 125.33 Group 2 1 mg/kg 271.03 23 296.05 23 298.04 23 308.18 23 329.20 23 389.69 23 25.03 1.99 12.13 33.15 93.64 60.45 118.67 Group 3 5 mg/kg 263.25 23 292.80 23 288.22 23 290.09 23 305.34 23 367.11 23 29.54 -4.58s" -2.70 12.54s" 74.32 61.77 103.86s- Group 4 10 mg/kg 269.30 22 297.72 22 293.63 22 276.25 22 265.12 22 301.91 22 28.43 -4.05s-21.48 -32.60s- 5.40 36.63 33.45s" 00055 N: Indicates the sample size on which the mean calculations were based. Only pregnant females were used n mean calculations. Table 3 Mean Maternal Food Consumptlon(g) Rat Teratology Study of T-3351 Interval Days Group 1 0 mg/kg 0-6 132.67 N: 24 7-8 37.48 N: 24 9-12 74.58 N: 24 13-16 78.52 N: 24 17-20F 97.25 N: 24 7-1 6b 190.58 N: 24 0-20b 420.49 N: 24 Group 2 1 mg/kg 128.01 23 35.03 23 68.38 23 68.45 23 97.17 23 171.85 23 397.03 23 Group 3 5 mg/kg 134.92 23 31.53 22 59.58 20 57.89 20 87.87 19 147.91s" 19 363.14s" 18 ' 154-160 I *4c* Group 4 10 mg/kg 133.33 22 37.64 22 36.86 18 22.75 19 39.33S14 97.63s" 17 262.89s" 13 ijt; > Hto 1 ti j % rr/- *- f 00055 ^ N:' Indicates the sample size on which the mean calculations were based. Only pregnant females were used In mean calculations. Invalid food consumption values were not Included 1n mean calculations. c- P** lv Group and Dose Level 1 0 mg/kg 2 1 mg/kg 3 5 mg/kg 4 10 mg/kg Table 4 Mean Terminal Body Weights, Gravid Uterine Weights, and Terminal Body Weights Minus Gravid Uterine Weights Rat Teratology Study of T-3351 Terminal Bodv Welqht 395.41 N: 24 389.69 N: 23 367.11 N: 23 301.91 N: 20 Gravid Uterine Weight8 74.35 24 75.59 23 73.46 22a 60.51s" 20 Terminal Body Weight Minus Gravid Uterine Weiqht 321.07 24 314.10 23 293.38s" 22a 241.40s" 20 154-160 -i y if Jr 1* >, \ ?w" aThe gravid uterine weight of one Group 3 female was inadvertently not recorded. N: Indicates the sample size on which the mean calculations were based. Only pregnant females were used In mean calculations. *v.- 000556 n *i Table 5 Summary of Maternal Gross Pathology Findings Rat Teratology Study of T-3351 154-160 Organ and Description Group: 1 2 3 4 Dose Level (mg/kg): 0 1 5 10 Number of animals examined Number with no gross pathology 25 25 25 23 (2) 22 24 19 16 (0) THYMUS Firm Enlarged 1 1 LUNG Focal areas - dark red 1 HEART Right atrium enlarged 1 SPLEEN Enlarged Cystic 1 1 KIONEY(S) Enlarged Irregularly shaped Pale Pelvis dilated Constricted across midline Mottled tan and dark red Pelvis had a firm, white calculus 1 1 12 1 5 2 (1) 1 1 1 ABDOMEN Tissue mass 1 000557 ( ) - Findings in animals found dead during the study. Table 5 - Continued Summary of Maternal Gross Pathology Findings Rat Teratology Study of T-3351 Organ and Description Group: Dose Level (mg/kg): 1 0 STOMACH Glandular mucosa - pitted areas - reddened - depressed area - red Nonglandular mucosa - raised area - dark (thin section in wall) - pinpoint, depressed areas - walls thin - thickened area - red - dark foci Distended with dark red material Contained yellow mucous Walls thickened Walls thin PEYER'S PATCHES Enlarged/promlnent ,1 MANDIBULAR LYMPH NODES Reddened ALL LYMPH NOOES Enlarged 1 URINARY BLADDER Walls thickened Contained thick white fluid OVARY(IES) Clear fluid-filled cyst 1 ( ) = Findings 1n animals found dead during the study. 2 ___3 15 154-160 \ *r. _4 10 1 (1 ) 0) 1 1 (1) ( 1) ( 1) 1 1 (1) 1 I, s. t ro ro V'y 1 i`>i* : 1 1 if at. 000558 A - 23 - 154-160 Key to Tables 6-14 Pregnancy rate (percent) - (number of pregnant rats/number of rats mated) 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). Mean Incidence of Resorptions (percent)8 - Group mean of ([resorptions per litter/implantations per litter] x 100). Mean Incidence ofFetal Mortality (percent) - Group mean of ([dead and resorbing fetuses per litter/ implantations per litter] x 100). Mean Incidence ofFetal Viability (percent) - Group meanof ([live fetuses per litter/implantations per Utter] x 100). Mean Incidence of External Variants (percent) - Group .mean of ([number of fetuses per litter with external variants/number of fetuses per litter examined externally] x 100). Mean Incidence ofExternal Anomalies (percent) - Group mean of ([number of fetuses per litter with external anomalies/number of fetuses per litter examined externally] x 100). Mean Incidence ofVisceral Variants (percent) - Group mean of ([number of fetuses per litter with visceral variants/number of fetuses per litter examined viscerally] x 100). aValues calculated separately for early, late, and total resorptions. 000559 - 24 - 154-160 Key to Tables 6-14 - Continued Mean Incidence of Visceral Anomalies (percent! - Group mean of ([number of fetuses per U t t e r with visceral anomal1es/number of fetuses per U t t e r examined viscerally] x 100). Mean Incidence of Skeletal Variants (percent) - Group mean of ([number of fetuses per U t t e r with skeletal varlants/number of fetuses per U t t e r examined skeletally] x 100). Mean Incidence of Skeletal Anomalies (percent) - Group mean of ([number of fetuses per U t t e r with skeletal anomal1es/number of fetuses per U t t e r examined skeletally] x 100). 000560 Table 6 Summary of Mean Ovarian and Uterine Data Rat Teratology Study of T-3351 154-160 Number of females with mating confirmed Number of pregnant females Pregnancy rate (X) Number of females surviving to Day 20 Survival rate (X) Mean number of: Corpora lutea Implantations Early resorptions Late resorptions Total resorptions Indices calculated on a per Utter basis: Mean Implantation efficiency (X) Mean Incidence of early resorptions (X) Mean Incidence of late resorptions (X) Mean incidence of total resorptions (X) Group: 1 2 3 4 Dose Level (mg/kg): 0 1 5 10 *t, 25 25 25 24 23 23 96 92 92 25 25 25 100 100 100 25 |* 22 T' 88 & 23 92 6 16.6 14.5 1.0 0.0 1.0 15.9 14.4 0.8 0.0 0.8 15.8 14.6 0.7 0.0 0.7 16.6 14.4 1.6 0.9 2.4 **; ft* h "h 87.90 7.00 0.00 7.00 91.14 5.53 0.00 5.53 92.70 4.70 0.29 5.00 87.72 11.32 5.10 16.42 kt<*. aOne late resorption was noted for female No. 27086, therefore, the actual mean was 0.04. 000561 Table 7 Summary of Mean Ut te r Data3 Rat Teratology Study of T-3351 154-160 Mean number of: Fetuses - dead - live Indices calculated on a per litter basis: Mean IncldeHte of fetal mortality (%)c Mean Incidence of fetal viability (%) Mean percent males ( % ) Live fetuses Mean body weight (g)d Males - unadjusted mean - covariance adjusted mean Females - unadjusted mean - covariance adjusted mean Group: Dose Level (mg/kg): 1 0 0 .0 13.5 7.00 93.00 44.01 2 1 0 .0 13.6 5.53 94.47 52.29 3 5 0.0b 13.8 5.28 94.72 54.24 4 10 0.5 11.6 19.43 80.59 60.38 3.28 3.28 3.17 3.16 3.23 3.23 3.10 3.10 3.10 3.10s" 2.97 2.97s" 2.64 2.63s" 2.57 2.59s" U _ V; V r If /ro 9.0> aSex, percent males, and mean body weight data Include values for live fetuses only, bone dead fetus was noted for female No. 27101, therefore, the actual mean was 0.04. cPercent mortality Includes resorptions as well as dead fetuses. ^Statistical analysis performed on covariance adjusted means. 000562 US Table 8 Summary of External Findings Rat Teratology Study of T -3351 154-160 Number of fetuses examined Number of fetuses within normal limits Number of fetuses with variants Number of fetuses with anomalies Number and type of anomalies Skin - edematous Palate - cleft Group: 1 2 3 4 Dose Level (mg/kg): 0 1 5 10 325 313 317 231 325 313 317 196 00 00 0 0 0 35 0 0 0 45 32 13 f 000563 Table 9 Summary of Visceral Findings Rat Teratology Study of T--3351 154-160 t Group: 1 2 3 4 Dose Level (mg/kg): 0 1 5 10 Number of fetuses examined Number of fetuses within normal limits Number of fetuses with variants Number of fetuses with anomalies 115 113 115 111 105 108 485 012 81 56 1 24 Number and type of variants Brain - cerebral hemisphere contained dark area Eye(s) - contained dark material Liver - dark areas K1dney(s) - pelvis dilated Ureter(s) - distended - undulated 4 10 5 1 1 1 1 42 352 1 Number and type of anomalies Skin t edematous Palate - cleft Cryptorchlsm 0 1 3 44 1 1 21a 15b 28 W & % r0o0, .r1* *V*t aTwelve fetuses with edematous skin seen externally were confirmed at visceral examination. *>Four fetuses with cleft palate seen externally were confirmed at visceral examination. 000564 Table 10 Summary of Skeletal Findings Rat Teratology Study of T-3351 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 (<75%) - Interparietal ossification 1ncomplete/nonoss1fled - parletals ossification Irregular - supraocdpltal ossification 1ncomplete/nonoss1fled - supraocdpltal nonfused - hyoid ossification 1ncomplete/nonoss1f1ed Pectoral girdle - scapula ossification Incomplete R1b cage - sternebrae bipartite - sternebrae 1 and 2 fused - sternebrae <3 ossified - ribs <13 ossified - ribs >13 ossified (cervical region) - ribs 13th pair small - ribs ossification Irregular Vertebral column - sacral arches nonosslfled - thoracic centra ossification Incomplete/nonosslfled - thoracic centra nonfused - caudals <3 ossified Pelvic girdle - pubis ossification Incomplete/nonosslfled -Ischium nonosslfled Forellmbs - <3 ossified HlndUmbs - <4 ossified Bone Alignment Ribs - angulated Sternebrae - checkered Poss1ble preparation damage at time of evisceration. 000565 Table 11 Incidence of External Findings Per Utter Rat Teratology Study of T-3351 154-160 | Number of litters examined Number of litters within normal limits Number and percent of Utters with variants Number and percent of Utters with anomalies Number and percent of litters with anomalies Skin - edematous Palate - cleft Group: Dose Level (mg/kg): 1 0 24 24 0/0.00 0/0.00 2 1 23 23 0/0.00 0/0.00 3 5 23 23 0/0.00 0/0.00 4 10 18 12 0/0.00 6/33.33 4/22.22 6/33.33 ' 's > i; < % & ?l 000566 Table 12 Incidence of Visceral Findings Per Utter Rat Teratology Study of T-3351 154-160 Number of Utters examined Number of Utters within normal limits Number and percent of Utters with variants Number and percent of Utters with anomalies Number and percent with variants Brain - cerebral hemisphere contained dark area Eye(s) - contained dark material Liver - dark areas K1dney($) - pelvis dilated Ureter(s) - distended - undulated Number and percent with anomalies Skin - edematous Palate - cleft Cryptorchlsm Group: Dose Level (mg/kg): 1 0 24 20 4/16.67 0/0.00 2 1 23 16 7/30.43 1/4.35 3 5 23 18 4/17.39 1/4.35 4 10 18 9 1/5.56 8/44.44 1/4.17 3/12.50 4/17.39 5/21.74 1/4.35 1/4.35 2/8.70 2/8.70 1/5.56 1/4.35 1/4.35 1/4.35 5/27.78 7/38.89 4/22.22 000567 7** A Table 13 Incidence of Skeletal Findings Rat Teratology Study of Group: Dose Level (mg/kg): Number of litters examined Number of litters within normal limits Number and percent of Utters with variants Number and percent of litters with anomalies Number and percent with variants Lagging ossification Skull - Incomplete closure (<75%) - Interparietal ossification Incomplete - parletals ossification Irregular - supraocclpltal ossification Incomplete - supraocclpltal nonfused - hyoid ossification Incomplete/nonosslfled Pectoral girdle - scapula ossification Incomplete Rib cage - sternebrae bipartite - sternebrae 1 and 2 fused - sternebrae <3 ossified - ribs <13 ossified3 - ribs >13 ossified (cervical region) - ribs 13th pair small3 - ribs ossification Irregular Vertebral column - sacral arches nonosslfled - thoracic centra ossification Incomplete/ nonosslfled - thoracic centra nonfused - caudals <3 ossified Pelvic girdle - pubis ossification 1ncomplete/nonoss1f1ed - Ischium nonosslfled Forellmbs - <3 ossified Hlndllmbs - <4 ossified Bone alignment Ribs - angulated Sternebrae - checkered atlon damane at time of 000568 Per Litter -3351 12 01 24 1 23/95.83 0/0.00 23 0 23/100.00 0/0.00 3 5 23 4 19/82.61 0/0.00 154-160 4 10 18 3 15/83.33 0/0.00 h I" % tT * *' '.C * V V 1.*if 4/16.67 15/62.50 1/4.17 12/50.00 1/4.17 10/41.67 1/4.17 3/12.50 1/4.17 1/4.17 2/8.33 9/37.50 6/25.00 6/25.00 4/16.67 1/4.17 1/4.17 2/8.33 1/4.17 5/21.74 11/47.83 4/17.39 12/52.17 16/69.57 1/4.35 1/4.35 1/4.35 1/4.35 16/69.57 7/30.43 4/17.39 1/4.35 2/8.70 6/26.09 8/34.78 1/4.35 10/43.48 9/39.13 4/17.39 2/8.70 1/4.35 1/4.35 1/4.35 11/47.83 2/8.70 5/21.74 1/4.35 1/4.35 1/4.35 2/8.70 2/8.70 9/50.00 9/50.00 11/61.11 4/22.22 6/33.33 2/11.11 13/72.22 3/16.67 6/33.33 9/50.00 4/22.22 7/38.89 4/22.22 1/5.56 3/16.67 7/38.89 4/22.22 1/5.56 fl (rao> i i- il V.*> 1 . 000569 Table 14 Mean Incidence of External, Visceral, and Skeletal Findings Per Utter Rat Teratology Study of T-3351 Mean values calculated on a per litter basis: Number with variants Number with anomalies Incidence of variants (%) Incidence of anomalies ( % ) Mean values calculated on a per Utter basis: Number with variants Number with anomalies Incidence of variants (%) Incidence of anomalies ( % ) Mean values calculated on a per Utter basis: Number with variants Number with anomalies Incidence of variants (%) Incidence of anomalies (%) Group: Dose Level (mg/kg): External Visceral Skeletal 1 0 0.0 0.0 0.0 0.0 0.2 0.0 4,0 0.0 3.2 0.0 36.3 0.0 2 1 0.0 0.0 0.0 0.0 0.3 0.0 7.0 0.7 3.8 0.0 44.6 0.0 3 5 0.0 0.0 0.0 0.0 0.2 0.1 4.3 1.5 2.9 0.0 32.1 0.0 154-160 4 10 0.0 1.9 0.0 18.9 h y `a S C Vi 'k : 0.1 1.3 1.1 31.7 4.8 0.0 60.2 0.0 i CO 1 r V % ' -V->V: - 34 - Appendix 1 Individual Clinical Signs3 Rat Teratology Study of T-3351 154-160 Maternal Number Group Observation Bodv Area Pay(s) 27032 27034 27042 27046 27049 27057 27059 27062 27063 27065 27066 27082 27083 27084 27085 27090 27091 27095 27099 27100 27101 1 Alopecia 1 Urine stains Bloody crust Swollen 1 Alopecia 1 Alopecia 1 Alopecia Alopecia 2 Alopecia Alopecia 2 Alopecia Alopecia Alopecia 2 Thin 2 Alopecia 2 Alopecia 2 Alopecia 3 Alopecia 3 Alopecia 3 Hunched Thin Alopecia Alopecia Rough haircoat 3 Rough haircoat 3 Rough haircoat 3 Alopecia Rough haircoat 3 Hunched. Rough haircoat 3 Alopecia Alopecia 3 Hunched Thin Anorexia Urine stains Rough haircoat Bloody crust Bloody crust Bloody crust Bloody crust 3 Rough haircoat Small Paw-fore-right Nose Neck Paws-fore-both Paws-fore-both Abdomen Paw-fore-right Paw-fore-left Paw-fore-both Hip-right Leg-hind-right Side-right Paw-fore-right Paw-fore-right Abdomen Hips-both Hip-right Leg-fore-right Leg-hind-right Paws-fore-both Hips-both Legs-h1nd-both Eyelids-both Mouth Nose Paws-fore-both Eye-left 15-17 . 18-20 20 9-20 8-20 10-11 18-20 19-20 15 16-20 10-14 15-20 10-20 6 17-20 17-20 15-20 15-20 14- 20 15- 19 10, 15-19 10-14 10-12,14 10-12 7-12 9-11 14-20 8-11,13 8-9,11 10-12,19-20 13-20 16-20 16-17,20 16,20 16,20 18-20 16,20 20 20 20 20 8-9 15-20 aAnimals not included in this table appeared normal throughout the study. 000570 \'*f*' Maternal Number GrouD 27107 4 27109 4 27111 27112 4 4 27113 4 27114 4 27115 27116 27117 4 4 4 Appendix 1 - Continued Individual Clinical Signs3 Rat Teratology Study of T-3351 Observation Hunched Thin Rough haircoat Hunched Thin Anorexia Sensitive to touch Alopecia Alopecia Rough haircoat Bloody crust Bloody crust Alopecia Alopecia Hunched Thin Anorexia Urine stains Rough haircoat Bloody crust Bloody crust Hunched Thin Anorexia Urine stains Alopecia Alopecia Alopecia Alopecia Rough haircoat Bloody crust Bloody crust Bloody crust Bloody crust Hunched Thin Anorexia Rough haircoat Alopecia Alopecia- ^ Alopecia "" Hunched Thin Anorexia Bodv Area Hips-both Hip-left Mouth Nose Abdomen Hips-both Mouth Nose Abdomen Hips-both Hip-left Neck Mouth Nose Paws-fore-both Vagina Sides-both Side-right Paw-fore-left Day(s) 18-20 13-17 13-20 9-12,14-20 10-20 16,18-20 10-14,16-18,20 11-20 10 13-20 20 20 10-20 10-20 18-20 15-20 17-20 19-20 16-20 20 20 20 12,20 12,17-18,20 14-18,20 11-19 9-18 8,19-20 8-18 15-20 16-20 16-20 16-20 18-19 13-20 12,20 17-20 18-19 8-13 14-20 19-20 14-20 17,19-20 16-20' aAnimals not included in this table appeared normal throughout the study. 000571 Appendix 1 - Continued Individual Clinical Signs3 Rat Teratology Study of T-3351 154-160 Maternal Number Group Observation Bodv Area 27117 27118 27119 27120 27121 27122 27123 27125 4 Urine stains Rough haircoat Bloody crust Bloody crust Bloody crust Bloody crust 4 Hunched Thin Anorexia Rough haircoat 4 Hunched Thin Anorexia Ataxia Soft feces Bloody discharge Urine stains Alopecia Alopecia Alopecia Alopecia Rough haircoat 4 Hunched Thin Anorexia Bloody discharge Rough haircoat Found dead 4 Hunched Thin Rough haircoat 4 Hunched 4 Alopecia Alopecia Alopecia Alopecia A Hunched Thin Anorexia Alopecia Rough haircoat Bloody crust Genitals Mouth Nose Paws-fore-both Vagina Hip-left Hip-right Inguinal-right Side-right Vagina Abdomen Hip-right Leg-hind-right Side-right Abdomen Paws-fore-both 16-20 9-20 20 16-20 18-20 16-20 16-20 16-17,19-20 19 16-18 12-20 16-20 16-18,20 18-20 8-10 19-20 18-20 11 12-20 13-18 15-20 20 16 16 16 16 16 17 7-9,11-17 7-16 7-11 16-17 10-20 12-20 20 18-20 16-20 16,18-20 16-17,20 15-20 8-9 19-20 aAnimals not included in this table appeared normal throughout the study. 000572 .# ^v Maternal Number Gr o u D 27126 4 27127 4 27128 4 27129 4 - 37 - Appendix 1 - Continued Individual Clinical Signs3 Rat Teratology Study of T-3351 Observation Hunched Thin Anorexia Alopecia Hunched Thin Bloody discharge Rough haircoat Found dead Hunched Thin Anorexia Alopecia Rough haircoat Hunched Thin Anorexia Urine stains Rough haircoat Bloody crust Bodv Area Hip-left Vagina Paw-fore-right \ Paws-fore-both : ' V.'V 154 Day(s) 18,20 19 16- 17,20 17- 20 16 16 16 16 17 14-20 14- 20 17- 18,20 15- 17 18- 20 14-20 16- 20 16 19 16-20 16 aAnimals not included in this table appeared normal throughout the study. 000573 - 38 Key to Appendices 2, 3 / and 4 154-160 P Pregnant NP Not Pregnant C - Cesarean Section Performed (preceded by day of gestation) 0 = Death (preceded by day of gestation) MS * Moribund Sacrifice (preceded by day of gestation) NO = Natural Delivery (preceded by day of gestation) () = Data excluded from mean calculation. Explanation of Footnotes a0nly data from pregnant animals surviving to Day 20 cesarean section were used in mean calculations. bInvalid food consumption value not included 1n mean calculations. cGavid uterine weight inadvertently not recorded. 000574 000575 Maternal Number 27030 27031 27032 27033 27034 27035 27036 27037 27038 27039 27040 27041 27042 27043 27044 27045 27046 27047 27048 27049 27050 27051 27052 27053 27054 N Mean S.O. OlsDosttlon 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 P. 20-C P. 20-C P. 20-C P, 20-C P. 20-C P. 20-C P. 20-C Individual and Appendix 2 in Maternal Body Weights and Body Weight Changes9 Rat Teratology Study of T-3351 Group 1 - 0 rog/kg __________________Body Height tul _________________ Day of Gestation 0 6 8 12 16 20 Body Weight Change |q> Days 0-6 6-8 6-12 6-16f 6-20 277.3 261.9 245.7 256.5 250.1 312.7 248.7 (266.4) 253.8 291.2 241.6 241.1 259.8 287.1 278.7 278.0 269.8 294.0 298.5 270.1 260.5 276.0 275.2 280.8 272.9 303.8 288.8 282.0 274.3 263.4 351.5 279.5 (260.8) 283.4 321.4 273.8 277.3 286.6 310.9 297.4 316.0 293.6 323.6 327.7 310.1 285.3 306.6 299.0 306.0 301.2 306.8 284.4 292.1 275.5 259.0 351.0 283.3 (278.7) 284.7 330.6 272.0 281.2 294.7 318.1 297.9 312.9 294.1 320.1 330.5 327.1 293.6 307.2 306.6 303.6 306.4 340.3 314.1 317.5 299.9 281.1 362.4 312.9 (272.8) 296.4 343.5 289.2 293.5 307.2 334.8 302.5 328.4 313.2 314.5 352.0 343.1 316.8 321.4 327.1 294.2 333.4 358.6 422.5 329.2 388.2 338.6 404.3 314.4 367.8 300.9 341.4 353.6 446.6 340.2 409.0 (279.2) (287.1) 309.1 373.1 365.1. 427.1 310.9 348.8 319.9 374.1 333.2 381.9 345.6 368.2 336.5 390.8 342.8 336.0 381.8 384.5 317.3 371.1 378.8 438.8 376.1 447.0 334.3 392.5 345.4 399.4 356.8 422.2 329.6 . 396.2 351.8 412.6 26.5 26.9 36.3 17.8 13.3 38.8 30.8 (-5.6) 29.6 30.2 32.2 36.2 26.8 23.8 18.7 38.0 23.8 29.6 29.2 40.0 24.8 30.6 23.8 25.2 2B.3 3.0 -4.4 10.1 1.2 -4.4 -0.5 3.8 (17.9) 1.3 9.2 -1.8 3.9 8.1 7.2 0.5 -3.1 0.5 -3.5 2.8 17.0 8.3 0.6 7.6 -2.4 5.2 36.5 25.3 35.5 25.6 17.7 10.9 33.4 (120) 13.0 22.1 15.4 16.2 20.6 23.9 5.1 12.4 19.6 -9.1 24.3 33.0 31.5 14.8 28.1 -11.8 32.2 54.8 40.4 56.6 40.1 37.5 2.1 60.7 (18.4) 25.7 43.7 37.1 42.6 46.6 34.7 39.1 26.8 42.4 -6.3 51.1 66.0 49.0 38.8 57.8 23.6 50.6 118.7 99.4 122.3 93.5 78.0 95.1 129.5 (26.3) 89.7 105.7 75.0 96.8 95.3 57.3 93.4 65.8 90.9 47.5 111.1 136.9 107.2 92.8 123.2 90.2 111.4 24 24 24 24 24 24 270.8 298.47 301.39 318.31 338.53 395.41 18.790 20.580 21.463 21.071 20.479 28.666 24 28.38 6.658 24 2.93 5.364 24 19.84 12.585 24 40.06 16.908 24 96.95 21.937 154-160 16-20f 0-20f 63.9 59.0 65.7 53.4 40.5 93.0 68.8 (7.9) 64.0 62.0 37.9 54.2 48.7 22.6 54.3 39.0 48.5 53.8 60.0 70.9 58.2 54.0 65.4 66.6 60.8 145.2 126.3 158.6 111.3 91.3 133.9 160.3 (20.7) 119.3 135.9 107.2 133.0 122.1 . 81.1 112.1 103.8 114.7 77.1 140.3 176.9 132.0 123.4 147.0 115.4 139.7 24 56.BB 13.752 24 125.33 24.174 Appendix 2 - Continued Individual and Mean Maternal Body Weights and Body Weight Changes8 Rat Teratology Study of T-3351 Group 2 - 1 mg/kg Mat Number ernal Disposition _________________ Body Weight (of___________________ ______________________ :_________ Body Weight Change (g) _________________Day of Gestation___________________ ______________________ !_________________ Bays__________ 0 6 8 12 16 20 0-6 6-8 6-12 6-16F 6-20 21055 21056 21051 21058 21059 21060 21061 21062 21063 21064 21065 21066 21061 21068 21069 21010 21011 21012 21013 21014 21015 21016 21011 21018 21019 P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C NP, 20-C P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P, 20-C P. 20-C P. 20-C 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 268.1 294.4 262.2 282.2 261.8 (253.4) 210.1 261.0 261.9 261.8 259.8 219.1 275.5 271.8 283.0 263.6 265.6 286.2 275.6 278.4 265.7 259.5 262.8 264.9 (258.5) 290.8 318.8 286.5 312.0 304.9 (272.7) 301.0 228.1 298.0 296.0 299.4 296.2 307.7 282.0 314.4 289.4 291.9 310.4 301.6 324.3 288.3 290.7 293.6 283.2 (281.7) 294.2 323.2 282.8 300.5 302.4 (272.7) 296.4 271.8 294.7 301.8 294.0 304.7 304.5 279.8 317.6 299.7 293.7 316.6 290.7 324.8 292.0 285.9 292.5 290.6 (275.7) 310.5 343.3 295.7 327.1 312.6 (289.5) 303.2 290.7 295.1 314.7 302.8 304.7 305.8 298.2 329.3 292.4 295.5 311.1 306.7 350.4 302.4 294.6 304.5 296.6 (275.5) 329.2 360.2 301.7 344.7 324.8 (269.3) 319.8 307.7 317.3 325.3 329.0 323.8 336.6 320.1 355.1 329.6 300.2 338.9 334.3 380.5 324.4 316.1 328.6 323.2 (274.5) 381.3 429.0 372.2 401.1 388.4 (212.1) 319.4 356.8 378.7 388.7 397.8 362.4 385.5 386.8 413.7 397.6 377.8 413.3 407.8 436.3 372.3 370.8 388.4 276.8 (273.1) 22.1 24.4 24.3 29.8 37.1 (19.3) 30.9 -38.9 30.1 34.2 39.6 17.1 32.2 10.2 31.4 25.8 26.3 24.2 26.0 45.9 22.6 31.2 30.8 18.3 (23.2) 3.4 4.4 -3.7 -11.5 -2.5 (0.0) -4.6 43.7 -3.3 5.8 -5.4 8.5 -3.2 -2.2 3.2 10.3 1.8 6.2 -10.9 0.5 3.7 -4.8 -1.1 7.4 (-6.0) 19.7 24.5 9.2 15.1 1.7 (16.8) 2.2 62.6 -2.9 18.7 3.4 8.5 -1.9 16.2 14.9 3.0 3.6 0.7 5.1 26.1 14.1 3.9 10.9 13.6 (-6.2) 38.4 41.4 15.2 32.7 19.9 (-3.4) 18.8 19.6 19.3 29.3 29.6 21.6 28.9 38.1 41.3 40.2 8.3 28.5 32.7 56.2 36.1 25.4 35.0 40.0 (-7.2) 90.5 110.2 85.7 89.1 83.5 (-0.6) 78.4 128.7 80.7 92.7 98.4 66.2 77.8 104.8 99.3 108.2 85.9 102.9 106.2 112.0 84.0 80.1 94.8 93.6 (-8.6) N Mean S.O. 23 23 23 23 23 23 271.03 296.05 298.04 308.18 329.20 389.69 9.265 18.650 13.221 15.771 18.312 20.073 23 25.03 15.895 23 1.99 10.774 23 12.13 13.617 23 33.15 14.547 23 93.64 14.164 16-20F 51.2 68.8 10.5 56.4 63.6 (2.8) 59.6 49.1 61.4 63.4 68.8 38.6 48.9 66.1 58.0 68.0 77.6 74.4 73.5 55.8 47.9 54.7 59.8 53.6 (-1.0 23 60.45 9.823 154-160 0-20F 112.6 134.6 110.0 118.9 120.6 (18.7) 109.3 89.8 110.8 126.9 138.0 83.3 110.0 115.0 130.7 134.0 112.2 127.1 132.2 157.9 106.6 111.3 125.6 111.9 (116) 23 118.67 16.015 oo o cn vJ CD Appendix 2 - Continued Individual and Mean Maternal Body Heights and Body Height Changes* Rat Teratology Study of T-3351 Group 3 - 5 mg/kg 154-160 Mat Nuaber ernal Dlsnosltlon __________________Body Height tol___________________ _________________Dav of Cestatlon___________________ 0 6 8 12 16 20 _______________________ Body Height Change fa! _________________________________Pays__________ 0-6 6-8 6-12 6-1 6f 6-20 16-20f 0-20F 27080 27061 27082 27083 270B4 270B5 27086 27087 27088 27089 27090 27091 27092 27093 27094 27095 27096 27097 27098 27099 27100 27101 27102 27103 27104 N Mean: S.O. 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 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 NP. 20-C 277.9 267.1 256.1 272.9 (258.7) 277.1 261.3 274.0 229.6 261.6 224.7 252.6 276.0 265.5 251.7 276.7 270.6 290.8 273.0 259.1 282.8 276.5 260.4 216.8 (272.7) 309.2 291.4 285.0 301.1 (300.9) 295.2 286.3 305.8 251.5 293.4 243.2 287.0 309.1 297.3 281.2 305.1 301.2 319.7 299.8 290.0 320.2 294.0 280.0 287.6 (282.9) 305.7 286.9 273.2 300.1 (276.1) 284.7 282.7 294.1 251.1 285.4 245.8 280.5 302.2 286.9 289.4 297.7 298.7 320.5 292.0 273.1 310.5 293.3 281.7 292.8 (274.9) 310.1 289.2 279.5 306.6 (286.3) 307.1 296.2 304.9 263.7 298.2 242.7 275.3 290.6 291.6 299.6 300.1 278.9 314.7 293.6 287.4 295.4 280.3 289.9 276.5 (251.1) 343.9 299.9 285.2 306.0 (246.5) 329.1 312.2 318.0 269.9 317.1 255.1 302.8 316.9 312.3 312.2 336.2 278.3 335.8 313.4 302.7 269.8 305.1 308.9 292.0 (253.7) 425.3 355.0 352.7 361.1 (279.4) 382.6 372.1 415.7 342.9 374.7 308.6 360.9 391.3 373.2 372.0 410.4 358.6 398.7 371.5 366.1 254.1 357.0 369.0 370.1 (275.4) 23 23 23 23 23 23 263.25 292.80 288.22 290.09 305.34 367.11 18.525 18.070 16.876 16.252 22.346 35.036 31.3 24.3 28.9 28.2 (42.2) 18.1 25.0 31.8 21.9 31.8 18.5 34.4 33.1 31.8 29.5 28.4 30.6 28.9 26.8 30.9 37.4 17.5 19.6 70.8 (10.2) -3.5 -4.5 -11.8 -1.0 (-24.8) -10.5 -3.6 -11.7 -0.4 -8.0 2.6 -6.5 -6.9 -10.4 8.2 -7.4 -2.5 0.8 -7.8 -16.9 -9.7 -0.7 1.7 5.2 (-8.0) 0.9 -2.2 -5.5 5.5 (-14.6) 11.9 9.9 -0.9 12.2 4.8 -0.5 -11.7 -18.5 -5.7 18.4 -5.0 -22.3 -5.0 -6.2 -2.6 -24.8 -13.7 9.9 -11.1 (-31.8) 34.7 8.5 0.2 4.9 (-54.4) 33.9 25.9 12.2 18.4 23.7 11.9 15.8 7.8 15.0 31.0 31.1 -22.9 16.1 13.6 12.7 -50.4 11.1 28.9 4.4 (-29.2) 116.1 63.6 67.7 60.0 (21.5) 87.4 85.8 109.9 91.4 81.3 65.4 73.9 82.2 75.9 90.8 105.3 57.4 79.0 71.7 76.1 -66.1 63.0 89.0 82.5 (-7.5) 23 29.54 10.523 23 -4.58s" 6.103 23 -2.70 11.235 23 12.54s" 18.834 23 74.32 34.272 81.4 55.1 67.5 55.1 (32.9) 53.5 59.9 97.7 73.0 57.6 53.5 58.1 74.4 60.9 59.8 74.2 80.3 62.9 58.1 63.4 -15.7 51.9 60.1 78.1 (21.7) 23 61.77 20.386 147.4 87.9 96.6 88.2 (20.7) 105.5 110.8 141.7 113.3 113.1 83.9 108.3 115.3 107.7 120.3 133.7 88.0 107.9 98.5 107.0 -28.7 80.5 108.6 153.3 (27) 23 103.86s" 34.851 ooo Materna) Nuaber 21105 21106 21101 21108 21109 21)10 21111 21)12 21113 21114 21115 21116 21111 21118 21119 21120 21121 21122 21123 21124 21125 21126 21121 21128 21129 N Mean S.O. Appendix 2 - Continued Individual and Mean Maternal Body Weights and Body Weight Changes3 Rat Teratology Study of T-3351 Group 4 - 1 0 mg/kg 154-160 Disposition P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C P. 20-C HP. 20-C P. 20-C P. 11-D P. 20-C P. 20-C P. 20-C P, 20-C P. 20-C P. 20-C P. 11-0 IIP. 20-C HP. 20-C __________________Body Weight (gl___________________ ______ :__________________Body Weight Change (g) I________________ Day of Gestation___________________ ________ _______________________________ Oays__________ 0 6 a 12 16 20 0-6 6-8 6-12 6-16F 6-20 16-20f 0-20F 219.5 214.9 239.1 285.4 213.2 254.1 269.9 251.1 294.6 281.0 242.9 241.8 303.0 (212.6) 255.6 295.4 264.4 253.4 310.8 264.3 251.8 211.2 259.9 (263.6) (291.0) 303.4 310.1 255.2 315.6 301.8 293.1 300.4 281.3 334.6 318.2 214.3 215.6 339.4 (213.3) 286.4 326.3 281.4 215.6 332.5 283.2 211.0 290.5 293.4 (286.2) (299.5) 293.2 302.2 255.3 312.0 281.1 219.3 301.1 281.0 318.1 313.0 211.1 218.1 339.1 (215.3) 219.3 329.7 269.3 211.7 338.2 292.5 275.9 286.2 280.2 (283.9) (293.5) 286.8 301.5 228.0 299.1 250.3 213.3 305.9 214.1 214.5 282.1 263.1 214.1 289.8 (256.5) 244.3 292.4 268.4 210.4 319.2 218.9 248.9 270.0 274.5 (270.1) (259.4) 281.4 322.7 212.1 291.7 230.3 261.4 309.8 238.2 254.1 254.4 265.6 210.3 211.4 (224.9) 221.8 271.0 265.2 265.5 335.4 296.7 223.2 243.9 245.9 (225.1) (234.6) 364.1 318.4 211.1 377.2 209.3 325.9 386.7 222.8 235.3 240.5 351.6 340.0 247.2 (206.6) 180.7 - 349.6 331.3 414.9 366.8 211.4 232.2 - (189.1) (256.8) 23.9 35.8 16.1 30.2 28.6 38.4 30.5 29.6 40.0 31.2 31.4 33. B 36.4 (0.7) 30.8 30.9 11.0 22.2 ' 21.1 18.9 25.2 19.3 \ 33.5 (22.6) (25) -10.2 -8.5 0.1 -3.6 -14.1 -13.8 0.7 -0.3 -16.5 -5.2 -3.2 3.1 -0.3 (2.0) -7.1 3.4 -12.1 2.1 5.7 9.3 -1.1 -4.3 -13.2 (-2.3) (-6.0) -16.6 -3.2 -21.2 -15.9 -51.5 -19.8 5.5 -6.6 -60.1 -36.1 -11.2 -0.9 -49.6 (-16.8) -42.1 -33.9 -13.0 -5.2 -13.3 -4.3 -28.1 -20.5 -18.9 (-16.1) (-40.1) -22.0 12.0 -42.5 -23.9 -71.5 -31.7 9.4 -43.1 -80.5 -63.8 -8.1 -5.3 -68.0 (-48.4) -64.6 -55.3 -16.2 -10.1 2.9 13.5 -53.8 -46.6 -41.5 (-61.1) (-64.9) 61.3 61.7 16.5 61.6 -92.5 32.8 86.3 -58.5 -99.3 -77.7 77.3 64.4 -92.2 (-66.7) -105.1 68.2 55.7 82.4 83.6 -65.6 -58.3 (-96.5) (-42.7) 83.3 55.1 59.0 85.5 -21.0 64.5 76.9 -15.4 -18.8 -13.9 86.0 69.7 -24.2 (-18.3) -41.1 84.4 65.8 79.5 80.1 -11.8 -11.1 (-35.4) (22.2) 85.2 103.5 32.6 91.8 -63.9 71.2 116.8 -28.9 -59.3 -46.5 108.7 98.2 -55.8 (-66.0) -74.9 85.2 11.9 104.1 102.5 -40.4 -39.0 (-73.9) (-40.2) 22 22 22 22 22 20 269.30 291.12 293.63 276.25 265.12 301.91 20.329 22.698 22.916 21.762 32.153 73.253 22 28.43 6.951 22 22 -4.05s ' -21.48 7.115 11.769 22 -32.60s ' 29.333 20 5.40 75.133 20 36.63 48.285 20 33.45s ' 13.412 I -I* to I c o C/t 0 00 Maternal _Number 27030 27031 27032 27033 27034 27035 27036 27037 27038 27039 27040 27041 27042 27043 27044 27045 27046 27047 27048 27049 27050 27051 27052 27053 27054 N Mean S.D. Appendix 3 Individual and Mean Food Consumption3 Rat Teratology Study of T-3351 Sroup 1 - 0 mg/kg ____________________ Food Consumption (a)_____ _______________ Interval (Days of Gestation! 0-6 7-8 9-12 13-16 17-20F 7-168 0-208 140.9 130.0 140.6 123.7 80.6 166.0 139.2 (113.8) 134.9 145.4 122.3 129.9 136.1 142.4 141.2 146.9 115.9 123.4 144.5 149.3 119.5 132.7 127.1 125.0 126.5 42.8 33.1 45.5 32.0 18.6 44.7 36.2 (30.1) 33.4 43.3 31 .8 37.2 42.9 44.6 34.2 39.1 37.6 29.7 42.4 51 .3 36.5 36.6 39.8 36.2 30.1 92.5 73.2 86.1 75.8 48.8 69.8 80.9 (52.2) 75.9 76.8 69.7 72.2 79.5 89.5 60.6 79.1 75.8 41.8 91.7 90.8 77.6 74.9 81.3 47.1 78.4 87.1 71.3 82.2 80.6 51.9 44.8 86.8 (55.2) 77.9 91.6 71.1 73.0 80.1 81.5 78.7 69.4 78.1 82.6 93.5 97.7 72.1 74.4 85.5 97.3 75.2 101 .7 91.1 106.4 96.6 67.8 109.1 106.4 (69.7) 107.0 107.8 84.5 86.5 95.8 93.0 99.0 78.4 95.4 71.8 113.4 116.4 92.5 112.2 106.4 96.7 98.1 222.4 177.6 213.8 188.4 119.3 159.3 203.9 (137.5) 187.2 211.7 172.6 182.4 202.5 215.6 173.5 187.6 191.5 154.1 227.6 239.8 186.2 185.9 206.6 180..6 183.7 465.0 398.7 460.8 408.7 267.7 434.4 449.5 (321.0) 429.1 464.9 379.4 398.8 434.4 451.0 413.7 412.9 402.8 349.3 485.5 505.5 398.2 430.8 440.1 402.3 408.3 24 132.67 15.924 24 37.48 6.812 24 74.58 13.416 24 78.52 12.317 24 24 24 97.25 190.58 420.49 12.693 25.916 47.701 000579 27055 27056 27057 27058 27059 27060 27061 27062 27063 27064 27065 27066 27067 27068 27069 27070 27071 27072 27073 27074 27075 27076 27077 27078 27079 N Mean S.D. - 44 Appendix 3 - Continued Individual and Mean Food Consumption3 Rat Teratology Study of T-3351 Group 2 - 1 mg/kg 154-160 0-6 122.0 136.0 130.8 136.5 141.7 (108.2) 131.5 55.7 135.6 143.0 145.9 99.3 144.9 111.5 145.8 133.0 119.6 145.4 105.6 147.3 127.0 131.2 126.4 128.5 (156.8) Food Consumption fol Interval (Oavs of Gestation) 7-8 9-12 13-16 17-20F 7-16B 0-208 35.2 42.1 35.2 29.1 38.2 (30.2) 31 .6 38.6 34.2 39.1 34.7 33.6 35.2 22.7 40.4 42.8 34.9 41.9 24.4 41.9 40.7 27.8 28.1 33.2 (23.8) 63.7 7648..10 70.2 64.5 (67.9) 62.8 81 .8 61 .4 73.5 63.1 60.3 63.6 64.2 72.6 61 .4 60.6 62.1 62.8 93.2 72.7 87.8 63.2 65.1 (53.4) 71 .0 69.7 49.6 69.0 71 .2 (636968...608) 70.9 55.3 81.3 63.0 72.8 59.2 77.0 67.6 41.5 68.2 100.6 88.8 68.2 59.0 70.0 65.8 (56.3) 92.5 18088..69 98.0 112.1 (77.9) 91 .3 70.3 98.7 99.4 116.9 92.1 88.5 97.7 94.0 98.5 101 .4 109.2 107.1 113.6 84.3 79.5 95.9 96.4 (64.9) 169.9 185.9 152.8 168.3 173.9 (137b.9) 160.4 189.0 166.5 167.9 179.1 156.9 171.6 146.1 190.0 171 .8 137.0 172.2 187.8 223.9 181 .6 174.6 161.3 164.1 (133.5) 384.4 430.8 372.2 402.8 427.7 (324.0)b 383.2 315.0 400.8 410.3 441.9 348.3 405.0 355.3 429.8 403.3 358.0 426.8 400.5 484.8 392.9 385.3 383.6 389.0 (355.2) 23 128.01 20.444 23 35.03 5.735 23 68.38 8.893 23 68.45 12.065 23 23 23 97.17 171.85 397.03 11 .147 17.544 35.568 000580 27081 27082 27083 27084 27085 27086 27087 27088 27089 27090 27091 27092 27093 27094 27095 27Q96 27097 27098 27099 27100 27101 27102 27103 27104 N Mean S.D. - 45 Appendix 3 - Continued Individual and Mean Food Consumption3 Rat Teratology Study of T-3351 Group 3 - 5 mg/kg 154-160 Food Consumotion (q) Interval (Days of Gestation) 0--6 7-8 9-12 13-16 17-20F 7-168 0-208 139 .2 139,.9 138,.5 136 .1 (141 5) 127,.7 113 .8 146 .0 118 .1 134,.4 97,.9 132,.3 147,.3 130,.5 168,.5 120,.0 136,.2 145..1 147,.3 177 .4 141 ,.8 118 .9 115,.4 130 .8 (138,8) 36.9 34.5 26.3 42.7 (21.4) 23.3 28.3 60.3 48.3 46.7 64.6 (53.2) 55.7 53.5 70.0 60.9 38.5 39.5 01.2) 66.7 59.6 104.7 82.8 83.1 73.4 (74.2) 80.5 88.0 167.2 143.7 111.5 146.8 (85.8) 145.7 141.4 411.1 366.4 333.1 356.3 (301.5) 353.9 343.2 32.2 (116.4)b 72.5 123.9 (221.l)b (491.0)b (156.2)b 35.0 28.3 26.8 36.2 24.4 40.4 24.9 (86.5)b 61 .0 46.9 44.6 153.0 51 .1 72.5 56.5 (88.1)b (109.3)b (330.8)b (558.2)b 61 .3 87.8 157.3 379.5 52.3 74.7 127.5 300.1 60.5 85.4 131.9 349.6 67.1 95.0 256.3 498.6 79.8 100.9 155.3 386.7 69.0 96.1 181.9 446.5 55.2 114.6 136.6 371.2 34.6 (119.9)b (160.8)b (100.6)b (315.3)b (552.l)b 40.9 57.8 53.6 100.9 152.3 398.3 32.9 75.0 89.4 (135.8)b 197.3 (480.4)b 26.6 28.9 30.1 28.4 31.1 (24.5) 67.0 34.2 44.0 56.5 42.4 (27.8) (110.3)b (108.9)b (203.9)b (490.2)b 1.5 0.0 64.6 206.4 65.1 91.9 139.2 350.0 51.9 90.5 136.8 342.7 43.4 95.3 116.9 343.0 (36.9) (64.3) (89.2) (292.3) 23 134,.92 17,.356 22 31.53 5.567 20 59.58 24.302 20 57.89 18.350 19 87.87 24.771 19 18 147.91s'' 363.14s 38.131 59.846 000581 27105 27106 27107 27108 27109 27110 27111 27112 27113 27114 27115 27116 27117 27118 27119 27120 27121 27122 27123 27124 27125 27126 27127 27128 27129 N Mean S.O. - 46 Appendix 3 - Continued Individual and Mean Food Consumption3 Rat Teratology Study of T-3351 Group 4 - 1 0 mg/kg 154-160 0-6 126.5 148.7 110.0 138.3 140.5 143.2 136.7 128.9 150.0 142.9 123.7 117.4 164.1 (115.8) 124.6 150.7 98.5 120.6 158.2 137.6 115.0 123.5 133.7 (122.7) (113.0) Food Consumption (q) Interval (Days of Gestation! 7-8 9-12 13-16 17-20F 7-168 0-208 30.6 40.0 144.4 37.3 31.7 31.3 36.7 33.8 21.2 30.8 29.7 29.0 44.5 (32.5) 28.9 42.3 24.3 33.5 41.4 34.5 28.1 26.6 27.5 (31.5) (27.9) 41.5 58.6 17.9 67.4 80.0 99.5 90.0 166.0 296.5 414.2 23.6 40.2 54.2 (200.2)b 222.2 (532.4)b 23.0 91.3 100.5 330.1 (145.5)b 55.7 48.3 40.1 1 .4 21 .3 39.2 0.0 35.6 75.1 1 .6 0.0 0.0 26.3 2.3 85.0 100.9 0.0 0.0 1.1 90.5 (177.2)b (320.0)b 122.6 350.8 160.1 397.7 75.5 204.4 22.6 172.6 52.3 196.1 95.2 309.4 86.5 10.6 57.1 0.0 (110.0)b 172.6 0 . 0 55.1 (400.0)b 219.2 (57.2) 15.2 31 .5 (41.l)b 0.2 0.0 (24.9) 0.0 - (130.8)b (271.5)b 44.3 168.9 73.8 - (48.0)b (126.3)b (96.8)b (198.6)b (393.9)b 44.3 (164.9)b (152.0)b (242.7)b (515.3)b (66.2)b 54.5 (119.8)b (162.1)b (440.l)b (129.3)b (196.3)b (117.8)b (360.1)b (615.5)b 17.1 0 . 0 0 . 0 45.2 160.2 39.9 7.5 0 . 0 74.0 197.5 48.4 11.8 - 87.7 - (41.1) (20.4)b (0.4) (93.0 ) b (216.l)b (15.7) (0.0) (72.2) (43.6) (228.8) 22 133.33 16.209 22 37.64 24.571 18 36.86 20.179 19 22.75 26.380 14 17 13 39.33s" 97.63s'' 262.89s ' 46.891 54.321 90.464 000582 :: - - 47 154-160 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-3351. Group 1 - 0 mg/kg Maternal Number Terminal Bodv Weiqht Gravid R Uterine Weiqht8 Terminal Body Weight Minus Gravid Uterine Weiqht F 27030 27031 27032 27033 27034 27035 27036 27037 27038 27039 27040 27041 27042 27043 27044 27045 27046 27047 27048 27049 27050 27051 27052 27053 27054 422.5 388.2 404.3 367.8 341.4 446.6 409.0 Not Pregnant 373.1 427.1 348.8 374.1 381.9 368.2 390.8 381.8 384.5 371.1 438.8 447.0 392.5 399.4 422.2 396.2 412.6 90.4 90.9 88.2 67.8 66.6 97.3 86.9 69.2 76.2 54.7 82.4 80.1 30.8 80.6 52.4 72.3 64.5 74.0 84.1 74.8 60.3 83.1 74.6 82.1 332.1 297.3 316.1 300.0 274.8 349.3 322.1 303.9 350.9 294.1 291.7 301.8 337.4 310.2 329.4 312.2 306.6 364.8 362.9 317.7 339.1 339.1 321.6 330.5 N Mean S.O. 24 395.41 28.666 24 74.35 14.704 24 321.07 23.215 000583 Appendix 4 - Continued Individual and Mean Terminal Body Weights, Gravid Uterine Weights, and Terminal 8ody Weights Minus Gravid Uterine Weights (g)a Rat Teratology Study of T-3351 Group 2 - 1 mg/kg Maternal Number Terminal Bodv Weiqht Gravid R Uterine Weiqht0 Terminal Body Weight Minus Gravid Uterine Weiqht 27055 27056 27057 27058 27059 27060 27061 27062 27063 27064 27065 27066 27067 27068 27069 27070 27071 27072 27073 27074 27075 27076 27077 27078 27079 381.3 429.0 372.2 401.1 388.4 Not Pregnant 379.4 356.8 378.7 388.7 397.8 362.4 385.5 386.8 413.7 397.6 377.8 413.3 407.8 436.3 372.3 370.8 388.4 376.8 Not Pregnant 72.5 88.5 73.3 86.5 69.1 69.2 64.0 67.4 74.6 80.0 37.9 76.1 80.4 83.7 90.0 77.8 85.3 84.7 84.8 77.3 60.7 83.2 71.6 308.8 340.5 298.9 314.6 319.3 310.2 292.8 311 .3 314.1 317.8 324.5 309.4 306.4 330.0 307.6 300.0 328.0 323.1 351.5 295.0 310.1 305.2 305.2 N Mean S.O. 23 389.69 20.073 23 75.59 11.458 23 314.10 14.093 000584 - 49 154-160 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-3351 Group 3 - 5 mg/kg Maternal Number Terminal Bodv Weight Gravid R Uterine Weight0 Terminal Body Weight Minus Gravid Uterine Weiqht 27080 27081 27082 27083 27084 27085 27086 27087 27088 27089 27090 27091 27092 27093c 27094 27095 27096 27097 27098 27099 27100 27101 27102 27103 27104 425.3 355.0 352.7 361.1 Not Pregnant 382.6 372.1 415.7 342.9 374.7 308.6 360.9 391 .3 373.2 372.0 410.4 358.6 ' 398.7 371.5 366.1 254.1 357.0 369.0 370.1 Not Pregnant 103.9 72.2 72.4 68.5 89.8 79.4 76.6 73.5 71 .2 61.6 75.3 88.0 - 71.2 87.1 65.4 65.2 68.0 61.6 48.2 73.9 72.9 70.2 321.4 282.8 280.3 292.6 292.8 292.7 339.1 269.4 303.5 247.0 285.6 303.3 - 300.8 323.3 293.2 333.5 303.5 304.5 205.9 283.1 296.1 299.9 N Mean S.D. 23 367.11 35.036 22 73.46 11.486 22 293.385- 28.235 000585 - 50 - 154-160 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-3351 Group 4 - 1 0 mg/kg Maternal Number Terminal Bodv Weight Gravid o Uterine Weight0 Terminal Body Weight Minus Gravid Uterine Weight 27105 27106 27107 27108 27109 27110 27111 27112 27113 27114 27115 27116 27117 27118 27119 27120 27121 27122 27123 27124 27125 27126 27127 27128 27129 364.7 378.4 271.7 377.2 209.3 325.9 386.7 222.8 235.3 240.5 351.6 340.0 247.2 Not Pregnant 180.7 Found Dead 349.6 331.3 414.9 366.8 211.4 232.2 Found Dead Not Pregnant Not Pregnant 82.3 58.9 54.6 79.8 72.2 64.4 86.5 40.8 43.3 42.3 82.4 55.4 38.5 32.4 71.7 66.0 79.4 76.0 39.7 43.6 282.4 319.5 217.1 297.4 137.1 261 .5 300.2 182.0 192.0 198.2 269.2 284.6 208.7 148.3 277 .9 265.3 335.5 290.8 171.7 188.6 N Mean S.D. 20 301.91 73.253 20 60.51S17.739 20 241.40S- 59.517 000586 Maternal JiOTiKr. 21030 27031 27032 27033 27034 27035 27036 27037 27038 2703 27040 27041 27042 27043 27044 27045 27046 27047 27048 27049 27050 27051 27052 27053 27054 Total N Mean S.O. Ovarian Coreara m 1st 15 17 19 19 16 20 14 Not Pregnant 16 19 16 15 17 14 18 19 13 12 15 19 17 16 16 18 18 398 24 16.6 2.12 Uterine Implantations 15 17 15 15 IS 18 14 14 17 13 IS 15 7 16 10 13 12 15 18 14 13 15 15 17 348 24 14.5 2.45 Appendix 5 Individual and Mean Ovarian and Uterine Oata Rat Teratology Study of T-33S1 Group 1 - 0 mg/kg Implantation Early Early Late Efficiency (XI Resorptions Resorptions 1%) Resorptions 100.0 100.0 78.9 78.9 93.8 90.0 100.0 0 0.0 1 5.9 1 6.7 3 20.0 1 6.7 1 5.6 0 0.0 0 0 0 0 0 0 0 87.5 89.5 81.3 100.0 88.2 50.0 88.9 52.6 100.0 100.0 100.0 94.7 82.4 81.3 93.8 83.3 94.4 2 14.3 4 23.5 1 7.7 0 0.0 1 6.7 2 28.6 1 6.3 0 0.0 0 0.0 1 8.3 1 6.7 1 5.6 0 0.0 2 15.4 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 87.90 13.472 23 24 1.0 1.04 24 7.00 8.024 0 24 0.0 - Late Resorptions (XI 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 .0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 24 0.00 - Total Resorptions 0 1 1 3 1 1 0 2 4 1 0 1 2 1 0 0 1 1 1 0 2 0 0 0 23 24 1.0 1.04 154-160 Total Resorptions (XI 0.0 5.9 6.7 20.0 6.7 5.6 0.0 14.3 23.5 7.7 0.0 6.7 28.6 6.3 0.0 0.0 8.3 6.7 5.6 0.0 15.4 0.0 0.0 0.0 24 7.00 8.024 o oo Cfl 00 Appendix 5 - Continued Individual and Mean Ovarian and Uterine Data Rat Teratology Study of T-3351 Group 2 - 1 mg/kg 154-160 Maternal Humber 27055 27056 27057 27058 27059 27060 27061 27062 27063 27064 27065 27066 27067 27068 27069 21070 27071 27072 27073 27074 27075 27076 27077 27078 27079 Total N Mean S.D. Ovarian Comoro Lutea 15 17 13 IS 14 Not Pregnant 12 15 14 15 17 11 16 19 25 17 15 18 17 18 18 15 13 16 Not Pregnant 365 23 15.9 2.85 Uterine Implantations 13 16 13 15 14 11 13 13 15 . 16 7 16 16 17 16 14 18 16 16 15 13 13 15 331 23 14.4 2.31 Implantation Efficiency (XI 66.7 94.1 100.0 100.0 100.0 91.7 86.7 92.9 100.0 94.1 63.6 100.0 64.2 68.0 94.1 93.3 100.0 94.1 68.9 63.3 86.7 100.0 93.8 23 91.14 9.694 Early Resorptions 1 1 0 1 2 0 0 1 1 0 1 2 1 2 0 0 1 0 1 1 1 0 1 18 23 0.8 0.67 Early Resorotlons (X> 7.7 6.3 0.0 6.7 14.3 0.0 0.0 7.7 6.7 0.0 14.3 12.5 6.3 11.8 0.0 0.0 5.6 0.0 6.3 6.7 7.7 0.0 6.7 23 5.53 4.804 Late Resorotlons 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 23 0.0 * Late Resorotlons (XI 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 23 0.00 - Total Resorotlons 1 1 0 1 2 0 0 1 1 0 1 2 1 2 0 0 1 0 1 1 1 0 1 18 23 0.8 0.67 Total Resorotlons (X) 7.7 6.3 0.0 6.7 14.3 0.0 0.0 7.7 6.7 0.0 14.3 12.5 6.3 11.8 0.0 0.0 5.6 0.0 6.3 6.7 7.7 0.0 6.7 23 5.53 4.804 oo 0 01 00 00 Appendix 5 - Continued Individual and Mean Ovarian and Uterine Data Rat Teratology Study of T--3351 Group 3 - 5 ag/kg 154-160 Maternal Number 27080 27081 27082 27083 27084 27085 27086 27087 27088 27089 27090 27091 27092 27093 27094 27095 27096 27097 27098 27099 27100 27101 27102 27103 27104 Total It Mean . S.0. V Ovarian Coroora Lutea 16 14 15 14 Not Pregnant 20 15 IS 15 13 13 15 19 15 U 17 17 16 18 ` 16 19 16 16 15 Not Pregnant ` 363 23 15.8 1.86 Uterine laolantatlons 16 13 14 14 17 15 IS 14 13 12 15 17 14 13 17 16 15 14 12 16 15 14 14 335 23 14.6 1.47 Iaplantatlon Efficiency (%) 100.0 92.9 93.3 100.0 85.0 100.0 100.0 93.3 100.0 92.3 100.0 89.5 93.3 92.9 100.0 94.1 93.8 77.8 75.0 84.2 93.8 87.5 93.3 23 92.70 7.017 Early Resorptions 0 0 1 2 0 0 0 1 1 0 0 1 1 0 1 3 2 2 0 0 1 0 0 16 23 0.7 0.88 Early Resorptions 1%) 0.0 0.0 7.1 14.3 0.0 0.0 0.0 7.1 7.7 0.0 0.0 5.9 7.1 0.0 5.9 18.8 13.3 14.3 0.0 0.0 6.7 0.0 0.0 23 4.70 5.859 Late Resorptions 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 23 0.0 0.21 Late Resorptions (%) 0.0 0.0 0.0 0.0 0.0 6.7 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 23 0.29 1.397 Total Resorptions 0 0 1 2 0 1 0 1 1 0 0 1 1 0 1 3 2 2 0 0 1 0 0 17 23 0.7 0.86 Total Resorptions IS) 0.0 0.0 7.1 14.3 0.0 6.7 0.0 7.1 7.7 0.0 0.0 5.9 7.1 0.0 5.9 18.8 13.3 14.3 0.0 0.0 6.7 0.0 0.0 23 5.00 5.781 o cn oo Appendix 5 - Continued Individual and Mean Ovarian and Uterine Data Rat Teratology Study of T--3351 Group 4 - 10 mg/kg 154-160 Maternal Hunter 27105 27106 27107 27108 27109 27110 27111 27112 27113 27114 27115 27116 27117 27118 27119 27120 27121 27122 27123 27124 27125 27126 27127 27128 27129 Total N Mean S.O. Ovarian Corpora 17 17 14 17 18 21 17 14 15 18 16 14 22 Not Pregnant 15 17 15 15 18 16 16 18 15 Not Pregnant Not Pregnant 365 22 16.6 2.09 Uterine Implantations 15 11 13 16 17 14 16 13 15 15 15 12 14 13 16 15 15 15 16 13 15 13 Inplantatlon efficiency (XI 88.2 64.7 92.9 94.1 94.4 66.7 94.1 92.9 100.0 83.3 93.8 85.7 63.6 86.7 94.1 100.0 100.0 83.3 100.0 81.3 83.3 86.7 Early Resorot1ons 0 1 3 1 1 0 1 1 2 2 0 1 0 13 0 3 0 1 0 1 Early Late Resorptions (X1 Resorptions 0.0 9.1 23.1 6.3 5.9 0.0 6.3 7.7 13.3 13.3 0.0 8.3 0.0 0 0 0 0 15 0 0 0 1 0 0 0 1 100.0 0 0.0 20.0 0.0 6.3 0.0 6.7 0 0 0 0 0 0 Late Resorptions (XI 0.0 0.0 0.0 0.0 88.2 0.0 0.0 0.0 6.7 0.0 0.0 0.0 7.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Total Resorptions 0 1 3 1 16 0 1 1 3 2 0 1 1 13 0 3 0 1 0 1 317 22 14.4 1.50 22 87.72 10.955 31 20 1.6 2.86 20 11.32 21.929 17 20 0.9 3.34 20 5.10 19.674 48 20 2.4 4.28 Total Resorptions (XI 0.0 9.1 23.1 6.3 94.1 0.0 6.3 7.7 20.0 13.3 0.0 8.3 7.1 100.0 0.0 20.0 0.0 6.3 0.0 6.7 20 16.42 28.471 Found dead on Day 11, therefore, fetal data not available 000591 Appendix 6 Individual and Mean Litter Data* Rat Teratology Study of T-3351 Group 1 - 0 mg/kg Maternal Number Total Resorptions Dead Number of Fetuses Fetal t Loss (X)b Live Uve Sex_______ Males Females 27030 27031 27032 27033 27034 27035 27036 27037 27038 27033 27040 27041 27042 27043 27044 27045 27046 27047 27048 27049 27050 27051 27052 27053 27054 0 1 1 3 1 1 0 Not Pregnant 2 4 1 0 1 2 1 0 0 1 1 1 0 2 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 5.9 6.7 20.0 6.7 5.6 0.0 14.3 23.5 7.7 0.0 6.7 28.6 6.3 0.0 0.0 8.3 6.7 5.6 0.0 15.4 0.0 0.0 0.0 15 100.0 16 94.1 14 93.3 12 80.0 14 93.3 17 94.4 14 100.0 12 85.7 13 76.5 12 92.3 15 100.0 14 93.3 5 71.4 15 93.8 10 100.0 13 100.0 11 91.7 14 93.3 17 94.4 14 100.0 11 84.6 15 100.0 15 100.0 17 100.0 78 88 77 75 59 12 5 77 57 67 75 4 11 4 10 14 12 3 37 58 56 68 98 68 56 78 2 13 6 11 Total N Unadjusted Mean Unadjusted S.O. Covariance Adjusted Mean Covariance Adjusted S.D. 23 24 1.0 1.04 0 24 0.0 " 24 7.00 8.024 325 24 13.5 2.64 24 93.00 8.024 146 24 6.1 2.59 179 24 7.5 2.30 * Sex, percent males, and mean weight data Include values for live fetuses only, b Percent fetal loss Includes resorptions as well as dead fetuses. c Statistical analysis performed on covariance adjusted means. Percent Males 46.7 50.0 50.0 58.3 35.7 70.6 50.0 41.7 46.2 58.3 26.7 28.6 20.0 80.0 30.0 38.5 45.5 42.9 52.9 42.9 45.5 46.7 13.3 35.3 24 44.01 14.828 154-160 c Mean Weight (ul Males Females 3.7 3.6 3.5 3.2 3.9 3.4 3.3 3.2 2.5 2.8 3.3 3.2 4.1 3.9 3.5 3.3 3.6 3.4 2.7 2.4 3.4 3.3 3.5 3.4 2.2 3.2 3.2 2.9 3.2 3.2 3.3 3.2 3.0 2.9 3.3 3.2 3.2 2.9 3.1 3.1 3.2 3.2 3.5 3.4 3.3 3.0 3.1 2.8 24 3.28 0.408 3.28 0.092 24 3.17 0.301 3.16 0.084 1 cn tn i Appendix 6 - Continued Individual and Hean Litter Oataa Rat Teratology Study of T-3351 Group 2 - 1 mg/kg Maternal Number 27055 27056 27057 27058 .27059 27060 27061 27062 27063 27064 27065 27066 27067 27068 27069 27070 27071 27072 27073 27074 27075 27076 27077 27078 2707% Total Resorptions Dead 1 1 0 1 2 Not Pregnant 0 0 1 1 0 1 2 1 2 0 0 1 0 1 1 1 0 1 Not Pregnant 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 .0 0 0 0 0 0 0 0 Number of fetuses Fetal Loss <X)b kiY live 1%) 7.7 6.3 0.0 6.7 14.3 12 92.3 15 93.8 13 100.0 14 93.3 12 85.7 0.0 0.0 7.7 6.7 0.0 14.3 12.5 6.3 11.8 0.0 0.0 5.6 0.0 6.3 6.7 7.7 0.0 6.7 11 100.0 13 100.0 12 92.3 14 93.3 16 100.0 6 85.7 14 87.5 15 93.8 15 88.2 16 100.0 14 100.0 17 .94.4 16 100.0 15 93.8 14 93.3 12 '92.3 13 100.0 14 93.3 Hales 8 8 9 8 5 7 8 3 6 8 2 5 7 10 15 7 9 6 5 8 10 5 6 Total N Unadjusted Mean Unadjusted S.O. Covariance Adjusted Mean Covariance Adjusted S.f). 18 23 0.8 0.67 0 23 0.0 - 23 5.53 4.804 313 23 13.6 2.27 23 94.48 4.802 165 23 7.2 2.66 a Sex, percent ales, and mean sleight data Include values for live fetuses only. b Percent fetal loss Includes resorptions as well as dead fetuses. c Statistical analysis performed on covariance adjusted means. 000592  54-160 Sex Females 4 7 4 6 7 4 5 9 8 8 4 9 8 5 1 7 8 10 10 b 2 a 8 148 23 6.4 2.45 Percent Hales 66.7 53.3 69.2 57.1 41.7 63.6 61.5 25.0 42.9 50.0 33.3 35.7 46.7 66.7 93.8 50.0 52.9 37.5 33.3 57.1 83.3 38.5 42.9 23 52.29 16.688 c Hean Weight (ql Nales Females 3.4 3.4 3.3 3.3 3.4 3.4 3.4 3.2 3.3 3.0 3.8 3.6 2.7 2.8 3.5 3.2 3.3 3.0 2.8 2.8 3.2 3.4 2.9 2.8 3.0 3.2 3.3 3.3 3.4 3.0 3.1 2.9 2.8 2.7 2.9 2.9 3.6 3.3 3.2 3.1 3.1 3.0 3.5 3.2 3.3 2.9 23 3.23 0.278 3.23 0.092 23 3.10 0.240 3.10 0.083 000593 Appendix 6 - Continued Individual and Mean Litter Data8 Rat Teratology Study of T-33S1 Group 3 - 5 mg/kg Maternal Number Total Sesorotlons Dead Number of Fetuses Fetal Loss i*lb Live Live fat) Sex Males females 27080 27081 27082 27083 27084 27085 27086 27087 27088 27089 27090 27091 27092 27093 27094 27095 27096 27097 27098 27099 27100 27101 27102 27103 27104 0 0 1 2 Not Pregnant 0 1 0 1 1 0 0 1 1 0 1 3 2 2 0 0 1 0 0 Not Pregnant 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0.0 0.0 7.1 14.3 0.0 6.7 0.0 7.1 7.7 0.0 0.0 5.9 7.1 0.6 5.9 18.8 13.3 14.3 0.0 0.0 13.3 0.0 0.0 16 100.0 13 100.0 13 92.9 12 85.7 17 100.0 14 93.3 15 100.0 13 92.9 12 92.3 12 100.0 15 100.0 16 94.1 13 92.9 13 100.0 16 94.1 13 81.3 13 86.7 12 85.7 12 100.0 16 100.0 13 86.7 14 100.0 14 100.0 88 85 85 39 5 12 77 11 4 67 93 84 96 12 4 94 76 88 67 76 66 66 10 6 58 68 86 Total N Unadjusted Mean Unadjusted S.O. Covariance Adjusted Mean ' Covariance Adjusted S.O. 17 23 0.7 0.86 1 23 0.0 0.21 23 5.28 6.028 317 23 13.8 1.57 23 94.72 6.018 172 23 7.5 2.04 145 23 6.3 2.01 8 Sex, percent aules, and mean weight data Include values for live fetuses only. > Percent fetal loss Includes resorptions as well as dead fetuses. c Statistical analysis performed on covariance adjusted aeans. Percent Males 50.0 61.5 61.5 25.0 29.4 50.0 73.3 46.2 75.0 66.7 60.0 75.0 69.2 53.8 50.0 46.2 53.8 50.0 50.0 62.5 38.5 42.9 57.1 23 54.24 13.293 154-160 c Mean Weight (g) Hales Females 3.7 3.4 3.2 2.9 3.2 3.1 3.1 2.8 3.0 2.9 3.1 3.0 2.8 2.8 3.4 3.3 3.4 3.3 3.0 2.9 3.1 2.9 3.2 3.2 3.3 2.9 3.2 3.1 3.2 3.1 3.2 3.1 3.0 3.0 3.0 3.0 3.1 3.1 1.5 1.7 3.2 3.0 3.1 2.8 3.3 3.1 23 3.10 0.392 3.10s ' 0.092 23 2.97 0.322 2.97s ' 0.083 1 cn i 000594 Appendix 6 - Continued Individual and Mean Litter Data9 Rat Teratology Study of T-3351 Group 4 - 1 0 mg/kg Maternal Number Total Resorotlons Dead Number of fetuses Fetal t Loss (X)b Live Live <*) Males 27105 27106 27107 27108 27109 27110 27111 27112 27113 27114 27115 27116 27117 27118 27119 27120 27121 27122 27123 27124 27125 27126 27127 27128 27129 0 1 3 1 16 0 1 1 3 2 0 1 1 Not Pregnant 13 Found Dead 0 3 0 1 0 1 Found Dead Not Pregnant Not Pregnant 0 0 0 0 1 0 0 0 6 0 0 0 2 0 0 0 0 0 0 0 0.0 9.1 23.1 6.3 100.0 0.0 6.3 7.7 60.0 13.3 0.0 8.3 21.4 100.0 0.0 20.0 0.0 6.3 0.0 6.7 15 100.0 10 90.9 10 76.9 15 93.8 0 0.0 14 100.0 15 93.8 12 92.3 6 40.0 13 86.7 15 100.0 11 91.7 11 78.6 0 0.0 15 100.0 12 80.0 15 100.0 15 93.8 13 100.0 14 93.3 10 6 4 9 8 7 10 4 6 9 8 8 9 6 10 9 7 9 Total N Unadjusted Mean Unadjusted S.O. Covariance Adjusted Mean Covariance Adjusted S.O. 48 20 2.4 4.28 9 20 0.5 1.39 20 19.43 30.777 231 20 11.6 4.61 '20 80.59 30.801 139 18 7.7 1.90 * Sex, percent ales, and mean weight data Include values for live fetuses only. Percent fetal loss Includes resorptions as well as dead fetuses. c Statistical analysis performed on covariance adjusted means. E Females 5 4 6 6 6 8 2 2 7 6 3 3 6 6 5 6 6 5 92 18 5.1 1.68 Percent Males 66.7 60.0 40.0 60.0 57.1 46.7 83.3 66.7 46.2 60.0 72.7 72.7 60.0 50.0 66.7 60.0 53.8 64.3 18 60.38 10.655 154-160 c Mean Weight (al Hales Females 3.1 3.0 3.2 3.2 3.1 3.0 3.2 3.2 2.7 2.5 3.2 3.2 1.7 1.7 1.9 2.0 1.8 1.7 3.3 3.0 2.8 2.6 1.6 1.5 3.1 3.0 3.2 3.4 3.2 3.0 2.8 2.9 1.8 1.7 1.8 1.7 18 2.64 0.656 2.63s" 0.105 18 2.57 0.660 2.59s 0.097 i c0n0 Appendix ? Individuel Visceral Findings In Fetuses Rat Teratology Study of T-3351 Group 1 - 0 m g A g 154-160 Maternal Nimber: Number of fetuses examined Number of fetuses within normal limits Number of fetuses with one or more visceral variants Percent of fetuses with one or more skeletal variants (X) Identification letter(s) of fetuses with: Brain - cerebral hemisphere contained dark area Eye(s) - contained dark material Liver - dark areas Kldney(s) - pelvis dilated Ureter(s) - distended - undulated Number of fetuses wlth-one or more visceral anomalies Percent of fetuses with one or more visceral anomalies (X) Identification letter(s) of fetuses with: . Skin - edematous Palate - cleft Cryptorchlsm 5 S 0 0.00 6 6 0 0.00 5 S 0 0.00 4 3 1 25.00 5 5 0 0.00 6 6 0 0.00 5 5 0 0.00 NP I 0000000 0.00 0.00 0.00 0.00 0.00 0.00 0.00 222 77 7 000 44 4 01 4 4 0 0.00 5 5 0 0.00 4 4 0 0.00 5 5 0 0.00 5 5 0 0.00 00000 0.00 0.00 0.00 0.00 0.00 U1 KO NP - Not Pregnant - o o 0 07 ( 01 Appendix 7 - Continued Individual Visceral Findings In Fetuses Rat Teratology Study of T-3351 Group 1 - 0 mg/kg 154-160 Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses with one or more visceral variants Percent of fetuses with one or more skeletal variants (X) Identification letter(s) of fetuses with: Brain - cerebral hemisphere contained dark area Eye(s) - contained dark material liver - dark areas K1dney($) - pelvis dilated Ureter(s) - distended - undulated Number of fetuses with one or more visceral anomalies Percent of fetuses with one or more visceral anoaulles (X) Identification letter(s) of fetuses with: Skin - edematous Palate - cleft Cryptorchlsm 22 77 00 44 4 2 2 0 0.00 5 4 1 20.00 4 3 1 25.00 5 5 0 0.00 4 3 1 25.00 2 7 0 4 8 5 5 0 0.00 2 7 0 4 6 6 0 0.00 2 7 0 5 0 5 5 0 0.00 2 7 0 5 1 4 4 0 0.00 2 7 0 5 5 5 0 0.00 2 7 0 5 3 5 5 0 0.00 2 7 0 5 6 6 0 0.00 AJ K 00 0.00 0.00 00 0.00 0.00 00 0.00 0.00 00 0.00 0.00 00 0.00 0.00 00 0.00 0.00 I C0Tl 1 oo 0 01 CO a Appendix 7 - Continued Individual Visceral Findings In Fetuses Rat Teratology Study of T-3351 group 2 - 1 ag/kg 154-160 Maternal Nuaber: Nuaber of fetuses exaalned Nuaber of fetuses within noraal Halts Nuaber of fetuses with one or aore visceral variants Percent of fetuses with one or aore skeletal variants (X) Identification letter(s) of fetuses with: Brain - cerebral healsphere contained dark area Eye(s) - contained dark aaterlal Liver - dark areas Kldney(s) - pelvis dilated Ureter(s) - distended - undulated Nuaber of fetuses with one or aore visceral anoaalles Percent of fetuses with one or aore visceral anoaalles (X) Identification letter(s) of fetuses with: Skin - edeaatous Palate - cleft CryptorcMsa 4 4 0 0.00 5 5 0 0.00 4 4 0 0.00 5 5 0 0.00 4 4 0 0.00 NP 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 2T 1 777 000 666 5 4 4 0 0.00 8 8 0 0.00 4 3 1 25.00 5 5 0 0.00 6 6 0 0.00 2 2 0 0.00 5 5 0 0.00 A 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 1 oH-\ 1 NP - Not Pregnant. oo o ;a Appendix 7 - Continued Individual Visceral Findings In Fetuses Rat Teratology Study of T-3351 Group 2 - 1 mg/kg Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses with one or more visceral variants Percent of fetuses with one or more skeletal variants (X) Identification 1etter($) of fetuses with: Brain - cerebral hemisphere contained dark area Eye(s) - contained dark material Liver - dark areas Kldney(s) - pelvis dilated . Ureter(s) - distended - undulatn Number of fetuses with one or more visceral anomalies Percent of fetuses with one or more visceral anomalies (X) Identification letter(s) of fetuses with: Skin - edematous Palate - cleft Cryptorchism 5 5 0 0.00 s 5 0 0.00 6 5 1 16.67 5 5 0 0.00 6 4 2 33.33 6 6 0 0.00 5 4 1 20.00 5 4 1 20.00 4 3 1 25.00 5 4 1 20.00 5 5 0 0.00 NP Q A AG AM AG 0 0.00 00 0.00 0.00 01 0.00 16.67 0 0.00 0 0.00 0 0.00 00 0.00 0.00 0 0.00 N NP Not Pregnant. Appendix 7 - Continued Individual Visceral Findings In Fetuses Rat Teratology Study of T-3351 6roup 3 - 5 mg/kg 154-160 Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses with one or more visceral variants Percent of fetuses with one or more skeletal variants (X) Identification letter(s) of fetuses with: 6 4 2 33.33 5 5 0 0.00 5 4 1 20.00 4 4 0 0.00 NP Brain - cerebral hemisphere contained dark area Eye(s) - contained dark material Liver - dark areas Ktdney(s) - pelvis dilated Ureter(s) - distended - undulated J AN Number of fetuses with one or more visceral anomalies Percent of fetuses with one or more visceral anomalies (X) Identification letter(s) of fetuses with: 0 O' 0 0 0.00 0.00 0.00 0.00 Skin - edematous Palate - cleft Cryptorchlsm 2 7 0 8 6 6 0 0.00 2 7 0 8 5 5 0 0.00 2 7 0 8 7 5 5 0 0.00 2222 7777 0000 8899 _2-- . 0 _ 1 __ 5 5 0 0.00 4 3 1 25.00 4 4 0 0.00 5 5 0 0.00 2 7 0 9 6 6 0 0.00 A 00000000 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 I COJl 1 NP - Not Pregnant Appendix 7 - Continued Individual Visceral Findings In Fetuses Rat Teratology Study of T-3351 6roup 3 - 5 ng/kg Maternal Number: Number of fetuses examined Number of fetuses within normalUnits Number of fetuses with oneoraorevisceral variants Percent of fetuses with one or more skeletal variants (X) Identification letter(s) of fetuses with: Brain - cerebral hemisphere contained dark area Eye(s) - contained dark material Liver - dark areas Kldney(s) - pelvis dilated Ureter(s) - distended - undulated Number of fetuses with one or aore visceral anomalies Percent of fetuses with one or aore. visceral anoaalles (X) Identification letter(s) of fetuses with: Skin - edematous Palate - cleft Cryptorchlsa 22 2 2222 2 222 77 7777777 777 00 0 0 0 0 0 1 1 1 1 1 9 99999900000 34 7890 1234 S 5 0 0.00 5 5 0 0.00 6 6 0 0.00 5 5 0 0.00 5 5 0 0.00 4 4 0 0.00 4 4 0 0.00 6 4 0 0.00 5 5 0 0.00 5 S 0 0.00 5 4 1 20.00 NP M 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 0 0.00 02 0.00 33.33 0 0.00 0 0.00 0 0.00 A Afi NP Not Pregnant Appendix 7 - Continued Individual Visceral Findings In Fetuses Rat Teratology Study of T-3351 Group 4 - 1 0 mg/kg 154-160 222 777 111 Maternal 0 0 0 Number: ' 5 6 7 Number of fetuses examined Number of fetuses within normal limits Number of fet-uses with one or more visceral variants Percent of fetuses with one or more skeletal variants (%) Identification letter(s) of fetuses with: Brain - cerebral hemisphere contained dark area Eye(s) - contained dark material Liver - dark areas Ktdney(s) - pelvis dilated Ureter(s) - distended - undulated Number of fetuses with one or more visceral anomalies Percent of fetuses with one or more visceral- anomalies (X) Identification letter(s) of fetuses with: Skin - edematous Palate - cleft Cryptorchism 5 4 1 20.00 4 4 0 0.00 4 4 0 0.00 5 5 0 0.00 0a H 0 0.00 0 0.00 0 0.00 0 0.00 5 5 0 0.00 5 5 0 0.00 4b 3 0 0.00 2C 0 0 0.00 5d 0 0 0.00 5 5 0 0.00 4C 4 0 0.00 4f 0 0 0.00 0 0.00 0 12 5 0.00 25.00 100.00 100.00 0 0.00 04 0.00 100.00 BE ADGJN A BE JN AEJM AEJ AEN All fetuses resorbed and/or dead. b Fetus t was noted to have cleft palate during external examination. All fetuses were noted to have edematous skin during external examination. Fetuses B and E were confirmed at visceral examination. Fetuses C and E were noted to have cleft palate during external examination. Fetus E was confirmed at visceral examination, d Fetuses H and N were noted to have edematous skin during external examination. Fetus N was confirmed at visceral examination. Fetuses H and I were noted to have cleft palate during external examination. e Fetus E was noted to have cleft palate during external examination. A H fetuses were noted to have edematous skin durlna external examination. Fetuses A, E, J, and N were confirmed at visceral examination. Fetuses A. J, and l were noted to have cleft palate during external examination. Fetuses A and 3 were confirmed at visceral examination. CcTnl i 000601 Appendix 7 - Continued Individual Visceral Findings 1n Fetuses Rat Teratology Study of T-3351 Group 4 - 1 0 mg/kg 154-160 2 22 22222 2 22 7 77 77777 7 77 111 11111 1 11 Haternal 1 1 2 2 2 2 2 2 2 2 2 Number: _8L_ _JL_ 1 2 3 4 5 7B Number of fetuses examined Number of fetuses within normal limits Number of fetuses with one or more visceral variants Percent of fetuses with one or more skeletal variants (X) Identification letter(s) of fetuses with: Brain - cerebral hemisphere contained dark area Eye(s) - contained dark material Liver - dark areas Ktdney(s) - pelvis dilated Ureter(s)*- distended - undulated Number of fetuses with one or more visceral anomalies Percent of fetuses with one or more visceral anomalies (X) Identification letter(s) of fetuses with: Skin - edematous Palate - cleft CryptorcMsm NP 0a FO 5 4 5 5 5b 5 FD NP NP 4 3550 0 000000 0.00 0.00 0.00 0.00 0.00 0.00 1100 5 5 20.00 25.00 0.00 0.00 100.00 100.00 AOGJN BEHKN OJH EHN G BHK NP Not Pregnant. FO > Found Bead. 8 All fetusgs resorbed and/or dead. b All fetuses were noted to have edematous skin during external examination. Fetuses A, 0, G, J, and N were confirmed at visceral examination. Fetuses B, F, 3 . and L were noted to have cleft palate during external examination. Fetus 3 was confirmed at visceral examination. i CTl cr> i 000602 >i Appendix 8 Individual Skeletal Findings In Fetuses9 Rat Teratology Study of T-3351 Group 1 - 0 mg/kg 154- H O 2 222 2222 7 777 7777 0 000 0000 Haternal 3 3 3 3 3 3 3 3 Number: 0 1 2 3 4 5 6 7 Number of fetuses examined Number of fetuses within normal limits Number of fetuses with one or more skeletal variants Percent of fetuses with one or more skeletal variants (X) Identification letter(s) of fetuses with: 10 5 5 50.00 10 6 4 40.00 9 6 3 33.33 8 7 1 12.50 9 4 5 55.56 u 8 3 27.27 9 7 2 22.22 NP Lagging Ossification Skull - Incomplete closure (<75X) - Interparietal ossification Incomplete/nonosslfled - parletals ossification Irregular - supraocclpttal ossification Incomplete/nonosslfled - supraocclpttal nonfused - hyoid ossification Incomplete/nonosslfled Pectoral girdle - scapula ossification Incomplete .Rib cage - sternebrae bipartite - sternebrae 1 and 2 fused - .sternebrae <3 ossified - ribs <13 ossified* - ribs >13 ossified (cervical region) - ribs 13th pair small1 - ribs ossification Irregular Vertebral colunn - sacral arches nonosslfled - thoracic centra ossification Incoaplete/ , nonosslfled - thoracic centra nonfused - caudals <3 ossified DI J JN FN GI 0J CFHI FH FK FIK H F E L B Pelvic girdle - pubis ossification Incomplete/ nonosslfled - Ischiumnonosslfled Forelimbs - <3ossified Hindi labs - <4ossified FIK F E Bone Alignment Ribs - angulated Sternebrae - checkered 2 7 0 3 8 8 5 3 37.50 2 2 22 7777 0000 3444 9 0 12 88 80 08 0.00 100.00 10 7 3 30.00 9 6 3 33.33 BGN JN H J BN J GLN F H B JIN FG BG CKO 0 BCFG1L N H NP *- Not Pregnant. a There were no skeletal anomalies noted In any fetuses. * Possible preparation damage at time of evisceration. I cVrJ> I 000603 Appendix 8 - Continued Individual Skeletal Findings In Fetuses3 Rat Teratology Study oi T-3351 Group 1 - 0 mg/kg 154-160 22222 222222 7 7 7 7 7 7 7 7 7 7 7 "5 0 0 0 0 0 0 0 0 0 0 0 0 Maternal 4 4 4 4 4 4 4 5 5 5 5 5 Number: 3 4 5 6 7 8 9 0 1 2 3 4 Number of fetuses examined Number of fetuses within normal limits Number of fetuses with one or more skeletal variants Percent of fetuses with one or more skeletal variants (X) Identification letter(s) of fetuses with: 3 1 2 66.67 10 8 2 20.00 6 5 1 16.67 8 7 1 12.50 7 3 4 57.14 9 5 4 44. 44 11 7 4 36.36 9 8 1 11.11 7 6 1 14.29 10 9 1 10.00 10 11 51 5 10 SO.00 90.91 lagging Ossification Skull - Incomplete closure (<75%) - Interparietal ossification Incomplete/nonosstfled 0R DE M C L F IL B E EHI 8CEH1K - partetals ossification Irregular - supraocdpltal ossification 1ncomplete/nonos$1f1ed D3 F 1 ILR LNQ E El BFHIKL - supraocdpltal nonfused - hyoid osslflcatton Incomplete/nonosslfled Q E El BEFHN Pectoral girdle - scapula ossification Incomplete Rib cage - stemebrae bipartite - stemebrae 1 and 2 fused - stemebrae <3 ossified R HI - ribs <13 ossified** - ribs >13 ossified (cervical region) - ribs 13th pair small1* - ribs ossification irregular E Vertebral column - sacral arches nonosslfled - thoracic centra ossification Incomplete/ nonosslfled -.thoracic centra nonfused BCFL fH N J FIK F - caudals <3 ossified D R H HI Pelvic girdle - pubis ossification Incomplete/ nonosslfled 3 R HIL . - .Ischium nonosslfled Forelimbs - <3 ossified Htndllmbs - <4 ossified R Bone Alignment Ribs - angulated Stemebrae - checkered E * There were no skeletal anomalies noted In any fetuses. ** Possible preparation damage at time of evisceration. 000604 Appendix 8 - Continued Individual Skeletal Findings In Fetuses3 Rat Teratology Study of T-3351 Group 2 - 1 mg/kg 154-160 2 22 22 2 7 77777 000 0 0 0 Maternal 5 5 55 56 Number: 5 __6 7 8 9 0 Number of fetuses examined Number of fetuses within normal limits Number of fetuses with one or more skeletal variants Percent of fetuses with one or more skeletal variants (X) Identification letter(s) of fetuses with: 8 6 2 25.00 10 9 1 10. t9> 97 2 22.22 9 5 4 44.44 8 1 7 87.50 NP Laoglnq Ossification Skull - incomplete closure (<75X) - Interparietal ossification 1ncoag>lete/nono$s1fied - parletals ossification Irregular - supraocclpttal ossification tncomplete/nonosslfled - supraoccipltal nonfused - hyoid ossification Incomplete/nonossIHed Pectoral girdle - scapula ossification Incomplete Rib cage - sternebrae bipartite - sternebrae 1 and 2 fused - sternebrae <3 ossified - ribs <13 ossified1* - ribs >13 ossified (cervical region) - ribs 13th pair small1* - ribs ossification Irregular Vertebral column - sacral arches nonosslHed - thoracic centra ossification Incomplete/ nonosslfled - thoracic centra nonfused - caudals <3 ossified Pelvic girdle - pubis ossification Incomplete/ nonosslfled - Ischium nonosslfled Forellmbs - <3 ossified HindiImbs - <4 ossified P P NP M 1 B BEGH3K BEGJK B6HJ I 8EGHJK M * BTTO K Bone Alignment Ribs - angulated Sternebrae - checkered J 2 2 22222 7 7 7 7777 0 0 00000 66 66666 1 2 3456 7 7 2 5 71.43 58 40 18 20.00 100.00 9 6 3 33.33 10 5 5 50.00 4 1 3 75.00 9 5 4 44 E CEHLM CE 8CEFH EFK 8CEFHI H BFNO B fl BF IP P I P I BCEHK 0 CE L C H OF I 0GM CEH NP - Not Pregnant. a There were no skeletal anomalies noted In any fetuses. ** Possible preparation damage at time of evisceration. 000605 000606 Appendix 8 - Continued Individual Skeletal Findings In Fetuses8 Rat Teratology Study of T-3351 Group 2 - 1 mg/kg 154-160 Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses with one or more skeletal variants Percent of fetuses with one or more skeletal variants (X) Identification letter(s) of fetuses with: 2 22222222222 7 77777777777 0 00000000000 6 67777777777 8 90 1234 5678 10 8 2 20.00 10 9 1 10.00 10 7 3 30.00 9 11 70 2 11 22.22 100.00 10 8 2 20.00 10 9 B0 29 20.00 100.00 8 3 5 62.50 8 6 2 25.00 9 6 3 33.33 NP Lagging Ossification Skull - Incomplete closure (<75%) - Interparietal ossification Incomplete/nonosslfled - parletals ossification Irregular - supraocclpltal ossification Incomplete/nonosslfled - supraocclpltal nonfused - hyoid ossification Incoaplete/nonosslfled Pectoral girdle - scapula osslflcatton Incomplete Rib cage - sternebrae bipartite - sternebrae 1 and 2 fused - sternebrae <3 ossified - ribs <13 ossified1* - ribs >13 ossified (cervical region) - ribs 13th pair small* - ribs ossification Irregular Vertebral column - sacral arches nonosslfled - thoracic centra ossification Incomplete/ nonosslfled - thoracic centra nonfused - caudals <3 ossified Pelvic girdle - pubis ossification Incomplete/ nonosslfled - Ischium nonosslfled forelimbs - <3 ossified Hlndltmbs - <4 ossified I 0C I CEFHIK L H BECFHK BCEFHJ IL L CO LNR LN0 CEF1KL tt BCEFKl N F FJMO 11 L c NR BHI H BCEFL0 R P CFHJLN EIL EL 10 LH FHB EJ HR F 0 R I Bone Alignment Ribs - angulated Sternebrae - checkered NP * Not Pregnant. a There were no skeletal anomalies noted In any fetuses. 1* Possible preparation damage at time of evisceration. i 0 1 Appendix 8 - Continued Individual Skeletal Findings in Fetuses* Rat Teratology Study of T-33S1 Group 3 - 5 ng/kg 154-180 000607 Maternal Number: Number of fetuses examined Number of fetuses within normal limits Number of fetuses with one or more skeletal variants Percent of fetuses with one or more skeletal variants (X) Identification letter(s) of fetuses with: 10 a 2 20.00 8 5 3 37.50 8 7 1 12.50 8 7 1 12.50 NP lagging Ossification Skull - Incomplete closure (<75X) - Interparietal ossification Incomplete/nonosslfled BH - parietals ossification Irregular - supraocc1p1ta,l ossification Incomplete/nonosslfled - supraocclpltal nonfused - hyoid osstflatlon Incomplete/nonosslfled B Pectoral girdle - scapula ossification Incomplete Rib cage - sternebrae bipartite - sternebrae 1 and 2 fused - sternebrae <3 ossified - ribs <13 ossified1* - ribs >13 ossified (cervical region) i - ribs 13th pair $ma11b ribs ossification Irregular Vertebral column - sacral arches nonosslfled , - thoracic centra ossification Incomplete/ *, nonosslfled I CH 0 - thoracic centra nonfused - caudals <3 ossified Pelvic girdle - pubis ossification Incomplete/ nonosslfled - Ischium nonosslfled forelimbs - <3 ossified Hlndllmbs - <4 ossified Bone Alignment Ribs - angulated Sternebrae - checkered NP Not Pregnant. * There were no skeletal anomalies noted In any fetuses. b Possible preparation damage at time of evisceration. 2 7 0 9 11 8 3 27.27 9 7 2 22.22 10 1 9 90.00 8 8 0 0.00 8 7 1 12.50 8 6 2 25.00 10 6 4 40.00 10 6 4 40.00 BE B H0B HF I E BEFHLO B El 0 0 FJOP BC 30 8CK HK 1N0 C BCF B B 0 f! i ->4 I flPCDOO 000608 Appendix 8 - Continued Individual Skeletal Findings in Fetuses1 Rat Teratology Study of T-33S1 Group 3 - 5 mg/kg 2 2 22 2 7 7 77 7 00 000 Maternal 9 9 9 9 9 Number: 34 56 7 Number of fetuses examined Number of fetuses within normal limits Number of fetuses with one or more skeletal variants Percent of fetuses with one or more skeletal variants (X) Identification letter(s) of fetuses with: 8 3 5 62.SO 8 8 0 0.00 10 7 3 30.00 8 3 5 62.SO 8 5 3 37.SO Lagoino Ossification Skull - Incomplete closure (<7SX) - Interparietal ossification Incomplete/nonosslfled - parietals ossification Irregular - supraocclpltal ossification Incomplete/nonosslfled UK CEI FI I - supraocclpltal nonfused - hyoid ossification Incomplete/nonosslfled Pectoral girdle - scapula ossification Incomplete Rib cage - sternebrae bipartite - sternebrae 1 and 2 fused - sternebrae <3 ossified - ribs <13 ossified1 - rtbs >13 ossified (cervicalregion) - rtbs 13th pair small1 - ribs ossification Irregular Vertebral column - sacral arches nonosslfled - thoracic centra ossification Incomplete/ nonosslfled - thoracic centranonfused - caudals <3 ossified K D 3N OG N FI 0 Pelvic girdle - pubis ossification Incomplete/ nonosslfled - Ischium nonosslfled Forelimbs - <3 ossified Hindiimbs - ossified Bone Alignment Ribs - angulated Sternebrae - checkered IK El NP Not Pregnant. 1 There were no skeletal anomalies noted In any fetuses. * Possible preparation damage at time of evisceration. 154-H O 22 77 01 90 90 8 10 40 4 10 S0.00 100.00 22 77 11 00 -i-- 2 7 1 0 3 2 7 1 0 4 8 8 0 0.00 9 7 2 22.22 9 6 3 33.33 NP BCEFHI KINO 0 l BCEFHI KLNO HI IN 8EFIK BLN N EFN NF F LN 1LN 8CEFHI KLNO BILN LN LN BEIKL l N i -vj ro Appendix 8 - Continued Individual Skeletal Findings In Fetuses3 Rat Teratology Study of T-3351 Group 4 - 1 0 ng/kg 154-160 2 2 2 2 2 2 2 2 2 2 222 7777777777 777 1 111 1111 11 111 Maternal 0 0 0 0 0 1 1 1 1 1 1 11 Number: 5 6 7 8 3 0 1 2 3 4 5 6 7 Number of fetuses examined Number of fetuses within normal limits Number of fetuses with one or more skeletal variants Percent of fetuses with one or more skeletal variants (X) Identification letter(s) of fetuses with: Lagging Ossification Skull - Incomplete closure (<75X) - Interparietal ossification Incomplete/nonossIHed - parletals ossification Irregular - supraocclpltal ossification Incomplete/nonossIHed - supraocclpltal nonfused - hyoid ossification incomplete/nonosstfled Pectoral girdle - scapula ossification Incomplete Rib cage - sternebrae bipartite - sternebrae 1 and 2 fused - sternebrae <3 ossified - ribs <13 ossified1* - ribs >13 ossified (cervical region) - ribs 13th pair saallb - ribs ossification Irregular Vertebral column - sacral arches nonosslfted - thoracic centra ossification Incomplete/ nonosslfled - thoracic centra nonfused - caudaIs <3 ossified Pelvic girdle - pubis ossification Incomplete/ nonosslfled - Ischium nonosslfled Forelimbs - <3 ossified Hlndllmbs - <4 ossified Bone Alignment Ribs - angulated Sternebrae - checkered NP *= Not Pregnant. a There were no skeletal anomalies noted in any fetuses. b Possible preparation damage at time of evisceration. c All fetuses resorbed and/or dead 10 3 7 70.00 6 6 0 0.00 6 2 4 66.67 10 10 0 0.00 o 9 3 6 66.67 10 8 4 8 70 0 0 3848 30.00 100.00 100.00 100.00 10 6 4 40.00 77 40 37 42.86 100.00 CFHILN 0 CFI 8 B CH BEFHK BCEFHI COFO KL CE COFO BCEFHI LN CFHI L BFHK COO CEIL F H E BCFHIK COO CH BCEFHI LN L L BCEFHI BFIN E L BCFGKL N BCFGKL N N BCFGKL CGKLN BFGKL CGKN X HN CH FO 1 It CH FO 81 BH . X BCEHIK COFO CEFI CH I C BCEFHK COFO L CEHI EF COFO 0 CGKN C BCFGKL N CFGXLN CN BCFGKL N N 000609 r 3' <T> Appendix 6 - Continued Individual Skeletal Findings In Fetuses9 Rat Teratology Study of T-3351 Group 4 - 1 0 mg/kg 154-160 Maternal Number: 2 7 1 1 0 Number of fetuses examined Number of fetuses within normal limits Number of fetuses with one or more skeletal variants Percent of fetuses with one or more skeletal variants (*) Identification letter(s) of fetuses with: lagging Ossification Skull - Incomplete closure (<75t ) - Interparietal ossification Incomplete/nonosslfted - parletals ossification Irregular - supraocclpltal ossification Incomplete/nonosslfled - supraocclpltal nonfused - hyoid ossification Incomplete/nonosslfled Pectoral girdle - scapula ossification Incomplete Rib cage - sternebrae bipartite - sternebrae 1 and 2 fused - sternebrae <3 ossified - ribs <13 ossified1* - ribs >13 ossified (cervical region) - ribs 13th pair smal1b - ribs ossification Irregular Vertebral column - sacral arches nonosslfled - thoracic centra ossification Incomplete/ nonosslfled - thoracic centra nonfused O - caudals <3 ossified Pelvic girdle - pubis ossification Incomplete/ nonosslfled - Ischium nonosslfled Forelimbs - <3 ossified Hindiimbs - <4 ossified NP Hone Alignment Ribs - angulated Sternebrae - checkered NP Not Pregnant. F0 - Found Oead. a There were no skeletal anomalies noted In any fetuses. b Possible preparation damage at time of evisceration. c All fetuses resorbed and/or dead. 2222222222 7777777777 1 1 1 1 1 1 1 1 11 2 2 2 2 2 2 2 2 22 01 34 5 6 7 FO 10 0 10 10 0 9 F0 NP NP 4 5 10 3 0 0 630709 60.00 37.50 0.00 70.00 100.00 100.00 0 CIK0 N CF FIK0 H 0 CJMP BCEFHI CDFI3L KL M0 BF1KL I 0CMP HK CIJLH0 BCEFIl K BCEFHI CDF61J L LNO CKL B CKl C BMP l IL HI BI BCEFHI CJL KL BCHIKL KL KL 8 BCEFHI C U L O KL I --FJ I OOOSi - 75 - Appendix 9 References Rat Teratology Study of T-3351 STATISTICAL METHOOS/LABORATQRY PROCEDURES 154-160 Armitage, P.f "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." 3. Royal Statist. Soc. Su d d !.. IV-.137-170, 1937. Cochran, W. G., "Some Methods of Strengthening the Common Chi-Square Tests." Biometrics. 10:417-451, 1954. Cochran, W. G., and Cox, G. M., Experimental Oesigns. 2nd Ed., John Wiley and Sons, Inc., New York, 1957. Draper, N. R., and Hunter,W. G., "Transformations: Revisited." Technometrics. 11:23-40, 1969. Some Examples 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, 3. L., Statistical Methods for Rates and Proportions. 2nd Ed., Wiley, New York, Ch. 9, 1981. 3onckheere, A. R., "A Distribution-free k-sample Test Against Ordered Alteratives." Biometrika 41:133-45. 1954. Kruskal, W. H. and Wallis, W. A., "Use of Ranks in One-Criterion Variance Analysis." 3. Am. Stat, Assoc.. 47:583-621, 1952. Kruskal, W. H. and Wallis, W. A., "Errata to Use of Ranks 1n One-Criterion Variance Analysis." 3. 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. Miller, R. G., 3r., Simultaneous Statistical Inference. McGraw-Hill, New York, 1966, Ch. 6.1. 000611 V - 76 - Appendix 9 - Continued References Rat teratology Study of T--3351 STATISTICAL METHOOS/IABORATORY PROCEDURES 154-160 Staples, R. E., "Detection of Visceral Alterations in Mammalian Fetuses." Teratology. 9(3):A--37, 1974. Staples, R. E. and Schnell, V. L., "Refinements in Rapid Clearing Technic in the KOH-Alizarin Red S Method for Fetal Bone." Stain Technology. 39:61-63, 1964. Terpstra, T. 0., "The Asymptotic Normality and Consistency of Kendall's Test Against Trend, When Ties are Present in One Ranking." Indag. Math. 14:327-333, 1952. Wilson, 0. G. and Warkany, J., editors. Teratology: Principles and Techniques. The Univ. of Chicago Press, Chicago, 1965, pp. 251-277. Winer, B. J., Statistical Principles in Experimental Design. 2nd Ed., McGraw-Hill, N.Y., Chs. 3-9, 1971. Winer, 8. J., Statistical Principles in Experimental Design. 2nd Ed., McGraw-Hill, N.Y., Ch. 10, 1971. 000612