Document yk5nkyG3D8qv4aEqpErwonGQV

gena - oi _373 FINAL REPORT PROTOCOL 418-011 ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS SPONSOR'S STUDY NUMBER: T-6316.7 FINAL REPORT DATE: 17 DECEMBER 1998 W 13gwon & EPA-OTS 000811803L D0061ia03L cn PROTOCOL 418-011 ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS SPONSOR'S STUDY NUMBER: T-6316.7 TABLE OF CONTENTS SUBJECT I. SUMMARY AND CONCLUSION A. Methods B. Results C. Conclusion II. DESCRIPTION OF TEST PROCEDURES A. Conduct of Study A.1. Sponsor A.2. Testing Facility A.3. Study Number A.4. Sponsor's Study Number * A.5. Purpose of the Study A.6. Study Design 00* 358S PAGE 1-1 1-1 I-2 I-4 11-1 11-1 11-1 11-1 11-1 11-1 11-1 11-1 SUBJECT A.7. Regulatory Compliance A.8. Ownership of the Study A.9. Study Monitor A.10. Alternate Study Monitor A.11. Study Director A.12. Technical Performance A.13. Report Preparation A.14. Report Review A. 15. Date Protocol Signed A. 16. Dates of Technical Performance A. 17. Records Maintained B. Test Article Information B.1. Description B.2. Lot/Batch Number B.3. Date Received and Storage Conditions B.4. Special Handling Instructions B.5. Analysis of Activity C. Vehicle Information C.1. Description C.2. Lot Number C.3. Date Received and Storage Conditions C.4. Special Handling Instructions 11003589 PAGE 11-1 II-2 II-2 II-2 II-2 II-2 II-2 II-2 II-2 II-3 II-3 II-3 II-3 II-3 II-3 II-3 II-4 II-4 II-4 II-4 II-4 II-4 SUBJECT C.5. Analysis of Purity D. Test Article Preparation D.1. Sample Information E. Test System E.1. Species E.2. Strain E.3. Supplier (Source) E.4. Sex E.5. Rationale for Test System E.6. Test System Data E.7. Breeder Male Rat Data E.8. Method of Randomization E.9. System of Identification F. Husbandry F.1. Research Facility Registration F.2. Study Room F.3. Housing F.4. Lighting F.5. Sanitization F.6. Feed F.7. Feed Analysis F.8. Water iii 003590 PAGE ll-4 II-4 II-5 II-5 II-5 II-5 II-5 II-5 II-6 II-6 II-6 II-6 II-6 II-7 II-7 II-7 II-7 II-7 II-7 II-7 II-7 II-8 SUBJECT , F. 9. Water Analysis G. Methods G.1. Dosage Administration G.2. Rationale for Dosage Selection G.3. Route of Administration G.4. Rationale for Route of Administration G.5. Frequency of Administration G.6. Length of Study G.7. Method of Study Performance G.8. Gross Necropsy G.9 Statistical Analyses III. RESULTS A. Mortality, Clinical and Necropsy Observations A.1. Mortality A.2. Clinical Observations A. 3. Necropsy Observations B. Maternal Body Weights and Body Weight Changes C. Maternal Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values D. Caesarean-Sectioning and Litter Observations E. Fetal Alterations ,, E.1. Summary of Fetal Alterations E.2. Fetal Gross External Alterations iv 003591 PAGE 11-8 11-8 II-8 II-9 II-9 II-9 II-9 II-9 II-9 11-10 11-12 111-1 111-1 II1-1 111-1 111-1 111-1 III-2 HI-2 III-3 HI-3 III-4 SUBJECT E.3. Fetal Soft Tissue Alterations E.4. Fetal Skeletal Alterations REFERENCES APPENDIX A - REPORT FIGURE Figure 1. Maternal Body Weights APPENDIX B - REPORT TABLES Table 1. Clinical Observations - Summary Table 2. Necropsy Observations - Summary Table 3. Maternal Body Weights - Summary Table 4. Maternal Body Weight Changes - Summary Table 5. Maternal Absolute Feed Consumption Values (g/day) Summary Table 6. Maternal Relative Feed Consumption Values (g/kg/day) Summary Table 7. Caesarean-Sectioning Observations - Summary Table 8. Litter Observations (Caesarean-Delivered Fetuses) Summary Table 9. Fetal Alterations - Summary Table 10. Fetal Gross External Alterations - Summary Table 11. Table 12. Fetal Soft Tissue Alterations - Summary * Fetal Skeletal Alterations - Summary Table 13. Fetal Ossification Sites - Caesarean-Delivered Live Fetuses (Day 20 of Gestation) --Summary Table 14. Clinical Observations - Individual Data PAGE MI-4 111-5 111-7 A-1 B-1 B-2 B-3 B-5 B-6 B-7 B-8 B-9 B-10 B-11 B-12 B-13 B-16 B-17 V 003592 SUBJECT PAGE Table 15. Necropsy Observations - Individual Data B-23 Table 16. Maternal Body Weights - Individual Data B-29 Table 17. Maternal Feed Consumption Values - Individual Data B-44 Table 18. Caesarean-Sectioning Observations - Individual Data B-50 Table 19. Litter Observations (Caesarean-Delivered Fetuses) Individual Data B-56 Table 20. Fetal Sex, Vital Status and Body Weight - Individual Data B-62 Table 21. Fetal Alterations - Individual Data B-74 APPENDIX 3 - PROTOCOL AND AMENDMENTS C-1 to C-33 APPENDIX 3 - DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING D-1 APPENDIX TEMPERATURE AND RELATIVE HUMIDITY REPORT E-1 APPENDIX - - PILOT REPORT F-1 to F-87 APPENDIX 3 - HISTORICAL CONTROL DATA G-1 to G -16 APPENDIX H - STATEMENT OF THE STUDY DIRECTOR H-1 APPENDIX I - QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT 1-1 to I-5 0 0 -3 5 9 3 vi 418-011:PAGE 1-1 TITLE: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS ARGUS RESEARCH LABORATORIES, INC. PROTOCOL NUMBER: 418-011 SPONSOR'S STUDY NUMBER: T-6316.7 I. SUMMARY AND CONCLUSION A. Methods8 Twenty-five Crl:CDBR VAF/Plus (Sprague-Dawley) presumed pregnant female rats were assigned to each of five dosage groups (Groups I through V). Nineteen additional female rats were assigned to one of five dosage groups for the satellite study (three, five, three, three and five rats assigned to Groups I through V, respectively). The test article, N-EtFOSE, or vehicle, 2% Tween 80 in Reverse Osmosis Membrane Processed Deionized Water (R.O. Deionized Water), was administered via gavage once daily to female rats on days 6 through 17 of presumed gestation (DGs 6 through 17). Dosages of 0 (Vehicle), 1, 5, 10 and 20 mg/kg/day were administered at a dosage volume of 5 ml_/kg, adjusted daily on the basis of individual body weights. The female rats were observed for viability at least twice each day of the study. The rats were also examined for clinical observations of effects of the test article, abortions, premature deliveries and deaths before and approximately one hour after dosage (DGs 6 through 17), and once daily during the postdosage period. a. Detailed descriptions of all procedures used in the conduct of this study are provided in the appropriate sections of this report and in APPENDIX C (PROTOCOL AND AMENDMENT). 003594 418-011 P A G E I-2 Body weights were'recorded on DGs 0 and 4 and daily during the dosage and postdosage periods. Feed consumption values were recorded on DGs 0, 4, 6, 8, 10, 12, 14, 16, 18 and 20. All rats in the main study were sacrificed by carbon dioxide asphyxiation on DG 20 and a gross necropsy of the thoracic, abdominal and pelvic viscera was performed. The number of corpora lutea in each ovary was recorded. The uterus of each rat was examined for pregnancy, number and distribution of implantations, live and dead fetuses and early and late resorptions. Each fetus was identified, weighed and examined for sex and gross external alterations. Approximately one-half of the fetuses in each litter were examined for soft tissue alterations and the remaining fetuses in each litter were examined for skeletal alterations. Rats in the satellite study were sacrificed on DG 18. Blood samples were collected and centrifuged. The liver was excised, weighed and sectioned. Fetuses were examined grossly to the extent possible as described for rats assigned to the main study. Fetuses and placentae were pooled per litter. After completion of sample collection, serum, liver section, fetal and placental samples were shipped to the Sponsor for analysis. B. Results No deaths, abortions or premature deliveries occurred during the study. All rats survived until scheduled sacrifice on gestation day 20 (DG 20). All clinical and necropsy observations were considered unrelated to the test article. Maternal body weight gains were significantly reduced in groups administered 5 mg/kg/day and higher dosages of the test article. The effect was minimal and transient in the 5 mg/kg/day dosage group, occurring only on DGs 8 to 10. In the 10 mg/kg/day dosage group, significant reductions in maternal body weight gains occurred on DGs 6 to 8 and 10 to 12, followed by a significant increase in weight gain on DGs 14 to 16. The 20 mg/kg/day dosage group had significant weight loss followed by significant reductions in maternal body weight gain on DGs 8 to 14 and 16 to 18. These effects of the test article resulted in a tendency for reduced weight gain in the 10 mg/J<g/day dosage group and significant reductions in the 20 mg/kg/day dosage group for the entire treatment period (DGs 6 to 10), the entire interval after initiation of treatment (DGs 6 to 20) and the entire gestation period (DGs 0 to 20). Maternal body weights were 003S95 418-011 P A G E I-3 significantly reduce'd in the 10 and 20 mg/kg/day dosage groups on DGs 11 through 13 and 8 through 20, respectively. Body weights and body weight gains were unaffected by the 1 mg/kg/day dosage of the test article. The absolute feed consumption value was significantly reduced in the 10 mg/kg/day dosage group on DGs 6 to 8 and absolute and relative feed consumption values were significantly reduced in the 20 mg/kg/day dosage group for the entire dosage period and at all intervals within this period. The absolute feed consumption value continued to be significantly reduced and the relative feed consumption value tended to be reduced in the 20 mg/kg/day dosage group during the postdosage interval. These effects of the 20 mg/kg/day dosage of the test article resulted in significantly reduced absolute and relative feed consumption values on DGs 6 to 20 and DGs 0 to 20. Absolute and relative feed consumption values were unaffected by dosages of the test article as high as 5 mg/kg/day. Fetal body weights (total, male and/or female) were significantly reduced in the 10 and 20 mg/kg/day dosage groups, as compared to the control group values. Dosages of N-EtFOSE as high as 20 mg/kg/day did not affect any other Caesarean-sectioning or litter parameters. The litter averages for corpora ltea, implantations, litter sizes, live fetuses, early resorptions, percent resorbed conceptuses and percent male fetuses, as well as the numbers of dams with any resorptions or with viable fetuses were comparable in the five dosage groups and did not significantly differ. No dams had litters with all conceptuses resorbed, and there were no dead fetuses or late resorptions. All placentae appeared normal. All of these values were within the ranges observed historically at the Testing Facility. Reversible delays in fetal ossification associated with the significantly reduced fetal body weights in the 10 and 20 mg/kg/day dosage groups, were evident as significant reductions in the litter averages for ossified caudal vertebrae in the 10 and 20 mg/kg/day dosage groups and a significant increase in the fetal incidence of wavy ribs in the 20 mg/kg/day dosage group. All other fetal gross external, soft tissue and skeletal alterations (malformations and variations) were considered unrelated to the test article because: 1) the incidences were not dosage-dependent; and/or 2) the incidences were within ranges observed historically at the Testing Facility. 418-011 P A G E I-4 C. Conclusion On the basis of these data, the maternal no-observable-effect-level (NOEL) of N-EtFOSE is 5 mg/kg/day (the 10 and 20 mg/kg/day dosages caused biologically important and statistically significant reductions in body weight gains or weight losses, and the 20 mg/kg/day dosage also persistently reduced the absolute and relative feed consumption values). The developmental NOEL is also 5 mg/kg/day (the 10 and 20 mg/kg/day dosages significantly reduced fetal body weights and caused minimal, but statistically significant reversible delays in ossification of the caudal vertebrae; the 20 mg/kg/day dosage also significantly increased the incidence of wavy ribs, an additional reversible delay in ossification associated with the reduced fetal body weights). D Zv c Pb Mildred S. Christian, Ph.D., Fellow, ATS Executive Director of Research Date Alan M. Hoberman, Ph.D., DABT. Director of Research Date ^ and Study Director _____ Date QQ3S97 418-011:PAGE 11-1 II. DESCRIPTION OF TEST PROCEDURES A. Conduct of Study: A.1. Sponsor: 3M CorporateToxicology, 3M Center, Building 220-2E-02, St. Paul, Minnesota 55144-1000 A.2. Testing Facility: Argus Research Laboratories, Inc., 905 Sheehy Drive, Building A, Horsham, Pennsylvania 19044-1297 A.3. Study Number: 418-011 A.4. Sponsor's Study Number: T-6316.7 A.5. Purpose of the Study: The purpose of this study was to detect adverse effects of N-EtFOSE on Crl:CDBR VAF/Plus presumed pregnant female rats and development of the embryo and fetus consequent to exposure of the dam from implantation to closure of the hard palate. This study evaluated ICH Harmonised Tripartite Guideline stages C and D of the reproductive process. A.6. Study Design: The requirements of the International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline0* were used as the basis of study design. A.7. Regulatory Compliance: The study was conducted in compliance with Good Laboratory Practice (GLP) regulations of the U.S. Food and Drug Administration (FDA)(2), the Japanese Ministry of Health and Welfare (MHW )(3) and the European Economic Community (EEC)(4). There were no significant deviations from the GLP regulations that affected the quality or integrity of th study. Qality Assurance Unit findings derived from the inspections during the conduct of this study are documented 003598 418-011 P A G E II-2 and have been provided to the Study Director and the Testing Facility Management. A.8. Ownership of the Study: The Sponsor owns the study. All raw data, analyses, reports and preserved tissues are the property of the Sponsor. A.9. Study Monitor: Marvin T. Case, D.V.M., Ph.D. A.10. Alternate Study Monitor: Andrew M. Seacat, Ph.D. A.11. Study Director: Raymond G. York, Ph.D., DABT (Associate Director of Research) A.12. Technical Performance: John F. Barnett, B.S. (Director of Laboratory Operations) Kristen landola Sherer, B.S. (Research Associate/Fetal Evaluation) Sharon Adamski (Laboratory Technician) A.13. Report Preparation: Raymond G. York, Ph.D., DABT Jo Ann Frazee, M.S. (Study Coordinator) Susan K. Bradshaw, B.S. (Data Management Specialist) Karen G. Parker, A.A. (Administrative Assistant) A.14. Report Review: Alan M. Hoberman, Ph.D, DABT (Director of Research) Mildred S. Christian, Ph.D., Fellow, ATS (Executive Director of Research) A.15. Date Protocol Signed: 29 July 1998 003599 418-011 P A G E II-3 A.16. Dates of Technical Performance: Rat Arrival Date Cohabitation Period Day 0 of Presumed Gestation (DG 0) Dosage Period (DGs 6 through 17) Toxicokinetic Sample Collection and Caesarean-Sectioning Period (DG 18) - Satellite Study Caesarean-Sectioning Period Main Study (DG 20) 11 AUG 98 18 AUG 98 PM - 23 AUG 98 AM 19 AUG 9 8 - 2 3 AUG 98 25 AUG 98 - 09 SEP 98 10 SEP 98 08 SEP 98 -1 2 SEP 98 A. 17. Records Maintained: The original report, raw data and reserve samples of the test article and vehicle are retained in the archives of Argus Research Laboratories, Inc. Any preserved tissues are retained in the archives of the Testing Facility for one year after the mailing of the draft final report, after which time the Sponsor will decide their final disposition. Prepared formulations were discarded at the Testing Facility. Unused bulk test article will remain at the Testing Facility until its disposition is decided by the Sponsor. B. Test Article Information: B.1. Description: N-EtFOSE - a waxy solid B.2. Lot/Batch Number: FM-3929 [30035, 30037, 30039 (Expiration date: May 2000)] B.3. Date Received and Storage Conditions: The test article was received on 20 May 1998, and stored at room temperature. Prepared formulations were stored refrigerated. B.4. Special Handling Instructions: Standard safety precautions (use of protective clothing, gloves, dust-mist respirator, safety goggles or safety.;glasses and a face-shield) were taken when handling the bulk test article and prepared formulations. 003600 418-011:PAGE II-4 B. 5. Analysis of Puritv: Information regarding the identity, composition, strength, and purity of the test article is on file with the Sponsor. C. Vehicle Information: C.1. Description: 2% Tween 80 in Reverse Osmosis Membrane Processed Deionized Water (R.O. Deionized Water). C.2. Lot Number: M03H05 C.3. Date Received and Storage Conditions: The vehicle was received on 8 July 1998 from J.T. Baker, Phillipsburg, New Jersey, and stored at room temperature. R.O. Deionized Water is available from a continuous source at the Testing Facility and is maintained at room temperature. C.4. Special Handling Instructions: Standard safety precautions (use of protective clothing, gloves, dust-mist respirator, safety goggles or safety glasses and a face-shield) were taken when handling the vehicle. C. 5. Analysis of Puritv: Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to be present in the vehicle that would interfere with the results of this study. D. Test Article Preparation: Suspensions of N-EtFOSE were prepared daily at concentrations of 0, 0.2, 1, 2 and 4 mg/mL. The test article was considered 100% pure for the purpose of dosage calculations. 903601 418-011:PAGE II-5 D.1. Sample Information: Sample Type Concentration (all levels) Bulk Test Article Reserve Vehicle Reserve Components N/A N/A Tween 80 R.O. Deionized Water Size 2mLa 1g 5 mL 5 mL Date Retained 25 AUG 98b 09 SEP 98c 25 AUG 98 25 AUG 98 25 AUG 98 Storage Conditions Frozen Room Temperature Room Temperature Room Temperature Shipped To Sponsor Testing Facility Archives Testing Facility Archives Testing Facility Archives Date Shipped 26 AUG 98 10 SEP 98 01 OCT 98 01 OCT 98 01 OCT 98 a. Duplicate samples were taken from the first and last preparation on the day prepared. One sample of each set was shipped to the Sponsor for analysis. The remaining samples were retained at the Testing Facility as backup samples. b. First day of preparation. c. Last day of preparation. Homogeneity and stability of prepared formulations are on file with the Sponsor. D. 2. Analytical Results: Concentration samples (2 mL) were taken on the first and last days of preparation for analyses by 3M Environmental Technology and Safety Services. The results of these analyses were not available at the time of this report. E. Test System : E.1. Species: Rat E.2. Strain: Crl:CDBR VAF/Plus (Sprague-Dawley) E.3. Supplier (Source): Charles River Laboratories, Inc., Raleigh, North Carolina E.4. Sex: Female (Note: Male rats were used only for the purposes of breeding and are not considered part of the Test System.) 0Q36O2 418-011 P A G E II-6 E.5. Rationale for Test System: The Crl:CDBR VAF/Plus (Sprague-Dawley) rat was selected as the Test System because: 1) it is one mammalian species accepted and widely used throughout industry for nonclinical studies of developmental toxicity (embryo-fetal toxicity/teratogenicity); 2) this strain has been demonstrated to be sensitive to developmental toxins; 3) historical data and experience exist at the Testing Facility(5'7>; and 4) the test article is biologically active in this species and strain. E.6. Test System Data: Number of Rats Approximate Date of Birth Approximate Age at Arrival Weight (g) on the Day after Arrival Weight (g) at Study Assignment 190 08 AUG 98 64 days 195-234 210-251 E.7. Breeder Male Rat Data: Number of Rats Approximate Date of Birth Approximate Age at Arrival Weight (g) on the Day after Arrival Weight (g) at Study Assignment Shipment 1 Shipment 2 110 120 13 JAN 98 26 JAN 98 87 days 75 days 300 - 356 300 - 356 498 - 784 E.8. Method of Randomization: Upon arrival, rats were assigned to individual housing on the basis of computer generated random units. Female rats were assigned to one of five dosage groups (Groups I through V), 25 rats per dosage group, using a computer generated (weight-ordered) randomization procedure based on body weights recorded on DG 0. Nineteen additional female rats were assigned to one of five dosage groups for the satellite study (three, five, three, three and five rats assigned to Groups I through V, respectively) using a computer-generated randomization based on body weights recorded on DG 0. E.9. System of Identification: Each rat was individually identified with a Monel self-piercing ear tag (Gey Band and Tag Co., Inc., No. M SPT 20101) inscribed with the rat's designated unique permanent number. Cage tags were marked with the study number and permanent rat number. . .* 003603 418-011 P A G E II-7 F. Husbandry: F.1. Research Facility Registration: USDA Registration No. 23-R-099 under the Animal Welfare Act, 7 U.S.C. 2131 et seq. F.2. Study Rooms: The study rooms were maintained under conditions of positive airflow relative to a hallway and independently supplied with a minimum of ten changes per hour of 100% fresh air that had been passed through 99.97% HEPA filters (Airo Clean room). Room temperature and humidity were monitored constantly throughout the study. Room temperature was targeted at 64F to 79F (18C to 26C); relative humidity was targeted at 30% to 70%. See APPENDIX E (TEMPERATURE AND RELATIVE HUMIDITY REPORT). F.3. Housing: Rats were individually housed except during the cohabitation period. During cohabitation, each pair of male and female rats was housed in the male rat's cage. All cage sizes and housing conditions were in compliance with the Guide for the Care and Use of Laboratory Animals<8). F.4. Lighting: An automatically-controlled fluorescent light cycle was maintained at 12-hours light: 12-hours dark, with each dark period beginning at 1900 hours EST. F.5. Sanitization: Cage pan liners were changed approximately three times each week. Cages were changed approximately every other week. F.6. Feed: Rats were given ad libitum access to Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, Missouri) in individual feeders. F.7. Feed Analysis: Analyses were routinely performed by the feed supplier. No contaminants at levels exceeding the maximum concentration for certified feed or deviations from 003604 418-011 P A G E II-8 expected nutritional requirements were detected by these analyses. Copies of the results of the feed analyses are available in the raw data. Neither the Study Director nor the Sponsor was aware of any agent present in the feed that was known to interfere with the results of this study. F.8. Water: Local water that had been processed by passage through a reverse osmosis membrane (R.O. water) was available to the rats ad libitum from individual water bottles attached to the cages and/or from an automatic watering system. Chlorine was added to the processed water as a bacteriostat. F. 9. Water Analysis: The processed water is analyzed twice annually for possible chemical contamination (Lancaster Laboratories, Lancaster, Pennsylvania) and monthly for possible bacterial contamination (Analytical Laboratories, Inc., Chalfont, Pennsylvania). Copies of the results of the water analyses are available in the raw data. Neither the Study Director nor the Sponsor was aware of any agent present in the water that was known to interfere with the results of this study. G. Methods: G.1. Dosage Administration: Dosage Group Number of Rats Dosage (mg/kg/day) Concentration (mg/mL) I 25 + 3a 0 (Vehicle) II 25 + 5" 1 0 0.2 Dosage Volume (mL/kg) 5 5 Assigned Numbers Main Study Satellite Study" 12801 - 12825 12826 - 12850 12573- 12575 12576-12580 III 25 + 3' 5 1 5 12851 - 12875 12581 - 12583 IV 25 + 3" 10 2 5 12876-12900 V 25 + 5" 20 4 5 12901 -19295 The test article was considered 100% pure for the purpose of dosage calculations, a. Rats assigned to the satellite group for blood collection. 12584 -12586 12587-12591 The test article was considered 100% pure for the purpose of dosage calculations. '' 003605 418-011:PAGE II-9 G.2. Rationale for Dosage Selection: Dosages were selected on the basis of a dosage-range study (Argus Research Laboratories, Inc., Protocol 418-011P) that tested 0, 1, 5, 10, 25 and 35 mg/kg/day. In that study, body weight gain was decreased at 10 mg/kg/day and higher dosages, and feed consumption values were reduced at all dosages tested. G.3. Route of Administration: Oral (gavage) G.4. Rationale for Route of Administration: The oral (gavage) route was selected for use because: 1) in comparison with the dietary route, the exact dosage can be accurately administered; and 2) it is a proposed route of human exposure. G.5. Frequency of Administration: Appropriate dosages of the test article were administered orally (via gavage) once daily to female rats on DGs 6 through 17. Dosages of 0 (Vehicle), 1, 5, 10 and 20 mg/kg/day of the test article were administered at a dosage volume of 5 mL/kg, adjusted daily on the basis of the individual body weights recorded before dosage. The rats were dosed at approximately the same time each day. G.6. Length of Study: Approximately 4 weeks G.7. Method of Study Performance: After acclimation, 190 healthy virgin female rats were placed into cohabitation with 190 breeder male rats (one male rat per female rat in the male rat's cage). Female rats with spermatozoa observed in a smear of the vaginal contents and/or a copulatory plug in situ were considered to be at DG 0 and returned to individual housing. The female rats were observed for viability at least twice each day of the study and for general appearance weekly during acclimation and on DG 0. The rats were also examined for clinical observations of effects of the test article, 0Q3606 418-011 P A G E 11-10 abortions, premature deliveries and deaths before and approximately one hour after dosage (DGs 6 through 17a), and once daily during the postdosage period. Body weights were recorded weekly during acclimation, on DGs 0 and 4 and daily during the dosage and postdosage periods (DGs 6 through 20). Feed consumption values were recorded on DGs 0, 4, 6, 8, 10, 12, 14, 16, 18 and 20. G.8. Gross Necropsvb: Rats Assigned to the Main Study: All rats were sacrificed by carbon dioxide asphyxiation on DG 20, Caesareansectioned and a gross necropsy of the thoracic, abdominal and pelvic viscera was performed. Uteri of apparently nonpregnant rats were stained with 10% ammonium sulfide to confirm the absence of implantation sites(9). Tissues with gross lesions were preserved in neutral buffered 10% formalin for possible future evaluation; all other maternal tissues were discarded. The number of corpora lutea in each ovary was recorded. The uterus of each rat was excised and examined for pregnancy, number and distribution of implantations, live and dead fetuses and early and late resorptions. An early resorption was defined as one in which organogenesis was not grossly evident. A late resorption was defined as one in which the occurrence of organogenesis was grossly evident. A live fetus was defined as a term fetus that responded to stimuli. Nonresponding term fetuses are considered to be dead (there were no dead fetuses). Dead fetuses and late resorptions are differentiated by the degree of autolysis present; marked to extreme autolysis indicated that the fetus was a late resorption. Each fetus was removed from the uterus, placed in an individual container and identified with a tag noting the study number, litter number, uterine distribution and fixative. Each fetus was subsequently weighed and examined for sex and gross external alterations. Live fetuses were sacrificed by an intraperitoneal a. See APPENDIX D (DEVIATIONS FROM THE PROTOCOL AND STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY), item 1. b. A table of random units was used to select one control group rat from which all tissues examined at necropsy were retained, in order to provide control tissues for any possible histopathological evaluations of gross lesions. 003607 418-011 P A G E 11-11 injection of Beuthanasia-D Special (Schering-Plough Animal Health). Photographs of gross external fetal alterations are available in the raw data. Approximately one-half of the fetuses in each litter were examined for soft tissue alterations using an adaptation of Wilson's sectioning technique005. The fetuses were initially fixed in Bouin's solution; sections were stored in alcohol. The remaining fetuses in each litter were eviscerated, cleared, stained with alizarin red S(11), fixed in alcohol and examined for skeletal alterations. Skeletal preparations were retained in glycerin with thymol added as a preservative. Rats Assigned to the Satellite Study: On DG 18, rats assigned to the toxicokinetic evaluation were sacrificed and the following samples collected. Blood samples (approximately 4 ml_ per rat) were collected from the inferior vena cava into serum separator tubes and centrifuged. The resulting serum (approximately 2 mL) was immediately frozen on dry ice and maintained frozen (-70C) until shipment to the Sponsor for analysis. The liver was excised, weighed, and a sample section (lateral lobe) was frozen and retained at -70C until shipment to the Sponsor for analysis. Rats were Caesarean-sectioned and fetuses were examined grossly to the extent possible as described above for rats assigned to the main study. Fetuses and placentae were pooled per litter and retained frozen (-70C) until shipment to the Sponsor for analysis. After completion of sample collection, serum, liver section (lateral lobe), fetal and placental samples were shipped (frozen on dry ice) to the Sponsor for analysis. i Q93608 418-011 P A G E 11-12 G.9. Statistical Analyses: The following schematic represents the statistical analyses of data: Type of Test3 I. Parametric II- Nonparametricb A. Bartlett's Testcd A. Kruskal-Wallis Test (<75% ties) Significant at p<0.05 Not Significant Nonparametric Analysis of Variance Significant atp<0.05 Dunn's Test Not Significant Significant at p<0.05 Not Significant B. Fisher's Exact Test (>75% ties) Dunnett's Test III. Test for Proportion Data Variance Test for Homogeneity of the Binomial Distribution a. Statistically significant probabilities are reported as either p<0.05 or p<0.01. b. Proportion data are not included in this category. c. Used only to analyze data with homogeneity of variance. d. Test for homogeneity of variance. O93609 418-011:PAGE 11-13 Clinical observation and other proportion data were analyzed using the Variance Test for Homogeneity of the Binomial Distribution(12). Continuous data (e.g., maternal body weights, body weight changes, feed consumption values and litter averages for percent male fetuses, percent resorbed conceptuses, fetal body weights, fetal anomaly data and fetal ossification site data) were analyzed using Bartlett's Test of Homogeneity of Variances035 and the Analysis of Variance045, when appropriate [i.e., Bartlett's Test was not significant (p>0.05)]. If the Analysis of Variance was significant (p<0.05), Dunnett's Test055 was used to identify the statistical significance of the individual groups. If the Analysis of Variance was not appropriate [i.e., Bartlett's Test was significant (p<0.05)], the Kruskal-Wallis Test065 was used, when less than or equal to 75% ties were present. In cases where the Kruskal-Wallis Test was statistically significant (p<0.05), Dunn's Method of Multiple Comparisons075 was used to identify the statistical significance of the individual groups. If there were greater than 75% ties, Fisher's Exact Test085 was used to analyze the data. Count data obtained at Caesarean-sectioning of the dams were evaluated using the procedures described above for the Kruskal-Wallis Test065. Dam 12868 (5 mg/kg/day dosage group) had a litter consisting of five live fetuses and two early resorptions and dam 12889 (10 mg/kg/day dosage group) had a litter consisting of three live fetuses. Because such occurrences can abnormally skew the distribution of data095, statistical analyses were made with and without the values for these rats and litters. Maternal body weights, feed consumption values and Caesarean-section data for these dams and litters were excluded from summarization and statistical analyses; all values are presented on the individual tables. 003610 418-011 P A G E 111-1 III. RESULTS ' A. Mortality. Clinical and Necropsy Observations (Summaries - Tables 1 and 2: Individual Data - Tables 14 and 15) A.1. Mortality No deaths, abortions or premature deliveries occurred during the study. All rats survived until scheduled sacrifice on gestation day 20 (DG 20). A.2. Clinical Observations All clinical observations were considered unrelated to the test article because: 1) the incidences were not dosage-dependent; 2) the observations occurred in only one rat; and/or 3) the observations are common events in the laboratory environment. Clinical observations included localized alopecia on the underside, limbs and/or neck, ungroomed coat, cold to touch and fused second and third digits on the right forepaw. A. 3. Necropsy Observations The only necropsy finding was a tan area (0.6 cm x 0.8 cm) on the median lobe of the liver in one 20 mg/kg/day dosage group dam (12913). This observation was considered unrelated to the test article because it occurred in only one rat. B. Maternal Body Weights and Body Weight Changes (Figure 1: Summaries - Tables 3 and 4: Individual Data - Table 16) Maternal body weight gains were significantly reduced (p<0.05 or p<0.01) in groups administered 5 mg/kg/day and higher dosages of the test article. The effect was minimal and transient in the 5 mg/kg/day dosage group, occurring only on DGs 8 to 10. In the 10 mg/kg/day dosage group, significant reductions (p<0.05) in maternal body weight gains occurred on DGs 6 to 8 and 10 to 12, followed by a significant increase (p<0.05) in weight gain on DGs 14 to 16. The 20 mg/kg/day dosage group had significant weight loss (p<0.01) on DGs 6 to 8 followed by significant reductions (p<0.05 or p<0.01) in maternal body weight gain on DGs 8 to 14 and 16 to 18. These effects of the test article resulted in a tendency for reduced weight gain irvthe 10 mg/kg/day dosage group and significant reductions (p<0.01) in the 20 mg/kg/day dosage group for the entire treatment period (calculated as DGs 6 to 18), the entire interval after initiation of treatment (DGs 6 to 20) and the entire gestation period (DGs 0 to 20). Maternal 003611 418-011 P A G E III-2 body weights were significantly reduced (p<0.05 orp<0.01) in the 10 and 20 mg/kg/day dosage groups on DGs 11 through 14 and 8 through 20, respectively. Body weights and body weight gains were unaffected by the 1 mg/kg/day dosage of the test article. C. Maternal Absolute fo/dav) and Relative (o/kg/davl Feed Consumption Values (Summaries - Tables 5 and 6: Individual Data - Table 17) The absolute (g/kg/day) feed consumption value was significantly reduced (p<0.05) in the 10 mg/kg/day dosage group on DGs 6 to 8 and absolute (g/day) and relative (g/kg/day) feed consumption values were significantly reduced (p<0.01) in the 20 mg/kg/day dosage group for the entire dosage period (calculated as DGs 6 to 18) and at all intervals within this period. The absolute feed consumption value continued to be significantly reduced (p<;0.01) and the relative feed consumption value tended to be reduced in the 20 mg/kg/day dosage group during the postdosage interval (DGs 18 to 20). These effects of the 20 mg/kg/day dosage of the test article resulted in significantly reduced (p^0.01) absolute and relative feed consumption values on DGs 6 to 20 (the entire interval after the first dosage was administered) and DGs 0 to 20 (the entire gestation period). Absolute and relative feed consumption values were unaffected by dosages of the test article as high as 5 mg/kg/day. The significant reduction (p<0.05) in the relative feed consumption value in the 1 mg/kg/day dosage group on DGs 6 to 8 was considered unrelated to the test article because the value was not dosagedependent. D. Caesarean-Sectioning and Litter Observations (Summaries -Tables 7 and 8: Individual Data - Tables 18 through 20) Pregnancy occurred in 24 (96%), 23 (92%), 24 (96%), 25 (100%) and 24 (96%) of the rats in the 0 (Vehicle), 1, 5, 10 and 20 mg/kg/day dosage groups, respectively. One 5 mg/kg/day dosage group litter consisted of five live fetuses and two early resorptions, and one 10 mg/kg/day dosage group litter consisted of three live fetuses. Because such occurrences can abnormally skew the distribution of the data(19>, values.for these dams and litters were excluded from data summarization and statistical analyses. As a result, Caesarean-sectioning observations were based on 24, 23, 23, 24 and 24 pregnant dams. 003612 418-011 P A G E III-3 Fetal body weights (total, male and/or female) were significantly reduced (p<.0.05 or p<;0.01) in the 10 and 20 mg/kg/day dosage groups, as compared to the control group values. The reduced fetal body weights in the 10 and 20mg/kg/day dosage groups were a reflection of body weight reduction of the dams at these higher dosage levels. Dosages of N-EtFOSE as high as 20 mg/kg/day did not affect any other Caesarean-sectioning or litter parameters. The litter averages for corpora ltea, implantations, litter sizes, live fetuses, early resorptions, percent resorbed conceptuses and percent male fetuses, as well as the numbers of dams with any resorptions or with viable fetuses were comparable in the five dosage groups and did not significantly differ. No dams had litters with all conceptuses resorbed, and there were no dead fetuses or late resorptions. All placentae appeared normal. All of these values were within the ranges observed historically at the Testing Facility3. E. Fetal Alterations (Summaries - Tables 9 through 13: Individual Data Table 211 Fetal alterations were defined as: 1) malformations (irreversible changes that occur at low incidences in this species and strain); and 2) variations (common findings in this species/strain, and reversible delays or accelerations in development). Litter averages were calculated for specific fetal ossification sites as part of the evaluation of the degree of fetal ossification. Fetal evaluations were based on 342, 349, 347, 354 and 326 DG 20 Caesareandelivered live fetuses in 24, 23, 24, 25 and 24 litters in the 0 (Vehicle), 1, 5, 10 and 20 mg/kg/day dosage groups, respectively. Each fetus was examined for gross external alterations. Of these respective fetuses 166, 167, 169, 170 and 158 were examined for soft tissue alterations and 176, 182,178, 184 and 168 were examined for skeletal alterations and fetal ossification site averages. E.1. Summary of Fetal Alterations (Summary - Table 9: Individual Data Table 21) In the five respective dosage groups, litters with fetuses with alterations present numbered 6 (25.0%), 8 (34.8%), 4 (16.7%), 7 (28.0%) and 8 (33.3%). The numbers of fetuses with any alteration observed were 15 (4.4%), 10 (2.9%), 6 (1.7%), 8 (2.2%) and 12 (3.7%), and the percentages of fetuses with any alteration were 4.4%, 2.8%, 1.6%, 2.1% and 4.0%, in these same respective dosage groups. a. See APPENDIX G (HISTORICAL CONTROL,DATA). 003613 418-011 PAGE III-4 Reversible delays in fetal ossification*20,2"0 associated with the significantly reduced (p<0.05 or p<0.01) fetal body weights in the 10 and 20 mg/kg/day dosage groups, were evident as significant reductions (p<0.05) in the litter averages for ossified caudal vertebrae in the 10 and 20 mg/kg/day dosage groups and a significant increase (p<0.05) in the fetal incidence of wavy ribs in the 20 mg/kg/day dosage group. All other fetal gross external, soft tissue and skeletal alterations (malformations and variations) were considered unrelated to the test article because: 1) the incidences were not dosage-dependent; and/or 2) the incidences were within ranges observed historically at the Testing Facility. E.2. Fetal Gross External Alterations (Summary - Table 10: Individual Data - Table 21) E.2.a. Malformations One 10 mg/kg/day dosage group fetus (12885-15) had a short trunk and absent tail. Subsequent skeletal examination of this fetus revealed that only four cervical vertebrae were present and that there were no thoracic, lumbar, sacral or caudal vertebrae, or ribs. This fetus also had a variation in pelvic ossification (the pubes were not ossified). E.2.b. Variations No gross external variations occurred in the fetuses in this study. E.3. Fetal Soft Tissue Alterations (Summary - Table 11: Individual Data Table 211 E.3.a. Malformations No fetal malformations were identified at visceral examination. E.3.b. Variations E.3.b.1. Vessels Three control group fetuses (12801-10; 12810-10; 12821-6), one 1 mg/kg/day dosage group fetus (12834-14) and two 5 mg/kg/day dosage group littermates Q03614 418-011:PAGE III-5 (12860-5, -9) had the umbilical artery descending to the left of the bladder. These fetuses had no external findings and no other soft tissue alterations. Two 1 mg/kg/day dosage group fetuses (12826-12; 12837-9) had an absent innominate artery. No additional alterations occurred in these fetuses. E.3.b.2. Lunas One control group fetus (12822-4) had an absent apical lung lobe, and one 1 mg/kg/day dosage group fetus (12850-16) had an absent diaphragmatic lung lobe. No additional alterations occurred in these fetuses. E.3.b.3. Kidneys Two control group fetuses (12802-11; 12803-2) and one 10 mg/kg/day dosage group fetus (12877-14) had slight or moderate dilation of the pelvis of one or both kidneys, a reversible developmental delay(22). No additional alterations occurred in these fetuses. E.4. Fetal Skeletal Alterations (Summaries - Tables 12 and 13: Individual Data - Table 211 E.4.a. Malformations Externally malformed 10 mg/kg/day dosage group fetus 12885-15 had only four cervical vertebrae and no thoracic, lumbar, sacral or caudal vertebrae or ribs, as well as a variation in pelvic ossification (not ossified pubes), as previously described. E.4.b. Variations E.4.b.1. Skull A large nasal-frontal suture occurred in one 10 mg/kg/day dosage group fetus (12893-13). No additional alterations occurred in this fetus. E.4.b.2. Ribs A cervical rib at the 7th cervical vertebra, a common variation in this strain of r a t(23), occurred in 0, 3, 1, 3 and 4 fetuses from 0, 2 , 1 , 3 and 4 litters in the 0 (Vehicle), 1, 5, 10 and 20 mg/kg/day dosage.groups, respectively. These fetuses had no other external or skeletal alterations. 003615 418-011 P A G E III-6 Wavy ribs, a reversible delay in ossification(21), occurred in one 1 mg/kg/day dosage group fetus (12848-1) and seven (p<;0.05) 20 mg/kg/day group fetuses (12904-1; 12909-5, -7, -10, -12; 12919-3, -9). One 20 mg/kg/day dosage group fetus (12909-7) also had incompletely ossified ribs. The significant increase in the fetal incidence of wavy ribs in the 20 mg/kg/day dosage group was considered a treatment-related developmental delay, associated with the significantly reduced (p<0.05 or p<0.01) fetal body weights in this dosage group. E.4.b.3. Sternum Delayed sternal ossification (incompletely ossified or not ossified 1st sternebra) occurred in 7, 2**, 1**, 1** and 1** fetuses from 3, 2, 1, 1 and 1 litters in the 0 (Vehicle), 1, 5, 10 and 20 mg/kg/day dosage groups, respectively. Of these fetuses, one control group fetus (12802-1) had incompletely ossified pubes in addition to an unossified 1st sternal centrum. E.4.b.4. Pelvis The ischia and/or pubes were incompletely or not ossified in 3, 0, 2, 2 and 0 fetuses from 1, 0, 1 , 2 and 0 litters in the 0 (Vehicle), 1, 5, 10 and 20 mg/kg/day dosage groups, respectively. One fetus in the control group (12802-1) and one 10 mg/kg/day dosage group fetus (12885-15) had additional skeletal alterations, as previously described. E.4.b.5. Fetal Ossification Site Averages The litter averages for ossified caudal vertebrae per fetus were significantly reduced (p<0.05) in the 10 and 20 mg/kg/day dosage groups. These delays in caudal vertebral ossification were considered effects of the test article associated with the significantly reduced (p<0.05 or p<0.01) fetal body weights in these dosage groups. Analyses of the average numbers of fetal ossification sites per fetus did not reveal any other statistically significant differences among the five dosage groups. Ossification of the hyoid, vertebrae (cervical, thoracic, lumbar and sacral), ribs, sternum (manubrium, sternal centers and xiphoid), forelimbs (carpals, metacarpals and phalanges) and hindlimbs (tarsals, metatarsals and phalanges) occurred at similar incidences in litters in all dosage groups. All values were within the ranges observed historically at the Testing Facility. Significantly different from the vehicle control group (p< 0.01). 0Q3616 418-011 P A G E III-7 REFERENCES ' 1. U.S. Food and Drug Administration (1994). International Conference on Harmonisation; Guideline on detection of toxicity to reproduction for medicinal products. Federal Register, September 22, 1994, Vol. 59, No. 183. 2. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. 3. Japanese Ministry of Health and Welfare (1988). Good Laboratory Practice Standard for Safety Studies on Drugs, Pharmaceutical Affairs Bureau, April 1, 1983, amended October 5, 1988. 4. European Economic Community (1989). Council decision on 28 July 1989 on the acceptance by the European Economic Community of an OECD decision/recommendation on compliance with principles of good laboratory practice. Official Journal of the European Communities: Legislation. 32(No. L 315; 28 October): 1-17. 5. Christian, M.S. and Voytek, P.E. (1982). In Vivo Reproductive and Mutagenicity Tests. Environmental Protection Agency, Washington, D.C. National Technical Information Service, U.S. Department of Commerce, Springfield, VA 22161. 6. Christian, M.S. (1984). Reproductive toxicity and teratology evaluations of naltrexone (Proceedings of Naltrexone Symposium, New York Academy of Sciences, November 7, 1983), J. Clin. Psychiat. 45(9):7-10. 7. Lang, P.L. (1988). Embryo and Fetal Developmental Toxicity (Teratology) Control Data in the Charles River Crl:CD7BR Rat. Charles River Laboratories, Inc., Wilmington, MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.) 8. Institute of Laboratory Animal Resources (1996). Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C. 9. Salewski, E. (1964). Farbemethode zum makroskopischen Nachweis von Implantationsstellen am Uterus der Ratte. Arch. Pathol. Exp. Pharmakol. 247:367. 003617 418-011 P A G E III-8 10. Wilson, J.G. (1965). Methods for administering agents and detecting malformations in experimental animals. Teratology: Principles and Techniques, Wilson, J.G. and Warkany, J.(eds.), University of Chicago Press, pp. 262-277. 11. Staples, R.E. and Schnell, V.L. (1964). Refinement in rapid clearing technique in the KOH-alizarin red S method for fetal bone. Stain Technol. 39:61-63. 12. Snedecor, G.W. and Cochran, W.G. (1967). Variance test for homogeneity of the binomial distribution. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 240-241. 13. Sokal, R.R. and Rohlf, F.J. (1969). Bartlett's test of homogeneity of variances. Biometry, W.H. Freeman and Co., San Francisco, pp. 370-371. 14. Snedecor, G.W. and Cochran, W.G. (1967). Analysis of Variance. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 258-275. 15. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1129. 16. Sokal, R.R. and Rohlf, F.J. (1969). Kruskal-Wallis Test. Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389. 17. Dunn, O.J. (1964). Multiple comparisons using rank sums. Technometrics 6(3):241-252. 18. Siegel, S. (1956). Nonparametric Statistics for the Behavioral Sciences, McGraw-Hill, New York, pp. 96-104. 19. Zambrama, M.A. and Greenwald, G.S. (1971). Effects of fetal ovarian and placental weight of various number of fetuses in the rat. Biol, of Reprod. 4:216-223. 20. Collins, T.F.X., Welsh, J.J., Black, T.N., Whitby, K.E. and O'Donnell, M.W., Jr. (1987). Potential reversibility of skeletal effects in rats exposed in utero to caffeine. Fd. Chem. Toxic. 25(9):647-662. 21. Nishimura, M., lizuka, M., Iwaki, Sy and Kast, A. (1982). Repairability of Drug-induced "Wavy Ribs" in Rat Offspring. Arzneim.-Forsch./Drug Res. 32(H), Nr. 12., pp. 1518-1522. 003618 418-011 P A G E III-9 22. Woo, D. and Hoar, R. (1972). "Apparent Hydronephrosis" as a Normal Aspect of Renal Development in Late Gestation of Rats: The Effect of Methyl Salicylate. Teratology 6:191-196. 23. Khera, K.S. (1981). Common fetal aberrations and their teratologic significance: a review. Fund, and Appl. Toxicol. 1:13-18. 003619 APPENDIX A REPORT FIGURE 003620 400 380 360 -- 340 g CD320 L 1- Ci tv) K* X CD ^300 -- 280 260 240 220 MATERNAL BODY WEIGHTS Figure 1 0 (VEHICLE) 1 MG/KG/DAY S MG/KG/DAY 10 MG/KG/DAY 20 MG/KG/DAY *p<0.05 p<0.01 } i 7 o T i 12 13 14 15 16 17 18 19 20 DAY OF GESTATION 418-011:PAGE A-1 APPENDIX B REPORT TABLES 003622 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 1 (PAGE 1): CLINICAL OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I II III IV V 0 (VEHICLE) 1 5 10 20 MAXIMUM POSSIBLE INCIDENCE 375/ 25 375/ 25 375/ 25 375/ 25 375/ 25 MORTALITY 00000 LOCALIZED ALOPECIA: TOTAL UNDERSIDE LIMBS NECK 12/ 1 0/ 0 12/ 1 0/ 0 29/ 3 28/ 3 2/ 1 0/ 0 9/ 3 7/ 2 0/ 0 2/ 1 15/ 2 11/ 1 7/ 2 0/ 0 33/ 5 18/ 3 15/ 2 0/ 0 UNGROOMED COAT 0/ 0 0/ 0 0/ 0 0/ 0 3/ 1 COLD TO TOUCH 0/ 0 0/ 0 0/ 0 0/ 0 3/ 1 RIGHT FOREPAW: SECOND AND THIRD DIGITS FUSED 0/ 0 0/ 0 4/ 1 0/ 0 0/ 0 STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS. MAXIMUM POSSIBLE INCIDENCE = (DAYS X RATS) /NUMBER OF RATS EXAMINED PER GROUP ON DAYS 6 THROUGH 20 OF PRESUMED GESTATION. N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION, a. Dosage occurred on days 6 through 17 of presumed gestation. C29C00 418-011: PAGE B-1 418-011 .PAGE B-2 003624 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 2 (PAGE 1): NECROPSY OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I II III IV V 0 (VEHICLE) 1 5 10 20 RATS EXAMINED N 25 25 25 25 25 MORTALITY N0 0 0 0 0 APPEARED NORMAL N 25 25 25 25 24 LIVER: MEDIAN LOBE, TAN AREA N 0 0 0 01 a. Dosage occurred on days 6 through 17 of presumed gestation. % PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-S316.7) TABLE 3 (PAGE 1) : MATERNAL BODY WEIGHTS - SUMMARY 418-011: PAGE B-3 003625 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 1 III 5 RATS TESTED N 25 25 25 PREGNANT N 24 23 24 INCLUDED IN ANALYSES N 24 23 23b MATERNAL BODY WEIGHT (G) DAY 0 MEAN+S.D . 230.8 + 9.9 231.0 + 9.6 230.1 + 10.5 DAY 6 MEAN+S.D . 267.1 + 12.1 265.4 + 14.0 265.4 + 15.4 DAY 7 MEAN+S.D . 271.3 + 12.7 269.0 + 14.2 271.5 + 15.0 DAY 8 DAY 9 MEAN+S.D. MEAN+S.D . 276.1 + 12.6 280.8 + 13.1 273.8 + 14.4 277.5 + 13.8 274.6 + 16.1 [ 22] d 277.6 + 17.0 DAY 10 MEAN+S.D . 285.2 + 13.6 283.2 + 15.4 281.6 + 18.2 DAY 11 MEAN+S.D. 290.8 + 14.8 287.8 + 15.8 287.9 + 17.3 DAY 12 MEAN+S.D . 295.1 + 15.3 291.6 + 16.0 291.9 + 17.7 DAY 13 MEAN+S.D . 300.7 + 16.2 297.8 + 17.1 296.5 + 20.2 DAY 14 DAY 15 MEAN+S.D . MEAN+S. D. 305.4 17.1 313.0 + 17.6 304.0 + 17.7 311.4 + 17.8 301.8 + 21.0 309.5 + 22.1 DAY = DAY OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 6 through 17 of gestation. b. Excludes values for dam 12868, which had a litter consisting of 7 conceptuses. c. Excludes values for dam 12889, which had a litter consisting of 3 conceptuses. d. Excludes a value that was not recorded. Significantly different from the vehicle control group value (p<0.05). * * Significantly different from the vehicle control group value (p<0.01). IV V 10 20 25 25 25 24 24c 24 230.5 + 10.0 263.2 + 12.5 267.3 + 12.2 268.1 + 14.7 272.2 + 14.1 277.1 + 13.6 279.6 + 13.4* 283.5 + 14.4* 289.2 + 17.1* 293.3 + 18.0* 302.9 + 16.5 231.0 + 9.5 263.4 + 8.1 263.2 + 9.6 262.7 + 9.3** 264.4 + 10.8** 266.7 + 9.8** 269.0 + 10.8** 271.0 + 12.8** 272.4 + 13.1** 276.4 + 14.3** 282.1 + 17.1** PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 3 (PAGE 2) : MATERNAL BODY WEIGHTS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 1 III 5 RATS TESTED N 25 25 25 PREGNANT N 24 23 24 INCLUDED IN ANALYSES N 24 23 23b MATERNAL BODY WEIGHT (G) DAY 16 MEAN+S.D . 323.5 + 19.3 321.3 + 18.5 321.3 + 22.7 DAY 17 MEAN+S.D . 336.5 + 19.6 333.3 + 17.8 333.6 + 23.4 DAY ; 18 MEAN+S.D . 350.3 + 19.9 348.6 + 19.3 348.5 + 24.7 DAY 19 MEAN+S.D . 364.8 + 19.5 363.3 + 20.6 363.9 + 27.5 DAY 20 MEAN+S.D . 388.7 + 21.6 386.7 + 23.2 386.6 + 29.4 DAY = DAY OF GESTATION a. Dosage occurred on days 6 through 17 of gestation. i>. Excludes values for dam 12868, which had a litter consisting of 7 conceptuses. c. Excludes values for dam 12889, which had a litter consisting of 3 conceptuses. ** Significantly different from the vehicle control group value (p<0.01). IV 10 25 25 24C 314.4 + 18.4 325.2 + 19.1 338.4 + 20.9 352.8 + 20.3 375.7 + 23.0 V 20 25 24 24 292.4 + 18.5** 302.7 + 17.7** 314.2 + 15.9** 327.8 + 17.3** 348.7 + 19.6** 929C00 418-011:PAGE B-4 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 4 (PAGE 1) : MATERNAL BODY WEIGHT CHANGES - SUMMARY 418-011: PAGE B-5 003627 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 1 III 5 RATS TESTED N 25 25 25 PREGNANT N 24 23 24 INCLUDED IN ANALYSES N 24 23 23b MATERNAL BODY WEIGHT CHANGE (G) DAYS 0 - 6 MEAN+S.D . +36.3 + 8.7 +34.4 + 12.0 +35.3 + 10.9 t)AYS 6 - 8 DAYS 8 - 10 DAYS 10 - 12 MEAN+S.D . MEAN+S.D . MEAN+S.D . +9.0 + 4.3 +9.1 + 4.0 +9.9 + 4.2 +8.4 + 3.0 +9.4 + 3.4 +8.4 + 5.0 +9.9 + 6.8 ( :22} d +6.0 + 4.6* [ :22} d +10.3 +_ 5.6 DAYS 12 - 14 MEAN+S.D . +10.3 + 4.4 +12.3 + 4.8 +9.9 + 5.3 DAYS 14 - 16 MEAN+S.D . +18.1 + 6.6 +17.3 + 4.7 +19.5 + 4.5 DAYS 16 - 18 MEAN+S.D . +26.8 + 3.8 +27.3 + 5.7 +27.3 + 5.2 DAYS 6 - 18 DAYS 18 - 20 DAYS 6 - 20 MEAN+S.D . MEAN+S.D . MEAN+S.D . +83.2 + 11.4 +38.3 + 6.3 +121.5 + 13.2 +83.3 + 11.2 +38.1 + 7.3 +121.3 + 15.9 +83.1 + 11.9 +38.0 + 7.9 +121.1 + 16.0 DAYS 0 - 20 MEAN+S.D . +157.9 + 17.9 +155.7 +_ 20.3 +156.5 + 24.3 DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 6 through 17 of gestation. b. Excludes values for dam 12868, which had a litter consisting of 7 conceptuses. c. Excludes values for dam 12889, which had a litter consisting of 3 conceptuses. d. Excludes values that were not recorded. * Significantly different from the vehicle control group value (p<0.05). ** Significantly different from the vehicle control group value (p<0.01). IV 10 25 25 24c +32.6 + 8.2 +4.9 + 5.4* +9.0 + 5.3 +6.4 + 4.5* +9.8 + 5.6 +21.1 + 3.9* +24.0 + 6.2 +75.2 + 12.0 +37.2 + 6.0 +112.5 + 15.1 +145.1 + 18.9 V 20 25 24 24 +32.5 + -0.8 +_ 8.0** +4.0 + 4.4** +4.3 + 9.0* +5.3 + 8.6* +16.1 + 6.9 +21.7 + 7.5** +50.7 + 15.8** +34.5 + 6.7 +85.2 + 19.2** +117.7 + 22.6** 00 o PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N--EtFOSE IN RATS (SPONSOR'S STUDY NUMBER : T-6316,.7) TABLE 5 (PAGE 1): MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY 82T9C00 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 1 III 5 RATS TESTED N 25 25 25 PREGNANT N 24 23 24 INCLUDED IN ANALYSES N 24 23 23b MATERNAL FEED CONSUMPTION (G/DAY) DAYS 0 - 6 DAYS 6 - 8 MEAN+S.D. MEAN+S.D. 21.5 + 3.0 [ 23]d 24.6 + 3.1 21.1 + 3.3 23.0 + 2.0 21.6 + 3.0 24.1 + 3.6 DAYS 8 - 10 MEAN+S.D . 23.9 + 2.3 22.9 + 1.9 22.6 + 3.0 DAYS 10 - 12 MEAN+S.D. 24.6 + 3.2 23.5 + 2.4 24.0 + 2.5 DAYS 12 - 14 MEAN+S.D . 25.7 + 2.8 24.5 + 2.8 24.7 + 3.4 DAYS 14 - 16 MEAN+S.D . 26.0 + 3.4 25.2 + 3.0 25.7 + 3.6 DAYS 16 - 18 MEAN+S.D . 27.6 + 2.3 26.6 + 2.8 27.2 + 3.3 DAYS 6 - 1 8 MEAN+S.D . 25.4 + 2.3 24.3 + 1.9 24.7 + 2.7 DAYS 18 - 20 MEAN+S.D . 26.4 + 2.4 25.2 + 2.8 25.9 + 3.1 DAYS 6 - 2 0 MEAN+S.D . 25.5 + 2.2 24.4 + 1.9 24.9 + 2.7 DAYS 0 - 20 MEAN+S.D. 24.6 + 2.4 23.4 + 2.1 23.9 + 2.7 DAYS = DAYS OF GESTATION [ J = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 6 through 17 of gestation. b. Excludes values for dam 12868, which had a litter consisting of 7 conceptuses. c. Excludes values for dam 12889, which had a litter consisting of 3 conceptuses. d. Excludes values that were incorrectly recorded, as well as those associated with spillage. * Significantly different from the vehicle control group value (p<0.05). ** Significantly different from the vehicle control group value (p^O.Ol). IV 10 25 25 24c 21.1 + 3.3 22.4 + 2.8* 22.6 + 2.4 23.6 + 2.3 [ 23]d 23.9 + 3.0 26.1 + 2.8 26.2 + 2.7 24.2 + 1.9 24.9 + 2.7 24.2 + 1.9 23.3 + 2.1 V 20 25 24 24 21.2 + 2.1 19.4 + 3.0** 19.2 + 3.2** 19.8 + 4.4** 20.5 + 4.2** 21.3 + 4.3** 22.5 + 2.5** 20.4 + 2.6** 22.5 + 2.4** 20.7 + 2.4** 20.9 + 2.0** 418-011 PAGE B-6 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 6 (PAGE I) : MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - SUMMARY 418-011: PAGE B-7 03629 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 1 III 5 RATS TESTED N 25 25 25 PREGNANT N 24 23 24 INCLUDED IN ANALYSES N 24 23 23b MATERNAL FEED CONSUMPTION (G/KG/DAY) DAYS 0 - 6 DAYS 6 - 8 MEAN+S.D . MEAN+S.D . 85.5 + 10.1 [ :23]d 90.3 + 8.4 84.4 + 11.4 85.3 + 5.5* 86.4 + 9.8 89.0 + 10.2 DAYS 8 - 10 MEAN+S.D . 85.1 + 6.4 82.3 + 5.0 81.3 + 8.5 DAYS 10 - 12 MEAN+S.D . 84.4 + 8.7 81.8 + 6.5 83.5 _+ 6.9 DAYS 12 - 14 MEAN+S.D . 85.4 + 6.3 82.3 + 6.9 83.1 + 8.6 DAYS 14 - 16 MEAN+S.D. 82.7 + 8.6 80.6 + 7.2 82.7 + 8.9 DAYS 16 - 18 MEAN+S.D . 82.0 + 6.0 79.6 + 8.2 81.5 + 8.3 DAYS 6 - 18 MEAN+S.D . 84.6 + 4.5 81.7 + 4.2 83.0 + 5.8 DAYS 18 - 20 MEAN+S.D . 71.6 + 5.6 68.8 + 6.2 70.6 + 6.3 DAYS 6 - 20 MEAN+S.D . 82.2 + 4.2 79.3 + 4.2 80.8 + 5.6 DAYS 0 - 20 MEAN+S.D . 80.2 + 4.3 77.8 + 4.4 79.4 + 5.8 DAYS DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 6 through 17 of gestation. b. Excludes values for dam 12868, which had a litter consisting of 7 conceptuses. c. Excludes values for dam 12889, which had a litter consisting of 3 conceptuses. d. Excludes values were incorrectly recorded, as well as those associated with spillage. * Significantly different from the vehicle control group value (p<0.05). ** Significantly different from the vehicle control group value (p<0.01). IV 10 25 25 24c 85.1 + 12.1 83.9 H- 8.5 82.9 + 7.3 84.3 + 6.2 ( 23] d 82.5 + 8.0 86.0 + 8.6 80.5 + 7.7 83.1 + 4.1 70.0 + 6.1 80.7 + 4.2 79.0 + 4.9 V 20 25 24 * 24 85.3 + 7.6 73.7 10.7** 72.4 + 10.2** 73.2 + 15.0** 74.6 + 14.0** 74.6 12.9** 74.3 + 6.5** 73.6 + 7.5** 68.2 + 5.3 72.6 + 6.5** 74.3 + 4.8** PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 7 (PAGE 1) : CAESAREAN-SECTIONING OBSERVATIONS - SUMMARY oe sfcoo DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 1 III 5 RATS TESTED N 25 25 25 PREGNANT N (%) 24( 96.0) 23 ( 92.0) 24( 96.0) RATS PREGNANT AND CAESAREAN-SECTIONED ON DAY 20 OF GESTATION N 24 23 24 INCLUDED IN ANALYSES CORPORA LUTEA N MEAN+S.D . 24 17.1 + 1.8 23 17.2 + 1.9 23b 17.2 + 2.1 IMPLANTATIONS MEAN+S.D . 15.1 + 1.8 15.6 + 2.0 15.6 + 1.4 LITTER SIZES MEAN+S.D. 14.2 + 1.8 15.2 + 2.1 14.9 + 1.9 LIVE FETUSES N MEAN+S.D. 342 14.2 + 1.8 349 15.2 + 2.1 342 14.9 + 1.9 DEAD FETUSES N 0 0 0 RESORPTIONS MEAN+S.D . 0.9 + 1.2 0.4 + 0.6 0.8 + 1.2 EARLY RESORPTIONS N MEAN+S.D . 21 0.9 + 1.2 10 0.4 + 0.6 18 0.8 + 1.2 LATE RESORPTIONS N 0 0 0 DAMS WITH ANY RESORPTIONS N(%) 12( 50.0) 9 ( 39.1) 11( 47.8) DAMS WITH ALL CONCEPTUSES RESORBED N(%) 0( 0.0) 0( 0.0) 0( 0.0) DAMS WITH VIABLE FETUSES N (%) 24(100.0) 23(100.0) 23(100.0) PLACENTAE APPEARED NORMAL N(%) 24(100.0) 23(100.0) 23(100.0) a. Dosage occurred on days 6 through 17 of gestation. b. Excludes values for dam 12868, which had a litter consisting of 7 conceptuses. c. Excludes values for dam 12889, which had a litter consisting of 3 conceptuses. IV 10 25 25 (100.0) 25 24c 16.8 + 2.0 15.1 + 1.3 14.6 + 1.6 351 14.6 + 1.6 0 0.5 + 0.8 12 0.5 + 0.8 0 9( 37.5) 0( 0.0) 24(100.0) 24(100.0) V 20 25 24( 96.0) 24 24 16.5 + 1.8 14.5 + 1.7 13.6 + 1.9 327 13.6 + 1.9 0 0.9 + 1.0 21 0.9 + 1.0 0 14( 58.3) 0( 0.0) 24(100.0) 24(100.0) 418-011: PAGE B-8 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 8 (PAGE 1) : LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - SUMMARY T c s ro o DOSAGE GROUP DOSAGE (MG/KG/DAY)a i 0 (VEHICLE) II 1 III 5 LITTERS WITH ONE OR MORE LIVE FETUSES N 24 23 24 INCLUDED IN ANALYSES N 24 23 23b IMPLANTATIONS MEAN+S.D . 15.1 + 1.8 15.6 + 2.0 15.6 + 1.4 LIVE FETUSES N MEAN+S.D . 342 14.2 + 1.8 349 15.2 + 2.1 342 14.9 + 1.9 LIVE MALE FETUSES N 166 171 165 % LIVE"MALE FETUSES/LITTER MEAN+S.D . 48.8 + 13.1 48.8 + 12.2 48.6 + 11.8 LIVE FETAL BODY WEIGHTS (GRAMS)/LITTER MEAN+S.D . 3.50 + 0.50 3.36 + 0.22 3.39 + 0.20 MALE FETUSES MEAN+S.D . 3.61 + 0.50 3.48 + 0.23 3.50 + 0.22 FEMALE FETUSES MEAN+S.D . 3.38 + 0.52 3.25 + 0.24 3.30 + 0.19 % RESORBED CONCEPTUSES/LITTER MEAN+S.D. 5.5 + 7.2 2.8 + 3.7 5.1 + 7.7 a. Dosage occurred on days 6 through 17 of gestation. b. Excludes values for dam 12868, which had a litter consisting of 7 conceptuses. c. Excludes values for dam 12889, which had a litter consisting of 3 concpetuses. Significantly different from the vehicle control group value (p<0.05). * * Significantly different from the vehicle control group value (p<0.01). IV 10 25 24C 15.1 + 1.3 351 14.6 + 1.6 180 51.7 + 10.6 3.32 + 0.20* 3.38 + 0.20** 3.25 + 0.23 3.4 + 5.0 V 20 24 24 * 1 4 .5 + 1.7 327 13.6 + 1.9 172 52.4 + 13.0 3.16 + 0.17** 3.26 + 0.19** 3.05 + 0.16** 6.0 + 6.8 418-011:PAGE B-9 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 9 (PAGE 1) : FETAL ALTERATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) LITTERS EVALUATED FETUSES EVALUATED LIVE N 24 N 342 N 342 LITTERS WITH FETUSES WITH ANY ALTERATION OBSERVED N (%) 6 ( 25.0) FETUSES WITH ANY ALTERATION OBSERVED N(%) 15( 4.4) % FETUSES WITH ANY ALTERATION/LITTER MEAN+S.D . 4.4 + 10.3 a . Dosage occurred on days 6 through 17 of gestation. II 1 23 349 349 8 ( 34.8) 10( 2.9) 2 . 8 + 4.4 hi 5 24 347 347 4( 16.7) 6( 1.7) 1 . 6 + 3.9 IV 10 25 354 354 7( 28.0) 8( 2.2) 2.1 + 3.9 V 20 24 326 326 8 ( 33.3) 12 ( 3.7) 4.0 + 7.6 418-011:PAGE B-10 003632 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 10 (PAGE 1) : FETAL GROSS EXTERNAL ALTERATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) LITTERS EVALUATED FETUSES EVALUATED LIVE N 24 N 342 N 342 BODY: TRUNK SHORT LITTER INCIDENCE FETAL INCIDENCE N (%) N (%} 0( 0.0) 0( 0.0) TAIL : ABSENT LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) 0( 0.0) 0( 0.0) a. Dosage occurred on days 6 through 17 of gestation. II 1 23 349 349 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) III 5 24 347 347 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) IV 10 25 354 354 1( 4.0) M 0.3) M 4.0) 1( 0.3) V 20 24 326 326 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) CC9COO 418-011: PAGE B-11 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 11 (PAGE 1) : FETAL SOFT TISSUE ALTERATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a i 0 (VEHICLE) II 1 LITTERS EVALUATED FETUSES EVALUATED LIVE N 24 N 166 N 166 23 167 167 VESSELS: UMBILICAL ARTERY DESCENDS TO THE LEFT OF URINARY BLADDER LITTER INCIDENCE N (%) 3 ( 12.5) K 4.3) FETAL INCIDENCE N(%) 3 ( 1.8) 1< 0.6) VESSELS: INNOMINATE, ABSENT LITTER INCIDENCE N(%) FETAL INCIDENCE N (%) 0 ( 0.0) 0 ( 0.0) M to 2 ( 8.7) 2( LUNGS: DIAPHRAGMATIC LOBE, ABSENT LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0 ( 0.0) 0 ( 0.0) K 4.3) 1< 0.6) LUNGS: APICAL LOBE, ABSENT .LITTER INCIDENCE FETAL INCIDENCE N<%) N (%) 1( 4.2) 1( 0.6) 0( 0.0) 0( 0.0) KIDNEYS: PELVIS, SLIGHT DILATION LITTER INCIDENCE N(%) FETAL INCIDENCE N (%) 2 ( 8.3) 2 ( 1.2) 0( 0.0) 0( 0.0) KIDNEYS: PELVIS, MODERATE DILATION LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0 ( 0.0) 0 ( 0.0) 0( 0.0) 0( 0.0) a. Dosage occurred on days 6 through 17 of gestation. III S 24 169 169 1( 4.2) 2 ( 1.2) 0( 0.0) 0< 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) of 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) IV 10 25 170 170 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) 1< 4.0) 1( 0.6) V 20 24 158 158 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) 418-011 PAGE B-12 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 12 (PAGE 1) : FETAL SKELETAL ALTERATIONS - SUMMARY (See footnotes on the last page of this table.) 418-011:PAGE B-13 003635 DOSAGE GROUP DOSAGE (MG/KG/DAY)a i 0 (VEHICLE) II 1 LITTERS EVALUATED FETUSES EVALUATED LIVE N 24 N 176 N 176 23 182 182 SKULL: NASAL - FRONTAL, SUTURE LARGE LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0 ( 0.0) 0 ( 0.0) 0( 0.0) 0 ( 0.0) CERVI&AL VERTEBRAE: CERVICAL RIB PRESENT AT 7TH CERVICAL VERTEBRA LiTTER INCIDENCE N (%) 0< 0.0) 2( 8.7) FETAL INCIDENCE N (%) 0 ( 0.0) 3 ( 1.6) CERVICAL VERTEBRAE: 4 PRESENT LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0( 0.0) 0 ( 0.0) 0( 0.0) 0 ( 0.0) THORACIC VERTEBRAE: 0 PRESENT LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0 ( 0.0) 0( 0.0) 0( 0.0) 0< 0.0) THORACIC VERTEBRAE: ARCH, NOT OSSIFIED LITTER INCIDENCE N (%) 0( 0.0) FETAL INCIDENCE N (%) 0( 0.0) 0( 0.0) 0( 0.0) THORACIC VERTEBRAE: CENTRUM, NOT OSSIFIED LITTER INCIDENCE N (%) 0( 0.0) FETAL INCIDENCE N (%) 0 ( 0.0) 0( 0.0) 0( 0.0) LUMBAR VERTEBRAE: 0 PRESENT LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) LUMBAR VERTEBRAE: ARCH, NOT OSSIFIED LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) LUMBAR VERTEBRAE: CENTRUM, NOT OSSIFIED LITTER INCIDENCE N (%) 0( 0.0) FETAL INCIDENCE N (%) 0( 0.0) 0 ( 0.0) 0( 0.0) III 5 24 178 178 0( 0.0) 0< 0.0) 1 ( 4.2) 1 ( 0.6) 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) IV 10 25 184 184 1( 4.0) 1 ( 0.5) 3 ( 12.0) 3 ( 1.6) 1 ( 4.0) 1 ( 0.5)b 1( 4.0) 11 0.5)b 1( 4.0) 1( 0.5)b 1( 4.0) 1( 0.5)b 1( 4.0) 1< 0.5)b 1< 4.0) 1( 0.5)b 1< 4.0) 1( 0.5)b V 20 24 168 168 0 ( 0.0) 0 ( 0.0) 4 ( 16.7) 4 ( 2.4) 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( 0.0) 0 ( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 0( 0.0) PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 12 (PAGE 2) : FETAL SKELETAL ALTERATIONS - SUMMARY (See footnotes on the last page of this table.) 9C9C0 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) LITTERS EVALUATED FETUSES EVALUATED LIVE N 24 N 176 N 176 SACRAL VERTEBRAE: 0 PRESENT LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0 ( 0.0) 0 ( 0.0) SACRAL VERTEBRAE: ARCH, NOT OSSIFIED LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0 ( 0.0) 0( 0.0) SACRAL VERTEBRAE: CENTRUM, NOT OSSIFIED LITTER INCIDENCE N (%) 0( 0.0) FETAL INCIDENCE N (%) 0 ( 0.0) CAUDAL VERTEBRAE: 0 PRESENT LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0{ 0.0) 0< 0.0) RIBS: WAVY LITTER INCIDENCE FETAL INCIDENCE N (%) N (% 0( 0.0) 0 ( 0.0) RIBS: 0 PRESENT LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) 0( 0.0) 0( 0.0) RIBS: NOT OSSIFIED LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) 0 ( 0.0) 0< 0.0) RIBS: INCOMPLETELY OSSIFIED (HYPOPLASTIC) LITTER INCIDENCE N (%) 0< FETAL INCIDENCE N (%) 0( 0.0) 0.0) II 1 23 182 182 0( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0( 0.0) 0< 0.0) I f 4.3) K 0.5) 0( 0.0) 0( 0.0) 0 ( 0.0) 0 ( 0.0) 0( 0.0) 0( 0.0) III 5 24 178 178 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) IV 10 25 184 1B4 1( 4.0) 1( 0.5)b 1( 4.0) 1( 0.5) b 1< 4.0) 1( 0.5)b 1< 4.0) 1< 0.5) b 0 ( 0.0) 0( 0.0) 1< 4.0) 1< 0.5) b 1( 4.0) 1< 0.5)b 0< 0.0) 0( 0.0) V 20 24 168 168 * 0< 0.0) 0< 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0< 0.0) 0( 0.0) 0< 0.0) 3 ( 12.5) 7 ( 4.2)* *C 0( 0.0) 0( 0.0) 0 ( 0.0) 0 ( 0.0) K 4.2) M 0.6 )c 418-011: PAGE B-14 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 12 (PAGE 3) : FETAL SKELETAL ALTERATIONS - SUMMARY 418-011 PAGE B-15 003637 DOSAGE GROUP DOSAGE (MG/KG/DAY) a I 0 (VEHICLE) II 1 LITTERS EVALUATED FETUSES EVALUATED LIVE N 24 N 176 N 176 23 182 182 STERNAL CENTRA: SUMMARIZATION (Includes incompletely ossified and not ossified sternal centra) LITTER INCIDENCE N (%) 3 ( 12.5) FETAL INCIDENCE N (%) 7 ( 4.0) 2 ( 8.7) 2 ( 1.1)** STERNAL CENTRA: 1ST, INCOMPLETELY OSSIFIED LITTER INCIDENCE N (%) 2 ( 8.3) FETAL INCIDENCE N (%) '4 ( 2.3) K 4.3) 1< 0.5) STERNAL* CENTRA : 1ST, NOT OSSIFIED LITTER INCIDENCE N (%) FETAL INCIDENCE N {%) 1 ( 4.2) 3 ( 1.7) d K 4.3) K 0.5) PELVIS: SUMMARIZATION (Includes incompletely ossified pubes and ischia, and not ossified pubes) LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 1< 4.2) 3 ( 1.7) o ( 0.0) 0< 0.0) PELVIS: PUBIS, INCOMPLETELY OSSIFIED LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) K 4.2) 3 ( 1.7) d 0( 0.0) 0 ( 0.0) PELVIS: PUBIS, NOT OSSIFIED LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0 ( 0.0) 0( 0.0) 0 ( 0.0) 0( 0.0) PELVIS: ISCHIUM, INCOMPLETELY OSSIFIED LITTER INCIDENCE N<%) 0 ( 0.0) FETAL INCIDENCE N (%) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) a. Dosage occurred on days 6 through 17 of gestation. b. Fetus 12885-15 had other skeletal alterations. c. Fetus 12909-7 had other skeletal alterations. d. Fetus 12802-1 had other skeletal alterations. ** Significantly different from the control group value (p<0.01). III 5 24 178 178 K 4.2) K 0.6)** l( 4.2) K 0.6) o ( 0.0) 0( 0.0) K 4.2) 2 ( 1.1) 0( 0.0) 0( 0.0) 0 ( 0.0) 0( 0.0) M 4.2) 2 ( 1.1) IV 10 25 184 184 K 4.0) K 0.5)** M 4.0) 1( 0.5) 0 ( 0.0) 0 ( 0.0) 2 ( 8.0) 2 ( 1.1) M 4.0) 1< 0.5) K 4.0) M 0.5 )b 0 ( 0.0) 0 ( 0.0) V 20 24 168 168 K 4.2) K 0.6)** o ( 0.0) 0( 0.0) K 4.2) K 0.6) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 0 ( 0.0) 0( 0.0) 0 ( 0.0) PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N* EtFOSE IN RATS (SPONSOR1S STUDY NUMBER:: T-6316..7) TABLE 13 (PAGE 1) : FETAL OSSIFICATION SITES - CAESAREAN-DELIVEREDi LIVE FETUSES (DAY 20 OF GESTATION) - SUMMARY 8C9C00 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) il 1 LITTERS EXAMINED N 24 FETUSES EXAMINED N 176 LIVE N 176 23 182 182 OSSIFICATION SITES PER FETUS PER LITTER HYOID MEAN+S.D . 0.97 + 0.08 0.98 + 0.06 VERTEBRAE CERVICAL THORACIC LUMBAR SACRAL CAUDAL MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D . 7.00 + 13.08 + 5.91 + 3.00 + 4.96 + 0.00 0.14 0.14 0.00 1.08 7.00 + 13.05 + 5.95 + 3.00 + 4.89 + 0.00 0.09 0.09 0.00 0.41 RIBS (PAIRS) MEAN+S.D . 13.06 + 0.10 13.03 + 0.06 STERNUM MANUBRIUM STERNAL CENTERS XIPHOID MEAN+S.D. MEAN+S.D. MEAN+S.D . 0.99 + 0.04 3.70 + 0.55 0.98 + 0.08 1.00 + 0.00 3.56 + 0.33 1.00 + 0.00 FORELIMB CARPALS METACARPALS DIGITS PHALANGES MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D . 0.00 + 3.72 + 5.00 + 5.20 + 0.00 0.27 0.00 0.73 0.00 + 3.73 + 5.00 + 5.12 + 0.00 0.29 0.00 0.30 HINDLIMB b TARSALS METATARSALS DIGITS PHALANGES MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. 0.00 + 3.99 + 5.00 + 4.82 + 0.00 0.28 0.00 0.90 0.00 + 4.00 + 5.00 + 5.00 + 0.00 0.00 0.00 0.00 a. Dosage occurred on days 6 through 17 of gestation. b. Calculated as average per limb. * Significantly different from the vehicle control group value (p<0.05). III 5 23 178 178 0.98 + 0.06 7.00 + 13.07 + 5.92 + 3.00 + 4.74 + 0.00 0.17 0.17 0.00 0.37 13.04 + 0.10 1.00 + 0.00 3.80 + 0.24 1.00 + 0.00 0.00 + 3.68 + 5.00 + 5.04 + 0.00 0.31 0.00 0.18 0.00 + 4.00 + 5.00 + 5.00 + 0.00 0.00 0.00 0.00 IV V 10 20 24 24 184 168 184 168 0.97 + 0.06 7.00 + 13.10 + 5.89 + 3.00 + 4.70 + 0.00 0.19 0.20 0.00 0.23* 13.09 + 0.17 1.00 + 0.02 3.68 + 0.25 1.00 + 0.02 0.00 + 3.72 + 5.00 + 5.09 + 0.00 0.27 0.00 0.28 0.00 + 4.00 + 5.00 + 4.98 + 0.00 0.02 0.00 0.12 1.00 + 0.02 7.00 + 13.13 + 5.84 + 3.00 + 4.59 + 0.00 0.16 0.16 0.00 0.43* 13.12 + 0.14 1.00 + 0.00 3.74 + 0.32 1.00 + 0.00 0.00 + 3.69 + 5.00 + 5.01 + 0.00 0.28 0.00 0.03 0.00 + 3.99 + 5.00 + 4.96 + 0.00 0.04 0.00 0.20 418-011:PAGE B-16 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 14 (PAGE 1): CLINICAL OBSERVATIONS - INDIVIDUAL DATA S C 9V 0 RAT # DOSAGE GROUP I 12801 12802 12803 12804 12805 12806 12807 12808 12809 12810 12&1.1 12812 12813 12814 12815 12816 12817 12818 12819 1J820 12821 12822 12823 12824 12825 D G ( 8- 19) D G ( 20 ) DG = DAY OF PRESUMED GESTATION DESCRIPTION 0 I(VEHICLE) MG/KG/DAY NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS ALOPECIA NO LONGER APPARENT NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS 418-011: PAGE B-17 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 14 (PAGE 2) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA OfrSCO RAT # DESCRIPTION DOSAGE GROUP II 1 MG/KG/DAY 12826 12827 12828 12829 12830 12831 12832 128-33 12834 12835 12836 12837 12838 12839 12840 1284-1 12842 12843 12844 12845 12846 12847 12848 12849 12850 DG ( 9- 19) DG ( 19- 20) DG ( 14- 19) DG ( 20 ) DG ( 10- 20) NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: UNDERSIDE LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: UNDERSIDE ALOPECIA NO LONGER APPARENT NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: UNDERSIDE NO ADVERSE FINDINGS DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. 418-011: PAGE B-18 T 9 C 0 0 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 14 (PAGE 3) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA RAT # DESCRIPTION DOSAGE GROUP III 5 MG/KG/DAY 12851 12852 12853 12854 12855 12856 12857 12858 12859 12860 12861 12862 12863 12864 12865 12866 12867 12868 ..12869 12870 12871 12872 12873 12874 12875 DG ( 18- 20) DG ( 17- 20) DG ( 19- 20) DG ( 17- 20) NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: UNDERSIDE a NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: UNDERSIDE a NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: NECK a NO ADVERSE FINDINGS RIGHT FOREPAW: SECOND AND THIRD DIGITS FUSED a NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS DG = DAY OF PRESUMED. GESTATION a. Observation confirmed at necropsy. * 418-011: PAGE B-19 PROTOCOL 418-011t ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 14 (PAGE 4) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA e ra c o ft RAT # DESCRIPTION DOSAGE GROUP IV 10 MG/KG/DAY 12876 12877 12878 12879 12880 12881 12882 12883 12884 12885 12886 12887 128*88* 12889 12890 *12891 12892 12893 12894 12895 12896 12897 12898 12899 12900 DG ( 10- 20) DG ( 18- 20) DG ( 17- 20) NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LOCALIZED ALOPECIA: NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS UNDERSIDE a LIMBS a LIMBS a DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. 418-011: PAGE B-20 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 14 (PAGE 5) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA C-9D00 RAT # DESCRIPTION DOSAGE GROUP V 20 MG/KG/DAY 12901 12902 12903 12904 12905 12906 12907 12908 12909 12910 * 12911 12912 12913 12914 12915 12916 12917 12918 12919 12920 12921 12922 12923 12924 12925 DG ( 10- 20) DG ( 13- 20) DG ( 16- 20) DG ( 16 - 20) DG ( 17- 20) DG ( 15- 17) DG ( 15- 17) NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LOCALIZED ALOPECIA: NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: COLD TO TOUCH UNGROOMED COAT LIMBS a UNDERSIDE a UNDERSIDE a UNDERSIDE LIMBS a DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. 418-011:PAGE B-; PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 14 (PAGE 6) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA RAT # DESCRIPTION SATELLITE DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 12573 12574 12575 NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS SATELLITE DOSAGE GROUP II 1 MG/KG/DAY 12576 12577 12578 1.2579 12580 NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS SATELLITE DOSAGE GROUP III 5 MG/KG/DAY 12581 12582 12583 D G ( 17- 18) NO ADVERSE FINDINGS LOCALIZED ALOPECIA: UNDERSIDE a NO ADVERSE FINDINGS SATELLITE DOSAGE GROUP IV 10 MG/KG/DAY 12584 12585 12586 NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS SATELLITE DOSAGE GROUP V 20 MG/KG/DAY 12587 12588 12589 12590 12591 NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. % 418-011:PAGE B-22 > ? u C/t PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 15 (PAGE 1) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) RAT NUMBER I 0 (VEHICLE) 12801 12802 12803 12804 12805 12806 12807 12808 12809 12810 12811 12812 12813 12814 12815 12816 12817 12818 12819 12820 12820 12821 12822 12823 12824 12825 P = PREGNANT NP = NOT PREGNANT DG = DAY OF GESTATION DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL, DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL, DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 NP 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL 418-011 PAGE B-23 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 15 (PAGE 2): NECROPSY OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) RAT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS 418-011: PAGE B-24 003646 12826 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12827 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12828 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12829 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12830 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12831 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12832 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12833 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12834 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12835 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12836 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12837 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12838 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12839 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12840 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12841 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12842 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12843 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12844 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12845 DG 20 NP 12 ALL TISSUES APPEARED NORMAL. 12846 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12847 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12848 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12849 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12850 DG 20 P 12 ALL TISSUES APPEARED NORMAL. P = PREGNANT NP = NOT PREGNANT DG = DAY OF GESTATION PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 15 (PAGE 3) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA 418-011:PAGE B-25 003647 DOSAGE GROUP DOSAGE (MG/KG/DAY) RAT NUMBER III 12851 12852 12853 12854 12855 12856 12857 12858 12859 12860 12861 12862 12863 12864 12865 12866 12867 12868 12869 12870 12871 12872 12873 12874 12875 P = PREGNANT NP = NOT PREGNANT DG = DAY OF GESTATION DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 NP 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL DG 20 P 12 ALL TISSUES APPEARED NORMAL PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316,7) TABLE 15 (PAGE 4) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) RAT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS 418-011 .PAGE B-26 003648 12876 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12877 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12878 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12879 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12880 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12881 DG 20 P 12 ALL TISSUES APPEARED NORMAL 12882 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12883 DG 20 P 12 ALL TISSUES APPEARED NORMAL, 12884 DG 20 P 12 ALL TISSUES a p p e a r e d NORMAL 12885 DG 20 P 12 ALL TISSUES APPEARED NORMAL. 12886 DG 20 P 12 ALL TISSUES APPEARED NORMAL, 12887 DG 20 P 12 ALL TISSUES APPEARED NORMAL 12888 DG 20 P 12 ALL TISSUES APPEARED NORMAL 12889 DG 20 P 12 ALL TISSUES APPEARED NORMAL 12890 DG 20 P 12 ALL TISSUES APPEARED NORMAL 12891 DG 20 P 12 ALL TISSUES APPEARED NORMAL 12892 DG 20 P 12 ALL TISSUES APPEARED NORMAL 12893 DG 20 P 12 ALL TISSUES APPEARED NORMAL 12894 DG 20 P 12 ALL TISSUES APPEARED NORMAL 12895 DG 20 P 12 ALL TISSUES APPEARED NORMAL 12896 DG 20 P 12 ALL TISSUES APPEARED NORMAL 12897 DG 20 P 12 ALL TISSUES APPEARED NORMAL 12898 DG 20 P 12 ALL TISSUES APPEARED NORMAL 12899 DG 20 P 12 ALL TISSUES APPEARED NORMAL 12900 DG 20 P 12 ALL TISSUES APPEARED NORMAL P = PREGNANT NP = NOT PREGNANT DG = DAY OF GESTATION PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 15 (PAGE 5) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA 6^9000 DOSAGE GROUP DOSAGE (MG/KG/DAY) V 20 RAT NUMBER 12901 12902 12903 12904 12905 12906 12907 12908 12909 12910 12911 12912 12913 12914 12915 12916 12917 12918 12919 12920 12921 12922 12923 12924 12925 P = PREGNANT NP = NOT PREGNANT DG = DAY OF GESTATION DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 NP 12 ALL TISSUES APPEARED NORMAL. DG 20 p 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 p 12 LIVER: MEDIAN LOBE, TAN ARE ALL OTHER TISSUES APPEARED ti DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 p 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 P 12 ALL TISSUES APPEARED NORMAL. DG 20 p 12 ALL TISSUES APPEARED NORMAL. DG 20 p 12 ALL TISSUES APPEARED NORMAL. DG 20 p 12 ALL TISSUES APPEARED NORMAL. X 0.8 CM) 418-011 P A G E B-27 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 15 (PAGE 6): NECROPSY OBSERVATIONS - INDIVIDUAL DATA 0S9C00 SATELLITE DOSAGE GROUP DOSAGE (MG/KG/DAY) RAT NUMBER I 0 (VEHICLE) 12573 12574 12575 II 1 12576 12577 12578 12579 12580 III 5 12581 12582 12583 IV 10 12584 12585 12586 V 20 12587 12588 12589 12590 12591 P = PREGNANT NP = NOT PREGNANT DG = DAY OF GESTATION DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. DG 18 P 12 ALL TISSUES APPEARED NORMAL. 418-011 PA G E B-28 418-011 PAGE B-29 003651 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 16 (PAGE 1) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 RAT # DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 12801 P 12802 P 12803 P 12804 P 12805 P 12806 P 12807 P 12808 P 12809 P-? 12*810 P X2811 P 12812 P 12813 NP 12814 P 12815 P 12816 P 12817 P 12818 P 12819 P 12820 P 12821 P 12822 P 12823 P 12824 P 12825 P 226. 212. 236. 221. 242. 229. 224 . 244 . 228 . 247. 238. 232. 228. 240. 226. 230 . 220. 237. 234 . 242. 222. 245. 215. 219. 230. 261. 242. 267. 245. 256 . 252. 263 . 267. 262. 273 . 253. 254 . 257. 274 . 259. a a a a a a a a a 246. 272 . 250. 285. 255. 276. 256. 273 . 277. 276 . 283 . 257. 266. 267. 288. 271. 275. 249. 277. 256. 265. 260. 280 . 249. 253 . 262. 277. 254 . 292. 256. 278. 266. 284 . 290. 280. 284 . 265. 270 . 273 . 284 . 274 . 277. 256. 280 . 261. 272. 266. 283 . 248. 249. 265. 284 . 262. 292. 261. 281. 270. 285. 293 . 287. 291. 276. 273 . 279. 292. 279. 279. 259. 283. 266. 274. 271. 291. 249. 256. 272. 286 . 263 . 301. 262. 286 . 275. 290 . 299. 288. 295. 281. 277. 283 . 293 . 286 . 285. 262 . 295. 268 . 276. 277. 298. 258. 264 . 273 . 297. 270 . 310. 269. 288 . 283 . 293 . 299. 297. 292 . 289. 278 . 285. 299 . 287. 292. 266 . 296. 268. 281. 283 . 299. 259. 262. 287. 304. 274 . 317. 273. 294 . 285. 300 . 308. 301. 298. 289. 289. 290. 303 . 294 . 297 . 272. 309. 273 . 287. 285. 305. 266. 261. 294 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Value was not recorded. 12 312 . 280. 319. 269. 299. 288 . 304 . 317. 308 . 307. 291. 291. 287. 312. 298 . 301. 281. 309. 279. 288. 287. 309. 268. 270. 295. 13 316. 282. 327. 279. 310 . 292. 309. 317. 308 . 316 . 295. 298. 286. 316. 303. 307. 288 . 316. 283 . 295. 299. 322. 270. 268. 301. 14 325. 288. 331. 281. 316. 299. 314. 321. 318. 320. 303 . 294 . 288 . 325. 310. 304. 289. 323 . 287. 299. 302. 322. 276. 270 . 312. 15 329. 297 . 345. 289. 315 . 302 . 314. 333. 332. 323 . 308. 308. 288 . 330. 317. 316. 298 . 331. 292. 306 . 309. 334. 280. 281. 322. 16 335. 303 . 357. 300. 333 . 314 . 326. 345. 357. 328. 314. 313 . 289. 344 . 327. 323 . 306. 338. 300. 317. 318. 352. 296. 289. 329. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 16 (PAGE 2) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA 418-011:PAGE B-30 003652 PREGNANCY STATUS DAY 17 18 19 20 RAT # DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 12801 P 12802 P 12803 P 12804 P 12805 P 12806 P 12807 P ,12808 P 12809 P 12810 P 12811 P 12812 P 12813 NP 12814 P 12815 P 12816 P 12817 P 12818 P 12819 P 12820 P 12821 P 12822 P 12823 P 12824 P 12825 P 354. 309. 373. 312. 345. 326 . 333 . 354. 367. 342. 325. 322 . 292. 360. 343. 341. 323. 354 . 313 . 328. 334 . 360. 308. 306 . 344 . 367. 323 . 387. 323 . 366. 338 . 353 . 367. 383 . 350. 343 . 341. 293 . 366. 357. 353. 336. 370 . 329. 340. 346. 374. 323. 315. 358. 379. 340 . 401 . 337. 374 . 350 . 365. 378. 387. 366 . 354 . 351. 295. 387. 373 . 365. 350. 382 . 347. 357. 363. 396. 334. 336. 384. 400. 356 . 429. 367. 393. 376. 385. 402. 421. 391. 382. 378. 311. 420 . 402. 388. 375. 399. 367. 382 . 394 . 419. 355. 347. 400. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 16 (PAGE 3): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA CS9CQO PREGNANCY STATUS DAY 0 4 6 7 8 9 10 RAT # DOSAGE GROUP II 1 MG/KG/DAY 12826 P 12827 P 12828 P 12829 P 12830 P 12831 P 12832 P 12833 P 12834 P 12835 P 12836 P 12837 P 12838 P 12839 P 12840 P 12841 P 12842 P 12843 P 12844 P 12845 NP 12846 NP 12847 P 12848 P 12849 P 12850 P 224. 236 . 212 . 212 . 228. 238. 227. 239. 225 . 230. 220. 240. 228. 243. 230. 222. 234 . 222. 242 . 217. 230. 236. 240. 237. 248. 258. 248 . 249. 224 . 256 . 252. 244 . 261. 236 . 274 . 247. 248. 239. a a a a a a a a a 256. 260 . 272. 273. 261. 269. 234 . 260 . 268. 254 . 274 . 249. 293 . 259. 255. 253 . 281. 263 . 272. 278. 241. 281. 233. 257. 263 . 267. 274. 282 . 280. 264 . 277. 245. 264 . 273. 260 . 275. 252. 298. 265. 249. 253 . 286. 268. 273 . 280. 246. 282. 232. 258. 261. 268. 282 . 287. 284 . 264 . 276 . 243 . 275 . 274 . 264 . 281. 253. 302 . 264 . 268. 261 . 292 . 270 . 279. 289 . 252. 287. 228. 263 . 270. 272 . 284 . 293 . 288. 272. 286 . 241. 275. 284. 268. 284 . 257. 291. 273 . 269. 266. 292 . 278. 285. 293 . 256 . 290. 227. 266. 275. 274. 290 . 296. 293 . 274 . 284 . 244 . 277. 286. 277. 292 . 265. 310. 275. 275. 267. 300. 283 . 292. 302 . 262. 294 . 232. 269. 277. 284. 298 . 302. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Value was not recorded. 11 295. 279. 293 . 248. 280. 296. 279. 290. 267 . 311. 281. 282 . 270 . 308. 288 . 295. 304 . 266 . 304 . 234. 268. 284. 288. 301. 310. 12 309. 286 . 302 . 257. 287. 292. 284 . 289. 274 . 316. 282. 282. 274 . 315. 292. 303 . 303 . 264 . 303 . 234. 269. 285. 288. 303 . 317. 13 314. 291. 298. 257. 291. 302. 287. 292. 279. 326. 292. 284 . 288. 321. 302. 312. 308 . 270. 311. 230. 272. 289. 298. 317. 320. 14 322. 291. 312 . 259. 292 . 311. 295. 298. 284 . 333. 296. 296 . 290. 325. 309. 320. 314. 276 . 314 . 239. 277. 303. 305. 322. 324. 15 330. 304 . 314 . 272. 305 . 316. 299. 302. 292 . 338. 303. 298 . 297. 332. 319. 330. 325. 278. 326. 239. 267. 306. 314. 333. 330. 16 340. 303 . 331. 278. 315. 323 . 312. 306 . 305. 347. 306. 315. 306 . 341. 329. 342. 339. 291. 340. 238. 266. 318. 327. 335. 341. 418-011:PAGE B-31 418-011 PAG E B-32 003654 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 16 (PAGE 4): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 17 18 19 20 RAT # DOSAGE GROUP II 1 MG/KG/DAY 12826 P 12827 P 12828 P 12829 P 12830 P 12831 P 12832 P 12833 P 12834 P 128.3S P 12836 P 12837 P 12838 P 12839 P 12840 P 12841 P 12842 P 12843 P 12844 P 12845 NP 12846 NP 12847 P 12848 P 12849 P 12850 P 352 . 317. 350. 293 . 323 . 340. 322. 318. 323. 354 . 313 . 327. 319. 357. 343 . 351. 346. 306. 342. 235. 265. 326. 340. 350. 354 . 364. 323 . 366. 306. 346. 356. 340. 335. 337. 362. 327. 341. 333. 377. 362. 364 . 368. 313. 358. 239. 266. 346. 363. 365. 367. 371. 340 . 383. 324 . 360 . 370. 343 . 340. 354 . 376. 342. 353 . 344. 396. 378. 374. 382 . 333. 372. 240. 261. 359. 384. 388. 391. 396. 362. 402. 331. 378 . 394 . 373 . 357. 381. 391. 359. 383. 372 . 418 . 408. 402. 414 . 352. 412. 245. 265. 387. 405. 407. 411. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). * PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 16 (PAGE 5) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA 418-011: PAGE B-33 003655 PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 12 13 14 15 RAT # DOSAGE GROUP III 5 MG/KG/DAY 12851 P 12852 P 12853 P 12854 P 12855 NP 12856 P 12857 P 12858 P. 12859 P 12860 P 12861 p 12862 P 12863 P 12864 p 12865 P 12866 p 12867 p 12868 P b 12869 P 12870 P 12871 P 12872 P 12873 P 12874 P 12875 P 225. 223 . 222. 232 . 244 . 228. 246 . 219. 233 . 230. 227. 210 . 221. 228. 220 . 247. 214 . 240 . 236. 238. 230. 252 . 233 . 242. 236. 268. 253. 259. 267. 259. 249. 264 . 236. 254 . 262 . 238 . 238. 247. a a a a a a 264. 249. 271. 258. 269. 252. 278. 265. 274 . 267. 269. 256. 276. 235. 281. 275. 236 . 248. 260. 272. 246. 289. 245. 278. 270. 278 . 252. 281. 274 . 282. 265. 288. 267. 273 . 289. 275. 259. 281. 244 . 286. 282 . 254 . 251. 265. 275. 256. 296. 247. 279. 268. 284. 261. 286. 278. 287. 267. 292. 276. 278 . 290 . 282. 256. 282. 260. 292. 291. 255. 254 . 270. 279 . 255. 301. 246 . 279. 281. 285. 258. a 284. 293 . 263 . 295. 281. 280 . 294 . 283 . 266. 287. 260. 297 . 281. 260. 258. 273 . 284 . 246 . 301. 246. 281. 281. 284 . 261. 302. 286. 297. 265 . 303 . 278 . 288 . 302 . 285 . 271. 291. 263 . 296 . 296 . 267 . 258 . 275. 283 . 250 . 307. 249. 287. 283 . 290 . 261. 304 . 290. 305 . 266. 310 . 283. 290 . 300 . 285. 279. 300 . 273 . 303 . 300 . 268 . 265. 283 . 297. 251. 311. 256 . 291. 292. 298. 272 . 310 . 294. 304 . 282. 314. 285. 299. 299. 286. 278. 306. 269. 301. 306. 268 . 269. 290 . 300 . 273. 321. 258. 292. 296. 299. 275. 318. 298. 311. 281. 325. 292. 302. 300. 280. 279. 312. 268. 316. 312. 274 . 276. 288. 303 . 266. 326. 265. 289. 302. 310. 274. 327. 301. 318. 284. 330. 298 . 308. 312. 271. 283 . 320 . 273 . 320. 317. 273 . 282. 290. 316. 271. 333. 266. 297. 307. 311. 279. 327. 314. 321. 290. 340. 305. 318. 317. 279. 288. 329. 273 . 333 . 328. 281. 286. 289. 320 . 289. 348. 275. 309. 312. 322. 290. 326. 317. 334 . 299. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Value was not recorded. b. Dam 12868 had a litter consisting of 7 conceptuses; values excluded from group averages and statistical analyses. 16 350. 315. ' 328 . 329. 280 . 305. 344 . 287. 344 . 339. 290 . 301. 307. 331. 299. 359. 284 . 315. 325. 335. 294 . 348. 324 . 347. 304. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 16 (PAGE 6): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA 9S9C0 PREGNANCY STATUS DAY 17 18 19 20 RAT # DOSAGE GROUP III 5 MG/KG/DAY 12851 P 12852 P 12853 P 12854 P 12855 NP 12856 P 12857 P 12858 P12859 P 12860 P 12861 P 12862 P 12863 P 12864 P 12865 P 12866 P 12867 P' 12868 P a 12869 P 12870 P 12871 P 12872 P 12873 P 12874 P 12875 P 364 . 333 . 346. 347. 274. 320. 358. 296. 361. 350. 300. 315. 314. 338. 310. 368. 294. 315. 337. 346. 307. 355. 339. 359. 315. 381. 353 . 362. 368. 268. 333 . 374. 313. 374 . 361. 309. 330 . 331. 357. 324 . 388. 308. 330. 352. 355. 320. 372 . 355. 373 . 323. 397. 367. 378 . 384 . 272. 348. 389. 320. 388. 380. 318. 338. 342. 368. 338 . 403 . 317. 333. 368. 387. 331. 372. 383 . 402. 352. 416. 393 . 400. 399. 282. 376. 420 . 341. 421. 409. 341. 363 . 357. 400. 358. 429. 344 . 349. 394. 405. 342. 400. 400. 422. 361. = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Dam 12868 had a litter consisting of 7 conceptuses; values excluded from group averages and statistical analyses. 418-011: PAGE B-34 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 16 (PAGE 7) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA 418-011:PAGE B-35 1/1 00 CO Q03657 PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 12 13 14 15 RAT # DOSAGE GROUP IV 10 MG/KG/DAY 12876 P 12877 P 12878 P 12879 P 12880 P 12881 P 12882 P 12883 P 12884 P P 12886 P 12887 P 12888 P 12889 P b 12890 p 12891 p 12892 P 12893 p 12894 p 12895 P 12896 p 12897 p 12898 P 12899 p 12900 P 219. 230. 212 . 228. 230. 211. 244 . 244 . 224 . 237. 235. 247. 239. 228. 242. 236. 226. 232. 221. 221. 236. 233 . 240. 220. 226. 266. 262. 242 . 244 . 248 . 235 . 254 . a a a a a a a a a a a a a a a 265. 244 . 237. 278. 273 . 247. 254 . 258 . 236. 274 . 276. 254 . 270. 266. 279. 270. 263. 274 . 256. 256. 278. 253 . 244 . 271. 269. 276 . 256. 248. 286 . 274 . 253. 258. 258. 242. 277. 284 . 270 . 274 . 273 . 279. 272 . 272. 271. 262 . 265. 276 . 251. 252 . 275. 278. 279. 261. 246. 290 . 276 . 258. 260. 259. 231. 282 . 286. 262. 274 . 273 . 289. 273 . 271. 273 . 262 . 263 . 278 . 242 . 254. 273. 275. 287. 260. 254. 297. 282 . 264 . 262 . 267. 239. 288. 288. 273 . 284 . 277. 288 . 278 . 272. 280 . 265. 260 . 286 . 256 . 257. 268. 275. . 284. 266. 250. 300 . 289. 268. 268. 268. 247. 291. 295. 282 . 286 . 279. 291. 283 . 271. 282 . 269. 263 . 294 . 259. 267. 279. 281. 286. 262. 261. 296 . 290 . 270 . 270 . 272 . 250 . 294 . 296. 280. 291. 284 . 296 . 284 . 271. 281. 272 . 265 . 295. 267. 266. 284 . 282. 297. 270. 259. 300. 294 . 266. 275. 274 . 250. 306 . 298. 283. 290. 286 . 301. 290 . 278. 293 . 274 . 275. 303 . 271. 267. 288. 284. 297. 274 . 265. 312. 298. 275. 274 . 279. 246. 313 . 308. 298. 297. 288. 308. 297. 281. 297. 280. 282 . 313 . 273 . 269. 297. 291. 301. 277. 268. 324 . 306. 277. 276. 282. 246. 318. 311. 292 . 300. 294 . 314 . 301. 283. 297. 286 . 289. 313 . 270. 279. 301. 292. 310. 285. 276. 324 . 313. 291. 290. 291. 263 . 327. 321. 304 . 310 . 301. 323 . 310. 286. 303 . 295. 292. 330. 284. 283. 305. 302. 322. 296. 290. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Value was not recorded. b. Dam 12889 had a litter consisting of 3 conceptuses; values excluded from group averages and statistical analyses. 16 341. 326 . 300. 300. 304 . 268. 339. 335. 312. 327. 311. 337. 317. 285. 317. 300 . 304 . 339. 296. 293. 323. 314. 336. 307. 300. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 16 (PAGE 8): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA 418-011 :PAGE B-36 003658 PREGNANCY STATUS DAY 17 18 19 20 RAT # DOSAGE GROUP IV 10 MG/KG/DAY 12876 P 12877 P 12878 P 12879 P 12880 P 12881 P 12882 P 12883 P 12884 P 12885 P 12886 P 12887 P 12888 P 12889 P a 12890 P 12891 P 12892 P 12893 P 12894 P 12895 P 12896 P 12897 P 12898 P 12899 P 12900 P 358. 329. 313 . 309. 314 . 280. 358. 348. 320. 330.' 315. 349. 329. 289. 328. 306. 319. 348. 309. 307. 331. 326. 350. 314 . 314. 360 . 344. 329. 326. 333 . 282. 378. 365. 334 . 344 . 332. 360. 337. 301. 339. 318. 328. 369. 321. 313 . 345. 335. 365. 327. 338. 375. 354. 346 . 342. 341. 298 . 385. 373 . 344 . 358. 344 . 373. 351. 309. 354. 331. 347. 383. 341. 328. 355. 344. 390. 352. 359. 390. 378. 374 . 367. 372 . 310. 420 . 392 . 371. 378 . 379. 396. 369. 321. 374 . 349. 371. 412. 364 . 343 . 380. 374. 414. 364 . 375. = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Dam 12889 had a litter consisting of 3 conceptuses; values excluded from group averages and statistical analyses. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 16 (PAGE 9): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA 6S9C00 PREGNANCY STATUS DAY 0 4 6 7 8 9 10 RAT # DOSAGE GROUP V 20 MG/KG/DAY 12901 P 12902 P 12903 P 12904 P 12905 P 12906 P 12907 P 12908 P 12909 P 12910 NP 12911 P 12912 P 12913 P 12914 P 12915 P 12916 P 12917 P 12918 P 12919 P 12920 P' 12921 P 12922 P 12923 P 12924 P 12925 P . 219. 229. 211. 227. 222 . 228 . 230. 238 . 239. 212. 215. 224. 243 . 225. 237. 248. 236. 245. 228. 222. 230. 233. 240. 234 . 240. 243 . 244 . 249. 255. 242. 242 . 251. 254. 257. 243. 241. a a a a a a a a a a a 268. 250. 260. 254 . 251. 260. 261. 259. 254. 271. 268. 268. 253. 253. 256. 272 . 274 . 267. 275 . 254 . 265. 269. 255. 268. 259. 278 259. 273 . 254 . 252. 260. 263 . 258. 253 . 278, 268. 265. 254 . 251. 258. 274 . 279. 279. 260. 252 . 266. 257. 250. 271. 258. 279. 262. 270. 264. 259. 263 . 259. 261. 257, 276. 276. 267. 259. 252. 262 . 274 . 274 . 275 . 256. 250 . 245. 271. 253 . 273 . 251. 269. 255. 262 . 269. 256. 258. 265. 261. 259. 276 . 275. 275 . 251. 253. 259. 278. 284 . 278. 264 . 251. 248 . 279. 254. 273 . 251. 271. 257. 253 . 266. 258. 267. 264. 269. 263. 272 . 272. 271. 256. 258 . 264. 282 . 285. 282 . 263 . 252 . 258. 277. 250 . 277 . 255. 277. 256. 263 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Value was not recorded. 11 273 . 264 . 271. 266 . 272. 266 . 267. 283 . 271. 260. 259. 266 . 280 . 290. 289. 245. 252 . 263 . 272. 256. 280 . 259. 276 . 266. 270 . 12 277. 265. 276. 260. 269. 274 . 283 . 285. 274 . 247. 260. 274. 284. 295. 292 . 238. 257. 264. 268. 272. 278. 260. 281. 261. 258. 13 282. 271. 267. 264 . 277. 269. 290. 284 . 268. 243 . 263 . 287. 286. 300. 287. 250 . 263 . 266. 276. 266. 278. 260. 280. 258. 247. 14 286. 274 . 282. 256. 279. 280 . 286. 285. 278 . 246. 268. 287. 292 . 301. 290 . 264 . 266. 264. 276 . 281. 281. 258. 292. 272. 235. 15 292. 275. 283 . 270. 285. 282. 294 . 288. 275. 246. 275. 287. 300. 315. 300. 271. 269. 266. 293. 284. 293 . 263 . 304. 276. 230. 16 306. 284 . " 295. 273 . 294 . 298. 302. 303 . 289. 240. 286. 298. 308. 325. 314 . 289. 282. 280. 304. 285. 304. 273 . 311. 285. 231. 418-011: PAGE B-37 099C00 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 16 (PAGE 10): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 17 18 19 20 RAT # DOSAGE GROUP V 20 MG/KG/DAY 12901 P 12902 P 12903 P 12904 P 12905 P 12906 P 12907 P 12908 P 12909 P' 12910 NP 12911 p 12912 p 12913 P 12914 P 12915 P 12916 p 12917 P 12918 P 12919 p 12920 p 12921 p 12922 P 12923 P 12924 P 12925 p 313. 295. 309. 279. 294 . 306. 301. 313 . 303 . 239. 296. 309. 310 . 336. 325. 304. 294 . 294. 311. 298. 313 . 283 . 328. 303. 247. 320 . 310. 322 . 292. 310. 320 . 310 . 323 . 315. 240. 303 . 322. 317. 337. 338. 317. 305. 302. 322. 313. 325. 292. 346. 307. 272. 333 . 320. 329. 301. 323. 337. 328. 330. 323. 245. 321. 338. 333 . 355. 350. 330. 322. 325. 335 . 322. 339. 298. 366. 325. 284. 360. 337. 353 . 309. 350. 352. 352 . 352. 343 . 252 . 345. 364 . 354 . 384 . 379. 352. 343 . 335. 347. 347. 358. 323. 385. 341. 303 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . % 418-011 .PAGE B-38 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 16 (PAGE 11): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 4 6 7 8 9 10 11 RAT # SATELLITE DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 12573 P 12574 P 12575 P 236. 233 . 248. 254. 259. 269. 266 . 273 . 283 . 271. 280. 288 . 271. 280 . 293 . 279. 290 . 296. 283 . 295. 299. 293. 299. 305. DAY 17 18 12573 P 12574 P 12575 P 332. 348. 350. 347. 367. 366. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 12 13 296. 304 . 309. 301. 309. 314. 14 305. 318. 320. 15 16 310. 328. 328 . 317. 333 .. 334 . 9 9 P 0 0 418-011: PAGE B-39 299C00 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 16 (PAGE 12) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 4 6 7 8 9 10 RAT # SATELLITE DOSAGE GROUP II 1 MG/KG/DAY 12576 P 12577 P 12578 P 12579 P 12580 P 227. 245. 221. 232. 248. 244. 259. 232. 253. 261. - 253 . 280. 258. 269. 273 . 259. 282 . 257. 271. 272. 260. 284 . 260. 282. 277. 260. 290. 265. 282. 280. 267. 296. 271. 288 . 291. DAY 17 18 125.76 P 12577 P 125.78 P 12579 P 12580 P 312. 358. 314 . 343. 353. 339 382 343 367 370 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ii 272 . 301. 271. 292. 296 . 12 280 . 306 . 278. 294. 302. 13 285. 308. 278. 302. 305. 14 290. 318. 286. 309. 312. 15 296. 328. 293. 317. 319. 16 310. 337. 305 . 325. 333. 418-011: PAGE B-40 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 16 (PAGE 13) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 4 6 7 8 9 10 RAT # SATELLITE DOSAGE GROUP III 5 MG/KG/DAY 12581 P 12582 P 12583 P 228. 243 . 251. 244 . 260 . 275. 257. 271. 296. 258. 274 . 306 . 258. 279. 309. 256. 283 . 313 . 258 . 290 . 319. DAY 17 18 12581 P 12582 P 12583 P 316. 338. 389. 334. 360. 412. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 11 267. 291. 322. 12 13 14 15 16 272 . 295. 328. 282 . 306 . 338. 287. 305. 344 . 297. 314 . 356. 301. 325. 373 . 418-011: PAGE 003663 03 k PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 16 (PAGE 14) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 4 6 7 8 9 10 RAT It SATELLITE DOSAGE GROUP IV 10 MG/KG/DAY 12584 P 12585 P 12586 P 228. 242. 250. 252. 265. 262 . 265. 276. 273 . 269. 273 . 275. 272 . 277. 277. 270 . 283 . 282. 274 . 287. 283 . DAY 17 18 12584 P 12585 P 12586 P 318. 334. 323. 340. 351. 339. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = -DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 11 275 . 290. 290. 12 281 . 296 . 289. 13 290. 303 . 294 . 14 290 . 308. 296. 15 297. 310. 306 . 16 309. 322. H 316. 418-011 PA G E B-42 003664 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 16 (PAGE 15) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 4 6 7 8 9 10 RAT # SATELLITE DOSAGE GROUP V 20 MG/KG/DAY 12587 P 12588 P 12589 P 12590 P 12591 P 228 . 243. 221. 236. 249. 232 . 262. 240 . 256. 267. 249. 282. 252. 270. 288. 232. 286. 258 . 266. 292 . 243 . 289. 262. 268. 293 . 241 288 267 268 295 243. 287 . 256 . 268. 300. DAY 17 18 12587 P 12588 P 12589 P 12590 P 12591 P 294 . 346. 299. 314. 345. 319. 360. 321. 336. 362. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). 11 258 . 291. 246. 274 . 306 . 12 260. 289. 254. 279. 302. 13 14 249. 294 . 267. 280. 297. 255. 305. 268. 284. 295. 15 16 266. 318 . 283 . 292. 316. 285. 328.' 284 . 304 . 327. S99C00 418-011: PAGE B-43 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 17 (PAGE 1) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA 418-011: PAGE B-44 00366e PREGNANCY STATUS DAYS 0 - 4 4 - 6 6 - 8 8 - 10 10 - 12 12 - 14 14 - 16 16 - 18 18 - 20 RAT # DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 12801 P 12802 P 12803 P 12804 P 12805 P 12806 P 12807 P 12808 P 12809 P 12810 P 12811 P 12812 P 12813 NP 12814 P 12815 P 12816 P 12817 P 12818 P 12819 P 12820 P 12821 P 12822 P 12823 P 12824 P 12825 P 56. 54 . 82. 86. 79. 53 . 71. 96. 91. 103. 88 . 190.a 89. 102. 94 . 97. 74 . 104 . 85 . 81. 84 . 85. 71. 81. 80. 48. 40. 51. 44 . 47. 41. 51. 45. 47. 45. 35. a 45. 54 . 49. 56. 43 . 61. 39. 42. 44 . 47. 45. 46. 44. 52. 43 . 55. 42 . 51. 49. 52. 61. 57. 53 . 51. 48 . 49. 48 . 50. 56. 45 . 58. 43 . 44 . 49. 53 . 41. 35. 44 . 50 . 44 . 53 . 41. 49. 48. 50. 49. 49. 47. 44 . 48. 53 . 50 . 47. 53. 45. 62 . 41. 42 . 51. 52. 44. 45. 44 . 58. 47. 57. 32 . 55. 47. 49. 51. 53 . 50. 40. 49. 41. 50. 49. 57. 46. 62. 44 . 48. 48. 54 . 42. 47. 44. 60 . 49. 59. 44. 52 . 51. 51. 47. 61. 56. 44 . 47. 44 . 54 . 49. 53 . 48. 63. 47. 50. 52. 55. 43. 45. 54. 50, 50. 62 , 50, 46, 45, 45, 52, 64. 46. 40 46 51 58 53 , 58, 53 65 46 54 54 62 47 48 53 60 . 49. 63. 58. 55. 54 . 50. 63. 50 . 58. 52. 48 . 54 . 61. 60. 59. 52 . 61. 49. 55. 51. 55. 54 . 54 . 53 . 59. 52. 60. 52. 54 . 53 . 53 . 56. 51. 58. 48. 48. 43 . 59. 56. 53. 45. 60 . 45 . 57. 53. 51. 48 . 50 . 44. = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses. 418-011: PAGE B-45 003667 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 17 (PAGE 2) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 0 - 4 4 - 6 6 - 8 8 - 10 10 - 12 12 - 14 14 - 16 16 - 18 18 - 20 RAT # DOSAGE GROUP II 1 MG/KG/DAY 12826 P 12827 P 12828 P 12829 P 12830 P 12831 P 12832 P 12833 P 12834.P 12835 P 12836 P 12837 P 12838 P 12839 P 12840 P 12841 P 12842 P 12843 P 12844 P 12845 NP 12846 NP 12847 P 12848 P 12849 P 12850 P 82 . 71. 91. 14 . 90. 89 . 87. 90 . 73 . 101. 91. 87. 70. 95. 80. 86 . 93. 76. 94 . 69. 64 . 77. 82. 82. 86. 49. 41. 47. 41. 38. 48 . 43 . 45. 44 . 57. 47 . 30 . 40 . 47 . 49. 47. 50 . 36 . 52. 35. 40 . 39. 43 . 45. 46. 49. 42. 49. 44 . 48 . 49. 48. 45. 40 . 55. 46 . 39. 43 . 50. 49. 45. 51. 41. 48. 77. 45. 40. 44 . 49. 44 . 47. 43 . 45. 33 . 45. 50 . 46. 47. 43 . 47. 50. 47. 43. 48 . 50. 48. 51. 43 . 47 . 47. 46 . 44 . 42 . 47. 48. 48. 45 . 50. 40. 43 . 50. 44 . 36. 44. 52. 49. 46. 41. 50. 55. 50. 47. 45. 56. 42 . 45. 45 . 44. 51. 52. 56. 47. 47. 43 . 45. 54 . 48. 43 . 45 . 62. 52 . 40 . 50. 51. 56 . 55. 52 . 42. 49 . 66. 45. 43. 45. 56. 48. 55. 41 . 45. 47. 46. 52 . 46. 40 . 47. 64 . 49. 49. 44 . 54. 62. 56. 54. 47. 57 . a 32 . 51. 50. 52 . 52. 57. 50. 58. 51. 55 . 60. 46. 50. 60 . 60. 50. 58. 50. 55. 62 . 42. 58. 48 . 54 . 40 . 33 . 52. 49. 54. 43 . 55. 45. 57. 44 . 52 . '57. 46. 40. 55. 55. 40 . 55 . 48. 52. 60 . 47. 54 . 46 . 57 . 43 . 30. 49. 44. 52. 51. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Spilled feed precluded the calculation of this value. ' PROTOCOL 418-011; ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 17 (PAGE 3) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA 418-011 PAGE B-46 003668 PREGNANCY STATUS DAYS 0 - 4 4 - 6 6 - 8 8 - 10 10 - 12 12 - 14 14 - 16 16 - 18 18 - 20 RAT # DOSAGE GROUP III 5 MG/KG/DAY 12851 P 12852 P 12853 P 12854 P 12855 NP 12856 P 12857 P 2858 P 12859 P 12860 P 12861 P 12862 P 12863 P 12864 P 12865 P 12866 P 12867 P 1268 P a 12869 P 12870 P 12871 P 12872 P 12873 P 12874 P 12875 P 97. 48. 69. 103 . 81. 88. 103 . 78. 101. 103 . 78. 82 . 80. 96. 56. 95. 76. 87. 76 . 87. 71. 90 . 83 . 96. 81. 48. 45 . 49. 39. 40 . 38. 49. 32. 57 . 57. 33 . 44 . 42. 54 . 54 . 52. 43. 50. 43 . 44 . 35. 44 . 52 . 46. 46. 53 . 47. 49. 60. 47. 39. SO . 42 . 63. 58. 47. 47. 46 . 53 . 41. 57. 36. 48. 48 . 45. 40. 46. 52 . 51. 37. 52. 44 . 48. 51. 41. 47. 49. 41. 55 . 49. 47. 47. 45. 46. 29. 51. 38. 48. 46. 42. 37. 45. 42 . 52 . 36 . 55. 43 . 50. 41. 38 . 41. 50. 43 . 52 . 56 . 45. 47. 48. 58. 39. 52 . 45. 49. 53 . 44 . 46 . 49. 50 . 50 . 46. 55. 49. 54. 48 . 32. 47. 55 . 39. 58. 63 . 47. 48. 42 . 58 . 37. 53. 45. 46 . 46 . 52. 38 . 50. 59. 50 . 44 . 59. 48 . 46 . 48. 37. 50. 56 . 40 . 58. 67. 43 . 46 . 40 . 61. 53 . 60 . 49. 58. 51 . 54 . 45 . 43 . 55. 59. 53 . 61. 53 . 57. 69. 31. 58. 52 . 45. 65. 62. 52 . 59. 46. 63 . 51. 57 . 48. 54 . 50 . 53. 43 . 48. 56. 54 . 51. 54 . 51. 59. 57. 34 . 52 . 57. 45. 61. 59. 53. 51. 44 . 60. 46 . 52 . 44 . 52 . 49. 54 . 35 . 52 . 53 . 54 . 48. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Dam 12868 had a litter consisting of 7 conceptuses; values excluded from group averages and statistical analyses. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 17 (PAGE 4) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 0 - 4 4-6 6-8 8 - 1 0 10 - 12 12 - 14 14 - 16 16 - 18 18 - 20 RAT # DOSAGE GROUP IV 10 MG/KG/DAY 12876 P 12877 P 12878 P 12879 P 12880 P 12881 P 12882 P 12883 P 12884..P 12885 P 12886 P 12887 P 12888 P 12889 P a 12890 P 12891 P 12892 P 12893 P 12894 P 12895 P 12896 P 12897 P 12898 P 12899 P 12900 P 101. 88. 20. 94. 90. 77. 86. 88. 84. 70. 100. 86. 85. 74 . 84 . 94. 91. 87. 74. 67. 77. 78 . 92. 77. 77. 56. 47. 36. 45. 43 . 26. 48. 52 . 43 . 43 . 50 . 47. 51. 48 . 48. 44 . 40 . 51. 47 . 35. 46. 43 . 51. 47. 38. 54 . 49. 42. 49. 43 . 35. 51. 47. 49. 45. 50. 53 . 46 . 45. 40 . 46. 42. 45. 32 . 37. 37. 46. 48. 47. 41. 52. 50. 46 . 43. 45. 38 . 49. 47. 52. 47. 54 . 50. 46. 42. 45. 46. 39. 49. 43 . 45. 37. 44 . 39. 43. 36. 50. 50. 41. 53 . 44 . 37. 54. 48. 46. 47. 53 . 53 . 50. 41. 51. 48. 47. b 44 . 39. 49. 45 . 46. 48. 41. 54 . 50 . 40. 41. 47. 31. 53 . 50. 48. 47. 50 . 54 . 54 . 46 . 49. 50. 55. 54 . 35. 44. 47. 44 . 52. 47. 50. 56 . 50 . 48 . 46. 48 . 43 . 45 . 56. 53 . 52 . 55. 59. 56 . 43 . 53. 48 . 49. 59. 55. 45. 50 . 47. 60. 54 . 66. 46. 47. 56. 56. 54 . 43 . 57. 52. 55. 50. 55. 56. 57. 50. 55. 52. 56. 62. 53 . 43. 52 . 40. 60. 49. 53. 50. 48. 54 . 55. 48. 38. 54 . 49. 54 . 44 . 59. 52. 49. 48. 48. 45. 55. 56. 51. 39. 48. 45. 57. 46. 51. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Dam 12889 had a litter consisting of 3 conceptuses; values excluded from group averages and statistical analyses. b. Spilled feed precluded the calculation of this value. 418-011 PAGE B-47 418-011:PAGE B-48 903G 7Q PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 17 (PAGE 5) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 0 - 4 4 - 6 6 - 8 8 - 10 10 - 12 12 - 14 14 - 16 16 - 18 18 - 20 RAT # DOSAGE GROUP V 20 MG/KG/DAY 12901 P 12902 P 12903 P 12904 P 12905 P 12906 P 12907 P 12908 P 12909 P 12910 NP 12911 P 12912 P 12913 P 12914 P 12915 P 12916 P 12917 P 12918 P 12919 P 12920 P, 12921 P 12922 P 12923 P 12924 P 12925 P 49. 83 . 71. 68. 83. 81. 97. 98. 92 . 84 . 84. 81. 87. 90. 101. 80. 76 . 68. 79. 74. 85. 76 . 89. 75. 90. 45. 43 . 48. 44 . 45 . 42. 52. 49. 46. 44 . 46. 43 . 45. 51. 44 . 44 . 40 . 52 . 44 . 43 . 46 . 42 . 49. 42. 48. 46 . 41. 45. 38 . 39. 38. 49. 50. 38. 38. 39. 41. 39. 42 . 45 . 29. 37. 26. 39. 34 . 43 . 33 . 35. 34. 31. 42. 37. 43 . 41. 43 . 37. 40 . 47 . 47. 37. 39. 41. 47. 45. 44 . 31. 30. 30. 45. 29. 39. 33 . 34. 30. 28. 44 . 41. 46 . 34 . 40. 45 . 39. 47. 40 . 36 . 39. 47. 40 . 55. 51. 9. 33 . 39. 31. 45. 39. 37. 39. 37. 32. 50 . 44. 42 . 31. 46 . 47. 49. 49. 33 . 31. 43 . 50 . 46 . 50. 46 . 42 . 39. 37. 41 . 42. 35. 35. 41. 33 . 12 . 49. 40 . 35. 35. 45. 40. 43 . 45. 33 . 32 . 48. 49. 49. 53. 53 . 53 . 39. 34 . 52. 38. 48. 37. 48. 41. 16. 45. 50. 46. 37. 48 . 48. 40. 41. 47 . 31. 46. 51. 40 . 45. 56 . 52. 44 . 40. 48 . 41. 48. 42. 49. 42. 36. 46. 40. 52. 39. 49. 46. 49. 42 . 48. 41. 40 . 51. 46 . 49. 54 . 47. 45. 46 . 43 . 40. 44 . 41. 50. 37. 38. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . % * 9 0 0 0 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 17 (PAGE 6) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 0 - 4 4- 6 6- 8 8 - 10 10 - 12 12 - 14 14 - 16 16 - 18 RAT # SATELLITE DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 12573 P 12574 P 12575 P 87. 89. 97 . 48. 48 . 53 . 44 . 49. 56. 48. 50. 50. 50 . 52 . 57. 48. 52. 59. 42 . 44 . 64 . 45. 45. 62. RAT # SATELLITE DOSAGE GROUP II 1 MG/KG/DAY 12576 P 12577 P .12578 P 12579 P 12580 P 85 . 92. 71. 86. 78. 42 . 56 . 40. 47. 41. 47. 53 . 42 . 53 . 39. 43 . 52 . 43 . 48. 45 . 48. 52. 44. 46. 48. 46. 50 . 42 . 49. 49. 53 . 55. 50. 53. 57. 43 . 54 . 48. 51. 52. RAT # SATELLITE DOSAGE GROUP III 5 MG/KG/DAY 12581 P 12582 P 12583 P 82 . 85. 92 . 52 . 43 . 49. 42. 41. 54 . 40 . 46. 50. 53. 45. 49. 57 . 47. 56. 52 . 51. 60 . 55. 48. 55. RAT # SATELLITE DOSAGE GROUP IV 10 MG/KG/DAY 12584 P 12585 P 12586 P 83 . 90. 85. 48 . 42 . 43 . 46. 40 . 42 . 45. 49. 43 . 46. 53 . 40 . 48 . 55 . 41. 54 . 53 . 51. 46. 48. 32. RAT # SATELLITE DOSAGE GROUP V 20 MG/KG/DAY 12587 P 12588 P 12589 P 12590 P 12591 P 74 . 37. 23. 34. 42. 32. 53. 46. 85. 50 . 48. 41. 42. 50. 51. 44 . 76. 42 . 44 . 33 . 24 . 44. 40. 39. 90. 46 . 43 . 40. 42 . 44. 55. 47. 100. 57. 54. 44. 43. 32. 61. 52 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . % 418-011: PAGE B-49 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 18 (PAGE 1) : CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA ^9C 00 VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION SITES CORPORA LUTEA SEX RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RAT # M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TOTAL DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 12801 9 4 8 5 13 0 0 0 0 1 1 0 0 0 8 6 14 8 9 17 12802 9 5 9 5 14 0 0 0 1 0 1 0 0 0 10 5 15 10 9 19 12803 9 7 8 8 16 0 0 0 0 0 0 0 0 0 B 8 16 9 8 17 12804 5 8 5 8 13 00 0 0 0 0 0 0 0 5 8 13 6 11 17 12805 7. 8 8 7 15 0 0 0 0 0 0 0 0 0 8 7 15 10 7 17 12806 9' 6 9 6 15 0 0 0 0 0 0 0 0 0 9 6 15 9 7 16 12807 6 8 4 10 14 0 0 0 1 1 2 0 0 0 5 11 16 5 12 17 12808 7 5 ' 6 6 12 0 0 0 2 3 5 0 0 0 8 9 17 9 11 20 12809 8 10 10 8 18 00 0 00 0 0 0 0 10 8 18 10 9 19 12810 6 4 0 10 10 0 0 0 0 0 0 0 0 0 0 10 10 5 10 15 12811 4 10 5 9 14 0 0 0 0 0 0 0 0 0 5 9 14 7 9 16 12812 7 7 8 6 14 00 0 1 0 1 0 0 0 9 6 15 10 6 16 12813 NOT PREGNANT 12814 7 9 7 9 16 00 0 2 1 3 0 0 0 8 10 18 9 10 19 12 8IS- 6 9 8 7 15 0 0 0 2 0 2 0 0 0 10 7 17 10 9 19 12816 7 5 5 7 12 0 0 0 2 0 2 0 0 0 7 7 14 7 7 14 12817 8 7 6 9 15 0 0 0 0 0 0 0 0 0 6 9 15 6 9 . 15 12818 3 10 9 4 13 0 0 0 1 1 2 0 0 0 10 5 15 12 6 18 12819 5 10 10 5 15 0 0 0 0 1 1 0 0 0 10 6 16 11 6 17 12820 6 8 8 6 14 00 0 0 1 1 0 0 0 8 7 15 8 7 15 12821 10 5 7 8 15 0 0 0 0 0 0 0 0 0 7 8 15 11 10 21 12822 10 5 7 8 15 00 0 0 0 0 0 0 0 7 8 15 7 10 17 12823 8 6 11 3 14 0 0 0 0 1 1 0 0 0 11 4 15 12 5 17 12824 4 8 6 6 12 00 0 0 0 0 0 0 0 6 6 12 7 7 14 12825 7 11 8 10 18 0 0 0 0 0 0 0 0 0 8 10 18 8 10 18 M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 418-011:PAGE B-50  SOO PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-S316.7) TABLE 18 (PAGE 2) : CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION SITES CORPORA LUTEA SEX RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RAT # M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TOTAL DOSAGE GROUP II 1 MG/KG/DAY 12826 8 6 9 5 14 0 0 0 0 0 0 0 0 0 9 5 14 12 5 17 12827 5 8 7 6 13 0000110 0 0 7 7 14 8 9 17 12828 10 8 11 7 18 0 0 0 0 0 0 0 0 0 11 7 18 11 8 19 12829 8 6 7 7 14 0001010 0 0 8 7 15 8 8 16 12830 7 8 * 8 7 15 0 0 0 0 0 0 0 0 0 8 7 15 9 7 16 12831 . 6 io 11 5 16 0 0 0 1 0 1 0 0 0 12 5 17 12 5 17 12832 7 7 6 8 14 0 0 0 1 0 1 0 0 0 7 8 15 10 10 20 12833 10 3 7 6 13 0 0 0 1 0 1 0 00 8 6 14 8 6 14 12834 9 6 5 10 15 0 0 0 0 0 0 0 0 0 5 10 15 5 10 15 12835 3 6 2 7 9 0 0 0 0 0 0 0 0 0 2 7 9 9 8 17 12836 6 9 7 8 15 0 0 0 1 0 1 0 0 0 8 8 16 8 10 18 12837 4 10 7 7 14 0 0 0 1 0 1 0 0 0 8 7 15 8 8 16 12838 8. 7 9 6 15 00 0 00 0 0 0 0 9 6 15 9 6 15 12839 6 11 7 10 17 0 0 0 0 0 0 0 0 0 7 10 17 7 11 18 12840 11 6 9 8 17 00 0 00 0 0 0 0 9 8 17 9 10 19 12841 9 8 9 8 17 00 0 00 0 0 0 0 9 8 17 9 8 17 12842 9 7 10 6 16 0 0 0 0 0 0 0 0 0 10 6 16 10 6 16 12843 5 8 7 6 13 00 0 0 1 1 0 0 0 7 7 14 7 8 15 12844 6 11 11 6 17 0 0 0 0 0 0 0 0 0 11 6 17 11 8 19 12845 NOT PREGNANT 12846 NOT PREGNANT 12847 11 7 14 4 18 0 0 0 0 0 0 0 0 0 14 4 18 15 6 21 12848 7 11 13 5 18 0 0 0 0 0 0 0 0 0 13 5 18 13 7 20 12849 9 6 9 6 15 0 0 0 0 0 0 0 0 0 9 6 15 9 6 15 12850 7 9 7 9 16 00 0 0 2 2 0 0 0 7 11 18 7 12 19 M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 418-011:PAGE B-: tn PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 18 (PAGE 3) : CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA ^9CO0 VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION SITES CORPORA LUTEA SEX RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RAT # M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TOTAL DOSAGE GROUP III 5 MG/KG/DAY 12851 7 8 4 11 15 0 0 0 1 0 1 0 0 0 5 11 16 6 12 18 12852 8 8 6 10 16 0 0 0 0 0 0 0 0 0 6 10 16 6 11 17 12853 5 9 10 4 14 0 0 0 0 1 1 0 0 0 10 5 15 10 7 17 12854 6 10 7 9 16 0 0 0 0 0 0 0 0 0 7 9 16 8 10 18 12855 NOT PREGNANT 12856 5 . 9 5 9 14 0 0 0 0 0 0 0 0 0 5 9 14 5 9 14 12857 11 . 8 9 10 19 0 0 0 0 0 0 0 0 0 9 10 19 12 11 23 12858. 7 7 5 9 14 0 0 0 1 0 1 0 0 0 6 9 15 6 11 17 12859 10 7 10 7 17 0 0 0 0 0 0 0 0 0 10 7 17 10 7 17 12860 7 8 6 9 15 0 0 0 1 0 1 0 0 0 7 9 16 9 ii 20 12861 6 6 8 4 12 0 0 0 1 1 2 0 0 0 9 5 14 10 8 18 12862 7 8 8 7 15 0 0 0 0 0 0 0 0 0 8 7 15 8 7 15 12863 5 9 4 10 14 0 001 0 1 0 00 5 10 15 5 10 15 12864 6 8 10 4 14 0 0 0 0 0 0 0 0 0 10 4 14 12 5 17 12865 5 10 7 8 15 0 0 0 1 1 2 0 0 0 8 9 17 8 9 17 12866 '9 10 ii 8 19 0 0 0 0 0 0 0 0 0 11 8 19 11 11 22 12867 9 5 4 10 14 0 0 00 0 0 0 0 0 4 10 14 5 10 15 12868 1 4 2 3 5 0 0 0 0 2 2 0 0 0 2 5 7 7 6 13 12869 9 6 7 8 15 0 0 0 0 0 0 0 0 0 7 8 15 7 8 15 12870 6 10 6 10 16 0 0 0 0 0 0 0 0 0 6 10 16 6 11 17 12871 8 6 6 8 14 0 0 0 0 2 2 0 0 0 6 10 16 6 11 17 12872 9 5 9 5 14 0 0 0 0 0 0 0 0 0 9 5 14 10 6 16 12873 5 9 4 10 14 0 0 0 1 0 1 0 0 0 5 10 15 5 13 18 12874 7 9 7 9 16 0 0 0 0 1 1 0 0 0 7 10 17 7 10 17 12875 8 2 2 8 10 0 0 0 4 1 5 0 0 0 6 9 15 7 9 16 : MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 418-011 PAGE B-52 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 18 (PAGE 4) : CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA S^9C O O VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION SITES CORPORA LUTEA SEX RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RAT # M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TOTAL DOSAGE GROUP IV 10 MG/KG/DAY 12876 9 6 8 7 15 0 0 0 0 0 0 0 0 0 8 7 15 9 8 17 12877 6 8 9 5 14 0 0 0 0 0 0 0 0 0 9 5 14 ii 6 17 12878 7 8 3 12 15 0 0 0 0 0 0 0 0 0 3 12 15 4 12 16 12879 9 6 8 7 15 0 0 0 0 0 0 0 0 0 8 7 15 10 9 19 12880 8 7 9 6 15 0 0 0 0 0 0 0 0 0 9 6 15 11 9 20 12881 6 6 8 4 12 0 0 0 1 1 2 0 0 0 9 5 14 10 5 15 12882 6 11 7 10 17 0 0 0 0 0 0 0 0 0 7 10 17 8 11 19 12883 8 6 5 9 14 0 0 0 1 2 3 0 0 0 6 11 17 6 ii 17 12884 6 6 9 3 12 0 0 0 0 1 1 0 0 0 9 4 13 9 6 15 12885 9 8 9 8 17 0 0 0 0 0 0 0 0 0 9 8 17 10 9 19 12886 9 4 8 5 13 0 0 0 1 0 1 0 0 0 9 5 14 10 7 17 12887 8 8 6 10 16 0 0 0 0 0 0 0 0 0 6 10 16 6 10 16 12888 6 7 7 6 13 0 0 0 0 1 1 0 0 0 7 7 14 8 10 18 12889 1 2 2 1 3 0 0 0 0 0 0 0 0 0 2 1 3 11 4 15 12890 7 8 4 11 15 0 0 0 1 0 1 0 0 0 5 11 16 5 11 16 12891 8 5 6 7 13 0 0 0 0 0 0 0 0 0 6 7 13 6 7 13 12892 5 10 8 7 15 0 0 0 0 0 0 0 0 0 8 7 15 8 7 15 12893 10 6 11 5 16 0 0 0 0 0 0 0 0 0 11 5 16 14 7 21 12894 7 7 8 6 14 0 0 0 0 1 1 0 0 0 8 7 15 8 7 15 12895 8 6 6 8 14 0 0 0 1 0 1 0 0 0 7 8 15 7 8 15 12896 6 8 5 9 14 0 0 0 0 0 0 0 0 0 5 9 14 5 10 15 12897 7 8 6 9 15 0 0 0 0 0 0 0 0 0 6 9 15 9 9 18 12898 6 12 11 7 18 0 0 0 0 0 0 0 0 0 11 7 18 11 8 19 12899 10 3 7 6 13 0 0 0 1 0 1 0 0 0 8 6 14 8 7 15 12900 9 7 10 6 16 0 0 0 0 0 0 0 0 0 10 6 16 11 6 17 M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 418-011:PAGE B-53 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 18 (PAGE 5) : CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA ^9eoo VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION SITES CORPORA LUTEA SEX RAT # M F RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TOTAL DOSAGE GROUP V 20 MG/KG/DAY 12901 11 6 9 8 17 0 0 0 0 0 0 0 0 0 9 8 17 9 8 17 12902 4 8 7 5 12 0 0 0 1 0 1 0 0 0 9 5 14 11 6 17 12903 8 6 8 6 14 0 0 0 1 0 1 0 0 0 9 6 15 10 7 17 12904,, 2 8 6 4 10 0 0 0 1 2 3 0 0 0 7 6 13 8 7 15 12905 5 7 6 6 12 0 0 0 0 0 0 0 0 0 6 6 12 7 8 15 12906 6 7 7 6 13 0 0 0 1 0 1 0 0 0 8 6 14 8 6 14 12907 6 3 0 9 9 0 0 0 0 1 1 0 0 0 0 10 10 8 10 18 12908 6 8 3 11 14 0 0 0 0 2 2 0 0 0 3 13 16 4 14 18 12909 8 4 7 5 12 0 0 0 0 1 1 0 0 0 7 6 13 9 8 17 12910 NOT PREGNANT 12911 9 4 5 8 13 0 0 0 1 0 1 0 0 0 6 8 14 6 8 14 12912 7 6 9 4 13 0 0 0 0 0 0 0 0 0 9 4 13 11 4 15 12913 7 5 5 7 12 0 0 0 1 0 1 0 0 0 6 7 13 9 8 17 12914 . 8 7 12 3 15 0 0 0 0 0 0 0 0 0 12 3 15 12 4 16 12915 '8 6 8 6 14 0 0 0 1 2 3 0 0 0 9 8 17 9 13 22 12916 8 8 8 8 16 0 0 0 0 1 1 0 0 0 8 9 17 8 9 17 12917 10 4 9 5 14 0 0 0 1 0 1 0 0 0 10 5 15 11 6 17 12918 5 10 12 3 15 0 0 0 01 1 0 0 0 12 4 16 12 5 17 12919 8 6 6 8 14 0 0 0 0 0 0 0 0 0 6 8 14 6 8 14 12920 8 8 9 7 16 0 0 0 0 0 0 0 0 0 9 7 16 10 9 19 12921 6 8 7 7 14 0 0 0 0 0 0 0 0 0 7 7 14 7 10 17 12922 7 5 7 5 12 0 0 0 1 2 3 0 0 0 8 7 15 8 8 16 12923 7 7 8 6 14 0 0 0 0 0 0 0 0 0 8 6 14 8 6 14 12924 7 8 8 7 15 0 0 0 0 0 0 0 0 0 8 7 15 8 8 16 12925 11 5 9 7 16 0 0 0 0 0 0 0 0 0 9 7 16 9 9 18 M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 418-011 PAGE B-54 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 18 (PAGE 6): CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA 9C 0 VIABLE !FETUSES DEAD FETUSES EARLY RESORPTIONS :LATE RESORPTIONS IMPLANTATION SITES CORPORA LUTEA RAT # RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT RIGHT LEFT HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TOTAL SATELLITE DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 12573 12574 12575 12 3 15 0 0 0 1 0 1 0 0 0 13 3 16 13 3 16 9 9 18 0 0 0 0 0 0 0 0 0 9 9 18 12 12 24 6 1 7 0 0 0 0 0 0 0 0 0 6 1 7 6 6 12 SATELLITE DOSAGE GROUP II 1 MG/KG/DAY 12576 12577 12578 12579 12580 11 3 14 0 0 0 1 0 1 0 0 0 12 3 15 15 5 20 7 11 18 0 0 0 0 0 0 0 0 0 7 11 18 8 12 20 6 10 16 0 0 0 0 1 1 0 0 0 6 11 17 8 11 19 10 5 15 0 0 0 0 0 0 0 0 0 10 5 15 10 5 15 10 4 14 0 0 0 0 1 1 0 0 0 10 5 15 11 5 16 SATELLITE DOSAGE GROUP III 5 MG/KG/DAY 12581 12582 12583 6 7 13 0 0 0 0 2 2 0 0 0 6 9 15 6 9 15 13 5 18 0 0 0 0 0 0 0 0 0 13 5 18 14 7 21 13 7 20 0 0 0 0 0 0 0 0 0 13 7 20 13 il 24 SATELLITE DOSAGE GROUP IV 10 MG/KG/DAY 12584 12585 12586 9 6 15 0 0 0 2 0 2 0 0 0 11 6 17 14 8 22 6 10 16 0 0 0 0 0 0 0 0 0 6 10 16 6 10 16 8 5 13 0 0 0 0 1 1 0 0 0 8 6 14 9 7 16 SATELLITE DOSAGE GROUP V 20 MG/KG/DAY 12587 12588 12589 12590 12591 9 5 14 0 0 0 0 0 0 0 0 0 9 5 14 9 5 14 9 6 15 0 0 0 0 0 0 0 0 0 9 6 15 9 6 15 7 7 14 0 0 0 0 0 0 0 0 0 7 7 14 7 7 14 11 3 14 0 0 0 1 1 2 0 0 0 12 4 16 12 4 16 9 7 16 0 0 0 1 0 1 0 0 0 10 7 17 10 9 19 PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 418-011: PAGE B-55 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 19 (PAGE 1) : LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA 418-011: PAGE B-56 003678 NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) --- CONCEPTUSES ----RESORBED RAT # MALE FEMALE TOTAL MALE FEMALE TOTAL a N ft % DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 12801 12802 12803 12804 12805 12806 12807 12808 12809 12810 12811 12812 12813 12814 12815 12816 12817 12818 12819 12820 12821 12822 12823 12824 12825 94 95 97 58 78 96 68 75 8 10 64 4 10 77 NOT PREGNANT 79 69 75 87 3 10 5 10 68 10 5 10 5 86 48 7 11 13 3.62 3.37 3.54 14 2.03 1.89 1.98 16 3.49 3.46 3.48 13 3.63 3.44 3.51 15 3.64 3.55 3.59 15 3.64 3.36 3.53 14 3.39 3.51 3.46 12 3.70 3.42 3.58 18 5.25 5.11 5.17 10 3.58 3.14 3.40 14 3.78 3.51 3.59 14 3.54 3.24 3.39 16 3.77 3.45 3.59 15 3.56 3.43 3.48 12 3.62 3.35 3.51 15 3.44 2.85 3.17 13 3.76 3.49 3.55 15 3.27 3.01 3.10 14 3.52 3.38 3.44 15 3.31 3.14 3.25 15 3.54 3.16 3.41 14 3.84 3.87 3.85 12 3.87 3.42 3.57 18 3.96 3.66 3.78 14 15 16 13 ' 15 15 16 17 18 10 14 15 18 17 14 15 15 16 15 15 15 15 12 18 1 7.1 1 6.7 0 0.0 0 0.0 0 0.0 0 0.0 2 12.5 5 29.4 0 0.0 0 0.0 0 0.0 1 6.7 2 11.1 2 11.8 2 14.3 0 0.0 2 13.3 i 6.2 i 6.7 0 0.0 0 0.0 1 6.7 0 0.0 0 0.0 a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 19 (PAGE 2) : LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA 6900 NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) RAT # MALE FEMALE TOTAL MALE FEMALE TOTAL a DOSAGE GROUP II 1 MG/KG/DAY 12826 12827 12828 12829 12830 12831 12832 12833 12834 12835 12836 12837 12838 12839 12840 12841 12842 12843 12844 12845 12846 12847 12848 12849 12850 86 58 10 8 86 78 6 10 77 10 3 96 36 69 4 10 87 6 ii 11 6 98 97 58 6 11 NOT PREGNANT NOT PREGNANT 11 7 7 ii 96 79 14 3.33 2.94 3.16 13 3.39 3.21 3.28 18 3.53 3.27 3.41 14 3.00 3.03 3.01 15 3.77 3.60 3.68 16 3.48 3.18 3.30 14 3.12 2.98 3.05 13 3.30 3.27 3.30 15 3.48 3.35 3.43 9 3.68 3.49 3.55 IS 3.48 3.20 3.32 14 3.85 3.67 3.72 15 3.48 3.21 3.35 17 3.42 3.22 3.29 17 3.23 2.85 3.10 17 3.46 3.18 3.33 16 3.78 3.56 3.68 13 3.74 3.58 3.64 17 3.90 3.63 3.72 18 3.29 2.96 3.16 18 3.36 3.08 3.19 15 3.52 3.24 3.41 16 3.34 3.05 3.18 a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. --- C O N C E P T U S E S ----RESORBED N N% 14 0 0.0 14 1 7.1 18 0 0.0 15 1 6.7 15 0 0.0 17 1 5.9 15 1 6.7 14 1 7.1 15 0 0.0 9 0 0.0 16 1 6.2 15 1 6.7 15 0 0.0 17 0 0.0 17 0 0.0 17 0 0.0 16 0 0.0 14 1 7.1 17 0 0.0 18 0 0.0 18 0 0.0 15 0 0.0 18 2 11.1 418-011:PAGE B-57 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-G316.7) TABLE 19 (PAGE 3) : LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA 0S9t>0 NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) RAT # MALE FEMALE TOTAL MALE FEMALE TOTAL a DOSAGE GROUP III 5 MG/KG/DAY 12851 12852 12853 12854 12855 12856 12857 12858 12859 12860 12861 12862 12863 12864 12865 12866 12867 12868 12869 12870 12871 12872 12873 12874 12875 78 88 59 6 10 NOT PREGNANT 59 11 8 77 10 7 78 66 78 59 68 5 10 9 10 95 14 96 6 10 86 95 59 79 82 15 3.69 3.36 3.51 16 3.34 3.20 3.27 14 3.78 3.65 3.70 16 3.52 3.07 3.24 14 3.55 3.24 3.35 19 3.34 3.16 3.26 14 3.55 3.43 3.49 17 3.20 3.20 3.20 15 3.82 3.55 3.67 12 3.12 2.98 3.04 15 2.95 2.91 2.93 14 3.67 3.37 3.48 14 3.76 3.52 3.62 15 3.67 3.44 3.52 19 3.42 3.21 3.31 14 3.44 3.15 3.34 5 3.35 3.16 3.19 15 3.35 3.20 3.29 16 3.69 3.40 3.51 14 3.46 3.26 3.37 14 3.32 3.19 3.27 14 3.54 3.41 3.45 16 3.66 3.54 3.59 10 3.68 3.38 3.62 a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. CONCEPTUSES ----RESORBED N N% 16 1 6.2 16 0 0.0 15 1 6.7 16 0 0.0 14 0 0.0 19 0 0.0 IS 1 6.7 17 0 0.0 16 1 6.2 14 2 14.3 15 0 0.0 15 1 6.7 14 0 0.0 17 2 11.8 19 0 0.0 14 0 0.0 7 2 28.6 15 0 0.0 16 0 0.0 16 2 12.5 14 0 0.0 15 1 6.7 17 1 5.9 15 5 33.3 418-011 PAG E B-58 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 19 (PAGE 4) : LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA T89C0 NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) RAT # MALE FEMALE TOTAL MALE FEMALE TOTAL a DOSAGE GROUP IV 10 MG/KG/DAY 12876 12877 12878 12879 12880 12881 12882 12883 12884 12885 12886 12887 12888 12889 12890 12891 12892 12893 12894 12895 12896 12897 12898 12899 12900 9 6 15 3.67 3.59 3.64 6 8 14 3.27 3.08 3.16 7 8 15 3.53 3.34 3.43 9 6 15 3.39 3.46 3.42 8 7 15 3.32 3.08 3.21 6 6 12 3.12 2.82 2.97 6 11 17 3.69 3.43 3.52 8 6 14 3.40 3.30 3.36 6 6 12 3.18 3.14 3.16 9 8 17 3.26 2.86 3.07 9 4 13 3.60 3.45 3.55 8 8 16 3.21 2.95 3.08 6 7 13 3.01 2.98 3.00 1 2 3 3.47 3.66 3.60 7 8 15 3.24 3.04 3.14 8 5 13 3.82 3.52 3.70 5 10 15 3.60 3.43 3.49 10 6 16 3.39 3.26 3.34 7 7 14 3.55 3.69 3.62 8 6 14 3.25 3.18 3.22 6 8 14 3.48 3.34 3.40 7 8 15 3.38 3.41 3.40 6 12 18 3.22 3.23 3.22 10 3 13 3.31 3.24 3.29 9 7 16 3.22 3.25 3.24 a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. --- CONCEPTUSES ---RESORBED N N % 15 0 0.0 14 0 0.0 15 0 0.0 15 0 0.0 IS 0 0.0 14 2 14.3 17 0 0.0 17 3 17.6 13 1 7.7 17 0 0.0 14 1 7.1 16 0 0.0 14 1 7.1 3 0 0.0 16 1 6.2 13 0 0.0 15 0 0.0 16 0 0.0 15 1 6.7 15 1 6.7 14 0 0.0 15 0 0.0 18 0 0.0 14 1 7.1 16 0 0.0 418-011: PAGE B-59 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631G.7) TABLE 19 (PAGE 5) : LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) RAT # MALE FEMALE TOTAL MALE FEMALE TOTAL a DOSAGE GROUP V 20 MG/KG/DAY 12901 12902 12903 12904 12905 12906 12907 12908 12909 12910 12911 12912 12913 12914 12915 12916 12917 12918 12919 12920 12921 12922 12923 12924 12925 11 6 48 86 28 57 67 63 68 84 NOT PREGNANT 94 76 75 87 86 88 10 4 5 10 86 88 68 75 77 78 11 5 17 3.28 12 3.23 14 3.21 10 3.20 12 3.34 13 3.41 9 2.96 14 3.15 12 3.12 13 3.27 13 3.74 12 2.97 15 3.43 14 3.59 16 3.05 14 3.18 15 3.27 14 3.24 16 3.35 14 3.36 12 3.18 14 3.44 15 3.39 16 2.91 3.07 3.05 3.00 3.01 3.28 3.24 2.86 2.98 2.68 2.95 3.34 2.99 3.20 3.20 2.85 2.82 3.05 2.99 3.09 3.27 3.07 3.25 3.13 2.91 3.21 3.11 3.12 3.04 3.31 3.32 2.93 3.05 2.97 3.17 3.55 2.98 3.32 3.42 2.95 3.07 3.12 3.13 3.22 3.31 3.14 3.35 3.25 2.91 a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. --- CONCEPTUSES ----RESORBED N N% 17 14 15 13 ' 12 14 10 16 13 14 13 13 15 17 17 15 16 14 16 14 15 14 15 16 0 0.0 2 14.3 1 6.7 3 23.1 0 0.0 1 7.1 1 10.0 2 12.5 1 7.7 1 7.1 0 0.0 1 7.7 0 0.0 3 17.6 1 5.9 1 6.7 1 6.2 0 0.0 0 0.0 0 0.0 3 20.0 0 0.0 0 0.0 0 0.0 418-011: PAGE B-60 418-011: PAGE 003683 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OP N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-S316.7) TABLE 19 (PAGE 6) : LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA NUMBER OF LIVE FETUSES RAT # TOTAL SATELLITE DOSAGE GROUP I 12573 12574 12575 15 18 7 SATELLITE DOSAGE GROUP II 12576 12577 12578 12579 12580 14 18 16 15 14 SATELLITE DOSAGE GROUP III 12581 12582 12583 13 18 20 SATELLITE DOSAGE GROUP IV 12584 12585 12586 15 16 13 SATELLITE DOSAGE GROUP V 12587 12588 12589 12590 12591 14 15 14 14 16 a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. AVERAGE FETAL BODY WEIGHT (G) --- CONCEPTUSES -----RESORBED TOTAL a N N% 0 (VEHICLE) MG/KG/DAY 1.15 1.19 1.43 16 1 6.2 18 0 0.0 7 0 0.0 1 MG/KG/DAY 1.31 1.38 1.28 1.37 1.46 15 1 6.7 18 0 0.0 17 1 5.9 15 0 0.0 15 1 6.7 5 MG/KG/DAY 1.43 1.30 1.34 15 2 13.3 18 0 0.0 20 0 0.0 10 MG/KG/DAY 1.22 1.17 1.26 17 2 11.8 16 0 0.0 14 1 7.1 20 MG/KG/DAY 1.16 1.35 1.32 1.41 1.32 14 0 0.0 15 0 0.0 14 0 0.0 16 2 12.5 17 1 5.9 00 6) PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 20 (PAGE 1) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA 418-011: PAGE B-62 003684 FETUS ft 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RAT # CLs 12801 8/ 9 MA MA FA FA MA MA MA MA / MA FA MA E FA MA 3.54 3.90 3.31 3.15 3.41 3.58 3.64 3.84 3.48 3.51 3.36 3.51 3.80 12802 10/ 9 MA FA FA FA MA MA E FA MA MA / MA MA MA FA MA 2.01 1.70 1.94 1.83 1.89 2.01 1.82 2.06 2.14 1.95 2.12 2.05 2.15 2.08 12803 9/ 8 MA MA MA FA FA MA FA MA / MA FA FA FA MA MA MA FA 3.28 3.60 3.72 3.44 3.66 3.82 3.24 3.40 3.26 3.88 3.51 3.08 3.39 3.30 3.65 3.43 12804 6/11 MA FA MA FA FA / FA FA FA FA MA MA FA MA 3.44 3.50 3.72 3.43 3.18 3.53 3.46 3.41 3.53, 3.59 3.51 3.45 3.88 12805 10/ 7 FA MA FA FA FA FA FA FA / MA MA MA MA FA MA MA 3.47 3.84 3.62 3.48 3.30 3.49 3.59 3.91 3.42 3.99 3.41 3.51 3.52 3.63 3.72 12806 9/ 7 MA FA MA MA MA MA FA FA FA / MA FA MA MA MA FA 3.65 3.36 3.67 3.62 3.81 3.31 3.18 3.27 3.49 3.62 3.50 3.46 3.76 3.85 3.34 12807 5/12 MA FA FA E MA / MA FA FA FA MA MA FA MA E FA FA 3.41 3.64 3.62 3.02 3.63 3.81 3.30 3.09 3.60 3.27 3.68 3.41 3.50 3.47 12808 9/11 FA E E FA MA FA MA MA / FA FA E MA MA MA E E MA 3.43 3.75 3.91 3.35 3.58 3.82 3.18 3.38 3.57 3.80 3.65 3.57 12809 10/ 9 FA FA FA FA FA MA FA FA MA MA / FA FA FA MA MA MA MA MA 5.33 5.24 4.95 5.36 5.03 5.52 4.86 5.06 5.08 5.47 4.83 5.05 5.41 4.91 5.32 4.84 5.43 5.43 12810 5/10 / FA FA FA MA MA MA MA MA MA FA 2.95 3.21 2.96 3.84 3.81 3.34 3.55 3.54 3.39 3.46 12811 7/ 9 FA FA FA FA MA / FA FA FA FA FA MA FA MA MA 3.46 3.38 3.72 3.30 3.81 3.61 3.75 3.56 3.45 3.46 3.86 3.43 3.77 3.68 12812 10/ 6 FA MA MA MA FA E MA MA FA /' FA MA FA FA FA MA 3.61 3.40 3.33 3.47 3.41 3.40 3.56 3.23 3.32 3.66 2.68 3.19 3.26 4.00 12813 NOT PREGNANT M = MALE F = FEMALE A = ALIVE E = EARLY RESORPTION "/" DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 20 (PAGE 2) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA 418-011:PAGE B-63 003685 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RAT # CLs 12814 9/10 12815 10/ 9 12816 7/ 7 12817 6/ 9 12818 12/ 6 12819 11/ 6 12820 8/ 7 12821 11/10 12822 7/10 12823 12/ 5 12824 7/ 7 12825 8/10 FA E MA FA MA FA FA MA / MA FA FA FA E FA MA MA FA MA 3.37 3.77 3.65 3.80 3.55 3.44 4.03 3.61 3.22 3.36 3.46 3.62 3.76 3.78 3.39 3.65 E E FA FA MA MA FA MA FA FA / FA FA FA MA MA MA FA 3.32 3.78 3.52 3.35 3.36 3.45 3.57 3.43 3.57 3.04 3.41 3.80 3.62 3.65 3.36 E MA FA MA FA MA E / FA FA FA MA MA MA MA 3.85 3.53 3.40 3.45 3.36 3.09 3.28 3.38 3.81 3.76 3.64 3.54 MA MA MA FA FA FA ,/ FA FA FA MA MA MA FA MA MA 3.67 3.78 3.25 2.99 1.82 3.25 3.13 2.93 3.22 3.35 3.29 3.73 2.63 3.16 3.31 FA FA FA MA FA E FA MA MA FA / E FA FA FA FA 3.14 3.29 3.80 3.60 3.43 3.30 3.90 3.77 3.71 3.54 3.35 3.56 3.77 FA FA FA MA FA FA MA FA FA MA / FA MA FA FA E MA 2.91 3.30 2.77 3.13 3.37 2.90 3.01 2.70 2.85 3.29 3.07 3.53 3.02 3.21 3.41 FA MA FA MA FA MA FA FA /' MA FA FA E MA FA MA 3.36 3.46 3.80 3.27 3.55 3.63 3.30 3.27 3.42 3.22 3.22 3.72 3.31 3.60 MA MA MA FA MA MA MA / MA MA MA FA FA FA MA FA 3.13 3.15 3.43 3.22 3.80 3.08 3.27 3.19 3.32 3.40 3.06 3.18 3.09 3.32 3.13 MA FA FA MA MA MA FA / MA MA MA MA FA FA MA MA , 3.46 3.17 2.71 3.78 3.89 3.58 3.34 3.45 3.19 3.38 3.34 3.31 3.27 3.48 3.80 MA MA FA MA MA MA FA FA FA MA MA / MA FA E FA 3.68 3.45 3.60 3.56 4.20 3.86 4.40 3.97 3.52 4.28 3.97 3.68 3.65 4.09 FA MA MA FA MA MA / FA FA FA FA FA FA 3.59 4.00 3.86 3.91 4.00 3.63 2.99 3.20 3.38 3.40 3.52 3.37 FA FA MA FA FA MA MA FA /' FA MA MA FA FA FA MA FA MA FA 3.67 3.59 3.97 3.74 3.54 4.08 4.05 3.59 3.61 3.98 3.75 3.69 3.58 3.69 3.80 3.78 4.12 3.75 M = MALE F = FEMALE A = ALIVE E = EARLY RESORPTION /" DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631S.7) TABLE 20 (PAGE 3) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA 418-011 PA G E B-64 003686 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 DOSAGE GROUP II 1 MG/KG/DAY RAT # CLs 12826 12/ 5 12827 8/ 9 12828 11/ 8 12829 8/ 8 12830 9/ 7 12831 12/ 5 12832 10/10 12833 8/ 6 12834 5/10 12835 9/ 8 12836 8/10 12837 8/ 8 12838 9/ 6 FA MA FA MA MA MA MA MA FA / FA MA MA FA FA 2.26 3.30 3.22 3.42 3.14 3.31 3.46 3.56 3.16 2.89 3.33 3.12 2.95 3.19 FA MA FA FA FA FA MA / MA MA FA MA FA E FA 2.95 3.39 3.12 3.55 3.21 3.16 3.30 3.60 3.40 3.09 3.24 3.30 3.32 FA MA MA MA MA MA FA MA MA MA FA / FA FA MA FA FA MA FA 3.29 3.57 3.53 3.26 3.59 3.50 3.47 3.65 3.35 3.23 3.23 3.08 3.05 3.63 3.49 3.12 3.98 3.44 MA G FA MA FA MA MA FA / MA MA FA FA FA MA MA 2.88 3.13 3.05 3.16 3.45 3.03 3.14 2.79 2.72 2.99 2.86 2.89 3.07 3.01 MA FA FA FA FA FA FA MA / FA FA MA MA MA MA MA 3.85 3.60 3.58 3.76 3.63 3.77 3.59 3.80 3.19 3.65 3.33 3.48 4.14 3.88 3.92 FA MA FA FA FA MA E FA FA FA FA FA ,/ MA MA FA MA MA 3.32 3.22 3.25 2.89 3.26 3.22 3.29 3.23 2.95 3.07 3.41 3.34 3.49 3.18 3.76 3.85 MA FA E FA MA FA MA /' FA MA MA FA FA MA MA FA 3.24 3.00 2.79 3.13 3.20 3.16 3.03 3.36 2.93 2.91 2.98 3.04 3.02 2.93 FA MA MA E MA MA MA MA / MA MA MA FA MA FA 3.46 3.40 3.42 3.07 3.20 3.45 3.09 3.56 2.95 3.33 3.08 3.56 3.27 FA FA FA MA FA ,/ FA MA MA MA MA MA MA FA MA MA 3.49 3.41 3.14 3.41 3.40 3.42 3.38 3.34 3.70 3.72 3.57 3.52 3.25 3.18 3.49 MA FA ,/ FA FA FA MA FA MA FA 3.52 3.60 3.73 3.80 2.36 3.77 3.92 3.76 3.52 FA E FA FA FA MA FA FA / MA MA MA FA MA FA MA FA 2.84 3.06 3.19 3.18 3.47 3.63 3.30 3.39 3.20 3.91 3.36 3.64 3.06 3.29 3.23 FA FA MA E FA FA FA FA / FA FA MA MA FA FA MA 3.54 3.49 3.74 3.80 3.69 3.78 3.64 3.58 3.74 3.84 3.91 4.26 3.14 3.92 MA FA FA MA MA FA MA MA FA / FA MA MA FA FA MA 3.12 3.25 3.43 3.60 3.46 3.51 3.67 3.23 2.40 3.26 3.84 3.51 3.17 3.46 3.39 M = MALE F = FEMALE A = ALIVE E = EARLY RESORPTION "/" DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G). PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 20 (PAGE 4) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA 418-011:PAGE B-65 003S87 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 DOSAGE GROUP 11 1 MG/KG/DAY RAT # CLs 12839 7/11 12840 9/10 12841 9/ 8 12842 10/ 6 12843 7/ 8 1.2844 11/ 8 12845 FA FA MA FA FA MA FA / MA FA MA FA FA FA MA FA FA MA 2.69 3.32 3.40 2.91 3.16 3.37 3.23 3.49 3.27 3.09 3.11 3.33 3.23 3.63 3.36 3.87 3.51 FA MA MA MA MA FA MA MA FA / MA MA FA FA FA MA MA MA 2.90 3.19 3.33 3.11 3.68 2.96 3.19 3.13 3.03 3.31 3.07 2.56 2.86 2.79 3.24 3.17 3.12 FA MA FA MA MA FA MA FA MA / MA MA FA FA MA FA FA MA 3.39 3.69 3.14 3.56 3.25 3.13 3.31 2.62 3.53 3.60 3.13 3.29 3.32 3.43 3.11 3.44 3.68 FA MA MA MA MA FA MA MA FA FA / MA MA FA MA FA FA 3.18 3.54 3.81 4.17 3.97 3.60 3.84 3.70 3.82 3.66 3.51 3.81 3.52 3.65 3.77 3.39 FA MA FA FA MA FA MA / FA FA FA FA MA E MA 3.66 3.34 3.57 3.51 3.99 3.40 3.39 3.58 3.41 3.62 3.91 3.98 4.02 MA FA FA FA FA FA MA MA MA FA MA / FA FA FA MA FA FA 3.70 3.94 3.49 3.75 3.65 3.74 3.73 3.93 3.88 3.55 4.22 3.36 3.58 3.43 3.93 3.92 3.51 NOT PREGNANT 12846 NOT PREGNANT 12847 15/ 6 * 12848 13/ 7 12849 9/ 6 12850 7/12 MA MA MA MA MA MA MA FA MA FA FA FA FA FA / MA MA MA FA 3.63 2.80 3.07 2.97 3.28 3.62 2.80 3.03 3.28 3.24 2.74 2.92 2.92 2.65 3.78 3.45 3.52 3.21 MA MA FA MA FA MA FA MA FA FA FA FA FA / MA FA MA FA FA 3.19 3.31 2.99 3.78 3.08 3.40 3.18 3.27 3.26 2.86 3.09 3.15 3.06 3.16 3.01 3.43 3.04 3.12 MA FA MA MA FA FA FA MA MA / MA FA FA MA MA MA 3.72 3.31 3.45 3.60 3.40 3.07 3.36 3.58 3.49 3.35 3.30 3.03 3.65 3.46 3.39 FA MA MA FA MA FA MA / MA FA FA E E FA FA FA MA FA MA 3.39 3.66 3.32 3.45 3.14 3.14 3.37 3.25 2.95 2.91 3.23 3.00 3.07 3.46 2.33 3.18 M = MALE F = FEMALE A = ALIVE E = EARLY RESORPTION "/" DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 20 (PAGE 5) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA 418-011: PAGE B-66 003688 FETUS # 1 2 3 4 5 e 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 DOSAGE GROUP III 5 MG/KG/DAY RAT # CLs 12851 6/12 12852 6/11 12853 10/ 7 12854 8/10 12855 FA MA E MA MA / FA FA MA FA FA FA MA MA FA FA MA 3.42 3.57 3.55 3.80 3.25 3.13 3.77 3.34 3.20 3.54 3.84 3.48 3.52 3.48 3.82 FA FA MA FA MA MA /' MA MA FA FA MA FA MA MA FA FA 3.09 3.31 3.29 3.22 3.23 3.58 3.12 3.44 3.10 2.98 3.36 3.21 3.30 3.39 3.29 3.38 MA FA MA FA FA FA FA FA MA FA / MA MA E FA FA 3.26 3.52 3.87 3.65 3.48 3.76 3.82 3.50 3.66 3.35 4.00 4.09 4.03 3.75 MA FA FA MA FA MA MA / FA FA FA FA MA FA MA FA FA 3.57 2.90 3.21 3.44 2.98 3.43 3.50 2.96 2.29 3.24 3.24 3.59 3.50 3.56 3.18 3.24 NOT PREGNANT 12856 5/ 9 12857 12/11 12858 6/11 12859 10/ 7 12360 9/11 12861 10/ 8 12862 8/ 7 12863 5/10 FA MA FA FA MA / FA MA FA FA FA FA MA FA MA 3.35 3.57 3.10 3.56 3.61 3.16 3.47 3.47 2.68 3.43 3.16 3.61 3.21 3.49 MA MA FA MA MA MA MA MA FA / MA FA MA MA MA FA FA FA FA FA 3.31 3.30 3.34 3.50 3.28 3.49 3.40 3.31 3.45 3.18 3.13 3.19 3.21 3.56 3.14 2.61 3.24 2.93 3.44 MA FA MA E FA FA /' MA MA FA FA MA FA MA FA MA 3.59 3.83 3.88 3.50 3.73 3.25 3.73 3.13 3.34 3.38 3.47 3.32 2.99 3.70 MA MA FA FA FA MA MA MA MA FA / MA MA FA FA MA MA FA 3.21 3.19 3.15 3.26 3.24 3.31 3.29 3.21 3.22 3.28 2.97 3.22 3.21 3.12 3.26 3.15 3.17 MA E MA MA FA MA MA / FA MA FA FA MA FA FA FA FA 3.54 3.43 3.64 3.70 4.31 4.00 3.50 3.85 3.47 3.55 3.95 3.51 3.53 3.36 3.76 MA MA FA FA MA FA MA MA / MA FA E FA FA 2.84 3.13 2.91 2.92 3.26 2.89 3.07 3.40 2.99 2.87 3.06 3.20 MA FA FA FA MA MA FA MA ,! FA MA MA FA FA MA FA 2.93 2.77 3.02 3.13 2.96 3.13 2.81 2.70 2.77 3.04 2.89 2.99 3.00 3.02 2.76 MA MA FA FA E / FA MA MA FA FA FA FA FA FA MA 3.65 3.48 3.40 3.37 3.64 3.78 3.75 3.19 3.24 3.47 3.56 3.14 3.29 3.69 M = MALE F = FEMALE A = ALIVE E = EARLY RESORPTION "/" DENOTES POSITION OF CERVIX CLs CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 20 (PAGE 6) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA 418-011: PAGE B-67 00368S FETUS # 1 2 3 4 5 6 7 8 9 10 il 12 13 14 15 16 17 18 19 20 21 22 23 DOSAGE GROUP III 5 MG/KG/DAY RAT # CLs 12864 12/ 5 12865 8/ 9 12866 11/11 12867 5/10 12868 7/ 6 12869 7/ 8 12870 6/11 12871 6/11 12872 10/ 6 12873 5/13 12874 7/10 12875 7/ 9 FA FA MA MA FA FA FA FA MA MA / FA MA MA FA 3.51 3.46 3.54 3.77 3.60 3.49 3.67 3.73 3.97 3.91 3.36 3.48 3.90 3.37 FA FA FA E MA FA FA MA / FA FA MA FA FA MA FA E MA 3.32 3.22 3.86 3.87 3.42 3.30 3.28 3.49 3.50 3.65 3.77 3.38 3.84 3.18 3.72 FA FA FA FA FA FA MA MA FA FA FA / MA FA MA MA MA MA MA MA 2.70 3.08 3.15 2.84 3.18 3.38 3.30 3.41 3.46 3.35 3.43 3.39 3.57 3.34 3.52 3.44 3.30 3.44 3.68 MA MA FA MA / MA MA MA MA FA MA FA FA MA FA 4.00 3.53 3.25 3.46 3.21 3.10 3.53 3.16 3.03 3.53 3.00 3.38 3.44 3.08 FA FA / FA FA MA E E 3.22 3.46 3.13 2.81 3.35 MA FA MA FA MA FA MA /' FA MA FA MA MA MA MA FA 3.50 3.38 3.30 3.30 3.22 3.20 3.35 3.01 3.19 3.21 3.44 3.41 3.55 3.20 3.07 FA MA MA FA FA FA / MA MA MA FA FA MA FA FA FA FA 3.48 3.92 3.91 3.28 3.32 3.09 3.64 3.61 3.37 3.63 3.22 3.68 3.49 3.75 3.33 3.45 MA FA FA MA MA FA / FA FA E MA FA MA MA E MA MA 3.26 3.46 3.33 3.62 3.72 3.55 2.66 3.34 3.29 3.21 3.58 3.19 3.54 3.46 FA MA MA MA FA MA FA MA FA / MA FA MA MA MA 3.21 3.36 3.34 3.45 3.15 3.25 3.29 3.50 3.16 3.11 3.12 3.37 3.44 3.07 FA E FA MA FA / FA FA FA FA FA MA MA MA MA FA 3.55 3.78 3.71 3.26 3.34 3.02 2.90 3.59 3.57 3.56 3.57 3.18 3.68 3.65 MA MA MA MA MA FA MA / FA E FA FA FA FA MA FA FA FA 3.67 3.53 3.75 3.67 3.79 3.62 3.66 3.43 3.36 3.53 3.39 3.77 3.58 3.28 3.54 3.92 E E E MA FA E /' MA FA MA E MA MA MA MA MA 4.04 3.51 3.73 3.25 3.76 3.56 3.71 3.43 3.62 3.57 V M = MALE F = FEMALE A = ALIVE E = EARLY RESORPTION "/" DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 20 (PAGE 7) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA Q 69C00 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 DOSAGE GROUP IV 10 MG/KG/DAY RAT # CLs 12876 9/ 8 12877 11/ 6 12878 4/12 12879 10/ 9 12880 11/ 9 12881 10/ 5 12882 8/11 12883 6/11 12884 9/ 6 12885 10/ 9 12886 10/ 7 12887 6/10 12888 8/10 MA FA FA MA FA MA MA MA /' FA MA MA MA FA MA FA 3.48 3.62 3.64 3.79 3.21 3.55 3.49 3.91 3.63 3.46 3.62 3.84 3.62 3.89 3.81 FA MA FA MA MA FA FA FA FA / MA MA MA FA FA 2.93 3.13 3.07 3.28 3.23 2.88 3.28 2.95 3.27 3.40 3.44 3.14 3.08 3.16 MA FA MA /1 MA MA FA FA FA MA MA MA FA FA FA FA 3.80 3.88 3.82 3.36 3.44 3.20 3.30 3.63 3.31 3.40 3.60 3.34 3.15 3.00 3.18 FA FA MA FA FA FA MA MA /' MA MA MA MA MA MA FA 3.21 3.83 3.61 3.34 3.49 3.44 3.08 3.60 3.41 3.20 3.55 3.10 3.62 3.31 3.45 FA MA MA FA FA MA FA FA MA / FA MA MA MA FA MA 3.01 3.40 3.65 3.01 3.19 3.30 3.16 3.25 3.21 2.83 3.17 3.35 3.23 3.11 3.28 FA E MA FA MA MA MA FA FA / MA FA FA E MA 2.31 3.03 2.91 3.03 3.07 3.27 2.88 2.93 2.95 2.89 3.00 3.39 MA FA FA FA MA FA FA /' MA MA FA MA FA FA FA FA FA MA 3.39 3.64 3.86 3.57 3.60 3.61 3.15 3.85 3.56 3.23 3.79 3.19 3.06 3.66 3.44 3.28 3.93 FA FA MA MA MA E /' MA FA MA FA MA MA FA G FA E MA 3.38 3.23 3.89 3.20 3.28 3.46 3.42 3.69 3.34 3.31 3.19 3.12 3.29 3.18 FA MA FA MA FA MA MA FA MA / MA FA G FA 3.02 3.41 3.23 2.97 3.02 3.24 3.09 3.00 3.52 2.84 3.19 3.40 FA FA MA MA MA MA FA MA FA / FA MA MA MA MA FA FA FA 3.02 3.15 3.52 3.38 3.22 3.24 3.17 3.44 3.01 2.87 3.36 2.10 3.76 3.32 1.67 3.00 3.03 MA FA FA MA MA MA E MA FA / MA FA MA MA MA 3.61 3.21 3.61 3.71 3.53 3.47 3.80 3.82 3.16 3.15 3.41 4.00 3.72 FA FA MA MA MA MA / MA FA FA MA FA FA MA FA FA MA 3.08 2.88 3.28 2.95 3.26 3.16 3.38 3.04 3.19 3.17 2.71 2.91 3.27 2.90 2.90 3.23 MA FA FA FA MA MA MA /' FA FA E FA FA MA MA 3.03 3.01 3.16 2.88 3.05 2.90 2.85 2.83 3.07 2.99 2.95 2.96 3.27 M = MALE F = FEMALE A = ALIVE E = EARLY RESORPTION "/ DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . 418-011 PAGE B-68 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 20 (PAGE 8) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA T69C 00 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 DOSAGE GROUP IV 10 MG/KG/DAY RAT # CLs 12889 11/ 4 12890 5/11 12891 6/ 7 12892 8/ 7 12893 14/ 7 12894" 8/ 7 12895 7/ 8 12896 5/10 12897 9/ 9 12898 11/ 8 12899 8/ 7 12900 11/ 6 FA MA / FA 3.54 3.47 3.79 MA MA FA FA E / MA MA FA MA FA FA FA FA MA MA FA 3.25 3.55 3.44 2.99 3.04 3.18 3.20 3.34 2.15 3.39 3.09 3.26 3.20 3.16 2.84 MA FA MA MA FA FA / MA MA MA MA MA FA FA 3.46 3.49 3.88 3.87 3.82 3.39 3.74 3.98 4.06 3.93 3.63 3.29 3.59 FA FA FA FA FA FA FA MA / FA MA FA MA MA MA FA 3.31 3.41 3.56 3.43 3.38 3.41 3.21 3.75 3.71 3.52 3.50 3.63 3.58 3.52 3.42 FA MA FA FA MA FA FA MA FA MA MA / MA MA MA MA MA 3.24 3.27 3.30 3.42 3.48 3.34 3.16 3.48 3.08 3.51 3.37 3.31 3.02 3.52 3.45 3.49 FA FA FA MA MA FA FA MA / MA MA FA E MA FA MA 3.24 3.74 3.72 3.55 3.58 3.72 3.60 3.66 3.32 3.52 4.16 3.50 3.68 3.73 MA MA MA MA MA MA E . MA MA FA FA FA FA FA FA 3.00 3.17 3.43 3.16 3.27 3.35 3.35 3.26 3.04 3.25 3.20 2.92 3.11 3.55 FA MA FA MA MA / FA FA MA FA FA MA MA FA FA 3.07 3.65 3.41 3.53 3.12 3.39 3.19 3.56 3.40 3.44 3.36 3.69 3.54 3.29 MA FA FA FA MA FA / FA MA FA FA FA MA MA MA MA 3.19 3.53 3.51 3.63 3.59 3.54 3.53 3.29 3.08 3.30 3.18 3.65 3.18 3.41 3.33 FA MA MA FA FA FA FA FA MA MA FA / MA FA FA FA FA MA FA 3.00 3.18 2.77 3.15 3.03 3.19 3.24 3.14 3.46 3.26 3.25 3.16 3.19 3.44 3.38 3.36 3.47 3.36 MA FA FA MA FA MA MA E /' MA MA MA MA MA MA 3.34 3.12 3.23 3.47 3.36 3.44 3.18 3.20 3.03 3.37 3.68 3.11 3.29 MA MA MA FA MA FA FA FA FA MA ,/ MA MA MA FA FA MA 2.96 2.95 3.47 3.39 3.00 3.05 3.35 3.59 3.37 3.31 3.56 3.12 3.22 2.66 3.33 3.43 M = MALE F = FEMALE A = ALIVE E = EARLY RESORPTION "/" DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . 418-011: PAGE B-69 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 20 (PAGE 9) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA 418-011 PAGE B-70 003692 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 DOSAGE: GROUP V 20 MG/KG/DAY RAT # CLs 12901 9/ 8 MA MA MA MA MA FA FA FA MA / FA FA FA MA MA MA MA MA 3.17 3.37 3.23 3.11 3.06 2.94 3.03 2.82 3.16 3.25 3.12 3.27 3.40 3.59 3.40 3.26 3.38 12902 11/ 6 FA E FA FA MA MA FA E FA / MA MA FA FA FA 2.93 3.01 3.00 3.31 3.07 2.70 3.07 3.16 3.37 3.18 3.41 3.09 12903 10/ 7 FA MA MA E MA MA FA MA FA / FA MA MA FA FA MA 3.08 3.48 3.37 3.27 3.32 2.85 2.80 3.12 3.04 3.16 3.09 2.84 3.07 3.18 129.04 8/ 7 FA FA MA FA E FA FA / FA E E MA FA FA 3.01 3.16 3.10 2.99 2.92 2.86 3.09 3.30 3.13 2.89 12905 7/ 8 MA FA FA MA FA MA / FA FA FA FA MA MA 3.37 3.10 3.37 3.76 3.37 3.24 3.04 3.44 3.22 3.46 3.12 3.19 12906 8/ 6 FA MA MA FA MA FA E MA / MA FA FA FA MA FA 3.10 3.44 3.48 3.11 3.49 3.37 3.38 2.96 3.17 3.34 3.24 3.71 3.37 12907 8/i0 / MA FA MA MA FA MA E MA MA FA 2.50 2.43 2.85 3.20 2.90 3.17 3.11 2.94 3.25 12908 4/14 FA MA FA / MA FA MA FA FA MA FA FA MA E MA FA E 3.09 3.49 3.01 3.02 3.05 3.08 2.80 2.61 3.16 3.22 3.12 3.17 2.99 2.92 12909 9/' 8 FA FA MA MA MA FA MA / MA E MA MA FA MA 2.47 3.13 3.31 3.18 3.01 2.38 2.88 3.32 3.23 2.97 2.76 3.03 12910 NOT PREGNANT H 12911 6/ 8 12912 11/ 4 12913 9/ 8 E FA MA MA MA FA / MA MA FA MA FA MA MA MA 3.15 3.12 3.29 2.97 3.07 3.37 3.40 2.54 3.22 3.05 3.25 3.47 3.32 FA FA FA MA FA FA MA MA MA / MA MA FA MA 3.06 3.34 3.15 3.82 3.98 3.49 3.62 3.57 4.10 3.52 3.64 2.99 3.89 MA MA E MA FA FA / MA MA FA MA MA FA FA 2.94 3.26 3.39 3.08 3.06 2.41 2.98 3.11 2.93 2.91 2.72 2.98 M = MALE F = FEMALE A = ALIVE E = EARLY RESORPTION "/" DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 20 (PAGE 10) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 DOSAGE GROUP V 20 MG/KG/DAY RAT # CLs 12914 12/ 4 12915 9/13 12916 8/ 9 12917 11/ 6 12918 12/ 5 12919 6/ 8 12920 10/ 9 12921 7/10 12922 8/ 8 12923 8/ 6 12924 8/ 8 12925 9/ 9 FA MA MA FA FA FA MA FA MA MA MA FA / FA MA MA 3.06 3.16 3.59 3.37 2.79 3.27 3.40 3.35 3.32 3.35 3.71 3.32 3.24 3.37 3.53 FA MA FA E MA MA FA FA MA / MA FA E E MA MA MA FA 2.94 3.58 3.41 3.43 3.65 2.98 2.99 3.72 3.27 3.21 3.87 3.38 3.81 3.66 FA MA MA FA MA MA MA MA / FA E FA MA FA FA FA FA MA 2.58 3.03 3.11 2.94 3.33 3.16 2.76 3.02 2.64 2.90 3.15 3.34 3.05 2.63 2.75 2.86 MA MA MA E MA MA MA FA FA MA / FA FA MA MA MA 3.13 3.07 3.07 3.39 3.22 3.24 2.79 2.77 3.12 2.76 2.94 3.14 3.37 3.02 FA FA FA FA MA FA MA FA FA MA FA MA /1 E FA MA FA 2.57 3.22 2.89 3.08 3.10 2.87 3.34 3.25 3.26 3.30 3.02 3.11 2.99 3.50 3.35 MA FA MA MA MA MA /' MA FA MA FA MA FA FA FA 3.05 2.87 3.15 3.61 3.26 3.17 3.22 3.07 3.28 2.97 3.14 3.00 3.05 2.97 FA MA MA MA MA MA FA FA MA / FA MA FA MA FA FA FA 3.25 3.52 3.31 3.32 3.43 3.23 2.91 3.17 3.43 3.03 3.28 3.16 3.26 2.93 3.15 3.14 MA FA FA FA MA MA MA ,/ FA MA FA FA MA FA FA 3.66 3.26 3.14 3.28 3.39 2.71 3.44 3.20 3.23 3.31 3.34 3.73 3.34 3.27 MA FA MA E MA FA FA MA / E E MA MA FA MA FA 2.80 2.95 3.36 3.58 3.35 2.96 2.96 3.16 3.06 3.07 3.38 3.01 MA MA MA FA FA FA FA FA / FA MA MA MA MA FA 3.54 3.39 3.16 3.08 3.58 3.24 3.38 2.94 3.12 3.55 3.55 3.31 3.58 3.44 MA MA FA MA MA FA FA MA / FA FA FA MA MA FA FA 3.27 2.92 3.45 3.68 3.61 2.98 2.93 3.59 3.10 3.03 3.26 3.04 3.63 3.47 2.85 MA FA FA FA MA MA MA MA FA / MA MA FA MA MA MA MA 2.45 2.65 3.04 3.17 3.17 2.79 2.74 2.93 2.93 2.86 3.06 2.76 2.82 3.08 3.06 3.06 H M = MALE F = FEMALE A = ALIVE E = EARLY RESORPTION "/ DENOTES POSITION OF CERVIX CLS = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . 418-011 PAGE B- 003693 ~sl PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631G.7) TABLE 20 (PAGE 11) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA 418-011: PAGE B-72 003694 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 SATELLITE! DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RAT # CLs 12573 13/ 3 12574 12/12 12575 6/ 6 E A A A A A A A A A A A A/ A A A 0.80 1.08 1.15 1.07 1.16 1.34 1.23 1.28 1.11 1.32 1.26 1.09 0.08al.22 1.05 A A A A A A A A A/ A A A A A A A A A 1.12 1.21 1.27 1.17 1.29 1.20 1.12 1.20 1.19 1.09 1.24 1.31 1.32 1.10 1.18 1.19 1.12 1.18 A A A A A A/ A 1.36 1.49 1.43 1.27 1.45 1.44 1.57 SATELLITEI DOSAGE GROUP ii 1 1MG/KG/DAY 12576 15/ 5 12577 8/12 12578 8/11 12579 10/ 5 12580 11/ 5 A A A A A A A A A A A E /' A A A 1.17 1.05 1.17 1.21 1.30 1.29 1.36 1.36 1.38 1.32 1.42 1.46 1.42 1.46 A A A A A A A /' A A A A A A A A A A A 1.08 1.38 1.51 1.40 1.45 1.39 1.47 1.36 1.45 1.39 1.42 1.49 1.31 1.44 1.45 1.30 1.29 1.29 A A A A A A/ A A A A A E A A A A A 1.17 1.35 1.28 1.27 1.28 1.29 1.23 1.24 1.28 1.30 1.36 1.23 1.30 1.30 1.18 1.38 A A A A A A A A A A/ A A A A A 1.32 1.32 1.23 1.39 1.34 1.46 1.50 1.36 1.26 1.26 1.52 1.51 1.34 1.28 1.50 A A A A A A A A A A/ A A E A A 1.23 1.39 1.49 1.50 1.51 1.46 1.52 1.49 1.39 1.54 1.48 1.36 1.55 1.54 SATELLITE DOSAGE GROUP III 5 MG/KG/DAY 12581 6/ 9 12582 14/ 7 12583 13/11 A A A A A A/ A A A A A E E A A 1.24 1.42 1.55 1.54 1.37 1.47 1.32 1.31 1.47 1.51 1.45 1.44 1.52 A A A A A A A A A A A A A/ A A A A A 1.10 1.12 1.34 1.21 1.37 1.23 1.40 1.43 1.50 1.29 1.26 1.22 1.32 1.29 1.43 1.32 1.02 1.49 A A A A A A A A A A A A A/ A A A A A A A 1.49 1.26 1.27 1.48 1.26 1.45 1.30 1.35 1.19 1.30 1.52 1.29 1.05 1.30 1.43 1.44 1.38 1.45 1.34 1.31 A = ALIVE E = EARLY RESORPTION */ DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . a. Value presumed incorrectly recorded; value excluded from group averages. PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 20 (PAGE 12) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 5 6 7 8 9 10 li 12 13 14 15 16 17 18 19 20 21 22 23 SATELLITE! DOSAGE GROUP IV 10 MG/KG/DAY RAT # CLs 12584 14/ 8 12585 6/10 12586 9/ 7 E A A E A A A A A A A/ A A A A A A 1.28 1.18 1.29 1.17 1.39 1.30 1.26 1.17 1.24 1.04 1.12 1.26 1.18 1.15 1.21 A A A A A A /' A A A A A A A A A A 1.18 1.32 1.25 1.30 1.19 1.07 1.17 1.10 0.71 1.21 1.17 1.30 1.20 1.13 1.24 1.17 A A A A A A A A/ A E A A A A 1.25 1.25 1.35 0.99 1.44 1.30 1.26 1.13 1.27 1.27 1.23 1.35 1.35 SATELLITE DOSAGE GROUP '7 20 MG/KG/DAY 12587 9/ 5 12588 9/ 6 12589 7/ 7 12590 12/ 4 12591 10/ 9 A A A A A A A A A/ A A A A A 1.03 1.15 1.16 1.25 1.17 1.07 1.13 1.12 1.19 1.05 1.23 1.32 1.17 1.26 A A A A A A A A A/ A A A A A A 1.25 1.27 1.32 1.28 1.47 1.11 1.42 1.35 1.28 1.40 1.36 1.37 1.47 1.47 1.38 A A A A A A A/ A A A A A A A 1.25 1.26 1.30 1.31 1.34 1.30 1.32 1.11 1.35 1.29 1.40 1.32 1.49 1.38 A A A A A A A E A A A A ,/ E A A A 1.25 1.37 1.56 1.38 1.38 1.43 1.31 1.25 1.41 1.32 1.52 1.65 1.50 1.46 A A A A A A A A A E/ A A A A A A A 1.20 1.28 1.36 1.36 1.37 1.17 1.22 1.35 1.36 1.31 1.41 1.30 1.40 1.34 1.29 1.32 A = ALIVE E = EARLY RESORPTION */" DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . 418-011: PAGE B-73 003695 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 21 (PAGE 1) : FETAL ALTERATIONS - INDIVIDUAL DATA 418-011 PAGE B-74 003696 DOSAGE GROUP I RAT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 12801 M 7.7) 12802 6( 42.8) GROSS EXTERNAL EXAMINATION 0 (VEHICLE) MG/KG/DAY SOFT TISSUE EXAMINATION N/N 0/13 DESCRIPTION 0/14 N/N 1/ 6 1/ 7 DESCRIPTION FETUS 10 VESSELS: UMBILICAL ARTERY DESCENDS TO THE LEFT OF URINARY BLADDER FETUS 11 KIDNEYS: PELVIS, SLIGHT DILATION, right 12803 1( 6.2) 0/16 1/ 8 FETUS 2 KIDNEYS: PELVIS, SLIGHT DILATION, bilateral N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 0/ 7 DESCRIPTION 5/ 7 0/8 FETUS 1 STERNAL CENTRA: 1ST, NOT OSSIFIED PELVIS: PUBIS, INCOMPLETELY OSSIFIED bilateral FETUS 3 PELVIS: PUBIS, INCOMPLETELY OSSIFIED, left FETUS 5 STERNAL CENTRA: 1ST, NOT OSSIFIED FETUS 8 PELVIS: PUBIS, INCOMPLETELY OSSIFIED, bilateral FETUS 10 STERNAL CENTRA: 1ST, NOT OSSIFIED PROTOCOL 418-0X1: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 21 (PAGE 2): FETAL ALTERATIONS - INDIVIDUAL DATA 418-011: PAGE B-75 003697 DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RAT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) GROSS EXTERNAL EXAMINATION N/N DESCRIPTION SOFT TISSUE EXAMINATION N/N DESCRIPTION 12804 0( 0.0) 0/13 0/ 6 12805 0( 0.0) 0/15 0/ 7 12806 0( 0.0) 0/15 0/ 7 12807 0( 0.0) 0/14 0/ 7 12808 0< 0.0) 0/12 0/ 6 12809 0( 0.0) 0/18 0/ 9 12810 1( 10.0) 0/10 1/ 5 FETUS 10 VESSELS: UMBILICAL ARTERY DESCENDS TO THE LEFT OF URINARY BLADDER 12811 0< 0.0) 0/14 0/ 7 12812 0( 0.0) 0/14 0/ 7 12813 NOT PREGNANT 12814 0( 0.0) 0/16 0/ 8 12815 0< 0.0) 0/15 0/ 7 12816 0( 0.0) 0/12 0/ 6 12817 0( 0.0) 0/15 0/ 7 12818 0( 0.0) 0/13 0/ 6 12819 0( 0.0) 0/15 0/ 7 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 0/ 7 0/ 8 0/ 8 0/ 7 0/ 6 0/ 9 0/ 5 DESCRIPTION 0/ 7 0/ 7 0/ 8 0/ 8 0/ 6 0/ 8 0/ 7 0/ 8 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 21 (PAGE 3) : FETAL ALTERATIONS - INDIVIDUAL DATA 8 6 9C0 DOSAGE GROUP I RAT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 12820 0( 0.0) 12821 4( 26.7) GROSS EXTERNAL EXAMINATION 0 (VEHICLE) MG/KG/DAY SOFT TISSUE EXAMINATION N/N 0/14 0/15 DESCRIPTION N/N 0/ 7 1/ 7 DESCRIPTION FETUS 6 VESSELS: UMBILICAL ARTERY DESCENDS TO THE LEFT OF URINARY BLADDER 12822 2( 13.3) 0/15 1/ 7 FETUS 4 LUNGS: APICAL LOBE, ABSENT 12823 0( 0.0) 0/14 0/ 7 12824 0( 0.0) 0/12 0/ 6 12825 0( 0.0) 0/18 0/ 9 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 0/ 7 3/ 8 1/ 8 0/ 7 0/ 6 0/ 9 DESCRIPTION FETUS 7 STERNAL CENTRA: 1ST, INCOMPLETELY OSSIFIED FETUS 11 STERNAL CENTRA: 1ST, INCOMPLETELY OSSIFIED FETUS 15 STERNAL CENTRA: 1ST, INCOMPLETELY OSSIFIED FETUS 9 STERNAL CENTRA: 1ST, INCOMPLETELY OSSIFIED 418-011: PAGE B-76 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OP N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631S.7) TABLE 21 (PAGE 4) : FETAL ALTERATIONS - INDIVIDUAL DATA 669C00 DOSAGE GROUP II RAT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 12826 1( 7.1) 12827 12828 12829 12830 12831 12832 0( 0.0) 0( 0.0) 0( 0.0) ( 0.0) 0< 0.0) 2 ( 14.3) GROSS EXTERNAL EXAMINATION 1 MG/KG/DAY SOFT TISSUE EXAMINATION N/N 0/14 DESCRIPTION 0/13 0/18 0/14 0/15 0/16 0/14 N/N 1/ 7 0/ 6 0/ 8 0/ 7 0/ 7 0/ 8 0/ 7 DESCRIPTION FETUS 12 VESSELS: INNOMINATE, ABSENT 12833 0< 0.0) 0/13 0/ 6 12834 1( 6.7) 0/15 1/ 7 FETUS 14 VESSELS: UMBILICAL ARTERY DESCENDS TO THE LEFT OF URINARY BLADDER N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 0/ 7 DESCRIPTION 0/ 7 0/10 0/ 7 0/ 8 0/ 8 2/ 7 0/ 7 0/ 8 FETUS 4 CERVICAL VERTEBRAE: CERVICAL RIB PRESENT AT 7TH CERVICAL VERTEBRA, right FETUS 6 CERVICAL VERTEBRAE: CERVICAL RIB PRESENT AT 7TH CERVICAL VERTEBRA, right 418-011: PAGE B-77 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 21 (PAGE 5) : FETAL ALTERATIONS - INDIVIDUAL DATA 418-011: PAGE B-78 003700 DOSAGE GROUP II RAT NUMBER SPECIMENS WITH ANY ALTERATIONS N {%) 12835 0( 0.0) 12836 o< 0.0) 12837 M 7.1) 12838 12839 12840 0( 0.0) 0( 0.0) M 5.9) GROSS EXTERNAL EXAMINATION 1 MG/KG/DAY SOFT TISSUE EXAMINATION N/N 0/ 9 0/15 0/14 DESCRIPTION 0/15 0/17 0/17 N/N 0/ 4 0/ 7 1/ 7 0/ 7 0/ 8 0/ 8 DESCRIPTION FETUS 9 VESSELS : INNOMINATE, ABSENT 12841. 12842 0( 0.0) K 6.2) 0/17 0/16 0/ 8 0/ 8 12843 0( 0.0) 0/13 0/ 6 12844 0( 0.0) 0/17 0/ 8 12845 NOT PREGNANT N/N = NUMBER OF SPECIMENS WITH ALTERATI0NS/NUM8ER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 0/ 5 0/ 8 0/ 7 DESCRIPTION 0/ 8 0/ 9 1/ 9 0/ 9 1/ 8 0/ 7 0/ 9 FETUS 13 STERNAL CENTRA: 1ST, INCOMPLETELY OSSIFIED FETUS 15 CERVICAL VERTEBRAE: CERVICAL RIB PRESENT AT 7TH CERVICAL VERTEBRA, right PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 21 (PAGE 6) : FETAL ALTERATIONS - INDIVIDUAL DATA DOSAGE GROUP II RAT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) GROSS EXTERNAL EXAMINATION N/N DESCRIPTION 12846 NOT PREGNANT 12847 o o o 0/18 12848 1( 5.6) 0/18 1 MG/KG/DAY SOFT TISSUE EXAMINATION N/N DESCRIPTION 0/ 9 0/ 9 1284? 0( 0.0) 0/15 0/ 7 12850 2( 12.5) 0/16 1/ 8 FETUS 16 LUNGS: DIAPHRAGMATIC LOBE, ABSENT N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION 0/ 9 1/ 9 0/ 8 1/ 8 FETUS 1 RIBS: WAVY, right 7th 10th FETUS 17 STERNAL CENTRA: 1ST, NOT OSSIFIED 418-011: PAGE B-79 003701 c o Co o0 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 21 (PAGE 7) : FETAL ALTERATIONS - INDIVIDUAL DATA DOSAGE GROUP III RAT NUMBER 12851 12852 12853 12854 12855 SPECIMENS WITH ANY ALTERATIONS N (%) GROSS EXTERNAL EXAMINATION N/N DESCRIPTION 0( 0.0) 0/15 0 ( 0.0) 0/16 0 ( 0.0) 0/14 0( 0.0) 0/16 NOT PREGNANT 12856 12857 0( 0.0) 0( 0.0) 0/14 0/19 12858 0( 0.0) 0/14 12859 2( 11.8) 0/17 5 MG/KG/DAY SOFT TISSUE EXAMINATION N/N 0/ 7 0/ 8 0/ 7 0/ 8 DESCRIPTION 0/ 6 0/ 9 0/ 7 0/ 8 12860 2 ( 13.3) 0/15 2/ 7 FETUS 5 VESSELS: UMBILICAL ARTERY DESCENDS TO THE LEFT OF URINARY BLADDER FETUS 9 VESSELS: UMBILICAL ARTERY DESCENDS TO THE LEFT OF URINARY BLADDER N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 0/ 8 0/ 8 0/ 7 0/ 8 DESCRIPTION 0/ 8 0/10 0/ 7 2/ 9 0/8 FETUS 11 PELVIS: ISCHIUM, INCOMPLETELY OSSIFIED, right FETUS 15 PELVIS: ISCHIUM, INCOMPLETELY OSSIFIED, right 418-011: PAGE B-80 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 21 (PAGE 8): FETAL ALTERATIONS - INDIVIDUAL DATA p O < iC O 0 DOSAGE GROUP III RAT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 12861 0 ( 0.0) 12862 0( 0.0) 12863 M 7.1) GROSS EXTERNAL EXAMINATION 5 MG/KG/DAY SOFT TISSUE EXAMINATION N/N 0/12 0/15 0/14 DESCRIPTION N/N 0/ 6 0/ 7 0/ 8 DESCRIPTION 12864 12865 0( 0.0) 1< 6.7) 0/14 0/15 0/ 7 0/ 7 12866 0( 0.0) 0/19 0/ 9 12867 0( 0.0) 0/14 0/ 7 12868 0( 0.0) 0/ 5 0/ 2 12869 0< 0.0) 0/15 0/ 7 12870 0( 0.0) 0/16 0/ 8 12871 0( 0.0) 0/14 0/ 7 12872 0( 0.0) 0/14 0/ 7 12873 0( 0.0) 0/14 0/ 7 12874 0( 0.0) 0/16 0/ 8 12875 0( 0.0) 0/10 0/ 5 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 0/ 6 0/ 8 1/ 6 0/ 7 1/ 8 0/10 0/ 7 0/ 3 0/ 8 0/ 8 0/ 7 0/ 7 0/ 7 0/ 8 0/ 5 DESCRIPTION FETUS 14 STERNAL CENTRA: 1ST, INCOMPLETELY OSSIFIED FETUS 6 CERVICAL VERTEBRAE: CERVICAL RIB PRESENT AT 7TH CERVICAL VERTEBRA, left 418-011: PAGE B-81 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 21 (PAGE 9) : FETAL ALTERATIONS - INDIVIDUAL DATA DOSAGE GROUP IV RAT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 12876 0( 0.0) 12877 K 7.1) 12878 12879 12880 12881 12882 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 1( 5.9) GROSS EXTERNAL EXAMINATION 10 MG/KG/DAY SOFT TISSUE EXAMINATION N/N 0/15 0/14 DESCRIPTION 0/15 0/15 0/15 0/12 0/17 N/N 0/ 7 1/ 7 0/ 7 0/ 7 0/ 7 0/ 6 0/ 8 DESCRIPTION FETUS 14 KIDNEYS : PELVIS, MODERATE DILATION, right 12883 0( 0.0) 0/14 0/ 7 12884 0( 0.0) 0/12 0/ 6 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 0/ 8 0/ 7 DESCRIPTION 0/ 8 0/ 8 0/ 8 0/ 6 1/ 9 0/ 7 0/ 6 FETUS 3 CERVICAL VERTEBRAE: CERVICAL RIB PRESENT AT 7TH CERVICAL VERTEBRA, left 418-011 PAGE B-82 003704 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 21 (PAGE 10) : FETAL ALTERATIONS - INDIVIDUAL DATA 418-011: PAGE B-83 003705 DOSAGE GROUP IV RAT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 12885 1< 5.9) GROSS EXTERNAL EXAMINATION 10 MG/KG/DAY SOFT TISSUE EXAMINATION N/N 1/17 DESCRIPTION FETUS 15 BODY: TRUNK SHORT TAIL: ABSENT N/N 0/ 8 DESCRIPTION N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED a. Excluded from ossification site group averages and statistical analyses. SKELETAL EXAMINATION N/N 1/ 9 DESCRIPTION FETUS 15 CERVICAL VERTEBRAE: 4 PRESENT a THORACIC VERTEBRAE: 0 PRESENT a ARCH, NOT OSSIFIED, bilateral 1st - 13th; CENTRUM, NOT OSSIFIED, 1st - 13th LUMBAR VERTEBRAE: 0 PRESENT a ARCH, NOT OSSIFIED, bilateral 1st - 6th; CENTRUM, NOT OSSIFIED, 1st - 6th SACRAL VERTEBRAE: 0 PRESENT a ARCH, NOT OSSIFIED, bilateral 1st - 3rd; CENTRUM, NOT OSSIFIED, 1st - 3rd CAUDAL VERTEBRAE: 0 PRESENT a PELVIS: PUBIS, NOT OSSIFIED, bilateral RIBS: 0 PRESENT a, NOT OSSIFIED, bilateral 1st - 13th PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-631G.7) TABLE 21 (PAGE 11) : FETAL ALTERATIONS - INDIVIDUAL DATA DOSAGE GROUP IV RAT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) GROSS EXTERNAL EXAMINATION 10 MG/KG/DAY SOFT TISSUE EXAMINATION N/N DESCRIPTION N/N DESCRIPTION SKELETAL EXAMINATION N/N DESCRIPTION 418-011: PAGE B-84 003706 12886 12887 12888 0( 0.0) 0( 0.0) 2( 15.4) 0/13 0/16 0/13 0/ 6 0/ 8 0/ 6 12889 12890 0( 0.0) 1( 6.7) 0/ 3 0/15 0/ 1 0/ 7 12891 0( 0.0) 0/13 0/ 6 12892 0( 0.0) 0/15 0/ 7 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED 0/ 7 0/ 8 2/ 7 0/ 2 1/ 8 0/ 7 0/ 8 FETUS 1 PELVIS: PUBIS, INCOMPLETELY OSSIFIED, left FETUS 14 STERNAL CENTRA: 1ST, INCOMPLETELY OSSIFIED FETUS 10 CERVICAL VERTEBRAE: CERVICAL RIB PRESENT AT 7TH CERVICAL VERTEBRA, left PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 21 (PAGE 12) : FETAL ALTERATIONS - INDIVIDUAL DATA DOSAGE GROUP IV RAT NUMBER SPECIMENS WITH ANY ALTERATIONS N <%) 12893 M 6.2) GROSS EXTERNAL EXAMINATION 10 MG/KG/DAY SOFT TISSUE EXAMINATION N/N 0/16 DESCRIPTION N/N 0/ 8 DESCRIPTION 12894 12895 12896 12897 12898 0< 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 1< 5.6) 0/14 0/14 0/14 0/15 0/18 0/ 7 0/ 7 0/ 7 0/ 7 0/ 9 12899 0< 0.0) 0/13 0/ 6 12900 0( 0.0) 0/16 0/ 8 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 1/ 8 0/ 7 0/ 7 0/ 7 0/ 8 1/ 9 0/ 7 0/ 8 DESCRIPTION FETUS 13 SKULL: NASAL - FRONTAL, SUTURE LARGE FETUS 15 CERVICAL VERTEBRAE: CERVICAL RIB PRESENT AT 7TH CERVICAL VERTEBRA, right 418-011: PAGE B-85 003707 PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 21 (PAGE 13): FETAL ALTERATIONS - INDIVIDUAL DATA 418-011: PAGE B-86 003708 DOSAGE GROUP V RAT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 12901 0 ( 0.0) 12902 0( 0.0) 12903 0 ( 0.0) 12904 K 10.0) GROSS EXTERNAL EXAMINATION 20 MG/KG/DAY SOFT TISSUE EXAMINATION N/N 0/17 0/12 0/14 0/10 DESCRIPTION N/N 0/ 7 0/ 6 0/ 7 0/ 5 DESCRIPTION 12905 12906 12907 o ( 0.0) 0( 0.0) . K 11.1) 0/12 0/13 0/ 9 0/ 6 0/ 6 0/ 4 12908 K 7.1) 0/14 0/ 7 12909 4 ( 33.3) 0/12 0/ 6 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 0/10 0/ 6 0/ 7 1/ 5 0/ 6 0/ 7 1/ 5 1/ 7 4/ 6 DESCRIPTION FETUS 1 RIBS: WAVY, right 5th 7th and 10th FETUS 1 STERNAL CENTRA: 1ST, NOT OSSIFIED FETUS 5 CERVICAL VERTEBRAE: CERVICAL RIB PRESENT AT 7TH CERVICAL VERTEBRA, left FETUS 5 RIBS: WAVY, bilateral 4th - llth PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER: T-6316.7) TABLE 21 (PAGE 14): FETAL ALTERATIONS - INDIVIDUAL DATA 418-011: PAGE B-87 003709 DOSAGE GROUP V RAT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 12909 (CONT) GROSS EXTERNAL EXAMINATION 20 MG/KG/DAY SOFT TISSUE EXAMINATION N/N DESCRIPTION N/N DESCRIPTION 12910 12911 12912 NOT PREGNANT 0 ( 0.0) 0/13 K 7.7) 0/13 0/ 6 0/ 6 12913 0< 0.0) 0/12 0/ 6 12914 0( 0.0) 0/15 0/ 7 12915 0( 0.0) 0/14 0/ 7 12916 0( 0.0) 0/16 0/ 8 N/N * NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION FETUS 7 RIBS: WAVY, right 4th 12th, left 3rd - 12th; INCOMPLETELY OSSIFIED (HYPOPLASTIC), right 9th - 12th, left 10th 12th FETUS 10 RIBS: WAVY, right 6th 11th, left 6th, 7th and 10th FETUS 12 RIBS: WAVY, right 4th 11th, left 6th - 9th 0/ 7 1/ 7 0/ 6 0/ 8 0/ 7 0/ 8 FETUS 5 CERVICAL VERTEBRAE: CERVICAL RIB PRESENT 1 7TH CERVICAL VERTEBRA, left PROTOCOL 418-011: ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RATS (SPONSOR'S STUDY NUMBER:: T-6316.7) TABLE 21 (PAGE 15): FETAL ALTERATIONS - INDIVIDUAL DATA 418-011 PAGE B-88 003710 DOSAGE GROUP V RAT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 12917 0( 0.0) 12918 0( 0.0) 12919 2( 14.3) GROSS EXTERNAL EXAMINATION 20 MG/KG/DAY SOFT TISSUE EXAMINATION N/N 0/14 0/15 0/14 DESCRIPTION N/N 0/ 7 0/ 7 0/ 7 DESCRIPTION 12920 1< 6.2) 0/16 0/ 8 12921 12922 12923 0( 0.0) 0( 0.0) 1( 7.1) 0/14 0/12 0/14 0/ 7 0/ 6 0/ 7 12924 0( 0.0) 0/15 0/ 7 12925 0( 0.0) 0/16 0/ 8 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 0/ 7 0/ 8 2/ 7 1/ 8 0/ 7 0/ 6 1/ 7 0/ 8 0/ 8 DESCRIPTION s FETUS 3 RIBS: WAVY, bilateral 4th - 12th FETUS 9 RIBS: WAVY, bilateral 4th - 12th FETUS 1 CERVICAL VERTEBRAE: CERVICAL RIB PRESENT AT 7TH CERVICAL VERTEBRA, left FETUS 7 CERVICAL VERTEBRAE: CERVICAL RIB PRESENT AT 7TH CERVICAL VERTEBRA, bilateral APPENDIX C PROTOCOL AND AMENDMENTS 003711 418-011: PAGE C-1 O P r im e d ic a Argus Research Laboratories, Inc. 9 05 Sheehy Drive, Building A Horsham, PA 19044 Telephone: (21 5)44 3-8 71 0 Telefax: (215) 443-8587 PROTOCOL 418-011 SPONSOR'S STUDY NUMBER: T-6316.7 STUDY TITLE: PURPOSE: TESTING FACILITY: STUDY DIRECTOR: SPONSOR: STUDY MONITOR: ALTERNATE STUDY MONITOR: Oral (Gavage) Developmental Toxicity Study of N-EtFOSE in Rats The purpose of this study is to detect adverse effects of N-EtFOSE on Crl:CDBR VAF/Plus presumed pregnant female rats and development of the embryo and fetus consequent to exposure of the dam from implantation to closure of the hard palate. This study evaluates ICH Harmonised Tripartite Guideline stages C and D of the reproductive process. Argus Research Laboratories, Inc. 905 Sheehy Drive, Building A Horsham, Pennsylvania 19044-1297 Telephone: (215)443-8710 Telefax: (215)443-8587 Raymond G. York, Ph.D.,DABT Associate Director of Research 3M Toxicology Services 3M Center, Building 220-2E-02 St. Paul, Minnesota 55144-1000 Marvin T. Case, D.V.M., Ph.D. Telephone: (651) 733-5180 Telefax: (651) 733-1773 Andrew M. Seacat, Ph.D. Telephone: (651) 575-3161 Telefax: (651)733-1773 003712 418-011 P AG E C-2 Protocol 418-011 Page 2 REGULATORY CITATIONS: U.S. Food and Drug Administration (1994). International Conference on Harmonisation; Guideline on detection of toxicity to reproduction for medicinal products. Federal Register, September 22, 1994, Vol. 59, No. 183. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard fo r Safety Studies on Drugs, MHW Ordinance Number 21, March 26,1997. European Economic Community (1989). Council decision on 2 8 July 1989 on the acceptance by the European Econom ic Community o f an O EC D decision/recom - m endation on com pliance with principles o f good laboratory practice. Official Journal of the European Communities: Legislation. 32(No. L 315; 28 October): 1-17. REGULATORY COMPLIANCE: This study will be conducted in compliance with the Good Laboratory Practice (GLP) regulations cited above. All changes or revisions of this protocol shall be documented, signed by the Study Director and the Sponsor, dated and maintained with the protocol. The Quality Assurance Unit (QAU) will audit the protocol, the raw data and the report, and will inspect critical phases of the study in accordance with the Standard Operating Procedures of Argus Research Laboratories, Inc. The final report will include a statement signed by the Study Director that the report accurately reflects the raw data obtained during the performance of the study and that all applicable GLP regulations were followed in the conduct of the study. Should significant deviations from GLP regulations occur, each will be described in detail, together with how the deviation might affect the quality or integrity of the study. SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE: See ATTACHMENT 1 to the protocol. 003713 418-011: PAGE C-3 Protocol 418-011 Page 3 TEST ARTICLE AND VEHICLE: Identification: Test Article: Name: Physical Description: Lot/Batch Number Specific Gravity: Purity: Expiration Date: N-EtFOSE. Waxy solid. FM-3929 (30035, 30037, 30039). -1.7. 99.1%: May, 2000. Information on the identity, composition, strength and purity of the test article is on file with the Sponsor. Vehicle: 2% Tween 80 in Reverse Osmosis Membrane Processed Deionized Water (R.O. Deionized Water). Supplier and lot identification of Tween 80 will be documented in the raw data. Neither the Sponsor nor the Study Director is aware of any potential contaminants likely to be present in the vehicle that would interfere with the results of this study. Therefore, no analyses other than those mentioned in this protocol will be conducted. Safety Precautions: Gloves, mask, appropriate eye protection and a uniform/lab coat are to be worn during formulation preparation and administration. The Material Safety Data Sheet (MSDS) is attached to the protocol (see ATTACHMENT 2). Storage: Bulk Test Article: Vehicle Components: Prepared Vehicle: Prepared Formulations: Room Temperature. Room Temperature. Room Temperature. Refrigerated (samples to be frozen). All test article shipments to the Testing Facility should be addressed to the attention of Julian Gulbinski, Manager of Formulations, at the previously cited address and telephone number. Shipments should include information concerning storage conditions and shipping cartons should be labeled appropriately. The recipient should be notified in advance of shipment. 003714 418-011: PAGE C-4 Protocol 418-011 Page 4 FORMULATION: Frequency of Preparation: Formulations suspensions will be prepared weekly at the Testing Facility. Detailed preparation procedures are attached to this protocol (ATTACHMENT 3). Adjustment for Puritv: The test article will be considered 100% pure for the purpose of dosage calculations. Testing Facility Reserve Samples: The Testing Facility will reserve a sample (1 g) of each lot of bulk test article used during the course of this study. The Testing Facility will reserve a sample (5 mi) of each lot of vehicle components used during the course of the study. Samples will be stored under the previously cited conditions. ANALYSES: Samples additional to those described below may be taken if deemed necessary during the course of the study. Bulk Test Article Sampling: No analyses of the bulk test article will be conducted during the course of this study. Information on the stability of the bulk test article is on file with the Sponsor. Analyses of Prepared Formulations: At the request of the Sponsor, no analyses of prepared test article formulations will be conducted during the course of the study. Homogeneity and stability information is on file with the Sponsor. However, records will be maintained to document how the test article formulations were prepared. Concentration of Test Article Formulations: Concentration of the prepared formulations will be verified during the course of this study. Duplicate samples (2 mL each) will be taken from the first and last preparation on the day prepared. One sample of each set will be shipped for analysis; the remaining samples will be retained at the Testing Facility as backup samples. Backup samples will be stored under the previously cited conditions and discarded at the Testing Facility upon request of the Sponsor. 003*715 418-011 .PAGE C-5 Protocol 418-011 Page 5 Shipping Instructions: Samples to be analyzed will be shipped (frozen on dry ice) to: Kris J. Hansen, Ph.D. 3M Environmental Technology and Safety Services 935 Bush Avenue Building 2-3E-09 St. Paul, Minnesota 55133-3331 Telephone: (612)778-6018 Telefax: (612) 778-6176 The recipient will be notified in advance of sample shipment. D IS P O S IT IO N : Prepared formulations will be discarded at the Testing Facility. All remaining bulk test article will be returned to the Study Monitor at the previously cited address. TEST SYSTEM: Species/Strain and Reason for Selection: The Crl:CDBR VAF/Plus (Sprague-Dawley) rat was selected as the Test System because: 1) it is one mammalian species accepted and widely used throughout industry for nonclinical studies of developmental toxicity (embryo-fetal toxicity/teratogenicity); 2) this strain has been demonstrated to be sensitive to developmental toxins; 3) historical data and experience exist at the Testing Facility0'3'; and 4) the test article is pharmacologically active in this species and strain. N um ber: Initial population acclimated: 190 virgin female rats. Population selected for study: 125 mated female rats (25 per dosage group). Population assigned to satellite study: Body W eight and Age: 19 mated female rats (five per Groups II and V and three per Groups I, III and IV) assigned to toxicokinetic evaluation. Female rats will be ordered to have body weights of 200 g to 225 g each at receipt, at which time they will be expected to be at least 60 days of age. Actual body weights will be recorded the day after receipt and will be documented in the raw data. The weight range will be included in the final report. 003716 418-011 PAG E C-6 Protocol 418-011 Page 6 Sex: Female rats will be given the test article. Male rats of the same source and strain will be used only as breeders and are not considered part of the Test System. Source: Charles River Laboratories, Inc. The rats will be shipped in filtered cartons by air freight and/or truck from Charles River Laboratories, Inc., to the Testing Facility. Identification: Rats are permanently identified using Monel self-piercing ear tags (Gey Band and Tag Co., Inc., No. MSPT 20101). Male rats are given unique permanent identification numbers upon assignment to the Testing Facility's breeder male rat population. Female rats are assigned temporary numbers at receipt and given unique permanent identification numbers when assigned to the study on the basis of day 0 of presumed gestation body weights. ANIMAL HUSBANDRY: All cage sizes and housing conditions are in compliance with the Guide for the Care and Use o f Laboratory A nim als^. Housing: The rats will be individually housed in stainless steel, wire-bottomed cages except during the cohabitation period. During cohabitation, each pair of rats will be housed in the male rat's cage. No nesting materials will be supplied because the female rats will be sacrificed before parturition is expected. Room Air. Tem perature and Hum idity: The animal room is independently supplied with at least ten changes per hour of 100% fresh air that has been passed through 99.97% HEPA filters (Airo Clean room). Room temperature will be maintained at 64F (18C) to 79F (26C) and monitored constantly. Room humidity will also be monitored constantly and maintained at 30% to 70%. Light An automatically controlled 12-hour light:12-hour dark fluorescent light cycle will be maintained. Each dark period will begin at 1900 hours EST. 003717 418-011: PAGE C-7 Protocol 418-011 Page 7 D ie t Rats will be given Certified Rodent Diet #5002 (PMI Nutrition International) available ad libitum from individual feeders. W ater: Water will be available ad libitum from individual bottles attached to the cages or from an automatic watering access system. All water will be from a local source and passed through a reverse osmosis membrane before use. Chlorine will be added to the processed water as a bacteriostat; processed water is expected to contain no more than 1.2 ppm chlorine at the time of analysis. Water is analyzed monthly for possible bacterial contamination and twice annually for possible chemical contamination. C ontam inants: Neither the Sponsor norths Study Director is aware of any potential contaminants likely to be present in the certified diet or in the drinking water at levels that would interfere with the results of this study. Therefore, no analyses other than those routinely performed by the feed supplier or those mentioned in this protocol will be conducted. RANDOMIZATION AND COHABITATION: Upon arrival, male and female rats will be assigned to individual housing on the basis of computer-generated random units. After acclimation, virgin female rats will be cohabited with breeder male rats, one male rat per female rat. The cohabitation period will consist of a maximum of five days. Female rats with spermatozoa observed in a smear of the vaginal contents and/or a copulatory plug observed in situ will be considered to be at day 0 of presumed gestation and assigned to individual housing. Healthy mated female rats will be assigned to dosage groups based on computergenerated (weight-ordered) randomization procedures. A D M IN IS TR A TIO N : Route and Reason fo r Choice: The oral (gavage) route was selected for use because: 1) in comparison with the dietary route, the exact dosage can be accurately administered; and 2) it is one of the proposed routes for clinical use. Method and Frequency: Female rats will be given the test article once daily on days 6 through 17 of presumed gestation, the period of organogenesis. Dosages will be adjusted for the most recently recorded body weight and given at approximately the same time each day. 003718 418-011 .PAGE C-8 Protocol 418-011 Page 8 Rationale for Dosage Selection: Dosages were selected on the basis of a dosage-range study (Argus Research Laboratories, Inc., Protocol 418-011P) that tested 0,1, 5,10,25 and 35 mg/kg/day. In that study, body weight gain was decreased at 10 mg/kg/day and higher dosages, and feed consumption values were reduced at all dosages tested. Dosage Levels. Concentrations and Volumes: Dosage Group 1 II III IV V Number of Rats 25 + 3* 25 + 5* 25 + 3* 25 + 3* 25 + 5* Dosage (m g/kg/day) 0 (Vehicle) 1 5 10 20 C o n cen tratio n (m g/m L) 0 0 .2 1 2 4 Dosage Volum e (m L/kg) 5 5 5 5 5 Argus Batch Number B-418-01 l-A (D ay.M onth.Year) B-418-011 -B(Day.M onth.Year) B-418-011-B(Day.M onth.Tear) B-418-01 l-C (D ay.M onth.Year) B-418-01 l-D (D ay.M onth.Year) The test article will be considered 100% pure for the purpose of dosage calculations. *. Rats assigned to the satellite group for blood collection. TESTS. ANALYSES AND MEASUREMENTS: Viability: All Periods: At least twice daily. Clinical Observations and/or General Appearance: Acclimation Period: Weekly. Predosage Period: Day 0 of presumed gestation. Dosage Period: Twice daily. Prior to dosage administration and once approximately one hour postdosage. Postdosage Period: Once daily. Clinical observations may be recorded more frequently than cited above, if deemed appropriate by the Study Director and/or Study Monitor. Body Weights: Acclimation Period: Weekly. Predosage Period: Day 0 and 4 of presumed gestation. 003719 418-011:PAGE C-9 Protocol 418-011 Page 9 Dosage Period: Daily. Postdosage Period: Daily. Feed Consumption Values (recorded and tabulated): Predosage Period: Day 0 and 4 of presumed gestation. Dosage Period: Days 6, 8,10,12,14 and 16 of presumed gestation. Postdosage Period: Days 18 and 20 of presumed gestation. Feed consumption values may be recorded more frequently if it is necessary to replenish the feed. These intervals will not be tabulated. Mating Performance: Mating will be evaluated daily during the cohabitation period and confirmed by observation of spermatozoa in a smear of the vaginal contents and/or a copulatory plug observed in situ. Caesarean-Sectioning Observations: Rats will be Caesarean-sectioned on day 20 of presumed gestation. The fetuses will be removed from the uterus and placed in individual containers. The rats will be examined for number and distribution of: Corpora Ltea. Implantation Sites. [Placentae appearance (size, color or shape if abnormal) will be noted in the raw data]. Live and Dead Fetuses. (A live fetus is defined as one that responds to stimuli; a dead fetus is defined as a term fetus that does not respond to stimuli and that is not markedly autolyzed; dead fetuses demonstrating marked to extreme autolysis are considered to be late resorptions.) Early and Late Resorptions. (A conceptus is defined as a late resorption if it is grossly evident that organogenesis has occurred; if this is not the case, the conceptus is defined as an early resorption.) 003720 418-011: PAGE C-10 Protocol 418-011 Page 10 Fetal Observations: Gross External Alterations and Sex: Fetuses will be examined for sex and for gross external alterations. Late resorptions and dead fetuses also will be examined for sex and for gross external alterations to the extent possible but such observations will not be included in either data summarization or statistical analyses. Body Weights and Identification: The body weight of each fetus will be recorded. Only body weights of live fetuses will be used to determine litter fetal body weight averages. Fetuses will be tagged with identification noting study number, litter number, uterine distribution and fixative. Soft Tissue Examination: Approximately one-half of the fetuses in each litter will be examined for soft tissue alterations by using an adaptation of Wilson's sectioning technique(S). The fetuses will be initially fixed in Bouin's solution; sections will be retained in alcohol. Skeletal Examination: The remaining fetuses (approximately one-half of the fetuses in each litter) will be examined for skeletal alterations after staining with alizarin red S(6>. The fetuses will be initially fixed in alcohol; skeletal preparations will be retained in glycerin with thymol added as a preservative. Representative photographs of fetal gross, soft tissue and skeletal alterations will be taken. METHOD OF SACRIFICE: Rats will be sacrificed by carbon dioxide asphyxiation. Live fetuses will be sacrificed by an intraperitoneal injection of euthanasia solution (Beuthanasia-D Special, manufactured by Schering-Plough Animal Health). NECROPSY: Gross lesions will be retained in neutral buffered 10% formalin for possible future evaluation (a table of random units will be used to select one control group rat from which all tissues examined at necropsy will be retained, in order to provide control tissues for any possible histopathological evaluations of gross lesions). Unless specifically cited below, ail other tissues will be discarded. 003721 418-011:PAGE C-11 Protocol 418-011 Page 11 Satellite Rats Assigned to Toxicokinetic Sample Collection: On day 18 of presumed gestation (the day following the last dosage), rats assigned to the toxicokinetic evaluation will be sacrificed and the following samples collected. Blood samples (approximately 4 mL per rat) will be collected from the inferior vena cava into serum separator tubes and centrifuged. The resulting serum (approximately 2 mL) will be immediately frozen on dry ice and maintained frozen (-70C) until shipment to the Sponsor for analysis. The liver will be excised, weighed, and a sample section (lateral lobe) will be frozen and retained at -70C until shipment to the Sponsor for analysis. Rats will be Caesarean-sectioned and fetuses will be examined grossly to the extent possible as described above for rats assigned to the main study. Fetuses and placentae will be pooled per litter and retained frozen (-70 C) until shipment to the Sponsor for analysis After completion of sample collection, serum, liver section (lateral lobe), fetal and placental samples will be shipped (frozen on dry ice) to Kris J. Hansen, Ph.D., at the previously cited address for analysis. Both the recipient and the Study Monitor will be notified in advance of sample shipment. Scheduled Sacrifice: On day 20 of presumed gestation, female rats will be Caesarean-sectioned, and a gross necropsy of the thoracic, abdominal and pelvic viscera will be performed. Uteri of apparently nonpregnant rats will be stained with 10% ammonium sulfide to confirm the absence of implantation sites575. Rate Found Dead or Moribund: Rats that die or are sacrificed because of moribund condition, abortion or premature delivery will be examined for the cause of death or moribund condition on the day the observation is made. The rats will be examined for gross lesions. Pregnancy status and uterine contents of female rats will be recorded. Aborted fetuses and/or delivered pups will be examined to the extent possible, using the same methods described for fetuses. Uteri of apparently nonpregnant rats will be stained with 10% ammonium sulfide to confirm the absence of implantation sites575. / 003722 418-011 .PAGE C-12 Protocol 418-011 Page 12 PROPOSED STATISTICAL METHODS**14: Averages and percentages will be calculated. Litter values will be used where appropriate. Additional procedures and/or analyses may be performed, if appropriate. Type of Test* I. Parametric II. Nonparametricb A. Bartlett's Test*" A. Kruskal-Wallis Test (75% ties) Significant at ps0.05 Not Significant Significant at psO.05 Not Significant Nonparametric Analysis of Variance Dunn's Test Significant at p<.0.05 Not Significant B. Fisher's Exact Test (>75% ties) Dunnett's Test III. Test for Proportion Data Variance Test for Homogeneity of the Binomial Distribution a. Statistically significant probabilities are reported as either p<;0.05 or ps0.01. b. Proportion data are not included in this category. c. Used only to analyze data with homogeneity of variance. d. Test for homogeneity of variance. 003723 418-011:PAGE C-13 Protocol 418-011 Page 13 DATA ACQUISITION. VERIFICATION AND STORAGE: Data will be hand- and/or computer-recorded. Records will be reviewed by the Study Director and/or appropriate management personnel within 21 days after generation. All original records will be stored in the archives of the Testing Facility. All original data will be bound and indexed. A copy of all raw data will be supplied to the Sponsor upon request. Preserved tissues will be stored at the Testing Facility at no charge for one year after mailing of the draft final report, after which time the Sponsor will be contacted to determine the disposition of these materials. RECORDS TO BE MAINTAINED: Protocol and Amendments. Test Article, Vehicle and/or Reagent Receipt, Preparation and Use. Animal Acquisition. Randomization Schedules. Mating History. Treatment (if prescribed by Staff Veterinarian). General Comments. Clinical Observations and/or General Appearance. Blood and Tissue Sample Collection, Processing and Shipment. Body Weights. Feed Consumption Values. Caesarean-Sectioning and Fetal Observations. Gross Necropsy Observations. Organ Weights. Photographs (if required). Study Maintenance (room and environmental records). Feed and Water Analyses. Packing and/or Shipment Lists. KEY PERSONNEL: Executive Director of Research: Mildred S. Christian, Ph.D., Fellow, ATS Director of Research: Alan M. Hoberman, Ph.D., DABT Associate Director of Research and Study Director: Raymond G. York, Ph.D., DABT Director of Laboratory Operations: John F. Barnett, B.S. Manager of Study Coordination: Valerie A. Sharper, M.S. Manager of Animal Operations and Member, Institutional Animal Care and Use Committee: Dena C. Lebo, V.M.D. Manager of Regulatory Compliance:. Kathleen A. Moran, M.S. Consultant, Veterinary Pathology:' W. Ray Brown, D.V.M., Ph.D., ACVP 003724 Protocol 418-011 Page 14 FINAL REPORT: A comprehensive draft final report will be prepared on completion of the study and will be finalized following consultation with the Sponsor. The report will include the following: Summary and Conclusion. Experimental Design and Method. Evaluation of Test Results. Appendices: Figures, Summary and Individual Tables Summarizing the Above Data, Protocol and Associated Amendments and Deviations, Study Director's GLP Compliance Statement, Reports of Supporting Data (if appropriate) and QAU Statement. INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE STATEMENT: The procedures described in this protocol have been reviewed by the Testing Facility's Institutional Animal Care and Use Committee. All procedures described in this protocol that involve study animals will be conducted in a manner to avoid or minimize discomfort, distress or pain to the animals. The Sponsor's signature below documents the fact that information concerning the necessity for conducting this study and the fact that this is not an unnecessarily duplicative study may be obtained from the Sponsor. No alternative (in vitro) procedures were available for meeting the stated purposes of the study. REFERENCES: 1. Christian, M.S. and Voytek, P.E. (1982). In Vivo Reproductive and M utagenicity Tests. Environmental Protection Agency, Washington, D.C. National Technical Information Service, U.S. Department of Commerce, Springfield, VA 22161. 2. Christian, M.S. (1984). Reproductive toxicity and teratology evaluations of naltrexone (Proceedings of Naltrexone Symposium, New York Academy of Sciences, November 7, 1983), J. Clin. Psychiat. 45(9):7-10. 3. Lang, P.L. (1988). Em bryo and Fetal Developm ental Toxicity (Teratology) Control D ata in the C harles R iver Cri:CDBR Rat. Charles River Laboratories, Inc., Wilmington, MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.) 4. Institute of Laboratory Animal Resources (1996). Guide for the Care and Use o f Laboratory Anim als. National Academy Press, Washington, D.C. 003725 418-011: PAGE C-15 Protocol 418-011 Page 15 5. Wilson, J.G. (1965). Methods for administering agents and detecting malformations in experimental animals. Teratology: Principles and Techniques (Wilson, J.G. and Warkany, J., eds.), University of Chicago Press, pp. 262-277. 6. Staples, R.E. and Schnell, V.L. (1964). Refinement in rapid clearing technique in the KOH-alizarin red S method for fetal bone. Stain Technol. 39:61-63. 7. Salewski, E. (1964). Frbemethode zum makroskopischen Nachweis von Implantationsstellen am Uterus der Ratte. Arch. Pathol. Exp. Pharmakol. 247:367. 8. Snedecor, G.W. and Cochran, W.G. (1967). Variance test for homogeneity of the binomial distribution. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 240-241. 9. Sokal, R.R. and Rohlf, F.J. (1969). Bartlett's test of homogeneity of variances. Biometry, W.H. Freeman and Co., San Francisco, pp. 370-371. 10. Snedecor, G.W. and Cochran, W.G. (1967). Analysis of Variance. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 258-275. 11. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1129. 12. Sokal, R.R. and Rohlf, F.J. (1969). Kruskal-Wallis Test. Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389. 13. Dunn, O.J. (1964). Multiple comparisons using rank sums. Technometrics 6(3):241-252. 14. Siegel, S. (1956). Nonparam etric Statistics for the Behavioral Sciences, McGraw-Hill, New York, pp. 96-104. 003726 PROTOCOL APPROVAL: FOR THE TESTING FACILITY U -Alan M. Hoberman, Ph.D.,DABT Director of Research 418-011 PAGE C-16 Protocol 418-011 Page 16 7-1 Date -)S Study Director 2 CDena C. Lebo, V.M.D. Member, Institutional Animal Care and Use Committee FOR THE SPONSOR Marvin T. Case, D.V.M., Ph.D. Study Monitor ______ 9? Date 3 Date /Y -fifL 003727 418-011 .PAGE C-17 ATTACHMENT 1 SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE 003728 ATTACHMENT 1 418-011: PAGE C-18 Protocol 418-011 Page 1 of2 STUDY SCHEMATIC DEVELOPMENTAL TOXICITY STUDY 8 Start of Dosage Cohabitation Female Rats Day 7 of Presumed Gestation End of Dosage CaesareanSectioningh Day 17 of Presumed Gestation Day 20 of F'resumed Gestation = Dosage Period a = For additional details see 'Tests, Analyses and Measurements" section of the protocol b = Fetal evaluations (all - external, 1/2 per litter - soft tissue or skeletal) 003729 ATTACHMENT 1 418-011: PAGE C-19 Protocol 418-011 Page 2 of2 SCHEDULE8 11 AUG 98 18 AUG 98 PM - 23 AUG 98 AM 19 AUG 98 23 AUG 98 25 AUG 98-09 SEP 98 08 SEP 9 8 -1 2 SEP 98 02 DEC 98 Arrival Date - Acclimation Begins. Cohabitation Period. First Possible Day 0 of Presumed Gestation. Last Possible Day 0 of Presumed Gestation Dosage Period (Days 6 through 17 of presumed gestation). Caesarean-Sectioning Period (Day 20 of presumed gestation). Draft Final Report. a. The study initiation date is.the date the Study Director signs the protocol. 418-011 .PAGE C-20 ATTACHMENT 2 MATERIAL SAFETY DATA SHEET 003731 418-011 P A G E C-21 MATERIAL SAFETY DATA SHEET 3M 3M Center St. Paul, Minnesota 55144-1000 1-000-364-3577 or (612) 737-6501 N-E+Fosr (24 hours) Copyright, 1998, Minnesota Mining and Manufacturing Company. All rights reserved. Copying and/or downloading of this information for the purpose of properly utilizing 3M products is allowed provided that: 1) the information is copied in full with no changes unless prior agreement is obtained from 3M, and 2) neither the copy nor the original is resold or otherwise distributed with the intention of earning a profit thereon. DIVISION: 3M CHEMICALS TRADE NAME: FC-10 FLUORAD Brand Fluorochemieal Alcohol ID NUMBER/U.P.C.: 98-0211-1113-7 00-51135-09495-2 9B-0211-1183-0 98-0211-1575-7 00-51135-02145-3 98-0211-6620-6 ZF-0002-0572-2 ISSUED: January 29, 1998 SUPERSEDES: November 05, 1997 DOCUMENT: 10-3778-7 00-51135-09542-3 00-51135-10439-2 1. INGREDIENT C.A.S. NO. PERCENT PERFLUOROOCTANESULFONAMIDO ALCOHOL .... PERFLUOROHEXANESULFONAMIDO ALCOHOL .... PERFLUOROHEPTANESULFONAMIDO ALCOHOI---PERFLUOROBUTANESULFONAMIDO ALCOHOL.... PERFLUOROPENTANESULFONAMIDO ALCOHOI____ 1691-99-2 34455-03-3 68555-73-7 34449-89-3 68555-72-6 80.0 3.0 2.0 2.0 1.0 - 90.0 - 7.0 - 6.0 - 6.0 - 3.0 2. PHYSICAL DATA B O I LING POINT:..... VAPOR PRESSURE:.... VAPOR D E N S I T Y : ..... EVAPORATION RATE:... SOLUBILITY IN WATER: S P E C I F I C GRAVITY:... PERCENT VOLATILE:... P H : .................. V I S C O S I T Y : .......... MELTING POINT:...... ca. 118 C 9 1 mm Hg < 1 0 mmHg Calc 9 20 C > 1 . 0 Air=1 Calc 9 20 C. < 1 . 0 Bu 0Ac =1 neglig. ca. 1.7 Water=l (of melt) 0% N/A N/D N/D 003732 418-011: PAGE C-22 MSOS: FC-10 FLUORAD Brand Flporochemical Alcohol January 29, 1998 PAGE 2 2. PHYSICAL DATA (continued) APPEARANCE AND ODOR: Amber waxy solid 3. FIRE AND EXPLOSION HAZARD DATA FLASH POINT:........... FLAMMABLE LIMITS - LEL: ....... FLAMMABLE LIMITS - UEL: AUTOIGNITION TEMPERATURE:..... N/A N/A EXTINGUISHING MEDIA: Water, Carbon dioxide, Dry chemical, Foam SPECIAL FIRE FIGHTING PROCEDURES: Wear full protective clothing, including helmet, self-contained, positive pressure or pressure demand breathing apparatus, bunker coat and pants, bands around arms, waist and legs, face mask, and protective covering for exposed areas of the head. UNUSUAL FIRE AND EXPLOSION HAZARDS: See Hazardous Decomposition section for products of combustion. 4. REACTIVITY DATA STABILITY: Stable INCOMPATIBILITY - MATERIALS/CONDITIONS TO AVOID: Not applicable. HAZARDOUS POLYMERIZATION: Hazardous polymerization will not occur. HAZARDOUS DECOMPOSITION PRODUCTS: Carbon Monoxide and Carbon Dioxide, Oxides of Nitrogen, Oxides of Sulfur, Hydrogen Fluoride, Toxic Vapors, Gases or Particulates. 5. ENVIRONMENTAL INFORMATION SPILL RESPONSE: Refer to other sections of this MSDS for information regarding physical and health hazards, respiratory protection, ventilation, and 0 0 3 7 * 3 3 personal protective equipment. Collect spilled material. Clean up residue. Place in a U.S. DOT-approved container. MSOS: FC-10 FLUORAD Brand Fluorochemical Alcohol January 29, 1998 ' 418-011: PAGE C-23 PAGE 3 5. ENVIRONMENTAL INFORMATION (continued) RECOMMENDED DISPOSAL: Incinerate in a permitted hazardous waste incinerator in the presence o f a combustible material. Combustion products will include HF. Dispose of waste product in a facility permitted to accept chemical waste. ENVIRONMENTAL DATA: Laboratory tests showed no biodegradation. 96-Hr. LD50 Fathead Minnow (Pimephales promelas) No mortality at water saturation. No statistically significant effect on % hatch, H survival, weight, and length in 30 day Fathead Minnow egg fry study. Lab tests showed 200 fold bioconcentration of FC-10 into muscle fillets of channel catfish. REGULATORY INFORMATION: Volatile Organic Compounds: N/A. VOC Less H20 & Exempt Solvents: N/A. This product complies with the chemical registration requirements of TSCA, EINECS, CDSL, AICS and Korea. EPCRA HAZARD CLASS: FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: Yes 6. SUGGESTED FIRST AID EYE CONTACT: Immediately flush eyes with large amounts of water. Get immediate medical attention. SKIN CONTACT: Immediately wash skin with soap and large amounts of water. Remove contaminated clothing. If signs/symptoms occur, call a physician. Hash contaminated clothing before reuse and dispose of contaminated shoes. INHALATION: If signs/symptoms occur, remove person to fresh air. If signs/symptoms continue, call a physician. IF SHALLOWED: Call a physician IMMEDIATELY If swallowed, induce vomiting immediately as directed by medical personnel. Never give anything by mouth to an unconscious person. 003734 MSDS: FC-10 FLUORAD Brand Fluorochemical Alcohol January 29, 1998 418-011: PAGE C-24 PAGE 4 7. PRECAUTIONARY INFORMATION EYE PROTECTION: Avoid eye contact. Wear safety glasses with side shields. SKIN PROTECTION: Avoid skin contact. Wear appropriate gloves when handling this material. A pair of gloves made from the following materialis) are recommended: butyl rubber. Use one or more of the following personal protection items as necessary to prevent skin contact: coveralls. RECOMMENDED VENTILATION: Use with appropriate local exhaust ventilation. Provide sufficient ventilation to maintain emissions below recommended exposure limits. If exhaust ventilation is not adequate, use appropriate respiratory protection. RESPIRATORY PROTECTION: Avoid breathing of airborne material. Select one of the following NIOSH approved respirators based on airborne concentration of contaminants and in accordance with OSHA regulations: half-mask dust respirator, full-face supplied air respirator. PREVENTION OF ACCIDENTAL INGESTION: Do not eat, drink or smoke when using this product. Wash exposed areas thoroughly with soap and water. Wash hands after handling and before eating. RECOMMENDED STORAGE: Store away from heat. Keep container closed when not in use. FIRE AND EXPLOSION AVOIDANCE: Nonflammable. OTHER PRECAUTIONARY INFORMATION: No smoking: Smoking while using this product can result in contamination of the tobacco and/or smoke and lead to the formation of the hazardous decomposition products mentioned in section 4 of this MSDS. HMIS HAZARD RATINGS: HEALTH: 1 FLAMMABILITY: 1 REACTIVITY: 0 PERSONAL PROTECTION: X (See precautions, section 7.) INGREDIENT EXPOSURE LIMITS VALUE UNIT 003735 TYPE AUTH SKIN PERFLUOROOCTANESULFONAMIDO ALCOHOL... 0.1 MG/M3 . TWA 3M PERFLUOROHEXANESULFONAMIDO ALCOHOL... 0.1 MG/M3 TWA 3M PERFLUOROHEPTANESULFONAMIDO A L C O H O L .............................. 0.1 MG/M3 TWA 3M Y Y Y 418-011 .PAGE C-25 MSDS: FC-10 FLUORAD Brand Fluorochemical Alcohol January 29, 1998 PAGE 5 EXPOSURE LIMITS (continued) INGREDIENT VALUE UNIT TYPE AUTH SKIN PERFLUOROBUTANESULFONAMIDO ALCOHOL. PERFLUOROPENTANESULFONAMIDO A L C O H O L ........................... 0.1 MG/M3 MG/M3 TWA 3M TWA 3M Y Y * SKIN NOTATION: Listed substances indicated with 'Y' under SKIN refer to the potential contribution to the overall exposure by the cutaneous route including mucous membrane and eye, either by airborne or, more particularly, by direct contact with the substance. Vehicles can alter skin absorption. SOURCE OF EXPOSURE LIMIT DATA: - 3M: 3M Recommended Exposure Guidelines 8. HEALTH HAZARD DATA EYE CONTACT: No adverse health effects are expected from eye contact. SKIN CONTACT: Product is not expected to be irritating to the skin. May be absorbed through the skin and persist in the body for an extended time. INHALATION: May be absorbed by inhalation and persist in the body for an extended time. IF SWALLOWED: Ingestion is not a likely route of exposure to this product. Illness may occur after a single swallowing of relatively large quantities of this material. MUTAGENICITY: Not mutagenic in in-vitro assays. REPRODUCTIVE/DEVELOPMENTAL TOXINS: Substance was not teratogenic in the rat at doses as high as 30 milligrams per kilogram per day via oral route. OTHER HEALTH HAZARD INFORMATION: This product is not known to contain any substances regulated under California Proposition 65. A Product Toxicity Summary Sheet is available. 00 3*736 418-011: PAGE C-26 MSDS: FC-10 FLUORAD Brand Fluorochenical Alcohol January 29, 1998 " PAGE 6 SECTION CHANGE DATES HEADING SECTION CHANGED SINCE November 05, 1997 ISSUE Abbreviations: N/D Not Determined N/A - Not Applicable CA Approximately T h e information in this Material Safety Data Sheet (MSDS) is believed to be correct as of the date issued. 3M MAKES NO WARRANTIES, EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR COURSE OF PERFORMANCE OR USAGE OF TRADE. User is responsible for determining whether the 3M product is fit for a particular purpose and suitable for user's method of use or application. Given the variety of factors that can affect the use and application of a 3M product, some of which are uniquely within the user's knowledge and control, it is essential that t h e user evaluate the 3M product to determine whether it is fit for a particular purpose and suitable for user's method of use or application. 3 M provides information in electronic form as a service to its customers. Du e to the remote possibility that electronic transfer, may have resulted i n errors, omissions or alterations in this information, 3M makes no representations as to its completeness or accuracy. In addition, information obtained from a database may not be as current as the infnrmatinn -in tho Msns available directlv from 3 M . 418-011: PAGE C-27 ATTACHMENT 3 TEST ARTICLE PREPARATION PROCEDURE 003738 418-011: PAGE C-28 ATTACHMENT 3 Protocol 418-011 Version: 418-011 (28 JUL 98) Page 1 of3 TEST ARTICLE AND CONTROL ARTICLE PREPARATION PROCEDURE Test Article: N-EtFOSE Vehicle: 2% Tween 80, in R.O. Water A. Purpose: The purpose of this procedure is to provide a method for the preparation of dosage suspensions of N-EtFOSE and the control article for oral administration to rats on Argus Study 418-011. B. General Information: 1. All suspension containers will be labeled and color coded. Each label will specify the protocol number, test article identification, Argus batch number, concentration, dosage level, preparation date, expiration date and storage conditions. 2a. Suspensions will be prepared: __ Daily X Weekly For___ days of use 2b. Vehicle will be prepared: __ Daily X Weekly For___ days of use 3. Suspensions will be prepared at a final dosage volume of 5 mL/kg. 4. Safety: X Gloves, lab coat, goggles or safety glasses and faceshield X Dust-Mist Respirator __ Half-Face Respirator _. Full-Face Respirator/Positive Pressure Hood __ Tyvek Suit/Apron 5. Dosage suspensions adjusted for Free base and % Purity. __ Yes X No (Calculations based on 100%) ___ Free Base ' Purity 6. Sampling requirements: Cited in protocol. 7. Storage: Cited in protocol. 003739 ATTACHMENT 3 Protocol 418-011 Version: 418-011 (28 JUL98) Page 2 of3 TEST ARTICLE AND CONTROL ARTICLE PREPARATION PROCEDURE NOTE: Test article will be prepared as a serial dilution from the high dosage to the low dosage. Once the final volumes are achieved, stir bars are to be added to the containers; mixing should occur during sampling and/or administration. C. Preparation of Vehicle 1. Add the required amount of R.O. deionized water to an appropriately labeled container. Heat the water to 50 5C, add the required amount of Tween 80 and mix until uniform (See TEST ARTICLE CALCULATIONS). D. Test Article Suspension Preparation: 1. To prepare the 4.0-mg/mL, Group V suspension, add the required amount of test article (See TEST ARTICLE CALCULATIONS) into an appropriately sized, labeled container. Add the required amount of vehicle and heat the mixture to 80 5C for approximately 30 minutes. 2. Once the test article has dissolved; spin over night while the solution cools. (Be sure there is a visible vortex, this will achieve the desired emulsion.) 3. To prepare the 2.0-mg/mL, Group IV suspension, remove the required amount of stock suspension (Group V) (See TEST ARTICLE CALCULATIONS), add the required amount of vehicle and mix. 4. To prepare the 1.0-mg/mL, Group III suspension, remove the required amount of stock suspension (Group IV) (See TEST ARTICLE CALCULATIONS), add the required amount of vehicle and mix. 003740 418-011: PAGE C-30 ATTACHMENT 3 Protocol 418-011 Version: 418-011 (28 JUL 98) Page 3 of3 TEST ARTICLE AND CONTROL ARTICLE PREPARATION PROCEDURE 5. To prepare the 0.2-mg/mL, Group II suspension, remove the required amount of stock suspension (Group III) (See TEST ARTICLE CALCULATIONS), add the required amount of vehicle and mix. Written by: _ Approved by !2 l Date: Clarification: (See attached clarification form.) Initials/Date : jJC Q oea?4i 418-011: PAGE C-31 O P r im e d ic a Argus Research Laboratories, Inc. 905 Sheehy Drive, Building A Horsham, PA 19044 Telephone: (215) 443-8710 Telefax: (215) 443-8587 PROTOCOL 418-011 ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS SPONSOR'S STUDY NUMBER: T-6316.7 Amendment 1-12 August 1998 1. Frequency of Preparation (page 4 and page 1 of Attachment 3 to the protocol): Formulations (suspensions) will be prepared daily at the Testing Facility, rather than weekly. Reason for Change: This chapge corrects the protocol. flan Hoberman, Ph.D., DABT Date >nd G. York Director of Research Associate Director Study Director _.C--- ______ a /-__________________________________ Dena C. Lebo, V.M.D. Date Marvin T. Case, D.V.M., Ph.D. Member, Institutional Animal Care and Study Monitor Use Committee Date O P r im e d ic a 418-011 PAG E C-32 A rgus Research Laboratories, Inc. 9 0 5 Sheehy Drive, Building A Horsham, PA 19044 Telephone: (215) 4 43 -8 71 0 Telefax: (215) 443 -8 58 7 PROTOCOL 418-011 ORAL (GAVAGE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RATS SPONSOR'S STUDY NUMBER: T-6316.7 Amendment 2 - 1 1 December 1998 1. Sponsor (page 1 of the protocol): The Sponsor is 3M Corporate Toxicology, rather than 3M Toxicology Services. Reason for Change: This change was made at the request of the Sponsor. 2. Species/Strain and Reason for Selection (page 5 of the protocol): The test article is biologically active, rather than pharmacologically active in this strain. Reason for Change: This change was made at the request of the Sponsor to correct the protocol. 3. Route and Reason for Choice (page 7 of the protocol): The oral (gavage) route is a possible route of human exposure, rather than the one proposed for clinical use. 003743 418-011: PAGE C-33 Amendment 2 Protocol 418-011 Page 2 Reason for Change: This change was made at the request of the Sponsor to correct the protocol. n -D fc ^ r? Hoberman, Ph.D., DABT Date Director of Research Rar yvmond G. York, Associate Director Study Director H -b tC -'ft ., DABT search Date Dena C. Lebo, V.M.D. Date Member, Institutional Animal Care and Use Committee __ __________________________ Marvin T. Case, D.V.M., Ph.D. Study Monitor Date 03744 APPENDIX D DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY 003745 418-011 P A G E D-1 DEVIATIONS FROM THE PROTOCOL AND STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY 1. 26 AUG 98 (Day 4 of presumed gestation): Clinical observations and body weights were not recorded for the following rats: Dosage Group I II III IV V Dosage (mg/kg/day) 0 (Vehicle) 1 5 10 20 Assigned Numbers 12814-12816 12839 -12847 12864-12872 12883-12897 12912-12922 This deviation did not adversely affect the outcome of the study because it occurred before initiation of the dosage period and represents a small loss of data across all dosage groups. All deviations are documented in the raw data. id G7York, Ph Asso Director of and Study Director Date 003746 APPENDIX E TEMPERATURE AND RELATIVE HUMIDITY REPORTS ARGUS 418-011 P A G E E-1 Temperature and Relative Humidity Report Location: Room 04 Protocol Number: 418-011 Range of Dates: 11-Aug-1998 13:45 to 12-Sep-1998 10:26 Target Range: Species: Rat Total Num ber o f Days: Total Num ber o f Hours: Total N um ber o f Data Points: Tem perature 64F to 79F 33 764.49 766 Relative Hum idity 30% to 70% 33 764.49 766 Mean ( SD): M ax im u m : M ed ia n : Minim um : N um ber o f Points in Range (%): N um ber o f Points H igh (%): N um ber o f Points L o w (%): 69.3 70.2 69.3 67.7 766 0 0 ( 0.4) (100.0) (0.0) (0.0) 47.7 54.1 47.7 41.3 766 0 0 ( 2.4) (100.0) (0.0) (0.0) Report Generated: 23-Oct-1998 at 09:15 COMMENTS: REVIEW ED BY: T DATE: C um ulative by Location (v04.01.97) 003748 APPENDIX F PILOT REPORT 0037m