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Z&H3- OZOO- 3 7 3 A R T&r-0667 ' j S3 * 'i r j , . FINAL REPORT PROTOCOL 418-010 ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RABBITS \, , SPONSOR'S STUDY NUMBER: 6316.8 FINAL REPORT DATE: 11 JANUARY 1999 00 auG2 1 filHu 000811804M o o D a iia o H fl 003S63 r PROTOCOL 418-010 ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RABBITS SPONSOR'S STUDY NUMBER: 6316.8 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 A.7. Regulatory Compliance A.8. Ownership of the Study A.9. Study Monitor 003864 ii PAGE 1-1 1-1 I-2 I-3 11-1 11-1 11-1 11-1 11-1 11-1 11-1 11-1 11-1 II-2 II-2 SUBJECT D.2. Analytical Results 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. Method of Randomization E.8. System of Identification F. Husbandry F.1. Research Facility Registration F.2. Study Rooms F.3. Housing F.4. Lighting F.5. Sanitization F.6. Feed F.7. Feed Analysis F.8. Water F.9. W ater Analysis G. Methods G.1. Dosage Administration 03 86 S IV PAGE 11-5 11-5 11-5 11-5 11-5 11-5 11-6 11-6 11-6 11-6 11-7 11-7 11-7 11-7 11-7 11-7 11-7 11-7 11-8 11-8 11-8 11-8 SUBJECT 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, Abortions, Clinical and Necropsy Observations A.1. Mortality A.2. Abortions A. 3. Clinical Observations A.4. Necropsy Observations B. Maternal Body W eights and Body W eight 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 E.3. Fetal Soft Tissue Alterations E.4. Fetal Skeletal Alterations 003866 PAGE II-8 II-9 II-9 II-9 II-9 11-10 11-10 11-12 111-1 111-1 111-1 111-1 III-3 III-4 III-4 MI-4 MI-5 MI-5 MI-5 MI-6 MI-6 ill-8 SUBJECT F. Satellite Rabbits REFERENCES APPENDIX A - REPORT FIGURE Figure 1. Maternal Body W eights APPENDIX B - REPORT TABLES Table 1. Clinical Observations - Summary Table 2. Uterine Contents and Litter Data for Rabbits that Died or Aborted Table 3. Necropsy Observations - Summary Table 4. Maternal Body W eights - Summary Table 5. Maternal Body W eight Changes - Summary Table 6. Maternal Absolute Feed Consumption Values (g/day) - Summary Table 7. Maternal Relative Feed Consumption Values (g/kg/day) - Summary Table 8. Caesarean-Sectioning Observations - Summary Table 9. Litter Observations (Caesarean-Delivered Fetuses) - Summary Table 10. Fetal Alterations - Summary Table 11. Fetal Gross External Alterations - Summary Table 12. Fetal Soft Tissue Alterations - Summary Table 13. Fetal Skeletal Alterations - Summary Table 14. Fetal Ossification Sites - Caesarean-Delivered Live Fetuses (Day 29 of Gestation) - Summary Table 15. Clinical Observations - Individual Data 003867 PAGE 111-10 111-12 A-1 B-1 B-3 B-5 B-6 B-8 B-9 B-1.0 B-11 B-12 B-13 B-14 B-15 B-17 B-22 B-23 SUBJECT PAGE Table 16. Necropsy Observations - Individual Data B-35 Table 17. Maternal Body W eights - Individual Data B-41 Table 18. Maternal Feed Consumption Values Individual Data B-56 Table 19. Caesarean-Sectioning Observations Individual Data B-71 Table 20. Litter Observations (Caesarean-Delivered Fetuses) - Individual Data B-77 Table 21. Fetal Sex, Vital Status and Body W eight Individual Data B-83 Table 22. Fetal Alterations - Individual Data B-95 APPENDIX C: - PROTOCOL AND AMENDMENT C-1 to C-31 APPENDIX Cl - DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY D-1 APPENDIX E; - TEMPERATURE AND RELATIVE HUMIDITY REPORTS AND DEVIATIONS REPORT E-1 to E-4 APPENDIX F - PILOT REPORT F-1 to F-98 APPENDIX G - HISTORICAL CONTROL DATA G-1 to G-15 APPENDIX HI - STATEMENT OF THE STUDY DIRECTOR H-1 APPENDIX I - QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT 1-1 to I-4 0038G8 VII 418-010:PAGE 1-1 TITLE: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RABBITS ARGUS RESEARCH LABORATORIES, INC. PROTOCOL NUMBER: 418-010 SPONSOR'S STUDY NUMBER: 6316.8 I. SUMMARY AND CONCLUSION A. Methods* Twenty-two New Zealand White [Hra:(NZW)SPF] timed-pregnant female rabbits were assigned to each of five dosage groups (Groups I through V). Nineteen additional female rabbits were assigned to one of five dosage groups for the satellite study (three, five, three, three and five rabbits assigned to Groups I through V, respectively). The test article, N-EtFOSE, or vehicle, 2% Tween 80 in Reverse Osmosis Membrane Processed Deionized W ater (R.O. Deionized Water), was administered orally (via stomach tube) once daily to these naturallybred rabbits on days 7 through 20 of presumed gestation (DGs 7 through 20). Dosages of 0 (Vehicle), 0.1, 1.0, 2.5 and 3.75 mg/kg/day were administered at a dosage volume of 5 mL/kg, adjusted daily on the basis of the individual body weights. The female rabbits were observed for viability at least twice each day of the study. The rabbits were also examined for clinical observations of effects of the test article, abortions, premature deliveries and deaths before and approximately 60 minutes after dosage and once daily during the postdosage period. Body weights were recorded on DG 0, the day of arrival at the Testing Facility and on DGs 7 through 29. Feed consumption values were recorded daily after arrival at the Testing Facility. On DG 21, toxicokinetic samples were collected from the satellite rabbits assigned to the toxicokinetic evaluation. Blood samples were collected from the inferior vena cava and centrifuged. The resulting serum was shipped to the a. Detailed descriptions of all procedures used in the conduct of this study are provided in the appropriate sections o f this report and in APPENDIX C (PROTOCOL AND AMENDMENT). 003869 418-010:PAGE I-2 Sponsor for analysis. The liver was excised, weighed and a sample was taken from the right lateral lobe and shipped to the Sponsor for analysis. Rabbits were Caesarean-sectioned and fetuses were examined grossly to the extent possible as described for rabbits assigned to the main study. Fetuses and placentae were pooled by litter shipped to the Sponsor for analysis. On DG 29, rabbits in the main study were sacrificed, Caesarean-sectioned 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 was excised and examined for pregnancy, number and distribution of implantations, early and late resorptions and live and dead fetuses. Each fetus was identified, weighed and examined for gross external alterations. All fetuses were examined internally to identify sex and visceral alterations; cavitated organs were evaluated by dissection; and the brain was cross-sectioned and examined in situ. All fetuses were examined for skeletal alterations after staining with alizarin red S. B. Results No compound-related deaths occurred during the study. One, two and five does aborted and were sacrificed in the 0 (Vehicle), 2.5 and 3.75 m g/kg/day dosage groups, respectively. These abortions occurred at the end of or after the completion of the dosing period. The abortions in the 2.5 and 3.75 mg/kg/day dosage groups were considered related to the test article because they occurred at dosage-dependent incidences in the two highest dosage groups. All other rabbits survived until scheduled sacrifice on gestation day 29 (DG 29). Increased numbers of does in the 0.1, 1.0, 2.5 and 3.75 mg/kg/day dosage groups had observations of abnormal stool (no, scant, and soft or liquid feces). All other adverse clinical observations were considered unrelated to the test article. One 3.75 mg/kg/day dosage doe had a pale liver that was considered possibly related to the test article because it occurred in a high dosage group. Groups administered the 1.0, 2.5 and 3.75 mg/kg/day dosages o f the test article had statistically significant reductions in body weight gain or body weight losses on DGs 7 to 10 and 10 to 13. Reflecting these effects of the test article, body weight gains were significantly reduced in the 2.5 and 3.75 mg/kg/day dosage groups for the entire dosage period. The 2.5 and 3.75 mg/kg/day dosage groups had significantly reduced body weights on DGs 14 through 25. 003870 418-010:PAGE I-3 Absolute and relative feed consumption values were significantly reduced at several tabulated intervals during the dosage period in the 2.5 and/or 3.75 mg/kg/day dosage groups. Reflecting these effects of the test article, the 3.75 mg/kg/day dosage group had significantly reduced absolute and relative feed consumption values for the entire dosage period. The litter averages for late resorptions were increased in the 2.5 and 3.75 mg/kg/day dosage groups. These increases in the number o f late resorptions were considered treatment-related because they occurred at the two highest dosages. No gross external, soft tissue or skeletal fetal alterations (malformations or variations) were caused by dosages of the test article as high as 3.75 mg/kg/day. C. Conclusion On the basis of these data, the maternal no-observable-effect-level (NOEL) of N-EtFOSE is 0.1 mg/kg/day (the 1.0 mg/kg/day and higher dosages caused statistically significant reductions in body w eight gains or w eight losses and the 2.5 and 3.75 mg/kg/day dosages also significantly reduced absolute and relative feed consum ption values). The developmental NOEL is 1.0 mg/kg/day (the 2.5 and 3.75 mg/kg/day dosages caused increased incidences of late resorptions and abortions). Based on these data, N-EtFOSE should not be identified as a selective developmental toxicant; the compound was not found to be teratogenic in the rabbit. /bT)W J Mildred S. Christian, Ph.D., Fellow, ATS Executive Director o f Research Date Q- ------------------------- Alan M. Hoberman, Ph.D., DABT Director of Research ! /-720as/ / Date ka iyh o n d G. Y o((, p|h.D,, DABT Associate Director-dr Research and Study Director 003871 Date 418-010: PAGE 11-1 II. DESCRIPTION OF TEST PROCEDURES A. Conduct of Study: A.1. Sponsor: 3M Corporate Toxicology, 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: 418-010 A.4. Sponsor's Study Number: 6316.8 A.5. Purpose of the Study: The purpose of this study was to detect adverse effects of N-EtFOSE on New Zealand White [Hra:(NZW)SPF] presumed pregnant female rabbits and development of the embryo and fetus consequent to exposure of the doe from implantation to closure of the hard palate. This study was designed to evaluate ICH Harmonised Tripartite Guideline stages C and D of the reproductive process in a nonrodent species. A.6. Study Design: The requirements of the International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline05 were used as the basis for 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 deviations from the GLP regulations that affected the quality of integrity of the study. Quality Assurance Unit findings derived from the 003872 418-010:PAGE II-2 inspections during the conduct of this study are documented 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) Joseph W. Lech, B.S. (Team Leader - General Laboratory) Betsy J. Kerns, B.S. (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. (Report Administrator) 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: 11 August 1998 003873 418-010:PAGE II-3 A.16. Dates o f Technical Perform ance: Rabbit Arrival Date Dosage Period [Days 7 through 20 of presumed gestation (DGs 7 through 20)] Toxicokinetic Sample Collection (DG 21) Caesarean-Sectioning Period (DG 29) 28 AUG 98 30 AUG 9 8 -1 6 SEP 98 17 SEP 98 21 SEP 9 8 - 2 5 SEP 98 A . 17. R ecords M aintained: The original report, raw data and reserve samples of the test article and vehicle are retained in the archives of Argus Research Laboratories, Inc. A ny 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. All unused test article suspensions were discarded at the Testing Facility. Unused bulk test article will be returned to the Study Monitor upon completion o f all work with the test article. B. Test A rticle Inform ation: B.1. D e scrip tio n : N-EtFOSE - a waxy solid B.2. Lot/B atch N um ber: FM-3929 [30035, 30037, 30039 (Expiration date: May 2000)] B.3. Date Received and Storage C on dition s: The test article was received on 20 May 1998, and stored at room temperature. B.4. Special H andling In s tru c tio n s : 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 suspensions. B.5. A nalysis o f P u ritv: Information regarding the identity, composition, strength, purity and stability of the test article is on file with the Sponsor. 003874 418-010:PAGE II-4 C. Vehicle Information: C.1. Description: 2% Tween 80 in Reverse Osmosis Membrane Processed Deionized W ater (R.O. Deionized Water). C.2. Lot Numbers: M03H05 and L06662 C.3. Date Received and Storage Conditions: The Tween 80 was received on 22 May 1998 and 8 July 1998 (lot M03H05) and 1 September 1998 (lot L06662), from J.T. Baker, Phillipsburg, New Jersey, and stored at room temperature. R.O. Deionized W ater 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 o f 0, 0.02, 0.2, 0.5 and 0.75 mg/mL. Prepared formulations were stored at room temperature. 003S75 418-010:PAGE II-5 D.1. Sam ple In fo rm a tio n : Sample Type Components Concentration (all levels) Bulk Test Article Reserve Vehicle Reserve N/A N/A Tween 80 (lot M03H05) Tween 80 (lot L06662) R.O. Deionized Water Size 2 mL` 19 5 mL 5 mL 5 mL Date Retained 30 AUG 98" 16 SEP 98c 03 SEP 98 Storage Conditions Frozen (dry ice) Room temperature 03 SEP 98 Room temperature 09 SEP 98 Room temperature 03 SEP 98 Room temperature Shipped To Sponsor Testing Facility Archives Testing Facility Archives Testing Facility Archives Testing Facility Archives Date Shipped 31 AUG 98 16 SEP 98 01 OCT 98 01 OCT 98 01 OCT 98 01 OCT 98 N/A = Not applicable 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 backups. b. First preparation. c. Last preparation. Homogeneity and stability of prepared formulations are on file with the Sponsor. D. 2. A n a lytica l R esu lts: Concentration samples (2 mL) were taken on the first and last days suspensions were prepared. Analyses were performed by 3M Environmental Technology and Safety Services. The results of these analyses have not yet been forwarded to the Testing Facility. E. Test S ystem : E.1. S pecies: Rabbit E.2. S tra in : New Zealand White [Hra:(NZW)SPF] E.3. S u p p lie r (S ource): Covance Research Products Inc., Denver, Pennsylvania E.4. S ex: Timed-pregnant female 003876 418-010:PAGEII-6 E.5. Rationale for Test System: The New Zealand White [Hra:(NZW)SPF] rabbit was selected as the Test System because: 1) it is one non-rodent mammalian species accepted and widely used throughout the industry for nonclinical studies of developmental toxicity (embryo-fetal toxicity/teratogenicity); 2) this strain of rabbit has been demonstrated to be sensitive to developmental toxins; 3) historical data and experience exist at the Testing Facility^'75; and 4) the test article is pharmacologically active in the species and strain. E.6. Test System Data: Number of Rabbits Approximate Date of Birth Approximate Age at Arrival Weight (kg) on DG 0 Weight (kg) at Arrival 129 28 FEB 98, 07 MAR 98, 28 MAR 98 5 - 6 months 2.8 - 4.4 2.9 - 4.2 E.7. Method of Randomization: Upon arrival, rabbits were assigned to individual housing on the basis of computer-generated random units. Rabbits were assigned to one of five dosage groups (Groups I through V), 22 rabbits per dosage group, for the main portion of the study. An additional 19 satellite rabbits were assigned for toxicokinetic evaluation; five rabbits were assigned to each of the low and high dosage groups (Groups II and V), and three rabbits were assigned to each of the remaining dosage groups (Groups I, III and IV). Rabbits were assigned to dosage groups using a computer-generated (weight-ordered) randomization procedure based on body weights recorded by and at the Supplier (Covance Research Products, Inc.) on DG 0. E.8. System of Identification: Each rabbit was individually identified with a Monel self-piercing ear tag (Gey Band and Tag Co., Inc., No. MSPT 20103) inscribed with the rabbit's designated unique permanent number. Cage tags were marked with the study number, permanent rabbit number, sex, test article identification and dosage level. 003877 418-010: PAGE II-7 F. Husbandry: F.1. Research Facility Registration: USDA Registration No. 23-R-099 under the Anim al 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 rooms). Room temperature and humidity were monitored constantly throughout the study. Room temperature was targeted at 61 F to 72F (16C to 22C); relative humidity was targeted at 30% to 70%. See APPENDIX E (TEMPERATURE AND RELATIVE HUMIDITY REPORTS). F.3. Housing: Rabbits were individually housed. All cage sizes and housing conditions are in compliance with the Guide for the Care and Use o f Laboratory Animals^. 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: Approximately 150 g of Certified Rabbit Chow #5322 (PMI Nutrition International, St. Louis, Missouri) was available to each rabbit each day until the first day of dosage, at which time approximately 180 g of the same certified feed was offered to each rabbit each day. The certified feed was available from individual stainless steel "J-type" feeders attached to each cage. 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 003878 418-010:PAGE 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 Sponsor nor the Study Director 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 rabbits ad libitum from an automatic watering system (individual sipper tubes). Chlorine was added to the processed water as a bacteriostat. F. 9. Water Analysis: The processed w ater 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 Sponsor nor the Study Director 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 I Number of Rabbits 22+3a Dosage (mg/kg/day) 0 (Vehicle) Concentration (mg/mL) 0 Dosage Volume (mL/kg) 5 Assigned Ra bbit Numbers Main Study Satellite Study* 8572 - 8593 8682 - 8684 II 22+5a 0.1 0.02 5 8594-8615 8685 - 8689 III 22+3a 1.0 IV 22+3a 2.5 0.2 5 861 6 -8 63 7 8690 - 8692 0.5 5 8638 - 8659 8693 - 8695 V 22+5a 3.75 0.75 5 8660 - 8681 8696 - 8700 The test article was considered 100% pure for the purpose of dosage calculations. a. Rabbits assigned to toxicokinetic evaluation. G.2. Rationale for Dosage Selection: Dosages were selected on the basis of a dosage-range study [Argus Research Laboratories, Inc., Protocol 418-01 OP (see APPENDIX F)]. 003879 418-010:PAGE II-9 In the 418-01 OP study, severe maternal body weight loss occurred in the 10, 25, 50 and 75 mg/kg/day dosage groups; there were no surviving rabbits in these groups. Abortions occurred in the 5 and 10 mg/kg/day dosage groups. Caesarean-section observations revealed increased late resorptions and reduced fetal body weights at 5 mg/kg/day. Increases in early resorptions were found at 1 mg/kg/day; however, there was no decrease in mean litter size. G.3. Route of Administration: Oral (stomach tube) G.4. Rationale for Route of Administration: The oral (stomach tube) route was selected for use because: 1) in com parison with the dietary route, the exact dosage can be accurately administered; and 2) it is one of the possible routes of human exposure. G.5. Frequency of Administration: Appropriate dosages of the test article or vehicle were administered orally (via stomach tube) once daily to naturally-bred rabbits on DGs 7 through 20a. Dosages of 0 (Vehicle), 0.1, 1.0, 2.5 and 3.75 mg/kg/day of the test article were administered at a dosage volume of 5 ml_/kg, adjusted daily on the basis o f the individual body weights recorded before intubation. The rabbits were intubated at approximately the same time each day. G.6. Length of Study: Approximately 4 weeks a . See APPENDIX D (DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY), item 1. 003880 418-010: PAGE 11-10 G.7. Method of Study Performance: The female rabbits were naturally bred by breeder male rabbits of the same source and strain before shipment to the Testing Facility. The rabbits were mated on five consecutive days and shipped to the Testing Facility on the day after the last day of mating. The day of mating was considered to be DG 0. A computer-generated (weight-ordered) randomization procedure was used to assign the rabbits to five dosage groups based on body weights recorded on DG 0 and supplied by Covance Research Products, Inc. All rabbits were observed for viability at least twice each day of the study and for general appearance at least once during acclimation. Additional examinations for clinical observations of effects of the test article, abortions, premature deliveries and deaths were made before each daily intubation (DGs 7 through 20) and approximately 60 minutes after intubation during the dosage period. These observations were also made once daily during the postdosage period (DG 21 through 29). Body w eights were recorded on DG 0, the day of arrival at the Testing Facility and on DGs 7 through 29. Feed consumption values were recorded daily after arrival at the Testing Facility. G.8. Gross Necropsy: G.8.a. Satellite Rabbits Assigned to Toxicokinetic Sample Collection: On DG 21 (the day following the last dosage), toxicokinetic sam ples were collected from the rabbits assigned to the toxicokinetic evaluation. Following anesthesia with pentobarbital, blood samples (approximately 4 mL per rabbit) 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 was taken from the right lateral lobe, frozen and retained at -70C until shipment to the Sponsor for analysis. Rabbits were Caesarean-sectioned and fetuses were examined grossly to the extent possible, as described for rabbits assigned to the main study. Fetuses and placentae were pooled by litter and retained frozen (-70C) until shipment to the Sponsor for analysis. After completion of sample collection, serum, liver sections, fetal and placental samples were shipped (frozen on dry ice) to 3M Environmental Technology and Safety Services, St. Paul, Minnesota. 003881 I 418-010-.PAGE 11-11 G.8.b. Scheduled Sacrifice: All surviving rabbits were sacrificed by intravenous injection of Beuthanasia-D Special euthanasia solution on DG 29. The rabbits were Caesarean-sectioned and a gross necropsy of the thoracic, abdominal and pelvic viscera was performed. Gross lesions were preserved in neutral buffered 10% formalin for possible future evaluation (with the exception of parovarian cysts, which are common, spontaneous lesions in rabbits); all other tissues were discarded. The number of corpora lutea in each ovary was recorded. The uterus was excised and examined for pregnancy, number and distribution of implantations, early and late resorptions and live and dead fetuses. Uteri from does that appeared nonpregnant were stained with 10% ammonium sulfide to confirm the absence of implantation sites(9). 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 mechanical 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 Caesarean-delivered fetus was weighed, examined for gross external alterations and individually identified with a tag noting study number, litter number, and uterine distribution. Live fetuses were sacrificed by an intraperitoneal injection of Beuthanasia-D Special. All fetuses were examined internally to identify sex and visceral alterations; cavitated organs were evaluated by dissection00'; and the brain was cross-sectioned (a single cross-section was made between the parietal and the frontal bones) and examined in situ. Fetal gross lesions were preserved in neutral buffered 10% formalin for possible future evaluation. All fetuses were examined for skeletal alterations after staining with alizarin red S(11>. Skeletal preparations were retained in glycerin with thym ol added as a preservative. Late resorptions were examined to the extent possible. Representative photographs of fetal alterations are available in the raw data. Rabbits that died or were sacrificed because of abortion or premature delivery were examined for cause of death on the day the observation was made. Pregnancy status and uterine contents were recorded. Aborted fetuses and/or delivered pups were examined to the extent possible, using the same methods described for fetuses. 003882 418-010:PAGE 11-12 G.9. Statistical Analyses: The following schematic represents the statistical analyses of the data: Type of Test3 I. Parametric13 A. Bartlett's Testd Nonparametricc A. Kruskal-Wallis Test {<,75% ties) Significant atp<;0.05 Not Significant Significant atp^0.05 Nonparametric Analysis of Variance Dunn's Test Not Significant Significant atp<;0.05 Not Significant Dunnett's Test B. Fisher's Exact Test (>75% ties) 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. Used only to analyze data with homogeneity of variance. c. Proportion data are not included in this category. d. Test for homogeneity of variance. 003883 418-010.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 Variances03' and the Analysis o f Variance04', 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 Test05' was used to identify the statistical significance o f the individual groups. If the Analysis of Variance was not appropriate [i.e., Bartlett's Test was significant (p<0.05)], the Kruskal-W allis Test06' was used, when less than or equal to 75% ties were present; when more than 75% ties were present, Fisher's Exact Test(17) was used. In cases in which the Kruskal-Wallis Test was statistically significant (p<0.05), Dunn's Method of Multiple Com parisons08' was used to identify the statistical significance of the individual groups. Count data obtained at Caesarean-sectioning were evaluated using the procedures previously described for the Kruskal-Wallis Test06'. 003884 418-010:PAGE 111-1 III. RESULTS A. Mortality. Abortions. Clinical and Necropsy Observations (Summaries - Tables 1 and 3: Individual Data - Tables 2.15 and 16) A.1. Mortality No deaths were attributable to EtFOSE. The only death occurred in a vehicle control group doe, an event attributable to an intubation accident. Vehicle control group doe 8587 was found dead approximately one hour after the seventh daily dosage on gestation day 13 (DG 13). No other adverse clinical observations occurred in this doe. This doe lost w eight after DG 9 and its feed consumption was reduced after DG 10. Necropsy o f the doe revealed a perforation (0.5 cm x 0.1 cm) in the right diaphragm atic lung lobe; all other tissues appeared normal. The litter consisted of eight fetuses that appeared normal for their developmental ages at gross external examination. A.2. Abortions One, two and five** does aborted at the end of or fter the completion of the dosage period (on DGs 19, 20, 21, 23, 26 or 29) in the 0 (Vehicle), 2.5 and 3.75 mg/kg/day dosage groups, respectively. The abortions in the 2.5 and 3.75 mg/kg/day dosage groups were considered effects of the test article because the incidences were dosage-dependent. 0 (Vehiclel ma/ka/dav Doe 8581 aborted on DG 26, six days after the last dosage was administered. No other adverse clinical observations occurred in this doe, and its body weight gain and feed consumption were comparable to other control group does. No gross lesions were revealed by necropsy of the doe. The litter consisted of nine late resorptions; autolysis of these specimens precluded further evaluation. 2.5 ma/ka/dav Doe 8647 aborted on DG 21, one day after the last dosage was administered. Additional adverse clinical observations in this doe included scant feces (DGs 14 to 21), soft or liquid feces (DGs 16 to 20) and red substance in cage pan (DG 21). This doe generally lost weight and had severely reduced feed consumption after DG 7. No gross lesions were revealed by necropsy of the doe. The litter consisted of two late resorptions, and two dead and nine live fetuses. Autolysis precluded evaluation of the late resorptions. The live and dead fetuses Significantly different from the vehicle control group value (p<0.01). 003885 418-010:PAGE III-2 appeared normal for their developmental ages at gross external and soft tissue examination. Ten of the eleven fetuses had not ossified pubes at skeletal examination. Doe 8652 aborted on DG 26, six days after the last dosage was administered. Additional adverse clinical observations in this doe included a red perioral substance (DG 8) that was probably associated with an intubation problem, no feces in cage pan (DGs 12, 22 and 24), soft or liquid feces (DGs 13 to 21), scant feces (DGs 13 to 21,23 , 25 and 26) and ungroomed coat (DGs 14 to 15 and 20 to 21). This doe lost weight and had severely reduced feed consumption after DG 10. No gross lesions were revealed by necropsy of the doe. The litter consisted of two live fetuses, one dead fetus and one late resorption. The fetuses and the late resorption appeared normal for their developmental ages at gross external, soft tissue and skeletal examinations. 3.75 mq/ka/dav Doe 8660 aborted on DG 20 before administration of the 14th daily dosage. Additional adverse clinical observations in this doe included soft or liquid feces (DGs 8 to 10), ungroomed coat (DGs 8 to 11), scant feces (DGs 11 to 14 and 16), no feces in cage pan (DGs 15 and 17 to 19), tan perianal substance (DG 19) and red substance in cage pan (DG 20). This doe generally lost weight and had severely reduced feed consumption after DG 7. No gross lesions were revealed by necropsy. The litter consisted of three dead and seven live fetuses. All fetuses appeared normal for their developmental ages at gross external examination. Soft tissue and skeletal examinations were not performed due to the early developmental ages of the fetuses. Doe 8661 aborted on DG 23, three days after the last dosage was administered. Additional adverse clinical observations in this doe included soft or liquid feces (DGs 10 to 12), scant feces (DGs 11 to 15 and 21 to 23), localized alopecia on the underside (DGs 11 to 23), no feces in cage pan (DGs 16 to 20), ungroomed coat (DGs 20 to 23) and red substance in cage pan (DG 23). This doe generally lost weight and had severely reduced feed consumption after DG 7. No gross lesions were revealed by necropsy of the doe. The litter consisted of six live fetuses, one dead fetus and two late resorptions. One fetus was edematous at gross external examination; all other fetuses appeared normal for their developmental ages at gross external examination. All fetuses appeared normal at soft tissue examination. All fetuses had not ossified pubes and one of these fetuses also had split ribs at skeletal examination. Doe 8663 aborted on DG 26, six days after the last dosage was administered Additional adverse clinical observations in this doe included soft or liquid feces (DGs 11 and 13 to 15), scant feces (DGs 11 to 19, 21 and 25), ungroomed coat (DGs 13 to 15 and 25) and no feces in cage pan (DGs 20 and 22 to 24). This 003886 418-010: PAGE III-3 doe generally lost weight and had severely reduced feed consumption. After DG 7. No gross lesions were revealed by necropsy of the doe. The litter consisted of nine dead fetuses and one late resorption. Autolysis precluded evaluation of the late resorption. All aborted fetuses were partially cannibalized but, within the limits of evaluation, appeared normal for their developmental ages at gross external and soft tissue examinations. Seven of the fetuses had not ossified pubes and one of these fetuses also had split ribs at skeletal examination. Doe 8667 aborted on DG 19, after the 13th daily dosage was administered. Additional adverse clinical observations in this doe included scant feces (DGs 12 and 14 to 19) and red substance in cage pan (DG 19). This doe generally lost weight after DG 7, and its feed consumption was severely reduced after DG 10. No gross lesions were revealed by necropsy of the doe. The litter consisted of four fetuses that appeared normal for their developmental ages at gross external examination. Soft tissue and skeletal examinations were not performed due to the early developmental ages of the fetuses. Doe 8669 aborted on DG 29, nine days after the last dosage was administered. Additional adverse clinical observations in this doe included scant feces (DGs 11 to 17, 20 and 23 to 26), soft or liquid feces (DGs 13 and 15 to 16) and no feces in cage pan (DGs 18 to 19, 21 to 22 and 27 to 28). This doe generally lost weight throughout the study and feed consumption was severely reduced after DG 9. No gross lesions were revealed by necropsy. The litter consisted o fte n late resorptions that were too autolyzed for further evaluation. A.3. Clinical Observations The incidences of scant, or soft or liquid fetuses were increased in does in the 0.1, 1.0, 2.5 and 3.75 mg/kg/day dosage groups; the incidence of scant feces was significant (p<0.01) in these four dosage groups. No feces in the cage pan also occurred in one, one and six** does in the 1.0, 2.5 and 3.75 mg/kg/day dosage groups, respectively. Additional adverse clinical observations attributable to the test article occurred in does that aborted and included red substance in the can pan in one doe in the 2.5 mg/kg/day and three does in the 3.75 mg/kg/day dosage group and a tan perianal substance in one doe in the 3.75 mg/kg/day dosage group. All other adverse clinical observations were considered unrelated to the test article because the incidences were not dosage-dependent. These observations included a red perioral substance, localized alopecia on the limbs, neck and/or underside, ungroomed coat, lacrimation and a scab or mass on the hindpaws. Significantly different from the vehicle control value (p<0.01j. 003887 A. 4. Necropsy Observations 418-010:PAGE III-4 One 3.75 mg/kg/day dosage doe (8662) that had a pale liver that was considered possibly related to the test article because it occurred in a high dosage group rabbit. Control rabbit 8587 had a perforation in the right diaphragmatic lung lobe as the result of an intubation error, as previously described. B. Maternal Body Weights and Body Weight Changes {Figure 1: Summaries - Tables 4 and 5: individual Data - Table 171 Groups administered the 1.0, 2.5 and 3.75 mg/kg/day dosages of the test article had statistically significant ( p i 0.05 or p i0 .0 1 ) reductions in body w eight gains or body w eight losses on DGs 7 to 10 and 10 to 13 (2.5 and 3.75 m g/kg/day only), as compared to the control group values. Reflecting these effects of the test article, body weight gains were significantly reduced ( p i 0.01) in the 2.5 and 3.75 mg/kg/day dosage groups for the entire dosage period (calculated as DGs 7 to 21). The 2.5 and 3.75 mg/kg/day dosage groups had significantly reduced ( p i0.05 or p i 0.01) body weights on DGs 14 through 25, as compared with the control group values. Body weights and body weight gains were unaffected by the 0.1 mg/kg/day dosage of the test article. C. Maternal Absolute fq/dav) and Relative (q/kq/dav) Feed Consumption Values (Summaries - Tables 6 and 7; Individual Data - Table 181 Absolute (g/day) and relative (g/kg/day) feed consumption values were reduced during the dosage period in the 2.5 and/or 3.75 mg/kg/day dosage groups. These reductions were significant ( p i0.05 or p i0 .0 1 ) for absolute feed consumption values on DGs 10 to 13 and 13 to 16 in the 2.5 mg/kg/day dosage group and DGs 7 to 10, 10 to 13 and 13 to 16 in the 3.75 mg/kg/day dosage group. Significant reductions ( p i 0.05 or p i0 .0 1 ) in relative feed consumption values occurred on DGs 10 to 13 and 13 to 16 in the 3.75 mg/kg/day dosage group. Reflecting these effects of the test article, the 3.75 mg/kg/day dosage group had significantly reduced (p i0 .01 ) absolute and relative feed consumption values for the entire dosage period (calculated as DGs 7 to 21). Feed consumption values were unaffected by dosages of the test article as high as 1.0 mg/kg/day. 003888 418-010:PAGE III-5 D. Caesarean-Sectioning and Litter Observations (Summaries - Tables 8 and 9: Individual Data - Tables 19 through 21) Pregnancy occurred in 18 (81.8%), 20 (90.9%), 20 (90.9%), 21 (95.4% ) and 21 (95.4%) rabbits in each dosage group. Caesarean-sectioning observations on DG 29 were based on 16, 20, 20, 19 and 16 pregnant rabbits in each of the five respective dosage groups. One, two and five does aborted in the 0 (Vehicle), 2.5 and 3.75 mg/kg/day dosage groups, respectively, and one vehicle control group rabbit was found dead on DG 13. The litter averages for late resorptions were increased in the 2.5 and 3.75 mg/kg/day dosage groups. These increases in the number of late resorptions were considered treatment-related because they occurred at the two highest dosages. No biologically important or statistically significant differences occurred in the litter averages for corpora lutea, implantations, live fetuses, total or early resorptions and fetal body weights. There were no dead fetuses, no does with all conceptuses resorbed. All placentae appeared normal. E. Fetal Alterations (Summaries - Tables 10 through 14: Individual Data - Table 22) 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 133, 167, 165, 141 and 129 DG 29 Caesareandelivered live fetuses in 16, 20, 20, 19 and 16 litters in the 0 (Vehicle), 0.1, 1.0, 2.5 and 3.75 mg/kg/day dosage groups, respectively. Each fetus was examined for gross external, soft tissue and skeletal alterations and fetal ossification site averages. E.1. Summary of Fetal Alterations (Summary - Table 10: Individual Data Table 22) Combination of malformations and variations resulted in the following incidences for fetal alterations. In the 0 (Vehicle), 0.1, 1.0, 2.5 and 3.75 m g/kg/day dosage groups, respectively, 10 (62.5%), 11 (55.0%), 10 (50.0%), 12 (63.2%) and 9 (56.2%) litters had fetuses with one or more alterations observed. In these same respective dosage groups, the total numbers of fetuses with any identified alterations were 23 (17.3%), 22 (13.2%), 29 (17.6%), 23 (16.3%) and 14 (10.8%). One or more alterations occurred in averages of 17.0%, 13.6%, 003889 418-010:PAGE III-6 16.5%, 16.1 % and 11.7% of the fetuses per litter in the five respective dosage groups. No gross external, soft tissue or skeletal fetal alterations (malformations or variations) were caused by dosages of the test article as high as 3.75 mg/kg/day. There were no dosage-dependent or significant differences in the litter or fetal incidences of any gross external, soft tissue or skeletal alterations. E.2. Fetal Gross External Alterations (Summary - Table 11: Individual Data - Table 22) E.2.a. Malformations Control group fetus 8586-8 had a short trunk and absent tail at gross external examination. Soft tissue examination revealed fused, displaced and small kidneys and situs inversus. Skeletal examination of this fetus revealed fused 1st through 4th sternal centra, fusion of the xiphoid and 4th sternal centrum, only six thoracic vertebrae present, no ossification of the centra and arches of the 5th and 6th thoracic vertebrae, fused 4th and 5th left ribs, an extra ossification site attached to the 6th ribs and absence of all lumbar, sacral and caudal vertebrae. One fetus in the 2.5 mg/kg/day dosage group (8644-5) had a short snout with a protruding tongue as the only alteration. High dosage group (3.75 mg/kg/day) fetus 8665-8 had an edematous neck, a short snout with a protruding tongue and small ears at gross external examination. Soft tissue examination revealed no additional alterations. Skeletal examination of this fetus revealed fused 3rd and 4th sternal centra and angulated alae of the hyoid. E.2.b. Variations One 0.1 mg/kg/day dosage group fetus (8600-11) had a distended abdomen. Soft tissue and skeletal examinations revealed no other additional alterations. E.3. Fetal Soft Tissue Alterations (Summary - Table 12: Individual Data Table 221 E.3.a. Malformations Externally malformed control group fetus 8586-8 had fused, displaced and small kidneys and situs inversus. This fetus had a short trunk and absent tail at gross external examination and associated skeletal malformations, as previously described. 003890 418-010:PAGE III-7 Small and fused lung lobes occurred in one 2.5 mg/kg/day dosage group fetus (8646-1). This fetus had common truncus arterious as the only other alteration. All other soft tissue malformations have been previously described. E.3.b. Variations E.3.b.1. Eyes One control group fetus (8579-4), one 0.1 mg/kg/day dosage group fetus (8597-8) and one 2.5 mg/kg/day dosage group fetus (8646-2) had a circumcorneal hemorrhage of one or both eyes, a variation generally attributable to trauma during processing. Fetus 8597-8 also had absence of the intermediate lobe of the lungs. No other alterations occurred in these fetuses. E.3.b.2. Vessels Common truncus arteriosus occurred in one 2.5 mg/kg/day dosage group fetus (8646-1). This fetus also had lung malformations, as previously described. E.3.b.3. Lunas Absence of the intermediate lobe of the lungs occurred in 2, 5, 1, 1 and 4 fetuses from 2, 4, 1, 1 and 4 litters in the 0 (Vehicle), 0.1, 1.0, 2.5 and 3.75 mg/kg/day dosage groups, respectively. One of the 0.1 mg/kg/day dosage group fetuses (8597-8) also had circumcorneal hemorrhage of the right eye, as previously described. One of the 3.75 mg/kg/day dosage group fetuses (8672-6) also had a variation in skull ossification (internasal), fused sternal centra and misaligned caudal vertebrae. E.3.b.4. Kidneys The left kidney was displaced caudally in 12, 1, 17 and 5 fetuses from 2, 1, 2, and 2 litters in the 0 (Vehicle), 0.1, 1.0 and 2.5 mg/kg/day dosage groups. The externally malformed vehicle control group fetus also had fused and small kidneys, as previously described. Another vehicle control group fetus (8590-8) also had a variation in skull ossification (internasal). E.3.b.5. Hindlimb The skin was constricted on the right hindlimb of one 3.75 mg/kg/day dosage group fetus (8673-3). No additional alterations occurred in this fetus. 003891 418-010:PAGE HI-8 E.4. Fetal Skeletal Alterations (Summaries - Tables 13 and 14: Individual Data - Table 221 E.4.a. Malformations E.4.a.1. Vertebrae/Ribs/Sternum Externally malformed vehicle control group fetus 8586-8 had skeletal malformations of the sternum, vertebrae and ribs related to the observations o f a short trunk and absent tail at gross external examination. The 1st through 4th sternal centra were fused, fusion of the xiphoid and 4th sternal centrum, only six thoracic vertebrae present, absent ossification of the centra and arches of the 5th and 6th thoracic vertebrae, fused 4th and 5th left ribs, an extra ossification site attached to 6th ribs and absence of all lumbar, sacral and caudal vertebrae. E.4.a.2. Thoracic Vertebrae/Ribs Interrelated vertebral/rib malformation or malformations of the thoracic vertebrae and ribs occurred in one 0 (Vehicle) mg/kg/day, two 1.0 mg/kg/day and one 3.75 mg/kg/day dosage group fetuses. These types of vertebral/rib malformations are relatively common at maternally toxic dosages in rabbits and generally considered to be secondary to maternal stress(19). Each of these fetuses is described below. Fetus 8582-8 (vehicle control group) had a small left arch and unilateral ossification (left) of the centrum of the 10th thoracic vertebra and fusion of the 10th and 11th ribs Fetus 8625-5 (1.0 mg/kg/day dosage group) had fused centra of the 8th and 9th thoracic vertebrae, a bifid centrum in the 9th thoracic vertebra and fused 8th and 9th right ribs. Fetus 8628-8 (1.0 mg/kg/day dosage group) had only 11 thoracic vertebrae and 11 ribs present; the 7th right rib and the 8th left rib were split. Fetus 8670-1 (3.75 mg/kg/day dosage group) had a right hemivertebra present as the 12th thoracic vertebra and a split 10th left rib. E.4.a.3. Lumbar Vertebrae One 0.1 mg/kg/day dosage group fetus (8612-6) had a right hemivertebra, present between the 6th and 7th lumbar vertebrae, as the only alteration. 003892 418-010:PAGE III-9 E.4.a.4. Caudal Vertebrae Misaligned caudal vertebrae occurred in three 0.1 mg/kg/day dosage group fetuses and 1 3.75 mg/kg/day dosage group fetus. One 0.1 mg/kg/day dosage group fetus and the 3.75 mg/kg/day dosage group fetus had additional skeletal alterations, as previously described. E.4.b. Variations E.4.b.1. Skull Common small irregularities in ossification of the skull(20) [the presence of small ossification sites within the sutures or calvaria (nasal, frontal or parietal bones) and/or irregular shaping or fusion of the bones] occurred in 5, 4, 4, 5 and 2 fetuses in 5, 3, 4, 4 and 2 litters in the 0 (Vehicle), 0.1, 1.0, 2.5 and 3.75 mg/kg/day dosage groups, respectively. Irregular ossification of the nasal bones (midline suture displaced or internasal ossification site) were the most common of these small irregularities in ossification patterns, occurring in 3, 4, 3, 4 and 2 fetuses in 3, 3, 3, 3 and 2 litters in the five respective dosage groups. One of the 2.5 mg/kg/day dosage group fetuses (8648-18) also had fused sternal centra and one 3.5 mg/kg/day dosage group fetus also had fused sternal centra and misaligned caudal vertebrae. No other skeletal alterations occurred in these fetuses. E.4.b.2. Hvoid One or both alae of the hyoid were angulated in 3, 4, 1 ,2 and 6 fetuses in 2, 4, 1, 1 and 4 litters in the 0 (Vehicle), 0.1, 1.0, 2.5 and 3.75 mg/kg/day dosage groups, respectively. One 0.1 mg/kg/day dosage group fetus (8596-1) and two 3.75 mg/kg/day dosage group fetuses (8665-8; 8678-7) also had fused sternal centra. Another 0.1 mg/kg/day dosage group fetus (8614-4) also had short hyoid alae and a misaligned caudal vertebra. E.4.b.3. Vertebrae One 0.1 mg/kg/day dosage group fetus (8601-5) had unilateral ossification of the centrum of the 13th thoracic vertebra as the only alteration. The centrum of the 12th thoracic vertebra was fused to the centrum of the 1st lumbar vertebra; the centrum of the 1st lumbar vertebra was bifid in one 1.0 mg/kg/day dosage group fetus (8628-6). 003893 418-010:PAGE 111-10 E.4.b.4. Sternum Fused 3rd and 4th sternal centra occurred in 1, 4, 3, 5 and 4 fetuses from 1 ,4 , 1, 3 and 3 litters in the five respective dosage groups. Additional alterations in these fetuses were described previously. E.4.b.5. Pelvis Three fetuses from two 2.5 mg/kg/day dosage group litters had unossified pubes as the only alteration. The significant increase (p<0.01) in the fetal incidence of this alteration was considered unrelated to the test article because it was not dosage-dependent. E. 4.b.6. Fetal Ossification Site Averages The average numbers of ossification sites in the hyoid, vertebrae (cervical, thoracic, lumbar, sacral and caudal), 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 and did not significantly differ. F. Satellite Rabbits (Individual Data - Tables 15 through 20) One satellite doe in the 1.0 mg/kg/day dosage group and another satellite doe in the 3.75 mg/kg/day dosage group aborted and were sacrificed. Satellite doe 8691 aborted on DG 18 after the 12th daily dosage was administered. No other adverse clinical observations occurred in this doe. This doe lost weight after DG 16; its feed consumption values were unremarkable. No gross lesions were revealed by necropsy of the doe. The litter consisted of three early resorptions. Satellite doe 8700 aborted on DG 19 after 12 daily dosages had been administered. Additional adverse clinical observations in this doe included scant feces (DGs 7, 11, 13 and 17 to 18), no feces in cage pan (DGs 12 and 14 to 16), localized alopecia on the underside (DGs 12 to 18) and soft or liquid feces (DG 13). Body w eight loss occurred in this doe after DG 8, and its feed consumption was severely reduced after DG 10. No gross lesions were revealed by necropsy of the doe. The litter consisted of four dead fetuses and two conceptuses that were presumed cannibalized. Adverse clinical observations in the satellite groups were similar to those in the main study groups. Observations of scant feces and soft or liquid feces occurred in the 0.1, 1, 2.5 and/or 3.75 mg/kg/day dosage groups. One doe in the 3.75 mg/kg/day dosage group had observations of no feces in cage pan. 03S94 418-010:PAGE 111-11 Patterns of body weight gain and feed consumption were generally comparable to the rabbits in the main study at the same dosage levels. Only one rabbit in the 2.5 mg/kg/day dosage group was not pregnant at Caesarean-sectioning on DG 21. Caesarean-sectioning and litter parameters were comparable among the five dosage groups. One doe in the 0.1 mg/kg/day dosage group had black and brown mottling of the lungs at necropsy; all other does appeared normal. Average liver weights for pregnant does on DG 21 were 134.4 10.0, 128.9 4 .2 , 106.6 4 2 .2 , 117.8 35.5 and 109.0 3 7 .5 in the 0 (Vehicle), 0.1, 1.0, 2.5 and 3.75 mg/kg/day dosage groups, respectively. The data for rabbits assigned to the satellite portion of the study are provided in individual tables only. 003895 418-010:PAGE 111-12 REFERENCES 1. U.S. Food and Drug Administration (1994). International Conference on Harmonisation; Guideline on detection of toxicity to reproduction 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 (1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW Ordinance Number 21, March 26, 1997. 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., Hoberman, A.M. and Smith, T.H.F. (1982). Dosage-range study of the teratogenic potential of suspensions of trinitrofluorenone (TNF) administered orally to New Zealand White rabbits. Toxicologist 2(1 ):40 (#143). 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. Feussner, E.L., Lightkep, G.E., Hennesy, R.A., Hoberman, A.M. and Christian, M.S. (1992). A decade of rabbit fertility data: Study of historical control animals. Teratology 46(4):349-365. 8. Institute of Laboratory Animal Resources (1996). Guide for the Care and Use of Laboratory Animals. National Academy Press, W ashington, D.C. 9. Salewski, E. (1964). FMrbemethode zum makroskopischen Nachweis von Implantationsstellen am Uterus der Ratte. Arch. Pathol. Exp. Pharmakol. 247:367. 10. Staples, R.E. (1974). Detection of visceral alterations in mammalian fetuses. Teratology 9(3):A37-38. 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. 003896 418-010:PAGE 111-13 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. 370371. 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. Siegel, S. (1956). Nonparametric Statistics for the Behavioral Sciences, McGraw-Hill, New York, pp. 96-104. 18. Dunn, O.J. (1964). Multiple comparisons using rank sums. Technometrics 6(3):241 -252. 19. Khera, K.S. (1985). Maternal toxicity: A possible etiological factor in embryo-fetal deaths and fetal malformations of rodent-rabbit species. Teratology 31:129-153. 20. Christian, M.S., McCarty, R.J., Cox-Sica, D.K. and Cao, C.P. (1987). Recent increases in the incidences of skull, lung and rib alterations in vehicle control New Zealand W hite rabbits. J. Amer. Col. Toxicol. 6(4):562 (#126). 003897 APPENDIX A REPORT FIGURE 0389B oo CJ 09 C CP 3.40 MATERNAL BODY WEIGHTS Figure 1 O (VEHICLE) 0.1 MG/KG/DAY --O -- 1.0 MG/KG/DAY -- -- 2.5 MG/KG/DAY --X -- 3.75 MG/KG/DAY *p<0.05 *p<0.01 418-010: PAGE A- APPENDIX B REPORT TABLES ^? 90o PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R AB BITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 1 (PAGE 1 ) : C L IN IC A L O BSERVATIO NS - SUMMARY TO6C0O DOSAGE GROUP DOSAGE (MG/KG/DAY)a I II III IV V 0 (VEHICLE) 0.1 1.0 2.5 3.75 MAXIMUM POSSIBLE INCIDENCE 487/ 22 506/ 22 506/22 495/ 22 478/ 22 FOUND DEAD lb 0 0 0 0 ABORTED SCANT FECES lc 16/ 6 0 58/ 13** 0 62/ 15** 2d 4 e 5**f-j 108/ 16**d,e 122/ 17**f-j SOFT OR LIQUID FECES 14/ 4 40/ 10 36/ 10 51/ 8d,e 41/ 12f-h,j NO FECES IN CAGE PAN 0/ 0 0/ 0 1/ 1 3/ le 34/ 6**f-h,j LOCALIZED ALOPECIA: TOTAL LIMBS NECK UNDERSIDE UNGROOMED COAT 6/ 4 5/ 3 0/ 0 4/ 3 11/ 5 14/' 2 0/ 0 0/ 0 14/ 2 14/ 5 11/ 3 2/ 1 2/ 1 7/ 1 27/ 4 33/ 4 12/ 2 1/ 1 21/ 2 10/ 3e 67/ 6 31/ 4 23/ i 13/ i g 15/ 4f-h RED SUBSTANCE IN CAGE PAN 0/ 0 0/ 0 0/ 0 1/ Id 3/ 3f,g,i TAN PERIANAL SUBSTANCE RED PERIORAL SUBSTANCE 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 1/ le 1/ If 1/ 1 LACRIMATION 0/ 0 2/ 1 0/ 0 2/ 1 0/ 0 STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RABBITS WITH OBSERVATIONS. MAXIMUM POSSIBLE INCIDENCE = (DAYS X RABBITS)/NUMBER OF RABBITS EXAMINED PER GROUP ON DAYS 7 THROUGH 29 OF PRESUMED GESTATION. N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RABBITS WITH OBSERVATION. a. Dosage occurred on days 7 through 20 of presumed gestation. b. Doe 8587 was found dead on day 13 of gestation. c. Doe 8581 aborted on day 26 of gestation. d. Doe 8647 aborted on day 21 of gestation. e. Doe 8652 aborted on day 26 of gestation. f. Doe 8660 aborted on day 20 of gestation. g. Doe 8661 aborted on day 23 of gestation. h. Doe 8663 aborted on day 26 of gestation. i. Doe 8667 aborted on day 19 of gestation. j. Doe 8669 aborted on day 29 of gestation. ** Significantly different from the vehicle control group value (p<0.01). 418-010: PAGE B-1 PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RABBITS (SPONSOR1S STUDY NUMBER: 6316.8) TABLE 1 (PAGE 2) : CLINICAL OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I II III IV V 0 (VEHICLE) 0.1 1.0 2.5 3.75 MAXIMUM POSSIBLE INCIDENCE 487/ 22 506/ 22 506/22 495/ 22 478/ 22 POUND DEAD lb 0 0 0 0 ABORTED lc 0 0 2d, e 5**f-j HINDPAWS: SCAB 0/ 0 0/ 0 7/ 1 0/ 0 0/ 0 HINDPAWS: MASS 0/ 0 0/ 0 4/ 1 0/ 0 0/ 0 STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RABBITS WITH OBSERVATIONS. MAXIMUM POSSIBLE INCIDENCE = (DAYS X RABBITS)/NUMBER OF RABBITS EXAMINED PER GROUP ON DAYS 7 THROUGH 29 OF PRESUMED GESTATION. N/N TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RABBITS WITH OBSERVATION. a. Dosage occurred on days 7 through 20 of presumed gestation. b. Doe 8587 was found dead on day 13 of gestation. c. 's Doe 8581aborted on day 26 of gestation. d. Doe 8647aborted on day 21 of gestation. e. Doe 8652aborted on day 26 of gestation. f. Doe 8660aborted on day 20 of gestation. g. Doe 8661aborted on day 23 of gestation. h. Doe 8663aborted on day 26 of gestation. i. Doe 8667aborted on day 19 of gestation. j. Doe 8669aborted on day 29 of gestation. ** Significantly different from the vehicle control group value (p<0.0l). 418-010.PAGE B-2 003902 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 2 (PAGE 1) : UTERINE CONTENTS AND LIT T ER DATA FOR RAB BITS THAT D IED OR ABORTED 418-010: PAGE B-3 003903 DOSAGE GROUP RABBIT DOSAGE (MG/KG/DAY)a NUMBER DAY OF DEATH CORPORA LUTEA RL T IMPLANTATIONS RL T I 0 (VEHICLE) 8581 ABORTED ON DAY 26 OF GESTATION 54 9 54 9 8587 FOUND DEAD ON DAY 13 OF GESTATION 54 9 44 8 II 0.1 III 1.0 869le ABORTED ON DAY 18 35 8 03 3 OF GESTATION IV 2.5 8647 ABORTED ON DAY 21 6 7 13 6 7 13 OP GESTATION 8652 ABORTED ON DAY 26 OF GESTATION 86 14 22 4 V 3.75 8660 ABORTED ON DAY 20 OF GESTATION 6 4 10 6 4 10 8661 ABORTED ON DAY 23 OF GESTATION 8 3 11 63 9 R = RIGHT L = LEFT A = ABORTED T = TOTAL a. Dosage occurred on day 7 through 20 of gestation. b. Conceptuses appeared normal for developmental ages. c. Late resorptions unless otherwise noted. d. Viability of fetuses unable to be determined because of maternal death. e. Doe 8691 was a satellite animal. f. Litter 8647 had two dead fetuses. g. Litter 8652 had one dead fetus. h. Litter 8660 had three dead fetuses. i. Fetus 8661-6 had edema on the dorsal and ventral neck. EMBRYOS OR FETUSES b RESORPTIONS C RL AT RL AT 00 00 53 19 44 0 8d 0 0 00 00 00 02 13 46 11 1 Ilf 1 0 1 3g 0 1 12 01 43 51 3 ioh 00 1 7i 1 1 00 02 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 8 3 1 6 .8 ) TABLE 2 (PAGE 2) : UTERINE CONTENTS AND LITTER DATA FOR RABBITS THAT DIED OR ABORTED DOSAGE GROUP RABBIT DOSAGE (MG/KG/DAY)a NUMBER DAY OF DEATH CORPORA LUTEA RL T IMPLANTATIONS RL T V 3 .75 8663 ABORTED ON DAY 26 OF GESTATION 8 4 12 7 3 10 8667 ABORTED ON DAY 19 OF GESTATION 23 5 22 4 8669 ABORTED ON DAY 29 OF GESTATION 5 6 11 4 6 10 8700e ABORTED ON DAY 19 OF GESTATION 61 7 51 6 R = RIGHT L = LEFT A = ABORTED T = TOTAL a. Dosage occurred on day 7 through 20 of gestation. b. Conceptuses appeared normal for developmental ages. c. Late resorptions unless otherwise noted. d. All fetuses were partially cannibalized. e. Doe 8700 was a satellite animal. f. Two aborted conceptuses were presumed to have been cannibalized. EMBRYOS OR FETUSES b RESORPTIONS C RL AT RL AT 00 9 9d 0 0 11 11 24 00 00 00 00 41 5 10 00 4 4f 0 0 00 418-010: PAGE B-4 003904 PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RABBITS (SPONSOR'S STUDY NUMBER: 6316.8) TABLE 3 (PAGE 1) : NECROPSY OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I II III IV 0 (VEHICLE) 0.1 1.0 2.5 RABBITS EXAMINED b N 22 22 22 22 FOUND DEAD N 1c 0 0 0 ABORTED N Id 0 0 2e,f APPEARED NORMAL N 21 22 22 22 LUNGS: RIGHT DIAPHRAGMATIC LOBE, PERFORATION N lc 0 0 0 LIVER: PALE N0 0 0 0 a. Dosage occurred on days 7 through 20 of presumed gestation. b. Refer to the individual clinical observations table (Table 15) for external observations confirmed at necropsy. c. Doe 8587 was found dead on day 13 of gestation. d. Doe 8581 aborted on day 26 of gestation. e. Doe 8647 aborted on day 21 of gestation. f. Doe 8652 aborted on day 26 of gestation. g. Doe 8660 aborted on day 20 of gestation. h. Doe 8661 aborted on day 23 of gestation. i. Doe 8663 aborted on day 26 of gestation. j. Doe 8667 aborted on day 19 of gestation. k. Doe 8669 aborted on day 29 of gestation. ** Significantly different from the vehicle control group value (p<0.01). V 3.75 22 0 5**g-k 21 0 1 418-010: PAGE B-5 003905 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 4 (PAGE 1) : MATERNAL BODY W EIGHTS - SUMMARY 418-010: PAGE B-6 003906 DOSAGE GROUP DOSAGE (MG/KG/DAY)a RABBITS TESTED N PREGNANT N MATERNAL BODY WEIGHT (KG) DAY 0 MEAN+S.D. DAY 7 MEAN+S.D. DAY 8 MEAN+S.D. DAY 9 MEAN+S.D. DAY 10 MEAN+S.D. DAY 11 MEAN+S.D. DAY 12 MEAN+S.D. DAY 13 MEAN+S.D . DAY 14 MEAN+S.D. DAY 15 MEAN+S.D . DAY 16 MEAN+S.D . DAY 17 MEAN+S.D . DAY 18 MEAN+S.D . DAY 19 MEAN+S.D . DAY 20 MEAN+S.D. I 0 (VEHICLE) 22 18 3.43 + 0.33 3.55 + 0.34 3.59 + 0.33 3.60 + 0.32 3.64 + 0.32 3.66 + 0.34 3.67 + 0.35 3.70 + 0.36 3.74 + 0.37 [ 17] b 3.77 + 0.39 ( 17]b 3.81 + 0.38 [ 17]b 3.79 + 0.36 [ 17]b 3.78 + 0.36 t 17]b 3.80 + 0.35 [ 17] b 3.82 + 0.35 II 0.1 22 20 3.40 + 0.27 3.50 + 0.29 3.51 0.25 3.54 + 0.26 3.54 +_ 0.27 3.55 0.26 3.56 + 0.27 3.58 + 0.29 3.61 _+ 0.28 3.66 + 0.28 3.68 + 0.26 3.68 + 0.28 3.68 0.28 3.69 + 0.28 3.71 + 0.28 III 1.0 22 20 3.42 + 0.30 3.51 + 0.26 3.53 0.27 3.54 + 0.28 3.53 _+ 0.29 3.54 + 0.28 3.54 + 0.28 3.57 + 0.29 3.61 + 0.28 3.64 + 0.29 3.66 + 0.30 3.65 + 0.28 3.64 +_ 0.29 3.65 + 0.29 3.67 + 0.28 DAY = DAY OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or aborted. * Significantly different from the vehicle control group value (p<0.05). ** Significantly different from the vehicle control group value (p<0.01). IV V 2.5 3.75 22 22 21 21 3.40 + 0.32 3.50 + 0.30 3.50 0.31 3.50 + 0.30 3.48 + 0.31 3.47 0.32 3.47 + 0.31 3.46 + 0.30 3.47 + 0.30* 3.49 + 0.30** 3.50 + 0.32** 3.50 + 0.30** 3.52 + 0.30* 3.51 + 0.30** 3.51 + 0.32** 3.43 jf 0.32 3.56 0.26 3.53 + 0.25 3.52 + 0.26 3.50 + 0.26 3.47 +_ 0.25 3.44 jf 0.25 3.45 + 0.25 3.45 + 0.29** 3.46 + 0.28** 3.46 + 0.28** 3.46 + 0.29** 3.44 + 0.31** 3.47 + 0.29** ( 20]b 3.47 + 0.31** PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OP N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 S .8 ) TABLE 4 (PAGE 2) : MATERNAL BODY W EIGHTS - SUMMARY 418-010: PAGE B-7 003907 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1 RABBITS TESTED N 22 22 PREGNANT N 18 20 INCLUDED IN ANALYSES N 17b 20 MATERNAL BODY WEIGHT (KG) DAY 21 MEAN+S.D. 3.86 + 0.33 3.74 + 0.28 DAY 22 MEAN+S.D. 3.86 + 0.35 3.77 0.29 DAY 23 MEAN+S.D. 3.87 + 0.35 3.79 + 0.30 DAY 24 MEAN+S.D. 3.89 + 0.35 3.81 + 0.31 DAY 25 MEAN+S.D . 3.90 + 0.36 3.84 + 0.32 DAY 26 MEAN+S.D. 3.93 + 0.35 3.85 + 0.34 DAY 27 . MEAN+S.D. 3.94 + 0.36 3.85 + 0.35 DAY 28 MEAN+S.D . 3.93 + 0.36 3.85 + 0.36 DAY 29 MEAN+S.D . 3.96 + 0.35 3.87 +_ 0.37 DAY = DAY OF GESTATION a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or aborted. * Significantly different from the vehicle control group value (p<0.05). ** Significantly different from the vehicle control group value (p<0.01). III 1.0 22 20 20 3.71 0.28 3.72 + 0.29 3.74 + 0.29 3.75 0.29 3.78 + 0.30 3.78 + 0.31 3.80 + 0.33 3.81 0.33 3.84 + 0.33 IV V 2.5 3.75 22 22 21 21 21 19b 3.52 + 0.34** 3.58 + 0.30* 3.60 + 0.31* 3.62 + 0.32* 3.64 + 0.32* 3.67 + 0.33 3.72 + 0.29 3.73 0.29 3.76 + 0.29 3.49 + 0.30** 3.51 + 0.32** 3.53 + 0.34** 3.58 + 0.34** 3.60 + 0.35* 3.64 + 0.37 3.65 + 0.38 3.66 + 0.40 3.73 + 0.39 PROTOCOL 4 1 8 -0 X 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 5 (PAGE 1) : MATERNAL BODY WEIGHT CHANGES - SUMMARY 418-010: PAGE B-8 003908 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0. 1 RABBITS TESTED N 22 22 PREGNANT N 18 20 MATERNAL BODY WEIGHT CHANGE (KG) DAYS 0 - 7 MEAN+S.D . +0.13 + 0.17 +0.10 +_ 0.15 DAYS 7 - 10 MEAN+S.D. +0.08 + 0.08 +0.05 + 0.10 DAYS 10 - 13 MEAN+S.D . +0.06 + 0.07 +0.03 0.07 DAYS 13 - 16 DAYS 16 - 19 DAYS 19 - 21 DAYS 21 - 24 DAYS 24 - 29 DAYS 7 - 21 DAYS 21 - 29 DAYS 7 - 29 DAYS 0 - 29 MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. +0.10 + 0.06 [ 17]b +0.00 + 0.07 t 17)b +0.05 + 0.10 [ 17]b +0.04 + 0.10 ( 17]b +0.05 + 0.14 ( 16]b +0.31 + 0.17 [ 17] b +0.09 + 0.18 l 16]b +0.39 + 0.19 [ 16]b +0.49 + 0.19 [ 16]b +0.10 + 0.05 +0.01 + 0.06 +0.05 + 0.03 +0.07 + 0.07 +0.06 + 0.12 +0.24 + 0.14 +0.14 + 0.14 +0.38 + 0.21 +0.48 + 0.27 DAYS = DAYS OF GESTATION [ ) = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or aborted. * Significantly different from the vehicle control group value (p^O.05). ** Significantly different from the vehicle control group value (p^O.Ol). III 1. 0 22 20 +0.10 + 0.11 +0.01 + 0.08* +0.04 + 0.06 +0.09 + 0.07 +0.00 + 0.09 +0.05 + 0.04 +0.04 + 0.07 +0.08 + 0.12 +0.20 + 0.17 +0.13 + 0.17 +0.32 + 0.23 +0.42 + 0.26 IV V 2.5 3.75 22 22 21 21 +0.10 + 0.09 -0.03 + 0.11* -0:01 + 0.11** +0.03 + 0.10 . +0.01 + 0.11 +0.01 + 0.06 +0.06 + 0.07 [ 20]b +0.11 + 0.07 [ 19]b +0.01 + 0.32** +0.18 + 0.09 [ 19]b +0.26 + 0.26 [ 19] b +0.36 + 0.26 [ 19] b +0.13 + 0.10 -0.07 + 0.16** -0.04 + 0.10** +0.00 + 0.13 -0.01 + 0.06 t 20]b +0.01 + 0.06 [ 19Jb +0.07 + 0.10 ( 18] b +0.12 + 0.10 [ 16] b -0.07 + 0.33** ( 19] b +0.21 + 0.17 l 16]b +0.22 + 0.37 [ 16] b +0.34 + 0.38 [ 16] b PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 6 (PAGE 1) : MATERNAL ABSOLU TE FEED CONSUM PTION VALU ES (G/DAY) - SUMMARY 418-010: PAGE B-9 003909 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.,1 RABBITS TESTED N 22 22 PREGNANT N 18 20 MATERNAL FEED CONSUMPTION (G/DAY) DAYS 7 - 1 0 MEAN+S.D . 163.5 + 28.2 165.1 + 24.6 DAYS 10 - 13 DAYS 13 - 16 DAYS 16 - 19 DAYS 19 - 21 DAYS 2 1 - 2 4 DAYS 24 - 29 DAYS 7 - 2 1 DAYS 21 - 29 DAYS 7 - 2 9 MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. 158.7 + 22.2 t 17]b 162.2 + 22.3 ( 17]b 146.5 + 40.1 [ 17] b 149.2 + 32.4 ( 17] b 138.2 + 28.3 [ 17]b 116.6 + 48.2 ( 16]b 157.0 + 24.4 [ 17]b 124.7 + 36.8 [ 16] b 144.9 + 19.9 ( 16]b 153.8 + 27.2 156.4 + 35.6 148.6 + 50.8 155.4 + 39.7 148.7 + 36.1 117.4 + 41.4 156.0 + 28.8 129.1 + 35.5 146.2 + 26.6 DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or aborted. c. Excludes values that were associated with spillage or wet feed. * Significantly different from the vehicle control group value (p<0.05). ** Significantly different from the vehicle control group value (p<0.01). III 1.0 22 20 147.8 + 45.3 131.7 + 46.4 [ 19] C 139.4 + 54.9 144.5 + 61.6 147.1 + 52.9 134.7 + 51.3 117.8 + 45.4 142.4 + 45.0 124.3 + 45.0 135.8 + 41.1 IV V 2.5 3.75 22 22 21 21 135.8 + 52.6 103.4 + 65.9* 97.1 + 73.6* 117.5 + 74.8 130.4 + 65.0 [ 20]b 130.7 + 55.9 [ 20] b 128.1 + 33.6 [ 18]b,C 119.7 + 58.1 [ 20]b 130.9 + 37.7 [ 18]b,C 124.5 + 46.6 [ 18]b,C 109.9 + 69.9* 71.2 + 66.4** 82.6 + 73.4* 94.5 + 81.1 [ 20]b 106.0 +73.0 [ 19] b 126.2 + 64.2 [ 18] b 140.7 + 45.8 [ 15]b,C 96.5 + 64.2* [ 19]b 141.0 + 45.2 ( 15]b,c 121.0 + 49.0 [ 15]b,c PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 7 (PAGE 1) : MATERNAL R ELA TIV E FEED CONSUMPTION VALUES (G/KG/DAY) - SUMMARY 418-010: PAGE B-10 003910 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1 RABBITS TESTED N 22 22 PREGNANT N 18 20 MATERNAL FEED CONSUMPTION (G/KG/DAY) DAYS 7 - 1 0 MEAN+S.D. 45.8 + 9.0 47.2 + 8.0 DAYS 10 - 13 DAYS 13 - 16 DAYS 16 - 19 DAYS 19 - 21 DAYS 21 - 24 DAYS 24 - 29 DAYS 7 - 2 1 DAYS 21 - 29 DAYS 7 - 2 9 MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. 43.3 + 5.9 [ 17] b 43.4 + 6.6 [ 17] b 38.8 + 11.1 [ 17] b 39.2 + 8.7 l 17]b 36.0 + 8.1 ( 17] b 29.7 + 12.3 [ 16]b 42.4 + 7.2 ( 17]b 32.0 + 9.8 I 16] b 38.3 + 6.0 l 16]b 43.2 + 6.8 43.4 + 10.3 40.4 + 13.4 41.8 + 10.0 39.3 + 8.8 30.0 + 9.6 43.3 + 7.8 33.5 + 8.1 39.6 + 6.4 DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or aborted. c. Excludes values that were associated with spillage or wet feed. * Significantly different from the vehicle control group value (p<0.05). ** Significantly different from the vehicle control group value (p<0.01). III 1.0 22 20 41.8 + 12.2 37.1 + 12.6 [ 19] C 38.5 + 15.0 39.6 + 16.8 39.9 + 14.4 35.9 + 13.5 30.7 + 11.1 39.6 + 12.2 32.7 + 11.2 37.0 + 10.8 IV 2.5 22 21 39.0 + 15.0 29.8 + 18.9 27.4 + 20.5 33.3 + 21.3 36.4 + 18.2 [ 20]]b 35.9 + 14.8 [ 20] b 34.6 + 8.5 [ 18]b,C 34.1 + 16.3 [ 20]b 35.6 + 9.5 [ 18]b,C 34.8 + 12.6 ( 18]b,c V 3.75 22 21 31.6 + 20.1 20.3 + 18.8** 23.5 + 20.3* 26.4 + 22.3 [ 20] b 29.6 + 19.8 [ 19]b 35.0 + 17.7 [ 18] b 38.0 + 12.6 [ 15]b,C 27.4 + 17.7* ( 19] b 38.6 + 12.4 [ 15]b,C 33.8 + 13.1 [ 15]b,c PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 8 (PAGE 1) : C A E SA R E A N -SE C T IO N IN G O BSER VA TIO N S - SUMMARY 418-010: PAGE B-11 003911 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) RABBITS TESTED N 22 PREGNANT FOUND DEAD ABORTED N (%) N (%) N (%) 18 ( 81.8) 1( 5.6) 1( 5.6) RABBITS PREGNANT AND CAESAREAN -SECTIONED ON DAY 29 OF GESTATION N 16 CORPORA LUTEA MEAN+S.D. 10.9 + 2.3 IMPLANTATIONS MEAN+S.D. 9.0 + 1.8 LITTER SIZES MEAN+S.D. 8.3 + 2.2 LIVE FETUSES N MEAN+S.D. 133 8.3 + 2.2 DEAD FETUSES N 0 RESORPTIONS MEAN+S.D . 0.7 + 1.8 EARLY RESORPTIONS N MEAN+S.D . 10 0.6 + 1.8 LATE RESORPTIONS N MEAN+S.D . 1 0.1 + 0.2 DOES WITH ANY RESORPTIONS N(%) 3( 18.8) DOES WITH ALL CONCEPTUSES RESORBED N (%) 0( 0.0) DOES WITH VIABLE FETUSES N (%) 16(100.0) PLACENTAE APPEARED NORMAL N(%) 16(100.0) a. Dosage occurred on days 7 through 20 of gestation. II 0.1 22 20( 90.9) 0( 0.0) 0( 0.0) 20 10.8 + 2.0 8.6 + 2.0 8.4 + 2.0 167 8.4 + 2.0 0 0.3 + 0.9 4 0.2 + 0.7 2 0.1 + 0.4 2( 10.0) 0( 0.0) 20(100.0) 20(100.0) III 1.0 22 20( 90.9) 0( 0.0) 0( 0.0) 20 10.3 + 2.3 8.6 + 1.9 8.2 + 1.9 165 8.2 + 1.9 0 0.3 + 0.7 3 0.2 + 0.4 3 0.2 + 0.7 4( 20.0) 0( 0.0) 20(100.0) 20(100.0) IV 2.5 22 21 ( 95.4) 0( 0.0) 2( 9.5) 19 9.4 + 3.8 7.8 + 3.1 7.4 + 2.2 141 7.4 + 2.2 0 0.4 + 1.2 1 0.0 + 0.2 6 0.3 + 1.0 2( 10.5) 0( 0.0) 19(100.0) 19(100.0) . V 3.75 22 21( 95.4) 0( 0.0) 5 ( 23.8) 16 10.4 + 2.4 8.9 + 1.8 8.1 + 2.1 129 8.1 + 2.1 0 0.8 + 1.2 2 0.1 + 0.3 11 0.7 + 1.1 6( 37.5) 0( 0.0) 16(100.0) 16(100.0) PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 9 (PAGE 1) : L IT T E R O BSERVATIO N S (CAESAREAN -D ELIVERED FETU SES) - SUMMARY 418-010: PAGE B-12 003912 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) LITTERS WITH ONE OR MORE LIVE FETUSES N 16 IMPLANTATIONS MEAN+S.D. 9.0 + 1.8 LIVE FETUSES N MEAN+S.D . 133 8.3 + 2.2 LIVE MALE FETUSES N 65 % LIVE MALE FETUSES/LITTER MEAN+S.D . 46.6 + 20.0 LIVE FETAL BODY WEIGHTS (GRAMS)/LITTER MEAN+S.D. 40.17 + 12.51 MALE FETUSES FEMALE FETUSES MEAN+S.D. MEAN+S.D. 40.37 + 12.68 [ 15] b 39.50 + 12.77 % RESORBED CONCEPTUSES/LITTER MEAN+S.D. 6.9 + 18.3 [ ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Litter 8582 had no male fetuses. c. Litter 8655 had no male fetuses. II 0.1 20 8.6 + 167 8.4 + 85 2.0 2.0 51.0 + 11.8 43.37 + 5.25 43.36 + 5.51 43.55 + 5.26 3.1 + 9.8 III 1.0 20 8.6 + 1.9 165 8.2 + 1.9 77 48.3 + 16.3 42.54 + 4.50 43.70 + 5.08 42.02 + 4.70 3.3 + 8.8 IV 2.5 19 7.8 + 3.1 141 7.4 + 2.2 76 52.9 + 21.2 41.54 + 7.87 41.07 + 7.08 ( 18] C 41.66 + 8.18 2.6 + 7.7 V 3.75 16 8.9 + 129 8.1 + 62 1.8 2.1 45.8 + 15.1 39.90 + 8.54 40.91 + 8.47 39.48 + 8.98 9.3 + 14.4 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 10 (PAGE 1) : FETAL ALTERATION S - SUMMARY W6Coo DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) LITTERS EVALUATED FETUSES EVALUATED LIVE N N N 16 133 133 LITTERS WITH FETUSES WITH ANY ALTERATION OBSERVED N(%) 10( 62.5) FETUSES WITH ANY ALTERATION OBSERVED N (%) 23( 17.3) % FETUSES WITH ANY ALTERATION/LITTER MEAN+S.D. 17.0 + 25.2 a. Dosage occurred on days 7 through 20 of gestation. II 0.1 20 167 167 11( 55.0) 22( 13.2) 13.6 + 16.5 III 1.0 20 165 165 10( 50.0) 29( 17.6) 16.5 + 29.8 IV 2.5 19 141 141 12( 63.2) 23( 16.3) 16.1 + 18.2 V 3.75 16 129 129 9 ( 56.2) 14 ( 10.8) 11.7 + 13.3 418-010:PAGE B-13 PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RABBITS (SPONSOR'S STUDY NUMBER: 6316.8) TABLE 11 (PAGE 1) : FETAL GROSS EXTERNAL ALTERATIONS - SUMMARY 418-010: PAGE B-14 003914 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) LITTERS EVALUATED FETUSES EVALUATED LIVE N 16 N 133 N 133 SNOUT: SHORT LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) 0( 0.0) 0( 0.0) ABDOMEN: DISTENDED LITTER INCIDENCE FETAL INCIDENCE N (%) N(%) 0< 0.0) 0( 0.0) TRUNK: SHORT LITTER INCIDENCE FETAL INCIDENCE N (%) N(%) 1( 6.2) 1< 0.8 )C TAIL: ABSENT LITTER INCIDENCE FETAL INCIDENCE N(%) N(%) 1( 6.2) 1( 0.8) c BODY: EDEMA LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) 0( 0.0) 0( 0.0) EARS: SMALL LITTER INCIDENCE FETAL INCIDENCE N (%) N () 0( 0.0) 0( 0.0) a. Dosage occurred on days 7 through 20 of gestation. b. Fetus 8665-8 had other gross external alterations. c. Fetus 8586-8 had other gross external alterations. II 0 .1 20 167 167 0( 0.0) 0( 0.0) M 5.0) 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) III 1 .0 20 165 165 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 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 2 .5 19 141 141 1( 5.3) M 0.7) 0( 0.0) ( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) V 3..75 16 129 129 1( 6.2) 1( 0.8)b 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) K 6.2) K 0.8) b 1( 6.2) K 0.8)b PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 12 (PAGE 1): FETAL SOFT TISSUE ALTERATIONS - SUMMARY (See footnotes on the last page of this table.) S T6 C O O DOSAGE GROUP DOSAGE (MG/KG/DAY)a LITTERS EVALUATED FETUSES EVALUATED LIVE N N N EYES: CIRCUMCORNEAL HEMORRHAGE LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) VESSELS: COMMON TRUNCUS ARTERIOSUS LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) LUNGS: SMALL LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) LUNGS: FUSED LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) LUNGS: INTERMEDIATE LOBE ABSENT LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) KIDNEYS: DISPLACED LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) KIDNEYS: SMALL LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) KIDNEYS: FUSED LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) I 0 (VEHICLE) 16 133 133 1< 6.2) K 0.8) 0( 0.0) 0( 0.0) 0< 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 2 ( 12.5) 2 ( 1.5) 2 ( 12.5) 12 ( 9.0)d K 6.2) K 0. B)d M 6.2) l( o.8)d II 0.1 20 167 167 M 5.0) 1( 0.61b 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 4( 20.0) 5 ( 3.0)b K 5.0) 1( 0.6)** 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) III 1.0 20 165 165 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) K 5.0) K 0.6) 2 ( 10.0) 17 ( 10.3) 0( 0.0) 0( 0.0) 0( 0.0) 0< 0.0) IV 2.5 19 141 141 1( 5.3) 1< 0.7) 1( 5.3) 1( 0.7) c 1( 5.3) K 0.7) C 1( 5.3) K 0.7) c M 5.3) K 0.7) 2 ( 10.5) 5( 3.5)* 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) V 3.75 16 129 129 0< 0.0) 0 ( 0.0) 0< 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 4( 25.0) 4 ( 3.1) 0( 0.0) 0< 0.0)** 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 418-010: PAGE B-15 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 12 (PAGE 2 ) : FETA L SO FT T IS S U E A LT E R A T IO N S - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1 LITTERS EVALUATED FETUSES EVALUATED LIVE N 16 N 133 N 133 20 167 167 ABDOMEN: SITUS INVERSUS LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) 1( 6.2) 1( 0.8)d 0( 0.0) 0( 0.0) HINDLIMB: SKIN CONSTRICTED LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) a. Dosage occurred on days 7 through 20 of gestation. b. Fetus 8597-8 had other soft tissue alterations. c. Fetus 8646-1 had other soft tissue alterations. d. Fetus 8586-8 had other soft tissue alterations. * Significantly different from the vehicle control group value (p<0.05). ** Significantly different from the vehicle control group value (p<0.01). III 1.0 20 165 165 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) IV 2.5 19 141 141 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) V 3.75 16 129 129 0( 0.0) 0( 0.0) K 6.2) 1( 0.8) 9T6 qo 418-010:PAGE B-16 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OP N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 13 (PAGE 1) : FETAL SKELETAL ALTERATIONS - SUMMARY (See footnotes on the last page of this table.) 418-010: PAGE B-17 003917 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) LITTERS EVALUATED FETUSES EVALUATED LIVE N 16 N 133 N 133 SKULL - IRREGULAR OSSIFICATION:b (SUMMARIZATION OF ALL IRREGULAR OSSIFICATION OF THE SKULL C; INDIVIDUAL SUBCATEGORIES CITED BELOW) LITTER INCIDENCE N (%) S( 31.0) FETAL INCIDENCE N (%) 5 ( 3.8) SKULL: NASAL(S), IRREGULAR OSSIFICATION (SUMMARIZATION OF INTERNASAL; MIDLINE SUTURE DISPLACED) LITTER INCIDENCE N (%) 3 ( 18.8) FETAL INCIDENCE N (%) 3 ( 2.2) SKULL: NASALS, MIDLINE SUTURE DISPLACED LITTER INCIDENCE N (%) M FETAL INCIDENCE N (t) M 6.2) 0.8) SKULL: NASALS, CONTAIN AN INTERNASAL LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 2( 12.5) 2 ( 1.5) SKULL: FRONTALS, CONTAIN AN INTERFRONTAL LITTER INCIDENCE N (%) 2 ( 12.5) FETAL INCIDENCE N (%) 2 ( 1.5) SKULL - OTHER ALTERATIONS:b HYOID: ALA, ANGULATED LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) 2 ( 12.5) 3 ( 2.2) HYOID: ALA, SHORT LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) 0( 0.0) 0( 0.0) II III 01.1 1 .0 20 20 167 165 167 165 3 ( 15.0) 4 ( 2.4) 4 ( 20.0) 4 ( 2.4) 3 ( 15.0) 4 ( 2.4) 2 ( 10.0) 3 ( 1.8) K 5.0) M 0.6) 1< 5.0) If 0.6) 4 ( 20.0) 4 ( 2.4)f,g 1( 5.0) K o.6)g 3 ( 15.0) 3 ( 1.8) K 5.0) l( 0.6) 2 ( 10.0) 2 ( 1.2) K 5.0) K 0.6) K 5.0) K 0.6) 0< 0.0) o< 0.0) IV V 2 .5 3..75 19 16 141 129 141 129 4 ( 21.0) 5 ( 3.5) 3 ( 15.8) 4 { 2.8) 2 ( 10.5) 3 ( 2.1) k K 5.3) K 0.7) 1( 5.3) If 0.7) K 5.3) 2 ( 1.4) 0( 0.0) 0( 0.0) 2 ( T2.5) 2 ( 1.6) 2 ( 12.5) 2 ( 1.6) K 6.2) K 0.8) 1 ( 6.2) K 0.8)n 0( 0.0) 0( 0.0) 4 ( 25.0) 6 ( 4.6)1, 0 0( 0.0) 0 ( 0.0) PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 13 (PAGE 2) : FETAL SKELETAL ALTERATIONS - SUMMARY (See footnotes on the last page of this table.) 418-010: PAGE B-18 003918 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0i (VEHICLE) LITTERS EVALUATED FETUSES EVALUATED LIVE N 16 N 133 N 133 THORACIC VERTEBRAE: HEMIVERTEBRA LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0( 0.0) 0( 0.0) THORACIC VERTEBRAE: CENTRA, FUSED LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0( 0.0) 0( 0.0) THORACIC VERTEBRAE: CENTRUM, BIFID LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0( 0.0) 0( 0.0) THORACIC VERTEBRAE: 11 PRESENT LITTER INCIDENCE N (%) FETAL INCIDENCE N(%) 0( 0.0) 0( 0.0) THORACIC VERTEBRAE: CENTRUM, UNILATERAL OSSIFICATION LITTER INCIDENCE N (%) 1( 6.2) FETAL INCIDENCE N (%) 1( 0.8)d THORACIC VERTEBRAE: 6 PRESENT LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 1( 6.2) 1< 0.8) e THORACIC VERTEBRAE: CENTRUM, NOT OSSIFIED LITTER INCIDENCE N(%) 1( 6.2) FETAL INCIDENCE N <%) M 0.8) e THORACIC VERTEBRAE: ARCH, NOT OSSIFIED LITTER INCIDENCE N (%) 1( 6.2) FETAL INCIDENCE N (%) 1( 0.8) e THORACIC VERTEBRAE: ARCH, SMALL LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 1( 6.2) 1( 0.8) d II 0 .1 20 167 167 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( 5.0) 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) III 1.0 20 165 165 0( 0.0) 0( 0.0) 2 ( 10.0) 2( 1.2) h, i K 5.0) K 0.6 )h l( 5.0) 1( 0.6) j 0( 0.0) 0( 0.0) 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 2 .5 19 141 141 0( 0.0) 0( 0.0) 0( 0.0) 0< 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) V 3. 75 16 129 129 1( 6.2) 1< 0.8) m 0( 0.0) 0< 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0< 0.0) 0( 0.0) 0( 0.0) 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 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 13 (PAGE 3) : FETAL SKELETAL ALTERATIONS - SUMMARY (See footnotes on the last page of this table.) 6T6C 00 DOSAGE GROUP DOSAGE (MG/KG/DAY)a LITTERS EVALUATED FETUSES EVALUATED LIVE N N N LUMBAR VERTEBRAE: CENTRUM, BIFID LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) LUMBAR VERTEBRAE: HEMIVERTEBRA LITTER INCIDENCE N(%) FETAL INCIDENCE N (%) LUMBAR VERTEBRAE: 0 PRESENT LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) SACRAL VERTEBRAE: 0 PRESENT LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) CAUDAL VERTEBRAE: MISALIGNED LITTER INCIDENCE N (%) FETAL INCIDENCE N<%) CAUDAL VERTEBRAE: 0 PRESENT LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) RIBS: SPLIT LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) RIBS: FUSED LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) RIBS: 11 PRESENT LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) I 0 (VEHICLE) 16 133 133 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) If 6.2) 1< 0.8) e 1( 6.2) 1( 0.8) e 0( 0.0) 0( 0.0) 1( 6.2) 1( 0.8)e 0( 0.0) 0( 0.0) 2( 12.5) 2 ( 1.5) d, e 0( 0.0) 0( 0.0) II 0.1 20 167 167 0 ( 0.0) 0 ( 0.0) 1( 5.0) K 0.6) 0( 0.0) 0( 0.0) 0( 0.0) 0< 0.0) 2 ( 10.0) 3 ( 1.8) g 0 ( 0.0) 0( 0.0) 0< 0.0) 0< 0.0) 0( 0.0) 0< 0.0) 0( 0.0) 0( 0.0) III 1.0 20 165 165 1( 5.0) 1( 0.6 )i 0( 0.0) 0( 0.0) 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( 5.0) 1( 0.6) j 1( 5.0) 1< 0.6 )h 1 ( 5.0) 1( 0.6) j IV 2.5 19 141 141 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 0( 0.0) 0( 0.0) 0< 0.0) 0 ( 0.0) 0 ( 0.0) V 3.75 16 129 129 0 ( 0.0) 0( 0.0) 0< 0.0) Of 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 1< 6.2) 1( o .8)n 0( 0.0) 0 ( 0.0) If 6.2) 1( 0.8) m 0( 0.0) 0< 0.0) 0( 0.0) 0( 0.0) 418-010:PAGE B-19 PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RABBITS (SPONSOR 'S STUDY NUMBER: 6316.8) TABLE 13 (PAGE 4) : FETAL SKELETAL ALTERATIONS - SUMMARY (See footnotes on the last page of this table.) DOSAGE GROUP DOSAGE (MG/KG/DAY)a LITTERS EVALUATED FETUSES EVALUATED LIVE N N N RIBS : EXTRA OSSIFICATION LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) STERNAL CENTRA: FUSED LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) XIPHOID: FUSED LITTER INCIDENCE FETAL INCIDENCE N (%) N(%) PELVIS: PUBIS, NOT OSSIFIED LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) I 0 (VEHICLE) IS 133 133 K 6.2) K 0.8) e M 6.2) H 0. B)e K 6.2) M 0.8) e 0( 0.0) 0< 0.0) II 10.1 20 167 167 0( 0.0) 0( 0.0) 4 ( 20.0) 4 ( 2.4 )f 0 ( 0.0) 0< 0.0) 0( 0.0) 0( 0.0) III 1 .0 20 165 165 0( 0.0) 0( 0,0) 1( 5.0) 3 ( 1.8) 0( 0.0) 0( 0.0) 0 ( 0.0) 0 ( 0.0) IV 2.5 19 141 141 0( 0.0) 0( 0.0) 3 ( 15.8) 5( 3.5) k 0( 0.0) 0< 0.0) 2 ( 10.5) 3 ( 2.1)** V 3.,75 16 129 129 0( 0.0) 0( 0.0) 3 ( 18.8) 4 ( 3.1)l,n,o 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 418-010:PAGE B-20 003920 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S TABLE 13 (PAGE S) : FETAL SK ELETA L ALTERATION S - SUMMARY (SPO N SO R'S STUDY NUMBER: 6 3 1 6 .8 ) FOOTNOTES: a. Dosage occurred on days 7 through 20 of gestation. b. Fetuses with alterations of the skull and/or hyoid are not separately identified in this summary table, except when alterations of other ossification sites were also present. c. Includes all alterations noted for the skull except hyoid, ala, angulated and ala, short. These categories are excluded because these alterations do not result from irregular ossification. d. Fetus 8582-8 had other skeletal alterations. e. Fetus 8586-8 had other skeletal alterations. f. Fetus 8596-1 had other skeletal alterations. g. Fetus 8614-4 had other skeletal alterations. h. Fetus 8625-5 had other skeletal alterations. i. Fetus 8628-6 had other skeletal alterations. j. Fetus 8628-8 had other skeletal alterations. k. Fetus 8648-18 had other skeletal alterations. l. Fetus 8665-8 had other skeletal alterations m. Fetus 8670-1 had other skeletal alterations. n. Fetus 8672-6 had other skeletal alterations. o. Fetus 8678-7 had other skeletal alterations. ** Significantly different from the vehicle control group value (p<0.01). 418-010: PAGE B-: 003921 rO PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 14 (PAGE 1) : FETAL OSSIFICATION SITES - CAESAREAN--DELIVEREDi LIVE FETUSES (DAY 29 OF GESTATION) - SUMMARY 418-010: PAGE B-22 003922 DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) LITTERS EXAMINED N 16 FETUSES EXAMINED N 133 LIVE N 133 OSSIFICATION SITES PER FETUS PER LITTER HYOID MEAN+S.D. 1.00 + 0.00 VERTEBRAE CERVICAL THORACIC LUMBAR SACRAL CAUDAL MEAN+S.D . MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. 7.00 + 12.77 + 6.22 + 3.00 + 17.04 + 0.00 0.19 0.20 0.00 0.45 RIBS (PAIRS) MEAN+S.D . 12.68 + 0.25 STERNUM MANUBRIUM STERNAL CENTERS XIPHOID MEAN+S.D. MEAN+S.D. MEAN+S.D . 1.00 + 0.00 3.95 + 0.10 0.89 + 0.14 FORELIMB b CARPALS METACARPALS DIGITS PHALANGES MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D . 0.00 + 4.99 + 5.00 + 13.86 + 0.00 0.02 0.00 0.25 HINDLIMB b TARSALS METATARSALS DIGITS PHALANGES MEAN+S.D. MEAN+S.D . MEAN+S.D. MEAN+S.D . 2.00 + 4.00 + 4.00 + 12.00 + 0.00 0.00 0.00 0.00 a. Dosage occurred on days 7 through 20 of gestation. b. Calculated as average per limb. II 0.1 20 167 167 1.00 + 0.00 7.00 + 12.68 + 6.32 + 3.00 + 17.00 + 0.00 0.30 0.30 0.00 0.37 12.62 + 0.28 1.00 + 0.00 3.94 + 0.09 0.96 + 0.06 0.00 + 4.98 + 5.00 + 13.91 + 0.00 0.04 0.00 0.17 2.00 + 4.00 + 4.00 + 12.00 + 0.00 0.00 0.00 0.00 III 1.0 20 165 165 1.00 + 0.00 7.00 + 12.60 + 6.38 + 3.00 + 16.90 + 0.00 0.26 0.26 0.00 0.31 12.50 + 0.33 1.00 + 0.00 3.88 + 0.16 0.96 + 0.14 0.00 + 4.96 + 5.00 + 13.90 + 0.00 0.16 0.00 0.24 2.00 + 4.00 + 4.00 + 11.99 + 0.00 0.00 0.00 0.04 IV 2.5 19 141 141 0.97 + 0.14 7.00 + 12.73 + 6.27 + 3.00 + 16.78 + 0.00 0.26 0.26 0.00 0.37 12.67 + 0.30 1.00 + 0.00 3.92 + 0.14 0.83 + 0.26 0.00 + 4.95 + 5.00 + 13.84 + 0.00 0.14 0.00 0.26 1.98 + 4.00 + 4.00 + 11.97 + 0.05 0.00 0.00 0.08 V 3.75 16 129 129 0.99 + .05 7.00 + 12.58 + 6.42 + 3.00 + 16.82 + 0.00 0.30 0.30 0.00 0.39 12.53 + 0.31 1.00 + 0.00 3.92 + 0.10 0.94 + 0.18 0.00 + 4.92 + 5.00 + 13.95 + 0.00 0.25 0.00 0.12 1.94 + 4.00 + 4.00 + 11.98 + 0.20 0.00 0.00 0.05 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE IS (PAGE 1) : C L IN IC A L OBSERVATIONS - IN D IVID U A L DATA 418-010: PAGE B-23 003923 RABBIT # DESCRIPTION DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8572 8573 8574 8575 8576 8577 8578 8579 8580 8581 8582 8583 8584 8585 8586 8587 8588 8589 8590 8591 8592 8593 DG( 16- 18) DG ( 17- 19) DG ( 17- 20) DG ( 23 ) DG( 23- 24) DG ( 28- 29) DG ( 28- 29) DG ( 29 ) DG ( 26- 27) DG ( 26 ) DG ( 27- 29) DG( 28 ) DG( 28- 29) DG ( 28- 29) DG ( 29 ) DG ( 13 ) DG< 29 ) DG ( 25- 26) DG( 27- 29) DG ( 28- 29) DG ( 28- 29) DG( 29 ) DG( 29 ) DG( 23- 27) DG ( 25- 27) DG ( 28 ) UNGROOMED COAT SOFT OR LIQUID FECES SCANT FECES SCANT FECES SOFT OR LIQUID FECES LOCALIZED ALOPECIA: UNDERSIDE a LOCALIZED ALOPECIA: LIMBS a LOCALIZED ALOPECIA: UNDERSIDE a NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS SCANT FECES ABORTED AND SACRIFICED NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS SCANT FECES UNGROOMED COAT SOFT OR LIQUID FECES LOCALIZED ALOPECIA: LIMBS a SCANT FECES FOUND DEAD UNGROOMED COAT a SCANT FECES UNGROOMED COAT a SOFT OR LIQUID FECES SCANT FECES LOCALIZED ALOPECIA: UNDERSIDE a LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS SOFT OR LIQUID FECES UNGROOMED COAT SCANT FECES NO ADVERSE FINDINGS NO ADVERSE FINDINGS DG = DAY OF PRESUMED GESTATION a . O b se rv a tio n co n firm ed a t n e cro p sy . PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R AB BITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 15 (PAGE 2) : C L IN IC A L OBSERVATIONS - IN D IV ID U A L DATA COO RABBIT # DESCRIPTION DOSAGE GROUP II 0.1 MG/KG/DAY 8594 8595 8596 8597 8598 8599 8600 8601 8602 8603 8604 8605 8606 8607 8608 DG ( 16- 23) DG ( 21- 23) DG ( 28- 29) DG ( 29 ) DG ( 29 ) DG ( 21- 25) DG ( 22- 29) DG ( 29 ) DG ( 28- 29) DG ( 12- 14) DG ( 21- 29) DG ( 24- 29) DG ( 17 ) DG ( 28- 29) DG ( 28- 29) DG ( 19 ) DG ( 27- 28) DG ( 27- 29) DG ( 27- 29) DG ( 7- 8) DG ( 14 ) DG ( 18 ) DG ( 21- 22) DG ( 26 ) DG ( 27- 29) DG ( 25- 29) DG( 21- 22) DG ( 27- 28) DG ( 27- 28) DG ( 19 ) DG ( 20 ) DG ( 26- 29) DG ( 26- 29) SCANT FECES SOFT OR LIQUID FECES UNGROOMED COAT a SOFT OR LIQUID FECES SCANT FECES SOFT OR LIQUID FECES SCANT FECES SOFT OR LIQUID FECES NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS SCANT FECES SOFT OR LIQUID FECES SOFT OR LIQUID FECES SCANT FECES SCANT FECES LOCALIZED ALOPECIA: UNDERSIDE a SCANT FECES SOFT OR LIQUID FECES UNGROOMED COAT SOFT OR LIQUID FECES SCANT FECES UNGROOMED COAT SOFT OR LIQUID FECES SOFT OR LIQUID FECES LACRIMATION UNGROOMED COAT SCANT FECES SCANT FECES SOFT OR LIQUID FECES SOFT OR LIQUID FECES SCANT FECES SOFT OR LIQUID FECES SCANT FECES SOFT OR LIQUID FECES SCANT FECES DG = DAY OF PRESUMED GESTATION a . O b se rv a tio n co n firm ed a t n e cro p sy . 418-010: PAGE B-24 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 15 (PAGE 3 ) : C L IN IC A L OBSERVATIONS - IN D IVID U A L DATA RABBIT # DESCRIPTION DOSAGE GROUP II 0.1 MG/KG/DAY 8609 8610 8611 8612 8613 8614 8615 DG( 15 ) DG ( 26- 27) DG ( 24- 29) DG ( 16- 18) DG ( 17- 19) DG ( 18- 29) DG ( 27- 29) DG ( 28- 29) DG ( 24 ) DG ( 24 ) SCANT FECES SCANT FECES NO ADVERSE FINDINGS SCANT FECES NO ADVERSE FINDINGS UNGROOMED COAT SCANT FECES LOCALIZED ALOPECIA: UNDERSIDE a UNGROOMED COAT SOFT OR LIQUID FECES UNGROOMED COAT SOFT OR LIQUID FECES NO ADVERSE FINDINGS DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. 5 2 ^^0 0 418-010: PAGE B-25 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SPO N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 15 (PAGE 4) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA 418-010: PAGE B-26 003926 RABBIT g DESCRIPTION DOSAGE GROUP III 1.0 MG/KG/DAY 8616 8617 8618 8619 8620 8621 8622 8623 8624 8625 8626 8627 8628 8629 8630 8631 DG ( 17- 23) DG ( 18- 24) DG ( 28- 29) DG ( 29 ) DG ( 29 ) DG ( 17- 19) DG ( 17- 24) DG ( 29 ) DG ( 16- 18) DG ( 23- 24) DG ( 16- 17) DG( 16- 17) DG ( 18 ) DG ( 19- 22) DG ( 19- 29) DG ( 23- 29) DG ( 11 ) DG ( 24 ) DG ( 28 ) DG ( 14 ) DG ( 14- 21) DG ( 23- 29) DG ( 23- 29) DG ( 23- 29) DG ( 28- 29) DG ( 27- 28) DG( 27 ) DG ( 27- 28) DG ( 27- 29) DG ( 27- 29) DG( 26 ) DG ( 26- 28) DG( 10 ) DG ( 14 ) SCANT FECES SOFT OR LIQUID FECES LOCALIZED ALOPECIA: LIMBS a SOFT OR LIQUID FECES SCANT FECES SOFT OR LIQUID FECES SCANT FECES SOFT OR LIQUID FECES SCANT FECES SOFT OR LIQUID FECES SOFT OR LIQUID FECES SCANT FECES NO FECES IN CAGE PAN SOFT OR LIQUID FECES SCANT FECES LOCALIZED ALOPECIA: UNDERSIDE a NO ADVERSE FINDINGS SCANT FECES SCANT FECES NO ADVERSE FINDINGS SOFT OR LIQUID FECES SOFT OR LIQUID FECES UNGROOMED COAT UNGROOMED COAT SOFT OR LIQUID FECES SCANT FECES LOCALIZED ALOPECIA: NECK a SCANT FECES SOFT OR LIQUID FECES SCANT FECES UNGROOMED COAT a SCANT FECES SOFT OR LIQUID FECES SCANT FECES NO ADVERSE FINDINGS UNGROOMED COAT UNGROOMED COAT DG = DAY OF PRESUMED GESTATION a . O b se rv a tio n co n firm ed a t n e cro p sy . PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 15 (PAGE 5) : C L IN IC A L OBSERVATIONS - IN D IV ID U A L DATA RABBIT # DESCRIPTION DOSAGE GROUP III 1.0 MG/KG/DAY 8632 8633 8634 8635 8636 8637 DG ( 16 ) DG ( 22- 29) DG ( 23 ) DG ( 28 ) DG ( 28 ) DG( 9- 10) DG ( 9- 13) DG ( 18 ) DG ( 18 ) DG ( 19- 22) DG ( 23- 29) DG ( 24 ) DG ( 28 ) SCANT FECES SCANT FECES SOFT OR LIQUID FECES SOFT OR LIQUID FECES SCANT FECES SOFT OR LIQUID FECES UNGROOMED COAT UNGROOMED COAT SOFT OR LIQUID FECES HINDPAWS: MASS (1.0 CM X 1.0 CM X 0.5 CM) HINDPAWS: SCAB (0.5 CM X 0.5 CM X 0.5 CM) a UNGROOMED COAT NO ADVERSE FINDINGS SCANT FECES DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. 418-010: PAGE B-27 003927 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 15 (PAGE 6) : C L IN IC A L OBSERVATIONS - IN D IVID U A L DATA 826C 00 RABBIT # DESCRIPTION DOSAGE GROUP IV 2.5 MG/KG/DAY 8638 8639 8640 8641 8642 8643 8644 8645 8646 8641 8648 DG ( 10- 11) DG( 10- 29) DG ( 11- 12) DG ( 16- 19) DG ( 16- 22) DG ( 11 ) DG ( 22- 24) DG ( 24 ) DG ( 29 ) DG ( 11- 29) DG ( 11- 22) DG ( 21- 29) DG ( 11- 22) DG ( 19- 20) DG ( 22- 23) DG ( 25 ) DG( 16- 29) DG ( 11- 18) DG( 11- 22) DG ( 26- 29) DG ( 29 ) DG ( 11 ) DG ( 19 ) DG ( 21- 23) DG ( 25- 29) DG ( 29 ) DG ( 10- 16) DG( 22 ) DG ( 14- 21) DG ( 16- 20) DG ( 21 ) DG ( 21 ) DG ( 14- 16) UNGROOMED COAT LOCALIZED ALOPECIA: UNDERSIDE a SCANT FECES SOFT OR LIQUID FECES SCANT FECES UNGROOMED COAT SOFT OR LIQUID FECES UNGROOMED COAT SCANT FECES SCANT FECES SOFT OR LIQUID FECES SOFT OR LIQUID FECES SCANT FECES SOFT OR LIQUID FECES LACRIMATION SOFT OR LIQUID FECES SCANT FECES UNGROOMED COAT SOFT OR LIQUID FECES LOCALIZED ALOPECIA: LIMBS a LOCALIZED ALOPECIA: NECK a SOFT OR LIQUID FECES SOFT OR LIQUID FECES SOFT OR LIQUID FECES SOFT OR LIQUID FECES SCANT FECES NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS SCANT FECES SCANT FECES SCANT FECES SOFT OR LIQUID FECES RED SUBSTANCE IN CAGE PAN ABORTED AND SACRIFICED SCANT FECES DG = DAY OF PRESUMED GESTATION a . O b se rv a tio n co n firm ed a t n e cro p sy . 418-010: PAGE B-28 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R AB BITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 15 (PAGE 7) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA RABBIT # DESCRIPTION DOSAGE GROUP IV 2.5 MG/KG/DAY (J) o Q Jo 8649 8650 8651 8652 8653 8654 8655 8656 8657 B658 8659 DG( 15- 16) DG ( 26- 27) DG ( 27 ) DG ( 26- 27) DG ( 29 ) DG( 8 ) DG ( 12 ) DG ( 13- 21) DG ( 13- 21) DG ( 14- 15) DG( 20- 21) DG ( 22 ) DG ( 23 ) DG ( 24 ) DG ( 25- 26) DG ( 26 ) DG ( 15- 16) DG ( 27 ) DG ( 29 ) DG( 16 ) DG ( 28 ) DG( 22- 29) DG ( 12- 17) DG ( 16- 17) DG ( 28- 29) SCANT FECES SCANT FECES SCANT FECES SCANT FECES LOCALIZED ALOPECIA: UNDERSIDE a RED PERIORAL SUBSTANCE NO FECES IN CAGE PAN SOFT OR LIQUID FECES SCANT FECES UNGROOMED COAT UNGROOMED COAT NO FECES IN CAGE PAN SCANT FECES NO FECES IN CAGE PAN SCANT FECES ABORTED AND SACRIFICED SCANT FECES SCANT FECES SCANT FECES SCANT FECES SCANT FECES LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS NO ADVERSE FINDINGS SCANT FECES SOFT OR LIQUID FECES SCANT FECES DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. 418-010: PAGE B-29 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE IS (PAGE 8) : C L IN IC A L OBSERVATIONS - IN D IV ID U A L DATA RABBIT # DESCRIPTION DOSAGE GROUP V 3.75 MG/KG/DAY 8660 8661 8662 8663 DG ( 8- 10) DG ( 8- 11) DG ( 11- 14) DG ( 15 ) DG ( 16 ) DG ( 17- 19) DG ( 19 ) DG ( 20 ) DG ( 20 ) DG ( 10- 12) DG ( 11- 15) DG ( 11- 23) DG( 16- 20) DG( 20- 23) DG l 21- 23) DG ( 23 ) DG ( 23 ) DG ( 9- 12) DG ( 10- 12) DG l 12 ) -DG ( 13- 19) DG ( 20- 22) DG ( 20- 22) DG ( 23- 29) DG ( 11 ) DG ( 11- 19) DG ( 13- 15) DG ( 13- 15) DG ( 20 ) DG ( 21 ) DG ( 22- 24) DG( 25 ) DG ( 25 ) DG ( 26 ) SOFT OR LIQUID FECES UNGROOMED COAT SCANT FECES NO FECES IN CAGE PAN SCANT FECES NO FECES IN CAGE PAN TAN PERIANAL SUBSTANCE RED SUBSTANCE IN CAGE PAN ABORTED AND SACRIFICED SOFT OR LIQUID FECES SCANT FECES LOCALIZED ALOPECIA: UNDERSIDE a NO FECES IN CAGE PAN UNGROOMED COAT SCANT FECES RED SUBSTANCE IN CAGE PAN ABORTED AND SACRIFICED SCANT FECES UNGROOMED COAT SOFT OR LIQUID FECES NO FECES IN CAGE PAN SOFT OR LIQUID FECES SCANT FECES NO FECES IN CAGE PAN SOFT OR LIQUID FECES SCANT FECES UNGROOMED COAT SOFT OR LIQUID FECES NO FECES IN CAGE PAN SCANT FECES NO FECES IN CAGE PAN UNGROOMED COAT SCANT FECES ABORTED AND SACRIFICED DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. 418-010:PAGE B-30 TC6 C0 0 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OP N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 15 (PAGE 9) : C L IN IC A L OBSERVATIONS - IN D IV ID U A L DATA RABBIT # DESCRIPTION DOSAGE GROUP V 3.75 MG/KG/DAY 8664 8665 8666 8667 8668 8669 8670 8671 8672 8673 DG ( 7- 29) DG ( 9- 23) DG ( 17- 19) DG ( 27- 29) DG ( 29 ) DG( 11- 15) DG ( 18 ) DG ( 27- 29) DG( 12 ) DG ( 14- 19) DG ( 19 ) DG ( 19 ) DG( 15- 29) DG ( 11- 17) DG ( 13 ) DG ( 15- 16) DG ( 18- 19) DG ( 20 ) DG ( 21- 22) DG ( 23- 26) DG ( 27- 28) DG ( 29 ) DG ( 28 ) DG ( 7- 8) DG ( 10 ) DG ( 27 ) DG ( 8 ) DG ( 10- 11) DG ( 12 ) DG ( 13- 16) DG ( 27 ) DG ( 12- 25) DG ( 19- 25) LOCALIZED ALOPECIA: NECK a SCANT FECES SOFT OR LIQUID FECES SOFT OR LIQUID FECES SCANT FECES SCANT FECES SCANT FECES LOCALIZED ALOPECIA: LIMBS NO ADVERSE FINDINGS SCANT FECES SCANT FECES RED SUBSTANCE IN CAGE PAN ABORTED AND SACRIFICED LOCALIZED ALOPECIA: LIMBS a SCANT FECES SOFT OR LIQUID FECES SOFT OR LIQUID FECES NO FECES IN CAGE PAN SCANT FECES NO FECES IN CAGE PAN SCANT FECES NO FECES IN CAGE PAN ABORTED AND SACRIFICED SCANT FECES SOFT OR LIQUID FECES SCANT FECES SCANT FECES RED PERIORAL SUBSTANCE SCANT FECES NO FECES IN CAGE PAN SCANT FECES SCANT FECES SCANT FECES SOFT OR LIQUID FECES DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. 418-010: PAGE B-: CO PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 15 (PAGE 10) : C L IN IC A L OBSERVATIONS - IN D IV ID U A L DATA ZC6C00 RABBIT # DESCRIPTION DOSAGE GROUP V 3.75 MG/KG/DAY 8673 8674 8675 8676 8677 8678 8679 8680 8681 DG { 27 ) DG ( 12- 19) DG ( 26 ) DG ( 28- 29) DG ( 14 ) DG ( 14- 15) DG ( 29 ) DG ( 18- 29) DG ( 19 ) DG ( 19 ) DG ( 14- 15) DG ( 15 ) DG ( 18- 19) DG ( 14- 22) DG ( 18- 20) DG ( 26 ) SOFT OR LIQUID FECES NO ADVERSE FINDINGS SCANT FECES SCANT FECES SCANT FECES SOFT OR LIQUID FECES SCANT FECES LOCALIZED ALOPECIA: LIMBS a LOCALIZED ALOPECIA: LIMBS a SOFT OR LIQUID FECES SCANT FECES NO ADVERSE FINDINGS SCANT FECES SOFT OR LIQUID FECES SOFT OR LIQUID FECES SCANT FECES SOFT OR LIQUID FECES SCANT FECES DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. 418-010: PAGE B-32 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE IS (PAGE 11) : C L IN IC A L OBSERVATIONS - IN D IV ID U A L DATA RABBIT # SATELLITE DOSAGE GROUP I 8682 8683 8684 SATELLITE DOSAGE GROUP II 868S 8686 8687 8688 8689 DG ( 14 ) DG( 14- 15) D G ( 21 ) SATELLITE DOSAGE GROUP III 8690 8691 8692 D G ( 18 ) DG( 13- 16) DG( 19 ) DG = DAY OF PRESUMED GESTATION DESCRIPTION 0 (VEHICLE) MG/KG/DAY NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS 0.1 MG/KG/DAY SOFT OR LIQUID FECES SCANT FECES NO ADVERSE FINDINGS SCANT FECES NO ADVERSE FINDINGS NO ADVERSE FINDINGS 1.0 MG/KG/DAY NO ADVERSE FINDINGS NO ADVERSE FINDINGS ABORTED AND SACRIFICED SCANT FECES SOFT OR LIQUID FECES 418-010:PAGE B-33 003933 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 S .8 ) TABLE 15 (PAGE 12) : C L IN IC A L OBSERVATIONS - IN D IV ID U A L DATA 418-OtO:PAGE B-34 003934 RABBIT # DESCRIPTION SATELLITE DOSAGE: GROUP IV 2.5 MG/KG/DAY 8693 8694 8695 DG ( 14 ) NO ADVERSE FINDINGS SCANT FECES NO ADVERSE FINDINGS SATELLITE DOSAGE GROUP V 3.75 MG/KG/DAY 8696 8697 8698 8699 8700 DG ( 14- 21) DG ( 15 ) DG ( 18- 19) DG ( 7- 10) DG ( 12- 18) DG ( 14- 21) DG ( 17- 20) DG ( 19- 21) DG ( 7 ) DG ( 11 ) DG ( 12 ) DG ( 12- 18) DG ( 13 ) DG ( 13 ) DG ( 14- 16) DG( 17- 18) DG ( 19 ) LOCALIZED ALOPECIA: UNDERSIDE a SOFT OR LIQUID FECES SOFT OR LIQUID FECES UNGROOMED COAT SCANT FECES SCANT FECES SOFT OR LIQUID FECES LOCALIZED ALOPECIA: UNDERSIDE a NO ADVERSE FINDINGS SCANT FECES SCANT FECES NO FECES IN CAGE PAN LOCALIZED ALOPECIA: UNDERSIDE SCANT FECES SOFT OR LIQUID FECES NO FECES IN CAGE PAN SCANT FECES ABORTED AND SACRIFICED DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SPO N SO R ' S STUDY NUMBER: 6 3 1 G .8 ) TABLE 16 (PAGE 1) : NECROPSY OBSERVATIONS - IN D IV ID U A L DATA 418-010: PAGE B-35 003935 DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a I 0 (VEHICLE) 8572 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8573 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8574 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8575 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8576 DG 29 NP 14 ALL TISSUES APPEARED NORMAL. 8577 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8578 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8579 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8580 DG 29 NP 14 ALL TISSUES APPEARED NORMAL. 8581 DG 26 P 14 ABORTED ON DAY 26 OF GESTATION. ALL TISSUES APPEASED NORMAL. 8582 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8583 DG 29 NP 14 ALL TISSUES APPEARED NORMAL. 8584 DG 29 NP 14 ALL TISSUES APPEARED NORMAL. 8585 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8586 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8587 DG 13 P 7 FOUND DEAD ON DAY 13 OP GESTATION (57 MINUTES AFTER DOSAGE). LUNGS: RIGHT DIAPHRAGMATIC LOBE, PERFORATION (0.5 CM :K 0.1 CM). ALL OTHER TISSUES APPEARED NORMAL. 8588 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8589 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8590 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8591 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8592 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8593 DG 29 P 14 ALL TISSUES APPEARED NORMAL. P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 15) for external observations confirmed at necropsy. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 16 (PAGE 2) : NECROPSY OBSERVATIONS - IN D IV ID U A L DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a II 0.1 8594 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8595 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8596 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8597 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8598 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8599 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8600 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8601 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8602 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8603 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8604 DG 29 NP 14 ALL TISSUES APPEARED NORMAL. 8605 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8606 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8607 DG 29 NP 14 ALL TISSUES APPEARED NORMAL. 8608 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8609 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8610 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8611 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8612 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8613 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8614 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8615 DG 29 P 14 ALL TISSUES APPEARED NORMAL. P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 15) for external observations confirmed at necropsy. 418-010:PAGE B-36 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OP N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 16 (PAGE 3) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA 418-010:PAGE B-37 003937 DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a III 8616 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8617 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8618 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8619 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8620 DG 29 NP 14 ALL TISSUES APPEARED NORMAL. 8621 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8622 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8623 DG 29 NP 14 ALL TISSUES APPEARED NORMAL. 8624 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8625 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8626 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8627 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8628 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8629 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8630 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8631 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8632 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8633 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8634 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8635 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8636 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8637 DG 29 P 14 ALL TISSUES APPEARED NORMAL. P = PREGNANT NP NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 15) for external observations confirmed at necropsy. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 16 (PAGE 4) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a 418-010:PAGE B-38 003938 8638 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8639 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8640 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8641 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8642 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8643 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8644 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8645 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8646 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8647 DG 21 P 14 ABORTED ON DAY 21 OF GESTATION ALL TISSUES APPEARED NORMAL. 8648 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8649 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8650 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8651 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8652 DG 26 P 14 ABORTED ON DAY 26 OF GESTATION ALL TISSUES APPEARED NORMAL. 8653 DG 29 NP 14 ALL TISSUES APPEARED NORMAL. 8654 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8655 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8656 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8657 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8658 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8659 DG 29 P 14 ALL TISSUES APPEARED NORMAL. P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 15) for external observations confirmed at necropsy. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SPO N SO R ' S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 16 (PAGE 5) : NECROPSY OBSERVATIONS - IN D IV ID U A L DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a 6 C6 Co 8660 DG 20 P 13 ABORTED ON DAY 20 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8661 DG 23 P 14 ABORTED ON DAY 23 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8662 DG 29 P 14 LIVER : PALE ALL OTHER TISSUES APPEARED NORMAL 8663 DG 26 P 14 ABORTED ON DAY 26 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8664 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8665 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8666 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8667 DG 19 P 13 ABORTED ON DAY 19 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8668 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8669 DG 29 P 14 ABORTED ON DAY 29 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8670 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8671 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8672 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8673 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8674 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8675 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8676 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8677 DG 29 NP 14 ALL TISSUES APPEARED NORMAL. 8678 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8679 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8680 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8681 DG 29 P 14 ALL TISSUES APPEARED NORMAL. P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 15) for external observations confirmed at necropsy. 418-010:PAGE B-39 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OP N -E tF O S E IN R A B B IT S (SPO N SO R' S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 16 (PAGE 6 ) : NECROPSY OBSERVATIONS - IN D IV ID U A L DATA 418-010: PAGE B-40 003940 SATELLITE DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a LIVER WEIGHT (G) I 0 (VEHICLE) 8682 DG 21 P 14 ALL TISSUES APPEARED NORMAL. 8683 DG 21 P 14 ALL TISSUES APPEARED NORMAL. 8684 DG 21 P 14 ALL TISSUES APPEARED NORMAL. 145.7 130.8 126.7 II 0.1 8685 DG 21 P 14 LUNGS: ALL LOBES, MOTTLED BLACK 123.6 AND BROWN (PINPOINT TO 1.0 CM IN DIAMETER). ALL OTHER TISSUES APPEARED NORMAL. 8686 DG 21 P 14 ALL TISSUES APPEARED NORMAL. 8687 DG 21 P 14 ALL TISSUES APPEARED NORMAL. 8688 DG 21 P 14 ALL TISSUES APPEARED NORMAL. 8689 DG 21 P 14 ALL TISSUES APPEARED NORMAL. 165.9 110.0 138.6 106.5 III 1.0 8690 DG 21 P 14 ALL TISSUES APPEARED NORMAL. 136.5 8691 DG 18 P 12 ABORTED ON DAY 18 OF GESTATION. ALL TISSUES APPEARED NORMAL. 105.1 8692 DG 21 P 14 ALL TISSUES APPEARED NORMAL. 76.8 IV 2.5 8693 DG 21 NP 14 ALL TISSUES APPEARED NORMAL. 100.9 8694 DG 21 P 14 ALL TISSUES APPEARED NORMAL. 142.9 8695 DG 21 P 14 ALL TISSUES APPEARED NORMAL. 92.7 V 3.75 8696 DG 21 P 14 ALL TISSUES APPEARED NORMAL. 8697 DG 21 P 14 ALL TISSUES APPEARED NORMAL. 8698 DG 21 P 14 ALL TISSUES APPEARED NORMAL. 8699 DG 21 P 14 ALL TISSUES APPEARED NORMAL. 145.2 81.9 71.8 137.3 8700 DG 19 P 12 ABORTED ON DAY 19 OF GESTATION. ALL TISSUES APPEARED NORMAL. 60.0 P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 15) for external observations confirmed at necropsy. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: TABLE 17 (PAGE 1) : MATERNAL BODY W EIGHTS - IN D IV ID U A L DATA 6 3 1 6 .8 ) 418-010.PAGE B-41 003941 PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 17 RABBIT # DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8572 P 8573 P 8574 P 8575 P 8576 NP 8577 P 8578 P 8579 P 8580 NP 8581 P 8582 P 8583 NP 8584 NP 8585 P 8586 P 8587 P 8588 P 8589 P 8590 P 8591 P 8592 P 8593 P 3.60 3.95 3.89 3.58 3.34 2.92 2.85 3.23 3.29 3.11 3.32 3.17 3.41 3.57 3.36 3.02 3.72 3.51 3.82 3.65 3.17 3.40 3.42 4.12 4.22 3.76 3.22 3.11 3.06 3.07 3.52 3.23 3.29 3.34 3.56 3.64 3.42 3.61 3.80 3.70 3.95 3.68 3.39 3.51 3.36 4.14 4.18 3.78 3.47 3.10 3.11 3.27 3.44 3.27 3.30 3.34 3.51 3.72 3.44 3.56 3.86 3.73 4.04 3.70 3.45 3.58 3.44 4.18 4.15 3.82 3.53 3.16 3.12 3.28 3.48 3.30 3.35 3.34 3.69 3.77 3.48 3.60 3.76 3.74 4.07 3.72 3.40 3.53 3.49 4.14 4.12 3.83 3.55 3.18 3.12 3.34 3.44 3.36 3.37 3.25 3.59 3.84 3.47 3.59 89 80 17 76 42 54 3.54 4.14 4.19 3.85 3.51 3.18 3.09 3.33 3.42 3.37 3.40 30 60 81 53 58 3.89 3.83 4.28 3.78 3.47 3.54 3.55 4.20 4.25 3.82 3.55 3.20 3.10 3.34 3.45 3.43 3.36 3.32 3.65 3.82 3.57 3.51 3.90 3.84 4.29 3.83 3.51 3.60 3.58 4.23 4.33 3.84 3.62 3.21 3.14 3.39 3.50 3.45 3.35 3.40 3.64 3.82 3.58 3.50 3.96 3.85 4.35 3.85 3.50 3.65 3.63 3.68 3.59 3.53 4.26 4.28 4.28 4.26 4.35 4.38 4.39 4.29 3.88 3.91 3.97 3.95 3.62 3.60 3.61 3.60 3.24 3.26 3.30 3.30 3.20 3.23 3.27 3.27 3.36 3.34 3.51 3.56 3.53 3.56 3.53 3.47 3.50 3.52 3.53 3.59 3.38 3.39 3.39 3.38 3.42 3.44 3.49 3.48 3.77 3.74 3.81 3.73 3.88 3.96 3.98 3.98 3.61 3.53 3.66 3.58 FOUND DEAD ON DAY 13 OF GESTATION 4.02 4.07 4.06 4.06 3.90 3.93 3.95 3.99 4.40 4.50 4.62 4.52 3.85 3.88 3.91 3.91 3.57 3.63 3.66 3.58 3.60 3.64 3.68 3.66 PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 18 3.48 4.24 4.32 3.96 3.56 3.36 3.29 3.57 3.52 3.48 3.38 3.46 3.73 3.99 3.60 4.06 4.00 4.47 3.94 3.56 3.66 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUD Y OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: TABLE 17 (PAGE 2) : MATERNAL BODY W EIGHTS - IN D IV ID U A L DATA 6 3 1 6 .8 ) 418-010: PAGE B-42 003942 PREGNANCY STATUS DAY 19 20 21 22 23 24 25 26 27 28 29 RABBIT # DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8572 P 8573 P 8574 P 8575 P 8576 NP 8577 P 8578 P 8579 P 8580 NP 8581 P 8582 P 8583 NP 8584 NP 8585 P 8586 P 8587 P 8588 P 8589 P 8590 P 8591 P 8592 P 8593 P 3.55 3.62 3.64 3.70 4.20 4.24 4.19 4.18 4.34 4.35 4.21 4.25 4.01 4.01 4.00 4.03 3.57 3.58 3.62 3.68 3.41 3.35 3.40 3.38 3.29 3.31 3.34 3.31 3.58 3.61 3.64 3.70 3.56 3.59 3.54 3.56 3.60 3.66 3.66 3.68 3.38 3.37 3.42 3.42 3.47 3.46 3.47 3.46 3.89 3.83 3.90 3.89 3.98 3.98 4.05 4.08 3.59 3.62 3.64 3.66 FOUND DEAD ON DAY 13 OF GESTATION 4.10 4.06 4.11 4.16 4.02 4.00 4.04 4.04 4.47 4.50 4.52 4.59 3.97 4.02 4.05 4.07 3.58 3.64 3.99 3.72 3.62 3.65 3.70 3.70 3.67 4.21 4.34 4.03 3.70 3.39 3.36 3.72 3.58 3.57 3.47 3.49 3.88 4.09 3.70 4.18 4.07 4.60 4.05 3.70 3.71 3.64 4.26 4.34 4.00 3.71 3.43 3.35 3.76 3.53 3.67 3.55 3.54 3.96 4.12 3.75 ' 3.71 4.32 4.38 4.04 3.73 3.51 3.34 3.81 3.48 3.49 3.54 3.58 4.10 4.10 3.75 4.24 4.09 4.65 3.98 3.70 3.68 4.25 4.08 4.67 3.91 3.69 3.69 3.80 3.83 3.84 3.85 4.34 4.34 4.33 4.37 4.38 4.44 4.45 4.49 4.02 4.05 4.00 4.07 3.73 3.76 3.77 3.76 3.56 3.57 3.54 3.65 3.33 3.31 3.35 3.36 3.86 3.89 3.88 3.92 3.39 3.45 3.51 3.50 ABORTED ON DAY 26 OF GESTATION 3.53 3.52 3.54 3.58 3.54 3.56 3.59 3.58 3.98 3.97 3.92 3.98 3.96 3.87 3.79 3.77 3.73 3.78 3.81 3.80 4.27 4.09 4.68 3.88 3.71 3.78 4.30 4.04 4.68 3.92 3.73 3.77 4.29 3.96 4.72 3.93 3.74 3.78 4.37 3.92 4.66 3.94 3.80 3.87 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 17 (PAGE 3 ) : MATERNAL BODY W EIGHTS - IN D IV ID U A L DATA Z 6 C 0 0 PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 RABBIT # DOSAGE GROUP II 0.1 MG/KG/DAY 8594 P 8595 P 8596 P 8597 P 8598 P 8599 P 8600 P 8601 P 8602 P 8603 P 8604 NP 8605 P 8606 P 8607 NP 8608 P 8609 P 8610 P 8611 P 8612 P 8613 P 8614 P 8615 P 3.91 3.43 3.10 3.28 3.22 3.37 3.34 3.26 2.89 3.73 3.99 3.58 3.76 3.03 2.91 3.32 3.16 3.53 3.47 3.59 3.70 3.40 3.95 3.48 3.31 3.61 3.44 3.61 3.55 3.03 3.00 3.79 4.04 3.65 3.81 3.24 3.08 3.42 3.16 3.20 3.72 3.80 3.80 3.53 3.86 3.52 3.31 3.68 3.43 3.58 3.58 3.26 3.01 3.76 4.01 3.64 3.83 3.29 3.11 3.52 3.18 3.22 3.72 3.77 3.72 3.48 3.92 3.54 3.32 3.69 3.48 3.60 3.66 3.30 2.99 3.83 3.94 3.63 3.84 3.32 3.06 3.52 3.29 3.23 3.74 3.76 3.76 3.59 3.93 3.50 3.35 3.69 3.49 3.64 3.73 3.38 2.98 3.83 3.97 3.70 3.80 3.30 3.03 3.55 3.29 3.19 3.69 3.72 3.81 3.56 3.96 3.50 3.41 3.71 3.49 3.66 3.65 3.39 2.99 3.85 4.01 3.66 3.79 3.33 3.03 3.56 3.32 3.16 3.69 3.72 3.82 3.58 3.95 3.52 3.43 3.72 3.46 3.71 3.66 3.37 2.96 3.90 4.06 3.65 3.83 3.35 3.07 3.55 3.36 3.19 3.74 3.68 3.87 3.65 3.93 3.51 3.43 3.73 3.53 3.81 3.70 3.36 2.98 3.96 4.03 3.70 3.87 3.38 3.12 3.47 3.18 3.22 3.73 3.74 3.88 3.69 3.90 3.55 3.45 3.82 3.53 3.84 3.67 3.37 3.00 3.97 3.98 3.81 3.95 3.42 3.19 3.45 3.28 3.27 3.82 3.79 3.88 3.69 3.91 3.58 3.48 3.83 3.56 3.87 3.71 3.44 3.04 3.99 3.96 3.85 4.00 3.40 3.20 3.48 3.42 3.33 3.87 3.86 3.96 3.75 3.88 3.60 3.54 3.87 3.66 3.90 3.75 3.49 3.07 4.03 3.98 3.87 3.93 3.43 3.24 3.59 3.36 3.36 3.90 3.80 3.95 3.73 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG). ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 17 3.88 3.56 3.55 3.92 3.62 3.89 3.77 3.47 3.02 4.02 4.01 3.87 3.99 3.42 3.21 3.63 3.42 3.36 3.92 3.67 3.97 3.78 18 3.83 3.56 3.55 3.88 3.65 3.90 3.71 3.47 3.08 4.01 4.02 3.86 4.01 3.43 3.09 3.65 3.50 3.38 3.96 3.66 3.98 3.83 418-010: PAGE B-43 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 17 (PAGE 4) : MATERNAL BODY W EIGHTS - IN D IV ID U A L DATA 418-010: PAGE B-44 003944 PREGNANCY STATUS DAY 19 20 21 22 23 24 25 26 27 28 29 RABBIT # DOSAGE GROUP II 0.1 MG/KG/DAY 8594 P 8595 P 8596 P 8597 P 8598 P 8599 P 8600 P 8601 P 8602 P 8603 P 8604 NP 8605 P 8606 P 8607 NP 8608 P 8609 P 8610 P 8611 P 8612 P 8613 P 8614 P 8615 P 3.80 3.65 3.57 3.92 3.66 3.90 3.76 3.48 3.05 4.02 4.05 3.86 4.02 3.49 3.12 3.63 3.48 3.37 3.94 3.69 4.02 3.84 3.79 3.65 3.58 3.98 3.68 3.94 3.74 3.53 3.03 4.01 4.04 3.87 4.06 3.51 3.16 3.65 3.51 3.41 3.95 3.72 4.00 3.89 3.84 3.68 3.63 3.98 3.72 3.96 3.83 3.52 3.05 4.09 4.06 3.91 4.03 3.53 3.24 3.66 3.54 3.40 3.98 3.76 4.04 3.91 3.88 3.63 3.64 4.02 3.73 3.98 3.86 3.56 3.07 4.14 4.12 3.95 4.04 3.54 3.31 3.75 3.57 3.36 4.00 3.73 4.14 3.97 3.99 3.63 3.63 4.06 3.71 4.00 3.81 3.58 3.08 4.17 4.16 3.98 4.07 3.57 3.32 3.71 3.62 3.41 4.03 3.78 4.15 4.00 4.05 3.61 3.69 4.02 3.74 3.99 3.84 3.58 3.09 4.24 4.16 4.06 4.15 3.56 3.36 3.73 3.64 3.37 4.01 3.82 4.18 4.04 4.11 3.60 3.75 4.02 3.74 4.04 3.90 3.60 3.06 4.26 4.20 4.08 4.16 3.61 3.38 3.71 3.66 3.42 4.12 3.89 4.24 4.08 4.17 3.60 3.75 4.01 3.75 4.05 3.93 3.61 3.07 4.28 4.26 4.07 4.17 3.68 3.28 3.78 3.67 3.33 4.11 3.96 4.28 4.05 4.13 3.60 3.77 3.98 3.75 4.04 3.96 3.63 3.08 4.20 4.11 4.09 4.18 3.51 3.22 3.79 3.70 3.25 4.16 4.03 4.32 4.06 4.09 3.55 3.75 4.02 3.78 4.03 3.97 3.63 3.05 4.20 4.06 4.10 4.22 3.50 3.18 3.82 3.74 3.29 4.20 3.95 4.30 4.08 4.02 3.46 3.78 4.05 3.81 4.07 4.07 3.69 3.05 4.16 4.09 4.16 4.31 3.48 3.16 3.81 3.80 3.38 4.28 3.98 4.30 4.15 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG). ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: TABLE 17 (PAGE 5) : MATERNAL BODY W EIGHTS - IN D IV ID U A L DATA 6316.8) 418-010:PAGE B-45 003945 PREGNANCY STATUS DAY 0 7 RABBIT # DOSAGE GROUP III 8 9 10 11 12 13 14 15 16 1.0 MG/KG/DAY 8616 P 8617 P 8618 P 8619 P 8620 NP 8621 P 8622 P 8623 NP 6624 P 8625 P 6626 P 8627 P 8628 P 8629 P 8630 P 8631 P 8632 P 8633 P 8634 P 8635 P ObJb P 8637 P 3.70 3.76 3.64 3.52 3.07 2.84 3.45 3.33 3.07 3.60 3.12 2.96 3.26 3.36 3.31 3.18 3.59 3.23 3.83 3.57 3.40 3.96 3.95 3.73 3.55 3.53 3.31 3.21 3.59 3.53 3.16 3.63 3.29 3.15 3.34 3.48 3.48 3.27 3.73 3.22 3.92 3.71 3.44 3.91 3.94 3.78 3.52 3.57 3.32 3.12 3.62 3.62 3.24 3.70 3.35 3.03 3.46 3.49 3.46 3.29 3.70 3.21 3.96 3.71 3.50 3.94 3.99 3.80 3.55 3.58 3.34 3.15 3.66 3.58 3.25 3.74 3.30 3.02 3.50 3.51 3.47 3.29 3.75 3.21 3.95 3.66 3.45 3.97 3.92 3.74 3.47 3.58 3.36 3.03 3.65 3.59 3.29 3.78 3.22 3.07 3.51 3.51 3.46 3.21 3.78 3.22 3.97 3.72 3.47 3.93 3.94 3.81 3.42 3.56 3.36 3.07 3.71 3.61 3.30 3.76 3.26 3.11 3.57 3.56 3.47 3.25 3.78 3.19 3.98 3.73 3.50 3.92 3.87 3.80 3.41 3.53 3.32 3.04 3.68 3.63 3.32 3.77 3.30 3.14 3.54 3.56 3.47 3.26 3.78 3.14 4.03 3.76 3.53 3.94 3.92 3.84 3.44 3.48 3.32 3.05 3.73 3.65 3.34 3.72 3.35 3.10 3.61 3.60 3.53 3.31 3.85 3.18 4.06 3.81 3.52 3.97 3.90 3.83 3.47 3.49 3.27 3.16 3.75 3.69 3.32 3.65 3.45 3.13 3.69 3.63 3.62 3.37 3.93 3.20 4.09 3.82 3.57 4.07 3.93 3.80 3.48 3.44 3.30 3.14 3.81 3.67 3.36 3.73 3.49 3.16 3.71 3.66 3.67 3.47 3.95 3.21 4.11 3.86 3.64 4.15 3.96 3.76 3.50 3.41 3.38 3.18 3.85 3.71 3.36 3.82 3.52 3.20 3.71 3.70 3.70 3.48 4.00 3.22 4.18 3.84 3.63 4.13 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 17 3.86 3.69 3.51 3.33 3.36 3.27 3.70 3.68 3.34 3.83 3.51 3.23 3.71 3.72 3.69 3.50 3.96 3.24 4.20 3.87 3.64 4.15 18 3.79 3.69 3.55 3.33 3.36 3.23 3.74 3.72 3.39 3.85 3.36 3.22 3.72 3.72 3.69 3.49 3.94 3.26 4.16 3.89 3.68 4.18 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 17 (PAGE 6) : MATERNAL BODY W EIGHTS - IN D IV ID U A L DATA 9 &6C00 PREGNANCY STATUS DAY 19 20 21 22 23 24 25 26 27 28 29 RABBIT # DOSAGE GROUP III 1.0 MG/KG/DAY 8616 P 8617 P 8618 P 8619 P 8620 NP 8621 P 8622 P 8623 NP 8624 P 8625 P 8626 P 8627 P 8628 P 8629 P 8630 P 8631 P 8632 P 8633 P 8634 P 8635 P 8636 P 8637 P 3.73 3.67 3.55 3.28 3.39 3.29 3.77 3.70 3.39 3.90 3.38 3.22 3.77 3.74 3.67 3.50 3.97 3.28 4.19 3.90 3.66 4.21 3.68 3.69 3.61 3.24 3.41 3.36 3.79 3.72 3.40 3.91 3.42 3.26 3.75 3.78 3.67 3.55 4.00 3.31 4.20 3.89 3.72 4.20 3.86 3.70 3.64 3.27 3.44 3.36 3.80 3.74 3.43 3.92 3.46 3.28 3.84 3.81 3.71 3.58 4.02 3.36 4.20 3.91 3.78 4.23 3.86 3.72 3.64 3.28 3.48 3.41 3.80 3.81 3.45 3.80 3.47 3.30 3.88 3.85 3.76 3.64 4.04 3.31 4.22 3.96 3.80 4.28 3.89 3.73 3.66 3.19 3.49 3.42 3.77 3.81 3.52 3.78 3.52 3.31 3.93 3.88 3.78 3.65 4.02 3.39 4.25 4.00 3.78 4.28 3.91 3.74 3.66 3.24 3.51 3.49 3.80 3.82 3.51 3.73 3.50 3.33 3.91 3.92 3.76 3.66 4.04 3.40 4.26 4.03 3.86 4.32 3.93 3.80 3.65 3.34 3.53 3.48 3.83 3.86 3.52 3.70 3.51 3.32 3.94 3.92 3.80 3.70 4.04 3.44 4.35 4.08 3.87 4.38 3.96 3.84 3.68 3.29 3.53 3.39 3.83 3.94 3.54 3.62 3.52 3.28 3.98 3.90 3.89 3.71 3.91 3.44 4.36 4.13 3.94 4.34 3.99 3.85 3.67 3.32 3.58 3.41 3.87 3.92 3.62 3.55 3.53 3.19 3.96 3.90 3.95 3.79 3.99 3.46 4.43 4.17 3.99 4.32 3.96 3.86 3.70 3.38 3.58 3.46 3.85 3.94 3.65 3.49 3.59 3.17 3.96 3.90 3.99 3.84 4.03 3.47 4.43 4.21 3.99 4.36 3.93 3.88 3.73 3.46 3.59 3.48 3.87 4.04 3.64 3.47 3.62 3.23 3.95 3.90 4.00 3.83 4.09 3.48 4.45 4.24 4.05 4.42 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 418-010: PAGE B-46 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: TABLE 17 (PAGE 7) : MATERNAL BODY W EIGHTS - IN D IV ID U A L DATA 6 3 1 6 .8 ) 418-010:PAGE B-47 003947 PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 IS 16 RABBIT # DOSAGE GROUP IV 2.5 MG/KG/DAY 8638 P 8639 P 8640 P 8641 P 8642 P 8643 P 8644 P 8645 P 8646 P 8647 P 8648 P 8649 P 8650 P 8651 P 8652 P 8653 NP 8654 P 8655 P 8656 P 8657 P 8658 P 8659 P 3.42 3.73 3.92 3.46 4.09 3.39 3.22 3.31 2.91 3.13 3.53 3.36 3.10 3.26 3.60 3.64 2.87 3.59 3.80 3.25 3.05 3.41 3.45 4.02 4.08 3.40 4.05 3.52 3.41 3.48 3.01 3.36 3.71 3.51 3.22 3.38 3.66 3.73 3.01 3.56 3.81 3.36 3.19 3.36 3.42 4.00 4.07 3.38 4.07 3.58 3.36 3.44 3.00 3.30 3.74 3.48 3.19 3.42 3.68 3.73 3.00 3.62 3.88 3.34 3.20 3.39 3.34 3.90 3.97 3.35 4.07 3.53 3.39 3.52 2.98 3.41 3.66 3.39 3.10 3.47 3.72 3.78 3.01 3.62 3.88 3.43 3.27 3.40 3.26 3.79 3.90 3.34 4.09 3.58 3.40 3.51 2.90 3.33 3.75 3.29 3.14 3.42 3.74 3.77 3.01 3.62 3.95 3.44 3.26 3.30 3.22 3.76 3.85 3.33 4.06 3.52 3.40 3.55 2.87 3.23 3.77 3.32 3.14 3.47 3.74 3.80 2.92 3.63 3.96 3.45 3.28 3.33 3.26 3.78 3.84 3.34 4.07 3.53 3.42 3.57 2.77 3.28 3.77 3.37 3.16 3.45 3.63 3.64 2.95 3.65 3.95 3.47 3.32 3.37 3.34 3.67 3.77 3.35 4.02 3.50 3.36 3.59 2.79 3.06 3.69 3.42 3.18 3.47 3.56 3.59 3.01 3.71 3.99 3.55 3.34 3.39 3.44 3.72 3.75 3.39 4.00 3.56 3.35 3.61 2.72 3.08 3.61 3.46 3.19 3.49 3.47 3.58 3.08 3.72 4.01 3.53 3.42 3.27 3.39 3.64 3.66 3.42 3.96 3.62 3.42 3.68 2.74 3.10 3.62 3.50 3.25 3.60 3.45 3.62 3.07 3.75 4.07 3.58 3.46 3.29 3.37 3.65 3.70 3.42 3.94 3.64 3.47 3.65 2.68 2.94 3.70 3.63 3.26 3.61 3.43 3.62 3.06 3.74 4.10 3.62 3.48 3.31 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. (KG) . 17 3.32 3.61 3.68 3.36 3.90 3.64 3.39 3.69 2.80 2.96 3.71 3.70 3.27 3.68 3.35 3.66 3.12 3.74 4.08 3.60 3.50 3.42 18 3.30 3.56 3.69 3.33 3.94 3.66 3.44 3.76 2.93 2.91 3.77 3.71 3.30 3.67 3.32 3.74 3.14 3.74 4.08 3.64 3.51 3.47 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 17 (PAGE 8) : MATERNAL BODY W EIGHTS - IN D IV ID U A L DATA 418-010: PAGE B-48 003948 PREGNANCY STATUS DAY 19 20 21 22 23 24 25 26 27 28 29 RABBIT # DOSAGE GROUP IV 2.5 MG/KG/DAY 8638 P 8639 P 8640 P 8641 P 8642 P 8643 P 8644 P 8645 P 8646 P 8647 P 8648 P 8649 P 8650 P 8651 P 8652 P 8653 NP 8654 P 8655 P 8656 P 8657 P 8658 P 8659 P 3.30 3.57 3.55 3.29 3.94 3.70 3.42 3.73 2.98 2.82 3.75 3.72 3.29 3.67 3.27 3.74 3.18 3.72 4.08 3.64 3.55 3.47 3.30 3.58 3.57 3.22 3.92 3.71 3.44 3.72 3.02 2.70 3.76 3.74 3.31 3.70 3.20 3.72 3.20 3.74 4.08 3.71 3.56 3.46 3.34 3.54 3.61 3.17 3.97 3.76 3.47 3.75 3.03 2.66 3.79 3.75 3.35 3.71 3.17 3.80 3.18 3.76 4.10 3.68 3.57 3.52 3.38 3.41 3.48 3.55 3.48 3.48 3.48 3.51 3.68 3.75 3.83 3.89 3.16 3.18 3.24 3.29 3.96 4.00 4.03 4.03 3.77 3.82 3.84 3.88 3.50 3.51 3.52 3.51 3.78 3.80 3.83 3.88 3.00 3.02 3.02 3.05 ABORTED ON DAY 21 OF GESTATION 3.85 3.88 3.83 3.89 3.78 3.80 3.81 3.82 3.32 3.33 3.36 3.39 3.73 3.75 3.78 3.72 3.14 3.08 3.04 3.01 3.80 3.85 3.84 3.81 3.24 3.26 3.26 3.30 3.80 3.83 3.82 3.86 4.15 4.18 4.22 4.24 3.72 3.74 3.76 3.77 3.63 3.64 3.69 3.72 3.53 3.54 3.56 3.53 3.61 3.51 3.95 3.32 4.02 3.89 3.52 3.92 3.07 3.89 3.84 3.42 3.73 2.97 3.89 3.35 3.89 4.33 3.78 3.73 3.58 3.65 3.44 3.94 3.37 4.03 3.92 3.50 3.92 3.10 3.68 3.52 3.98 3.37 4.02 3.94 3.50 3.92 3.10 3.67 3.59 3.96 3.39 4.06 3.97 3.49 3.95 3.15 3.90 3.91 3.99 3.86 3.87 3.88 3.45 3.50 3.47 3.70 3.78 3.77 ABORTED ON DAY 26 OF GESTATION 3.92 3.94 4.00 3.39 3.40 3.42 3.91 3.87 3.91 4.35 4.35 4.41 3.80 3.80 3.83 3.75 3.71 3.73 3.63 3.67 3.76 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: TABLE 17 (PAGE 9) : MATERNAL BODY W EIGHTS - IN D IV ID U A L DATA 6 3 1 6 .8 ) 418-010: PAGE B-49 003949 PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 RABBIT # DOSAGE GROUP V 3.75 MG/KG/DAY 8660 P 8661 P 8662 P 8663 P 8664 P 8665 P 8666 P 8667 P 8668 P 8669 P 8670 P 8671 P 8672 P 8673 P 8674 P 8675 P 8676 P 8677 NP 8678 P 8679 P 8680 P 8681 P 3.76 3.44 3.49 3.95 4.18 2.99 3.58 2.97 2.89 3.70 3.12 3.35 3.21 3.23 3.55 3.26 3.70 3.09 3.37 3.61 3.31 3.39 3.92 3.55 3.68 4.04 4.12 3.24 3.78 3.26 3.26 3.81 3.24 3.41 3.40 3.38 3.57 3.30 3.71 3.12 3.58 3.64 3.39 3.54 3.63 3.47 3.55 4.00 4.04 3.19 3.71 3.20 3.20 3.78 3.28 3.44 3.31 3.40 3.55 3.29 3.75 3.15 3.61 3.72 3.43 3.54 3.69 3.35 3.51 3.84 3.99 3.11 3.73 3.17 3.29 3.76 3.32 3.33 3.23 3.39 3.61 3.24 3.80 3.18 3.60 3.86 3.43 3.61 3.42 3.29 3.41 3.84 3.98 3.12 3.89 3.22 3.35 3.72 3.22 3.36 3.11 3.44 3.58 3.21 3.76 3.26 . 3.59 3.67 3.53 3.69 3.54 3.31 3.39 3.83 3.86 3.09 3.82 3.11 3.30 3.66 3.25 3.38 3.09 3.38 3.56 3.22 3.76 3.22 3.61 3.65 3.51 3.62 3.41 3.17 3.34 3.68 3.86 2.96 3.86 3.14 3.30 3.55 3.23 3.42 3.09 3.33 3.58 3.25 3.78 3.22 3.63 3.62 3.49 3.60 3.50 3.24 3.33 3.68 3.79 2.97 3.80 3.07 3.35 3.59 3.27 3.50 3.05 3.28 3.62 3.27 3.80 3.21 3.66 3.66 3.48 3.56 3.52 3.17 3.23 3.69 3.81 2.87 3.93 3.03 3.44 3.54 3.31 3.56 3.03 3.19 3.66 3.31 3.79 3.22 3.70 3.69 3.48 3.50 3.56 3.18 3.22 3.60 3.73 3.01 3.99 3.01 3.48 3.54 3.36 3.60 3.09 3.12 3.67 3.33 3.82 3.23 3.73 3.70 3.46 3.40 3.40 3.12 3.21 3.63 3.64 3.13 3.99 2.93 3.49 3.49 3.38 3.62 3.21 3.10 3.64 3.32 3.79 3.23 3.77 3.83 3.48 3.40 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 17 3.52 3.14 3.15 3.65 3.74 3.16 4.00 2.87 3.52 3.44 3.36 3.62 3.30 3.05 3.63 3.28 3.80 3.21 3.74 3.86 3.48 3.29 18 3.54 3.09 3.13 3.53 3.73 3.13 4.00 2.81 3.50 3.41 3.38 3.67 3.27 3.04 3.62 3.27 3.85 3.21 3.78 3.82 3.50 3.29 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OP N -E tF O S E IN R A B B IT S (SPO N SO R' S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 17 (PAGE 10) : MATERNAL BODY W EIGHTS - IN D IV ID U A L DATA S 6C o o PREGNANCY STATUS DAY 19 20 21 22 23 24 25 26 27 28 29 RABBIT # DOSAGE GROUP V 3.75 MG/KG/DAY 8660 P 8661 P 8662 P 8663 P 8664 P 8665 P 8666 P 8667 P 8668 P 8669 P 8670 P 8671 P 8672 P 8673 P 8674 P 8675 P 8676 P 8677 NP 8678 P 8679 P 8680 P 8681 P 3.37 ABORTED ON DAY 20 OF GESTATION 3.07 3.03 3.10 3.12 3.02 3.07 3.05 3.05 2.97 2.96 3.56 3.57 3.48 3.48 3.54 3.63 3.62 3.63 3.71 3.82 3.14 3.13 3.17 3.22 3.24 4.00 4.00 4.05 4.08 4.12 ABORTED ON DAY 19 OF GESTATION 3.57 3.61 3.48 3.55 3.52 3.41 3.37 3.35 3.30 3.25 3.37 3.34 3.35 3.42 3.48 3.68 3.71 3.74 3.75 3.75 3.25 3.28 3.35 3.37 3.38 3.05 2.98 3.01 3.01 3.06 3.63 3.63 3.63 3.66 3.69 3.29 3.33 3.39 3.38 3.39 3.87 3.88 3.91 3.92 3.97 3.26 3.26 3.29 3.38 3.41 3.88 3.83 3.81 3.89 3.84 3.81 3.84 3.91 3.90 3.97 3.52 3.54 3.62 3.61 3.62 3.32 3.26 3.31 3.29 3.43 ABORTED ON DAY 23 OF GESTATION 2.90 2.90 2.86 2.81 2.76 2.74 3.47 3.42 ABORTED ON DAY 26 OF GESTATION 3.90 3.89 3.93 3.92 3.95 4.00 3.29 3.27 3.28 3.31 3.31 3.35 4.17 4.22 4.25 4.28 4.27 4.32 3.60 3.23 3.48 3.77 3.39 3.10 3.71 3.40 4.02 3.38 3.88 4.01 3.63 3.55 3.62 3.20 3.54 3.82 3.42 3.18 3.71 3.41 3.97 3.40 3.96 4.05 3.63 3.63 3.63 3.18 3.56 3.91 3.49 3.25 3.77 3.42 4.01 3.41 3.95 4.10 3.66 3.64 3.65 3.17 3.53 3.92 3.57 3.32 3.80 3.40 4.02 3.44 3.98 4.12 3.67 3.64 3.64 3.11 3.58 3.94 3.54 3.37 3.84 3.42 4.06 3.48 4.02 4.16 3.69 3.66 3.75 a 3.62 3.92 3.60 3.36 3.87 3.44 4.14 3.53 4.10 4.11 3.70 3.71 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE, a. Doe 8669 aborted on day 29 of gestation. (KG). 418-010: PAGE B-50 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 17 (PAGE 11) : MATERNAL BODY W EIGHTS - IN D IV ID U A L DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 RABBIT # SATELLITE DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8682 P 8683 P 8684 P 3.66 3.44 3.26 3.78 3.59 3.49 3.81 3.65 3.56 3.84 3.65 3.55 3.86 3.69 3.58 3.94 3.71 3.60 3.96 3.77 3.62 3.96 3.80 3.66 3.98 3.86 3.63 4.04 3.91 3.72 4.02 3.91 3.77 DAY 19 20 21 8682 P 8683 P 8684 P 4.12 3.96 3.76 4.12 3.98 3.80 4.20 4.10 3.86 P = PREGNANT NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VLUE. 17 4.03 3.94 3.77 18 4.12 3.88 3.75 418-010: PAGE B-i 003951 tn PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 17 (PAGE 12) : MATERNAL BODY W EIGHTS - IN D IV ID U A L DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 RABBIT # SATELLITE DOSAGE g r o u p :II 0.1 MG/KG/DAY 8685 P 8686 P 8687 P 8688 P 8689 P 3.68 3.48 3.51 3.57 3.27 3.75 3.44 3.67 3.61 3.47 3.75 3.46 3.70 3.67 3.48 3.76 3.50 3.70 3.68 3.53 3.75 3.55 3.72 3.71 3.50 3.77 3.54 3.74 3.68 3.46 3.72 3.60 3.83 3.64 3.44 3.76 3.62 3.85 3.64 3.51 3.73 3.62 3.85 3.67 3.54 3.74 3.70 3.91 3.74 3.64 3.86 3.70 3.92 3.73 3.70 DAY 19 20 21 8685 P 8686 P 8687 P 8688 P 8689 P 3.94 3.79 4.00 3.84 3.71 3.94 3.80 4.09 3.86 3.73 3.99 3.90 3.97 3.94 3.74 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 17 3.90 3.73 3.95 3.76 3.66 18 3.96 3.76 3.96 3.80 3.69 418-010:PAGE B-52 003952 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 17 (PAGE 13) : MATERNAL BODY W EIGHTS - IN D IV ID U A L DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 RABBIT # SATELLITE DOSAGE GROUP III 1.0 MG/KG/DAY 8690 P 8691 P 8692 P 4.05 3.46 3.01 4.03 3.59 3.30 4.00 3.57 3.33 4.04 3.54 3.29 4.01 3.61 3.22 3.99 3.65 3.17 4.07 3.64 3.19 4.15 3.68 3.17 4.21 3.69 3.18 4.21 3.74 3.20 4.26 3.80 3.23 STATUS DAY 19 20 21 8690 P 8691 P 8692 P 4.28 4.30 4.35 ABORTED ON DAY 18 OF GESTATION 3.30 3.34 3.26 P = PREGNANT NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 17 4.28 3.73 3.28 ' 18 4.28 3.72 3.29 ^6C 00 418-010:PAGE B-53 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 17 (PAGE 14) : MATERNAL BODY W EIGHTS - IN D IV ID U A L DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 RABBIT # SATELLITE DOSAGE GROUP IV 2.5 MG/KG/DAY 8693 NP 8694 P 8695 P 3.70 3.42 2.88 3.79 3.47 3.03 3.81 3.48 3.06 3.84 3.55 3.02 3.84 3.56 2.99 3.85 3.56 3.04 3.89 3.54 3.05 3.87 3.56 3.04 3.92 3.61 3.10 3.98 3.68 3.11 3.81 3.64 3.14 STATUS DAY 19 20 21 8693 NP 8694 p 8695 p 3.74 3.70 3.18 3.78 3.73 3.18 3.86 3.84 3.25 P - PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. (KG) . 17 3.76 3.62 3.14 18 3.74 3.64 3.18 418-010:PAGE B-54 003954 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 17 (PAGE 15) : MATERNAL BODY W EIGHTS - IN D IV ID U A L DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 RABBIT # SATELLITE DOSAGE GROUP V 3.75 MG/KG/DAY 8696 P 8697 P 8698 P 8699 P 8700 P 4.18 3.42 3.53 3.63 3.24 4.12 3.34 3.76 3.71 3.25 4.13 3.31 3.77 3.73 3.42 4.17 3.24 3.75 3.73 3.39 4.21 3.27 3.80 3.76 3.35 4.20 3.24 3.84 3.72 3.26 4.20 3.26 3.82 3.74 3.27 4.28 3.23 3.85 3.79 3.24 4.31 3.24 3.80 3.90 3.12 4.32 3.20 3.80 3.95 3.27 4.34 3.22 3.73 3.93 3.21 STATUS DAY 19 20 21 8696 P 8697 P 8698 P 8699 P 8700 P 4.42 4.38 4.50 3.29 3.28 3.34 3.50 3.46 3.51 3.94 3.98 4.03 ABORTED ON DAY 19 OF GESTATION P PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 17 4.35 3.24 3.64 3.92 3.26 18 4.37 3.28 3.54 3.94 3.14 418-010:PAGE B-55 003955 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R AB BITS (SPO N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 18 (PAGE 1) : MATERNAL FEED CONSUMPTION VALUES - IN D IV ID U A L DATA 418-010:PAGE B-56 003956 PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 1 0 1 0 - 1 1 1 1 - 1 2 1 2 - 1 3 1 3 - 1 4 1 4 - 1 5 1 5 - 1 6 1 6 - 1 7 17 - 18 18 - 19 19 - 20 RABBIT # DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8572 P 8573 P 8574 P 8575 P 8576 NP 8577 P 8578 P 8579 P 8580 NP 8581 P 8582 P 8583 NP 8584 NP 8585 P 8586 P 8587 P 8588 P 8589 P 8590 P 8591 P 8592 P 8593 P 8. 184. 124. 152. 182. 183. 185. 184 . 180. 180. 142. 161. 182. 185. 182. 112. 185. 168. 181. 184. 130. 182. 86. 185. a 173 . 182. 177. 181. 173. 176. 185. 171. 160. 181. 184. 167. 133 . 181. 181. 180. 184. 158. 162. 126. 144. 158. 169. 185. 174. 176. 139. 124. 182. 151. 0. 181. 185. 176. 121. 180. 185. 185. 180. 163. 180. 96. 123. 184. 164. 180. 159. 134. 133. 164. 185. 121. 147. 181. 182. 166. 78. 181. 170. 185. 180. 185. 185. 110 160 166 113 185 185 163 185 165 175 92 170 184 181 176 51 180 171 183 185 162 100 141. 125. 145. 67. 179. 182. 181. 183. 166. 141. 162. 162. 160. 151. 180. 174. 185. 185. 185. 180. 145. 175. 180. 185. 135. 183. 182. 173. 136. 156. 127. 182. 182. 181. 157. 143. 180. 153. 162. 179. 112. 103. 110. 137. 181. 185. 183. 178. 180. 182. 183. 185. 180. 181. 185. 185. 134. 133. 158. 162. FOUND DEAD ON DAY 13 OF GESTATION 182. 185. 184. 182. 152. 174. 164. 180. 181. 183. 184 . 155. 182. 185. 181. 182. 153. 185. 163. 120. 155. 141. 130. 149. 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. 13. 181. 72. 153. 178. 184. 175. 183. 128. 167. 113. 162. 183 . 183. 102. 182. 182. 141. 182. 87. 141. 31. 162. 156. 167. 164 . 185. 163. 182. 169. 67. 97. 114. 183. 184. 133. 181. 180. 142. 185. 116. 141. 60. 98. 159. 164. 171. 181. 184. 182. 182. 182. 95. 139. 184. 166. 110. 184 . 184. 149. 183. 127. 152. 115 139 126 166 150 141 183 183 157 164 99 134 167 161 128 184 183 182 181 165 149 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 18 (PAGE 2) : MATERNAL FEED CONSUMPTION VALUES - IN D IV ID U A L DATA 418-010:PAGE B-57 003957 PREGNANCY STATUS DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 RABBIT # DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8572 P 8573 P 8574 P 8575 P 8576 NP 8577 P 8578 P 8579 P 8580 NP 8581 P 8582 P 8583 NP 8584 NP 8585 P 8586 P 8587 P 8588 P 8589 P 8590 P 8591 P 8592 P 8593 P 126. 139. 74. 65. 73. 86. 124. 170. 10. 53. 101. 157. 132. 128. 104. 95. 143. 177. 180. 164. 156. 181. 181. 181. 148. 142. 136. 109. 173. 176. 183. 162. 123. 167. 111. 32. 151. 162. a 114. 118. 145. 149. 183. 142. 130. 115. 143. 180. 182. 184. 185. 184. 163. 145. 113 . 146. 122. 138. 124. FOUND DEAD ON DAY 13 OF GESTATION 184. 184. a 184. 148. 116. 119. 136. 184. 184. 185. 181. 184. 153. 144. 93. 166. 131. 122. 108. 142. 122. 128. 133. 104. 146. 102. 84. 154. 182. 89. 138. 16. 51. 180. 147. 182. 81. 135. 185. 91. 181. 6. 111. 103 . 134. 161. 136. 160. 152. 124. 131. 129. 132. 146. 131. 135. 51. 84 . 85. 111. 166. 174. 182. 133. 183. 184. 183. 181. 58. 61. 114. 70. 146. 123. 148. 95. 80. 156. 165. 111. ABORTED ON DAY 26 OF GESTATION 182. 182. 164. 106. 135. 168. 151. 93. 183. 182. 183. 181. 11. 0. 0. 1. 140. 110. 103. 87. 183. 114 . 185. 73. 108. 155. 182. 34 . 183. 78. 86. 122- 181. 4. 172. 89. 109. 130. 147. 6. 152. 43. 119. 124. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G) . a. Spilled feed precluded the calculation of this value. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 18 (PAGE 3) : MATERNAL FEED CONSUM PTION VALUES - IN D IV ID U A L DATA 418-010: PAGE B-58 003958 PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 1 0 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 RABBIT # DOSAGE GROUP II 0.1 MG/KG/DAY 8594 P 8595 P 8596 P 8597 P 8598 P 8599 P 8600 P , 8601 P 8602 P 8603 P 8604 NP 8605 P 8606 P 8607 NP 8608 P 8609 P 8610 P 8611 P 8612 P 8613 P 8614 P 8615 P 95. 136. 184. 182. 183. 182. 184. 183 . 180. 184. 51. 183. 182. 181. 181. 182. 183. 170. 185. 95. 182. 181. 147. 168. 181. 184. 184 . 184. 174. 184 . 150. 181. 86. 183. 122. 184. 160. 174. 180. 141. 183. 100. 182. 180. 157. 101. 182. 182. 166. 184. 161. 184. 125. 183. 89. 164. 100. 180. 152. 180. 169. 114. 182. 94. 182. 184. 177. 133. 181. 182. 140. 180. 148. 176. 105. 181. 162. 185. 129. 184. 119. 146. 170. 73. 182. 97. 185. 184. 113. 140. 182. 182. 183. 181. 154. 170. 126. 180. 138. 126. 122. 182. 147. 132. 184. 125. 181. 93. 181. 180. 185. 149. 183. ISO. 185. 185. 116. 145. 111. 185. 183. 169. 143. 185. 153. 87. 92. 135. 183. 121. 181. 182. ' 63. 142. 185. 185. 183 . 180. 180. 180. 151. 126. 130. 185. 157. 184. 142. 62. 156. 104. 185. 140. 185. 185. 64. 171. 183 . 180. 180. 180. 168. 182. 150. 90. 124. 184. 159. 184. 161. 109. 183. 164. 184. 148. 183. 185. 26. 126. 185. 181. 180. 184. 148. 182. 157. 127. 172. 183. 168. 182. 155. 158. 180. 168. 182. 46. 181. 184. 30. 77. 184. 184. 185. 185. 164. 183. 68. 119. 162. 183. 185. 181. 110. 181. 184. 185. 184. 18. 183. 181. 15. a 184. 185. 185. 185. 137. 121. 149. 118. 141. 185. 182. 184. 7. 181. 185. 184. 181. 89. 180. 182. 11. 127. 183. 185. 185. 182. 145. 110. 163. 114. 144. 185. 180. 185. 76. 180. 180. 172. 183. 83. 180 . 181. 32. 154. 181. 183. 184. 181. 101. 126. 80. 158. 119. 185. 178. 185. 127. 182. 183. 162. 182. 123 . 184. 184. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OP PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G). a. Spilled feed precluded the calculation of this value. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SPO N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 18 (PAGE 4) : MATERNAL FEED CONSUMPTION VALUES - IN D IV ID U A L DATA 418-010: PAGE B-59 003959 PREGNANCY STATUS DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 RABBIT # DOSAGE GROUP II 0.1 MG/KG/DAY 8594 P 8595 P 8596 P 8597 P 8598 P 8599 P 8600 P 8601 P 8602 P 8603 P 8604 NP 8605 P 8606 P 8607 NP 8608 P 8609 P 8610 P 8611 P 8612 P 8613 P 8614 P 8615 P 53. 150. 180. 182. 180. 180. 142. 110. 74. 176. 163. 180. 184. 184. 184. 180. 181. 124. 181. 141. 180. 182. 74. 106. 184. 184. 184. 181. 175. 134. 101. 184 . 159. 185. 3. 184. 146. 181. 181. 43 . 182. 49. 183. 181. 124. 90. 184. 182. 182. 180. 173. 152. 130. 157. 165. 184. 158. 183. 143. 159. 185. 98. 183. 160. 185. 182. 164. 73. 181. 119. 181. 141. 121. 73 . 110. 159. 161. 166. 158. 184. 146. 147. 172. 45. 184. 183. 184. 183. 182. 67. 164. 103. 172. 145. 151. 83. 37. 182. 159. 102. 155. 183. 99. 92. 150. 63. 184. 185. 183. 184. 167. 71. 149. 104. 183. 139. 147. 86. 66. 145. 169. 112. 143. 184. 43. 132. 146. 9. 180. 183. 172. 117. 165. 76. 151. 82. 182. 136. 132. 88. 67. 49. 97. 116. 166 . 83. 19. 130. 123. 6. 184. 183 . 151. 99. 142. 41. 152. 134. 183. 141. 176. 122. 101. 71. 94. 118. 144. 132. 9. 113. 128. 55. 181. 117. 118. 110. 100. 9. 109. 107. 122. 100. 95. 103. 25. 56. 69. 100. 121. 91. 29. 90. 141. 88. 172. 109. 96. 125. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G). PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 18 (PAGE S) : MATERNAL FEED CONSUMPTION VALUES - IN D IV ID U A L DATA 418-010: PAGE B-60 003960 PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 1 0 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 RABBIT # DOSAGE GROUP III 1.0 MG/KG/DAY 8616 P 8617 P 8618 P 8619 P 8620 NP 8621 P 8622 p 8623 NP 8624 P 8625 P 8626 P 8627 P 8628 P 8629 P 8630 P 8631 P 8632 P 8633 P 8634 P 8635 P 8636 P 8637 P 149. 154. 37. 121. 182. 182. 185. 183. 185. 180. 156. 52. 184. 185. 184. 182. 183. 146. 185. 182. 184. 182. 173. 144. 2. 129. 182. 175. 185. 184. 180. 183. 89. 92. 182. 181. 172. 5. 183. 125. 181. 163. 183. 183. 150. 92. 0. 104. 182. 46. 183. 126. 172. 185. 35. 126. 181. 181. 168. 135. 183. 149. 182. 143. 162. 183. 95. 138. 0. 69. 98. a 180. 185. 174 . 167. 133. 156. 183. 180. 141. 143. 184. 86. 185. 155. 183. 146. 34. 126. 60. 4. 145. 79. 184. 181. 160. 130. 159. 134. 182. 154. 122. 145. 180. 109. 180. 151. 150. 144 . 79. 111. 49. 34. 135. 95. 185. 178 . 171. 113. 113 . 114. 180. 125. 120. 149. 184. 117. 182. 181. b 164. 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. b. Wet feed precluded the calculation of this value. 57. 81. 30. 11. 106. 180. 180. 174. 112. 59. 163. 110. 185. 134. 154. 185. 185. 101. 184. 184. 176. 182. 72. 99. 40. 8. 167. 180. 180. 182. 127. 133. 144. 94. 174. 151. 182. 185. 185. 107. 185. 185. 185. 181. 76. 21. 66. 2. 185. 183. 181. 184. 135. 164. 174. 148. 185. 185. 182. 184. 185. 117. 180. 183. 184. 181. 35. 10. 77. 0. 176. 185. 126. 185. 160. 183. 185. 162. 185. 185. 182. 180. 180. 149. 180. 182. 180. 182. 1. 22. 109. 0. 184 . 184. 115. 181. 182. 182. 147. 157. 184. 184. 185. 183. 182. 135. 185. 185. 181. 185. 2. 29. 135. 2. 180. 185. 150. 185. 185. 183 . 98. 122. 180. 182. 180. 180. 183 . 147. 181. 183. 181. 184. 17 57 132 6 180 183 168 182 182 167 113 133 180 184 184 180 183 158 180 185 185 177 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 18 (PAGE 6) : MATERNAL FEED CONSUMPTION VALUES - IN D IV ID U A L DATA 418-010: PAGE B-61 003961 PREGNANCY STATUS DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 RABBIT # DOSAGE GROUP III 1.0 MG/KG/DAY 8616 P 8617 P 8618 P 8619 P 8620 NP 8621 P 8622 P 8623 NP 8624 P 8625 P 8626 P 8627 P 8628 P 8629 P 8630 P 8631 P 8632 P 8633 P 8634 P 8635 P 8636 P 8637 P 74. 53. 127. 3. 174. 182. 145. 184. 182. 137. 126. 135. 182. 184. 183. 182. 181. 166. 180. 184. 177. 146. 43. 56. 131. 1. 170. 182. 140. 184. 184. 93. 143. 157. 175. 172. 174. 169. 181. 43. 183. 183. 181. 3. 76. 65. 122. 3. 182. 183. 139. 183. 158. 39. 116. 119. 174. 163. 153. 184. 184. 128. 185. 183. 180. 181. 103. 111. 117. 17. 166. 180. 109. 183. 150. 13 . 134. 93. 159. 173. 161. 182. 185. 130. 184. 185. 184. 184. 95. 104. 80. 8. 156. 156. 116. 183. 129. 15. 125. 54 . 146. 140. 171. 184. 181. 116. 184. 184. 183. 169. 109. 100. 109. 35. 154. a 122. 183 . 93. 2. 140. 34. 166. 112. 180. 184. 184. 108. 183. 149. 182. 98. 133. 99. 91. 66. 170. 102. 135. 181. 167. 2. 167. 3. 129. 89. 183. 185. 183. 68. 169. 143. 174. 86. 100. 87. 112. 96. 185. 154. 160. 181. 154. 7. 151. 82. 89. 47. 159. 165. a 54. 160. 139. 153. 112. 71. 114. 109. 106. 128. 118. 139. 184 . 86. 2. 96. 63. 87. 88. 132. 126. 180. 51. 142. 120. 142. 113. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G) . a. Spilled feed precluded the calculation of this value. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 8 3 1 6 .8 ) TABLE 18 (PAGE 7) : MATERNAL FEED CONSUMPTION VALUES - IN D IV ID U A L DATA 418-010: PAGE B-62 003962 PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 1 0 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 RABBIT # DOSAGE GROUP IV 2.5 MG/KG/DAY 8638 P 8639 P 8640 P 8641 P 8642 P 8643 P 8644 P 8645 P 8646 P 8647 P 8648 P 8649 P 8650 P 6651 P 8652 P 8653 NP 8654 P 8655 P 8656 P 8657 P 8658 P 8659 P 59. 154. 146. 71. 184. 181. 182. 185. 180. 104. 180. 139. 152. 184. 183. 185. 184. 185. 185. 181. 184. 183. 10. 60. 54. 57. 185. 182 . 169. 181. 114. 99. 155. 76. 63. 180. 178. 182. 161. 144. 184. 178. 168. 185. 5. 2. 7. 52. 174. 183 . 183. 185. 18. 2. 137. 36. 132. 185. 181. 174. 144. 183. 181. 165. 159. 69. 2. 0. 0. 48. 158. 131. 109. 184. 1. 42. 136. 113 . 124. 180. 119. 118. 183. 182. 185. 152. 185. 101. 48. 3. 1. 59. 139. 122. 128. 183. 3. 14. 101. 151. 169. 185. 0. 26. 138. 180. 183. 136. 182. 59. 84. 2. 3. 62. 151. 124. 80. 162. 1. 1. 37. 130. 112. 162. 1. 73. 140. 181. 183. 140. 184. 57. 83. 4. 5. 55. 120. 165. 82. 168. 3. 1. 14. 133. 102. 162. 2, 87. 141. 184. 185. 185. 185. 4. 5. 2. 3. 49. 113. 180. 130. 169. 1. 2. 49. 131. 102. 181. 0. 129. 142. 182. 183. 161. 180. 2. 23. 0. 2. 24. 89. 182. 168. 182. 36. 0. 84. 182. 130. 154. 2. 127. 127. 183. 180. 181. 181. 55. 16. 1. 3. 2. 101. 185. 154. 185. 127. 4. 109. 185. 123. 174. 0. 184 . 176. 170. 185. 185. 182. 114 . 21. 0. 0. 0. 100. 184. 165. 185. 183. 1. 152. 183 . 122. 184. 10. 173. 181. 148. 184. 180. 185. 150. 63. 3. 2. 3. 115. 180. 157. 185. 179. 12. 97. 180. 114. 169. 0. 152. 157. 159. 184. 184. 180. 181. 55. 1. 79. 0. 108. 182. 155. 182. 163. 0. 101. 175. 136. 162. 0. 170. 172. 182. 183. 181. 185. 184 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G) . PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 18 (PAGE 8) : MATERNAL FEED CONSUMPTION VALUES - IN D IV ID U A L DATA 418-010: PAGE B-63 003963 PREGNANCY STATUS DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 RABBIT # DOSAGE GROUP IV 2.5 MG/KG/DAY 8638 P 8639 P 8640 P 8641 P 8642 P 8643 P 8644 P 8645 P 8646 P 8647 P 8648 P 8649 P 8650 P 8651 P 8652 P 8653 NP 8654 P 8655 P 8656 P 8657 P 8658 P 8659 P 74. 86. 89. 120. 5. 2. 4. 12. 105. 147. 167. 182. 3. 37. 33 . 89. 123. 123. 129. 156. 184. 185. 185. 181. 147. 152. 164. 116. 185. 182. 184. 182. 146. 113. 134. 100. ABORTED ON DAY 21 OF GESTATION 112. 122. 112. 89. 163. 129. 124. 130. 150. 107. 108. 127. 182. 139. 123. 143. 0 . 5. 0. 1 . 183. 149. 157. 159. 159. 149. 126. 159. 181. 184. 182. 181. 181. 170. 180. 185. 163. 170. 164. 183. 185. 182. 183. 185. 182. 183. 184. 180. 109. 11. 174. 75. 111. 176. 113. 184. 122. 97. 119. 145. 54. 1 180 152 184 183 170 181 120 117. 24. 184. 74. 107. 165. 106. 183 . 109. 110. 44. 184. 100. 114. 159. 101. 165. 115. 91. 93. 154. 115. 31. 184. 110. 182. 162. 105. 96. 112. 121. 71. 147. 58. 142. 134 . 95. 135. 95. 73. 160. 132. 127. 121. 169. 134. 118. 111. 101. 138. 132. 130. ABORTED ON DAY 26 OF GESTATION 184. 185. 166. 129. 173. 145. 106. 116. 170. 135. 130. 129. 185. 178. 168. 164. aaaa 150. 130. 119. 96. 182. 170. 160. 174. 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 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OP N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: TABLE 18 (PAGE 9) : MATERNAL FEED CONSUMPTION VALUES - IN D IV ID U A L DATA 316.8) 418-010:PAGE B-64 003964 PREGNANCY STATUS DAYS 7 - 8 8- 9 RABBIT # DOSAGE GROUP V 9-10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 3.75 MG/KG/DAY 8660 P 8661 P 8662 P 8663 P 8664 P 8665 P 8666 P 8667 P 8668 P 8669 P 8670 P 8671 P 8672 P 8673 P 8674 P 8675 P 8676 P 8677 NP 8678 P 8679 P 8680 P 8681 P 0. 23. 14 . 38. 20. 183. 183 . 181. 183. 158. 184. 182. 95. 184. 180. 184 . 184. 181. 183. 183. 182. 183. 0. 1. 0. 2. 2. 97. 182. 162. 185. 109. 181. 1. 2. 152. 185. 138. 143. 181. 165. 182. 181. 182. 1. 1. 0. 0. 0. 41. 183. 141. 185. 12. 1. 72. 6. 174. 163. 97. 111. 182. 125. 104. 180. 168. 0. 1. 0. 1. 2. 2. 163. 1. 183. 4. 124. 88. 7. 59. 147. 81. 118. 184. 154. 69. 177. 170. 1. 2. 1. 0. 1. 12. 181. 64. 182. 1. 74 . 160. 8. 48. 168. 52. 101. 182. 123. 63. 123. 110. 3. 2. 1. 0. 1. 3. 132. 41. 184. 2. 110. 181. 0. 1. 185. ' 80. 93. 150. 140. 111. 99. 90. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Doe 8660 aborted on day 20 of gestation. b. Doe 8667 aborted on day 19 of gestation. 10. 2. 0. 2. 4. 6. 184. 23 . 183. 116. 113. 185. 4. l. 156. 96. 43. 155. 163. 156. 78. 34 . 3. 4. 1. 5. 2. 111. 184. 17. 180. 0. 110. 185. 119. 0. 169. 120. 53. 180. 185. 183. 72. 7. 0. 0. 1. 1. 1. 154. 185. 1. 185. 0. 133. 183. 168. 1. 164. 133. 120. 181. 182. 184. 138. 2. 0. 0. 1. 1. 1. 148. 184. 0. 184. 4. 153. 184. 182. 0. 165. 94. 158. 120. 183. 182. 143. 0. 0. 0. 0. 0. 0. 133. 184. 3. 181. 1. 127. 183. 156. 9. 155. 86. 169. 139. 183. 180. 146. 0. 1. 0. 0. 1. 1. 124. 185. b 181. 7. 115. 180. 123. 0. 116. 100. 167. 152. 184. 183. 143 . 1. a 0. 0. 0. 12. 110. 181. 185. 0. 106. 181. 145. 0. 111. 130. 169. 164 . 181. 184. 180 i. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 18 (PAGE 10) : MATERNAL FEED CONSUMPTION VALUES - IN D IV ID U A L DATA S96C00 PREGNANCY STATUS DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 RABBIT # DOSAGE GROUP V 3.75 MG/KG/DAY 8660 P 8661 P 8662 P 8663 P 8664 P 8665 P 8666 P 8667 P 8668 P 8669 P 8670 P 8671 P 8672 P 8673 P 8674 P 8675 P 8676 P 8677 NP 8678 P 8679 P 8680 P 8681 P ABORTED ON DAY 20 OF GESTATION 7. 0. ABORTED ON DAY 23 OF GESTATION 7. 0. 0. 1. 0. 0. 5. 0. 0. 9. 0. 0. 1. 0. ABORTED ON DAY 26 OF GESTATION 43 . 91. 101. 125. 119- 123. 131. 162. 160. 134. 162. 182. 148. 120. 107. 136. 181. 130. 185. 183. 185. 181. 185. 174. 168. 182. 157. ABORTED ON DAY 19 OF GESTATION 180. 182. 182. 181. 185. 182. 180. 180. 148. 0. 0. 1. 4. 2. 6. 3. 2. ABORTED ON DAY 29 OF GESTATION 129. 181. 172. 170. 180. 170. 182. 185. 114. 182. 133. 164. 158. 166. 183. 116. a b 181. 185. 184. 182. 184. 182. 184. 180. 182. 66. 83. 93. 91. 144. 181. 181. 177. 118. 120. 115. 151. 164. 154 . 185. 168. 155. 164. 142. 115. 128. 126. 114. 73. b 88. 81. 134. 116. 127. 131. 96. 151. 131. 136. 150. 181. 183. 184. 182. 185. 180. 183. 184. 185. 181. b 181. 181. 176. b b 180. 140. 183. 183. 185. 185. 182. 171. 150. 135. 77. 155. 133. 131. 143. 127. 121. 118. 129. 108. 113. 84. 162. 184. 180. 183. 151. 159. 144. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G). a. Value was not recorded. b. Spilled feed precluded the calculation of this value. 418-010.PAG E B-65 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 18 (PAGE 11) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 RABBIT # SATELLITE DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8682 P 8683 P 8684 P 183. 184. 184. DAYS 20 - 21 181. 109. 184. 182. 171. 180. 181. 180. 181. 176. 184. 184. 183. 180. 155. 184. 184. 140. 185. 143. 181. 182. 172. 184. 172. 180. 181. 184. 185. 156. 184. 184. 143. 185. 185. 181. 8682 P 8683 P 8684 P 180. 174. 162. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G). 418-010: PAGE B-66 003966 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 18 (PAGE 12) : MATERNAL FEED CONSUMPTION VALUES - IN D IV ID U A L DATA PREGNANCY STATUS DAYS 7 - 8 8-9 9 - 1 0 1 0 - 1 1 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 RABBIT # SATELLITE DOSAGE GROUP II 0.1 MG/KG/DAY 8685 P 8686 P 8687 P 8688 P 8689 P 180. 181. 182. 181. 160. 180. 184. 184. 184. 176. 150. 182. 183. 153. 164. 157. 180. 180. 154. 73 . 113. 181. 181. 123. 80. 112. 157. 183. 92. 142. 55. 163. 182. 150. . 168. 67. 183. 184. 181. 168. 168. 185. 181. 181. 183. 181. 183. 181. 180. 182. 157. 180. 181. 181. 146. 154. 184. 185. 180. 145. 149. 184. 180. 183. 181. DAYS 20 - 21 8685 P 8686 P 8687 P 8688 P 8689 P 138. 184. 33. 184. 131. P * PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS WERE RECORDED IN GRAMS (G). 418-010:PAG E B-67 003967 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 18 (PAGE 13) : MATERNAL FEED CONSUMPTION VALUES - IN D IV ID U A L DATA PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 1 0 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 RABBIT # SATELLITE DOSAGE GROUP III 1.0 MG/KG/DAY 8690 P 8691 P 8692 P 180. 180. 157. 181. 182. 137. 182. 182. 100. 184. 180. 77. 182. 181. 78. 184. 182. 47. 183. 184. 51. 184. 185. 53. 183. 184. 95. 184. 183. 116. 180. a 127. 184. 108. 182. 163. DAYS 20 - 21 8690 P 8691 P 8692 P 180. ABORTED ON DAY 18 OF GESTATION 67. ` P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G). a. Doe 8691 aborted on day 18 of gestation. 96C 00 418-010: PAGE B-68 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 18 (PAGE 1 4 ): MATERNAL FEED CONSUMPTION VALUES - IN D IV ID U A L DATA PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 RABBIT # SATELLITE DOSAGE GROUP IV 2.5 MG/KG/DAY 8693 NP 8694 P 8695 P 181. 181. 181. 181. 180. 144. 181. 172. 124. 181. 161. 141. 181. 115. 148. 181. 127. 128. 183. 183 . 146. 165. 185. 134. 103. 181. 147. 51. 185. 162. 78. 183. 155. 102. 184. 140. 137. 184. 155. DAYS 20 - 21 8693 NP 8694 P 8695 P 122. 175. 144. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G) . 418-010: PAGE B-69 003969 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 18 (PAGE 1 5 ): MATERNAL FEED CONSUMPTION VALUES - IN D IV ID U A L DATA 418-010: PAGE B-70 003970 PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 1 0 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 RABBIT # SATELLITE DOSAGE GROUP V 3.75 MG/KG/DAY 8696 P 8697 P 8698 P 8699 P 8700 P 181. 106. 180. 183. 184 . 185. 51. 182. 181. 134. 136. 75. 182. 156. 121. 180. 60. 176. 156. 2. 163. 76. 130. 109. 1. 156. 39. 130. 128. 0. 184. 34 . 62. 183. 2. 185. 17. 46. 182. 0. 164. 84. 13. 181. 0. 180. 95. 3. 184. 0. 177. 134. 1. 184. 1. 181. 135. 2. 181. a 182. 144. 4. 184. DAYS 20 - 21 8696 P 8697 P 8698 P 8699 P 8700 P 181. 101. 4. 182. ABORTED ON DAY 19 OF GESTATION P = PREGNANT NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G) . a. Doe 8700 aborted on day 19 of gestation. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R AB BITS (SPO N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 19 (PAGE 1) : CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA * 6 COO 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 RABBIT # M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TOTAL DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8572 1 6 3 4 7 0 0 0 0 0 0 0 0 0 3 4 7 4 5 9 8573 5 2 6 1 7 0 0 0 0 0 0 0 0 0 6 1 7 6 3 9 8574 4 5 6 3 9 0 0 0 0 0 0 0 0 0 6 3 9 7 4 11 8575 5 5 8 2 10 0 0 0 0 0 0 0 0 0 8 2 10 8 3 11 8576 NOT PREGNANT 8577 4 3 2 5 7 0 0 0 0 0 0 0 0 0 2 5 7 2 7 9 8578 4 3 2 5 7 0 0 0 0 0 0 0 0 0 2 5 7 3 6 9 8579 5 2 5 2 7 0 0 0 0 0 0 0 0 0 5 2 7 6 3 9 8580 NOT PREGNANT 8581 ABORTED ON DAY 26 OF GESTATION 8582 0 3 1 2 3 0 0 0 6 1 7 0 0 0 7 3 10 8 4 12 8583 NOT PREGNANT 8584 NOT PREGNANT 1 8585 4 4 7 1 8 0 0 0 0 2 2 1 0 1 8 3 11 8 4 12 8586 5 5 8 2 10 0 0 0 0 0 0 0 0 0 8 2 10 9 4 13 8587 FOUND DEAD ON DAY 13 OF GESTATION 8588 2 5 4 3 7 0 0 0 0 1 1 0 0 0 4 4 8 4 4 8 8589 5 4 4 5 9 0 0 0 0 0 0 0 0 0 4 5 9 5 5 10 8590 8 3 4 7 11 0 0 0 0 0 0 0 0 0 4 7 11 6 9 15 8591 3 6 2 7 9 0 0 0 0 0 0 0 0 0 2 7 9 6 9 15 8592 6 7 7 6 13 0 0 0 0 0 0 0 0 0 7 6 13 7 7 14 8593 4 5 4 5 9 0 0 0 0 0 0 0 0 04 5 9 4 5 9 M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 418-010: PAGE B- PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 19 (PAGE 2) : CAESAREAN -SECTION IN G OBSERVATIONS - IN D IV ID U A L DATA 418-010: PAGE B-72 003972 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 RABBIT # M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TOTAL DOSAGE GROUP II 0. 1 MG/KG/DAY 8594 2 3 2 3 5 0 0 0 1 2 3 0 0 0 3 5 8 3 8 11 8595 3 2 3 2 5 0 0 0 0 0 0 0 0 0 3 2 5 3 4 7 8596 3 4 3 4 7 0 0 0 0 0 0 0 0 0 3 4 7 5 7 12 8597 5 4 5 4 9 0 0 0 0 0 0 0 0 0 5 4 9 5 4 9 8598 2 1 0 3 3 0 0 0 0 0 0 0 0 0 0 3 3 4 3 7 8599 3 6 4 5 9 0 0 0 0 0 0 0 0 0 4 5 9 5 6 il 8600 3 6 4 5 9 0 0 0 1 0 1 0 2 2 5 7 12 5 8 13 8601 4 5 3 6 9 0 0 0 0 0 0 0 0 0 3 6 9 3 6 9 8602 3 4 0 7 7 0 0 0 0 0 0 0 0 0 0 7 7 3 7 10 8603 6 3 7 2 9 0 0 0 0 0 0 0 0 0 7 2 9 7 4 11 8604 NOT PREGNANT 8605 6 4 8 2 10 0 0 0 0 0 0 0 0 0 8 2 10 9 6 15 8606 5 4 3 6 9 0 0 0 0 0 0 0 0 0 3 6 9 4 6 10 8607 NOT PREGNANT 8608 6 5 5 6 11 0 0 0 0 0 0 0 0 0 5 6 11 5 7 12 8609 5 4 2 7 9 0 0 0 0 0 0 0 0 0 2 7 9 2 8 10 8610 4 5 5 4 9 0 0 0 0 0 0 0 0 0 5 4 9 6 6 12 8611 3 6 5 4 9 0 0 0 0 0 0 0 0 0 5 4 9 5 4 9 8612 4 4 5 3 8 0 0 0 0 0 0 0 0 0 5 3 8 6 5 11 8613 7 3 5 5 10 0 0 0 0 0 0 0 0 0 5 5 10 6 5 11 8614 6 3 4 5 9 0 0 0 0 0 0 0 0 0 4 5 9 6 7 13 8615 5 6 3 8 11 00 0 0 0 0 0 0 0 3 8 11 4 8 12 M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 19 (PAGE 3) : CAESAREAN -SECTION IN G OBSERVATIONS - IN D IV ID U A L DATA 418-010: PAGE B-73 003973 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 RABBIT # M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TOTAL DOSAGE GROUP III 1. 0 MG/KG/DAY 8616 3 2 4 1 5 0 0 0 0 0 0 2 1 3 6 2 8 6 3 9 8617 3 5 4 4 8 0 0 0 1 0 1 0 0 0 5 4 9 7 6 13 8618 5 5 4 6 10 0 0 0 0 0 0 0 0 0 4 6 10 6 8 14 8619 4 3 4 3 7 0 0 0 0 0 0 0 0 0 4 3 7 6 5 11 8620 NOT PREGNANT 8621 5 4 3 6 9 0 0 0 0 0 0 0 0 0 3 6 9 4 6 10 8622 3 1 3 1 4 0 0 0 0 0 0 0 0 0 3 1 4 4 3 7 8623 NOT PREGNANT 8624 3 6 3 6 9 0 0 0 1 0 1 0 0 0 4 6 10 4 B 12 8625 5 2 3 4 7 0 0 0 0 0 0 0 0 0 3 4 7 4 5 9 8626 4 3 4 3 7 0 0 0 0 0 0 0 0 0 4 3 7 4 3 7 8627 4 6 6 4 10 0 0 0 0 0 0 0 0 0 6 4 10 6 4 10 8628 6 3 5 4 9 0 0 0 0 0 0 0 0 0 5 4 9 5 6 11 8629 5 5 4 6 10 0 0 0 0 0 0 0 0 0 4 6 10 5 6 11 8630 3 5 5 3 8 0 0 0 0 0 0 0 0 0 5 3 8 5 4 9 8631 1 8 7 2 9 0 0 0 0 0 0 0 0 0 7 2 9 8 3 11 8632 3 5 4 4 8 0 0 0 0 0 0 0 0 0 4 4 8 4 4 8 8633 5 3 4 4 8 0 0 0 0 0 0 0 0 0 4 4 8 4 5 9 8634 3 6 5 4 9 0 0 0 0 0 0 0 0 0 5 4 9 6 5 11 8635 5 3 4 4 8 0 0 0 0 0 0 0 0 0 4 4 8 6 5 11 8636 2 5 4 3 7 0 0 0 0 0 0 0 0 0 4 3 7 4 3 7 8637 5 8 9 4 13 0 0 0 1 0 1 0 0 0 10 4 14 12 4 16 M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 19 (PAGE 4): CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA fcvi6coo 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 RABBIT # M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TOTAL DOSAGE GROUP IV 2.5 MG/KG/DAY 8638 2 5 2 5 7 0 0 0 0 0 0 0 0 0 2 5 7 2 5 7 8639 2 5 4 3 7 0 0 0 0 0 0 1 1 2 5 4 9 6 5 11 8640 3 3 0 6 6 0 0 0 0 0 0 0 0 0 0 6 6 1 6 7 8641 7 2 3 6 9 0 0 0 0 0 0 0 0 0 3 6 9 4 6 10 8642 5 3 5 3 8 0 0 0 0 0 0 0 0 0 5 3 8 6 4 10 8643 5 2 5 2 7 0 0 0 0 0 0 0 0 0 5 2 7 5 4 9 8644 6 3 3 6 9 0 0 0 0 0 0 0 0 0 3 6 9 3 6 9 8645 6 1 3 4 7 0 0 0 0 0 0 0 0 0 3 4 7 4 5 9 8646 4 2 3 3 6 0 0 0 0 0 0 0 0 0 3 3 6 3 3 6 8647 ABORTED ON DAY 21 OF GESTATION 8648 4 10 7 7 14 0 0 0 0 1 1 0 4 4 7 12 19 9 14 23 8649 2 4 3 3 6 0 0 0 0 0 0 0 0 0 3 3 6 3 3 6 8650 4 2 2 4 6 0 0 0 0 0 0 0 0 0 2 4 6 2 4 6 8651 5 2 3 4 7 0 0 0 0 0 0 0 0 0 3 4 7 4 5 9 8652 ABORTED ON DAY 26 OF GESTATION 8653 NOT PREGNANT 8654 4 3 2 5 7 0 0 0 0 0 0 0 0 0 2 5 7 3 7 10 8655 0 3 1 2 3 0 0 0 0 0 0 0 0 0 1 2 3 6 4 10 8656 6 4 4 6 10 0 0 0 0 0 0 0 0 0 4 6 10 5 8 13 8657 4 4 4 4 8 0 0 0 0 0 0 0 0 0 4 4 8 4 4 8 8658 4 4 3 5 8 0 0 0 0 0 0 0 0 0 3 5 8 3 5 8 8659 3 3 3 3 6 0 0 0 0 0 0 0 0 0 3 3 6 4 4 8 M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 418-010: PAGE B-74 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 19 (PAGE 5) : CA ESA REA N -SECTIO N IN G OBSERVATIONS - IN D IV ID U A L 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 RABBIT # M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TOTAL DOSAGE GROUP \r 3 .75 MG/KG/DAY 8660 ABORTED ON DAY 20 OF GESTATION 8661 ABORTED ON DAY 23 OF GESTATION 8662 1 3 2 2 4 0 0 0 0 0 0 1 2 3 3 4 7 3 5 8 8663 ABORTED ON DAY 26 OF GESTATION 8664 3 4 2 5 7 0 0 0 0 0 0 0 3 3 2 8 10 4 9 13 866S 3 7 6 4 10 0 0 0 0 0 0 0 0 0 6 4 10 6 5 11 8666 5 6 8 3 11 0 0 0 0 0 0 0 0 0 8 3 11 9 3 12 8667 ABORTED ON DAY 19 OF GESTATION 8668 2 4 2 4 6 0 0 0 0 1 1 1 1 2 3 6 9 5 6 11 8669 ABORTED ON DAY 29 OF GESTATION 8670 2 3 2 3 5 0 0 0 0 0 0 0 1 1 2 4 6 2 5 7 8671 5 4 6 3 9 0 0 0 0 0 0 0 0 0 6 3 9 6 5 11 8672 6 3 2 7 9 0 0 0 0 1 '1 0 1 1 2 9 11 3 9 12 8673 4 4 4 4 8 0 0 0 0 0 0 0 0 0 4 4 8 5 6 11 8674 2 4 3 3 6 0 0 0 0 0 0 0 0 0 3 3 6 3 3 6 8675 4 4 5 3 8 0 0 0 0 0 0 0 0 0 5 3 8 5 3 8 8676 8 3 4 7 11 0 0 0 0 0 0 1 0 1 5 7 12 6 8 14 8677 NOT PREGNANT 8678 2 6 3 5 8 0 0 0 0 0 0 0 0 0 3 5 8 5 6 11 8679 7 4 4 7 11 0 0 0 0 0 0 0 0 0 4 7 11 6 8 14 8680 3 5 4 4 8 0 0 0 0 0 0 0 0 0 4 4 8 4 4 8 8681 5 3 4 4 8 0 0 0 0 0 0 0 0 0 4 4 8 4 5 9 M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 418-010:PAG E B-75 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 19 (PAGE 6) : CAESAREAN -SECTION IN G OBSERVATIONS - IN D IV ID U A L DATA 6C00 VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION SITES CORPORA LUTEA RABBIT # 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 8682 8683 8684 5 6 11 0 0 0 0 0 0 0 0 0 5 6 11 5 6 11 3580000000003 58358 9090 0000 0 00 0 9 0 990 9 SATELLITE DOSAGE GROUP II 0. 1 MG/KG/DAY 8685 8686 8687 8688 8689 9 4 13 0 0 0 0 0 0 0 0 0 9 4 13 9 4 13 6 3 9 0 0 0 0 1 1 0 0 0 6 4 10 6 5 11 6390 000000006 3 963 9 5 5 10 0 0 0 0 0 0 0 0 0 5 5 10 5 5 10 4 6 10 0 0 0 0 0 0 1 0 1 5 6 11 6 7 13 SATELLITE DOSAGE GROUP III 1. 0 MG/KG/DAY ' 8690 8691 8692 7 6 13 0 0 0 0 0 0 0 0 0 7 6 13 7 6 13 ABORTED 'ON DAY 18 OF GESTATION 35800000 00003 5836 9 SATELLITE DOSAGE GROUP IV 2 .5 MG/KG/DAY 8693 8694 8695 NOT PREGNANT 3 7 10 0 0 0 0 0 0 0 0 0 3 7 10 3 7 10 5 4 9 0 0 0 0 0 0 0 0 0 5 4 9 6 4 10 SATELLITE DOSAGE GROUP V 3. 75 MG/KG/DAY 8696 8697 8698 8699 8700 6 4 10 0 0 0 0 0 0 0 0 0 6 4 10 6 5 11 224 0 000 0 00 00 2 2424 6 4370000000004 37538 5 6 il 0 0 0 0 0 0 0 0 0 5 6 il 6 7 13 ABORTED ON DAY 19 OF GESTATION PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 418-010: PAGE B-76 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 20 (PAGE 1) : LITTER OBSERVATIONS (CAESAREAN- DELIVERED FETUSES) - INDIVIDUAL DATA 418-010: PAGE B-77 003977 NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) RABBIT # MALE FEMALE TOTAL MALE FEMALE TOTAL a DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8572 8573 8574 8575 8576 8577 8578 8579 8580 8581 8582 8583 8584 8585 8586 8587 8588 8589 8590 8591 8592 8593 1 6 7 43.53 5 2 7 47.62 4 5 9 46.23 5 5 10 49.26 NOT PREGNANT 4 3 7 47.38 4 3 7 42.95 5 2 7 53.07 NOT PREGNANT ABORTED ON DAY 26 OF GESTATION 0 3 3-- NOT PREGNANT NOT PREGNANT 4 4 8 36.96 5 5 10 36.42 FOUND DEAD ON DAY 13 OF GESTATION 2 5 7 50.22 5 4 9 35.40 8 3 11 41.82 3 6 9 38.50 6 7 13 33.41 4 5 9 46.37 49.55 51.76 45.97 49.60 45.97 41.32 49.48 47.26 ' 28.55 32.98 50.92 35.12 40.81 39.62 31.14 41.46 48.69 48.80 46.09 49.43 46.77 42.25 52.04 47.26 32.75 34.70 50.72 35.27 41.54 39.24 32.19 43.64 TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. -- CONCEPTUSES ----RESORBED N N% 7 0 0.0 7 0 0.0 9 0 0.0 10 0 0.0 7 0 0.0 7 0 0.0 7 0.0 10 7 70.0 11 3 27.3 10 0 0.0 8 1 12.5 9 0 0.0 11 0 0.0 9 0 0.0 13 0 0.0 9 0 0.0 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 20 (PAGE 2) : L IT T E R OBSERVATIONS (CAESAREAN -DELIVERED FETUSES) - IN D IV ID U A L DATA 418-010: PAGE B-78 003978 NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) RABBIT # MALE FEMALE TOTAL MALE FEMALE TOTAL a DOSAGE GROUP II 0.1 MG/KG/DAY 8594 2 3 5 52.83 51.01 51.74 8595 3 2 5 50.16 48.91 49.66 8596 3 4 7 41.29 40.53 40.86 8597 54 9 37.25 40.29 38.60 8598 2 1 3 50.72 49.07 50.17 8599 3 6 9 37.81 39.44 38.90 8600 3 6 9 43.30 43.35 43.33 ' 8601 4 5 9 43.08 41.06 41.96 8602 3 4 7 35.41 37.97 36.87 8603 6 3 9 45.86 47.66 46.46 8604 NOT PREGNANT 8605 6 4 10 44.98 49.26 46.69 8606 5 4 9 51.78 49.54 50.79 8607 NOT PREGNANT 8608 6 5 11 32.37 33.51 32.89 8609 5 4 9 43.88 39.60 41.98 8610 4 5 9 40.08 42.68 41.52 8611 3 6 9 40.54 34.81 36.72 8612 4 4 8 47.92 49.91 48.92 8613 7 3 10 40.52 41.04 40.68 8614 6 3 9 42.46 46.68 43.86 8615 5 6 11 44.92 44.74 44.82 a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. CONCEPTUSES --RESORBED N N% 8 3 37.5 5 0 0.0 7 0 0.0 9 0 0.0 3 0 0.0 9 0 0.0 12 3 25.0 9 0 0.0 7 0 0.0 9 0 0.0 10 0 0.0 9 0 0.0 11 0 0.0 9 0 0.0 9 0 0.0 9 0 0.0 8 0 0.0 10 0 0.0 9 0 0.0 11 0 0.0 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OP N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 20 (PAGE 3) : LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) RABBIT # MALE FEMALE TOTAL MALE FEMALE TOTAL a DOSAGE GROUP III 1.0 MG/KG/DAY 8616 8617 6618 8619 8620 8621 8622 8623 8624 8625 8626 8627 8628 8629 8630 8631 8632 8633 8634 8635 8636 8637 32 35 55 43 NOT PREGNANT 54 31 NOT PREGNANT 36 52 43 46 63 55 35 18 35 53 36 53 25 58 5 40.05 8 46.14 10 37.87 7 30.79 9 42.08 4 45.20 9 46.70 7 36.79 7 50.61 10 40.45 9 43.27 10 39.54 8 49.55 9 50.67 8 42.71 8 46.72 9 45.63 8 47.21 7 48.70 13 43.34 47.74 48.29 38.60 32.05 42.82 45.02 42.91 36.38 46.28 37.46 42.23 35.42 44.33 41.77 42.87 46.72 40.56 44.37 48.43 36.16 43.13 47.48 38.23 31.33 42.41 45.16 44.17 36.67 48.75 38.66 42.92 37.48 46.29 42.76 42.81 46.72 42.25 46.14 48.50 38.92 TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES --- CONCEPTUSES ..... RESORBED N N% 8 3 37.5 9 1 11.1 10 0 0.0 7 0 0.0 9 0 0.0 4 0 0.0 10 1 10.0 7 0 0.0 7 0 0.0 10 0 0.0 9 0 0.0 10 0 0.0 8 0 0.0 9 0 0.0 8 0 0.0 8 0 0.0 9 0 0.0 8 0 0.0 7 0 0.0 14 1 7.1 418-010: PAGE B-79 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: G 3 1 S .8 ) TABLE 20 (PAGE 4) : L IT T E R OBSERVATIONS (CAESAREAN -DELIVERED FETUSES) - IN D IV ID U A L DATA 418-010: PAGE B-80 003980 NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) RABBIT # MALE FEMALE TOTAL MALE FEMALE TOTAL a DOSAGE GROUP IV 2.5 MG/KG/DAY 8638 8639 8640 8641 8642 8643 8644 864S 8646 8647 8648 8649 8650 8651 8652 8653 8654 8655 8656 8657 8658 8659 2 5 7 39.30 2 5 7 28.30 3 3 6 38.83 7 2 9 38.93 5 3 8 29.41 5 2 7 44.31 6 3 9 33.66 6 1 7 46.81 4 2 6 44.36 ABORTED ON DAY 21 OF GESTATION 4 10 14 31.64 2 4 6 50.56 4 2 6 39.30 5 2 7 47.49 ABORTED ON DAY 26 OF GESTATION NOT PREGNANT 4 3 7 47.50 0 3 3-- 6 4 10 35.96 4 4 8 48.11 4 4 8 44.99 3 3 6 49.84 41. 20 21.,15 36.,92 44 .42 27.,29 47..06 39..04 46..20 41..34 32..64 47..86 38..74 47..44 50 .89 55 .17 38 .16 47 .03 45 .96 42 .97 40. 66 23. 19 37. 88 40. 15 28. 62 45. 09 35..45 46.,72 43.,35 32..35 48..76 39.,12 47..48 48 .95 55 .17 36 .84 47 .57 45 .47 46 .40 a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. --- CONCEPTUSES ---RESORBED N N 4f 7 0 0. 0 9 2 22. 2 6 0 0. 0 9 0 0. 0 8 0 0. 0 7 0 0. 0 9 0 0. 0 7 0 0..0 6 0 0..0 19 5 26..3 6 0 0..0 6 0 0..0 7 0 0..0 7 0 0 .0 3 0 0 .0 10 0 0 .0 8 0 0 .0 8 0 0 .0 6 0 0 .0 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 20 (PAGE S) : LIT T E R OBSERVATIONS (CAESAREAN -DELIVERED FETU SES) - IN D IV ID U A L DATA NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) RABBIT # MALE FEMALE TOTAL MALE FEMALE TOTAL a DOSAGE GROUP V 3.75 MG/KG/DAY 8660 8661 8662 8663 8664 8665 8666 8667 8668 8669 8670 8671 8672 8673 8674 8675 8676 8677 8678 8679 8680 8681 ABORTED ON DAY 20 OF GESTATION ABORTED ON DAY 23 OF GESTATION 1 3 4 19.01 ABORTED ON DAY 26 OF GESTATION 3 4 7 44.05 3 7 10 34.61 5 6 11 42.90 ABORTED ON DAY 19 OF GESTATION 2 4 6 47.20 ABORTED ON DAY 29 OF GESTATION 2 3 5 50.20 5 4 9 38.32 6 3 9 29.33 4 4 8 35.84 2 4 6 52.72 4 4 8 42.89 8 3 11 39.19 NOT PREGNANT 2 6 8 50.63 7 4 11 42.01 3 5 8 43.71 5 3 8 41.90 15.77 30.09 34.43 44.00 47.91 51.33 41.36 34.07 33.07 50.08 36.69 39.02 46.32 47.04 41.13 39.44 16.58 36.07 34.48 43.50 47.68 50.88 39.67 30.91 34.46 50.96 39.79 39.14 47.40 43.84 42.10 40.98 a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. --- CONCEPTUSES ----RESORBED N N% 7 3 42.8 10 3 30.0 10 0 0.0 11 0 0.0 9 3 33.3 6 1 16.7 9 0 0.0 11 2 18.2 8 0 0.0 6 0 0.0 8 0 0.0 12 1 8.3 8 0 0.0 11 0 0.0 8 0 0.0 8 0 0.0 418-010:PAG E B-81 003981 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 20 (PAGE 6) : L IT T E R OBSERVATIONS (CAESAREAN -DELIVERED FETUSES) - IN D IV ID U A L DATA 418-010: PAGE B-82 003982 NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) RABBIT # TOTAL TOTAL SATELLITE DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8682 8683 8684 11 8 9 4.65 4.59 4.41 SATELLITE DOSAGE GROUP II 0.1 MG/KG/DAY 8685 8686 8687 8688 8689 13 9 9 10 10 5.50 4.81 4.52 5.17 4.76 SATELLITE DOSAGE GROUP III 1.0 MG/KG/DAY' 8690 8691 8692 13 5.11 ABORTED ON DAY 18 OF GESTATION 8 4.69 SATELLITE DOSAGE GROUP IV 2.5 MG/KG/DAY 8693 8694 8695 NOT PREGNANT 10 9 4.81 5.45 SATELLITE DOSAGE GROUP V 3.75 MG/KG/DAY 8696 8697 8698 8699 8700 10 4.74 4 5.15 7 4.18 11 5.16 ABORTED ON DAY 19 OF GESTATION -- CONCEPTUSES ----RESORBED N N% 11 0 0.0 8 0 0.0 9 0 0.0 13 0 0.0 10 1 10.0 9 0 0.0 10 0 0.0 11 1 9.1 13 0 0.0 8 0 0.0 10 0 0.0 9 0 0.0 10 0 0.0 4 0 0.0 7 0 0.0 11 0 0.0 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OP N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 21 (PAGE 1) : PETAL S E X , V IT A L STATU S AND BODY W EIGHT - IN D IV ID U A L DATA 418-010: PAGE B-83 003983 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RABBIT # 8572 8573 8574 8575 8576 CLS 4/ 5 6/ 3 7/ 4 8/ 3 MA FA FA / FA FA FA FA 43.53 50.14 49.78 54.40 50.22 47.14 45.60 FA MA FA MA MA MA / MA 52.56 51.49 50.96 47.26 51.38 38.53 49.44 MA MA FA MA FA FA / FA MA FA 40.53 45.04 50.45 53.16 44.29 47.55 50.74 46.20 36.84 FA MA MA MA MA FA FA FA / MA FA 54.15 54.58 51.71 49.10 38.16 32.73 48.47 55.37 52.75 57.31 NOT PREGNANT 8577 8578 8579 8580 2/ 7 3/ 6 6/ 3 MA MA / FA FA MA FA MA 52.03 50.09 46.67 44.60 41.97 46.65 45.41 FA FA / MA MA MA MA FA 38.84 42.66 44.36 45.46 42.37 39.60 42.45 MA MA MA FA MA / FA MA 56.80 52.82 55.31 43.40 47.53 55.55 52.91 NOT PREGNANT 1 8581 ABORTED ON DAY 26 OF GESTATION 8582 8/ 4 E E E E E E FA / FA FA E 46.39 46.23 49.15 8583 NOT PREGNANT 8584 NOT PREGNANT M = MALE F = FEMALE A = ALIVE E = EARLY RESORPTION L = LATE RESORPTION "/" DENOTES POSITION OF CERVIX CLS = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 21 (PAGE 2) : FETAL S E X , V IT A L STATUS AND BODY W EIGHT - IN D IV ID U A L DATA 418-010: PAGE B-84 003984 FETUS # 1 2 3 4 S 6 7 8 9 10 11 12 13 14 IS 16 17 18 19 DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RABBIT # 8585 8586 8587 CLs 8/ 4 9/ 4 MA MA L FA MA FA FA FA / E E MA 44.74 32.38 6.56 34.83 33.94 25.22 22.73 31.43 36.77 MA FA FA FA MA MA MA FA / MA FA 44.88 42.44 31.76 25.46 37.67 27.94 32.46 26.05 39.15 39.19 FOUND DEADi ON DAY 13 OF GESTATION 8588 8589 8590 8591 8592 8593 4/ 4 5/ 5 6/ 9 6/ 9 7/ 7 4/ 5 FA FA FA MA / FA MA FA E 51.46 48.08 52.60 50.53 51.20 49.91 51.26 FA FA MA FA / MA MA MA MA FA 39.63 33.12 37.70 37.56 37.35 35.47 32.25 34.21 30.17 MA FA FA FA / MA MA MA MA MA MA MA 50.64 43.50 36.13 42.80 40.31 39.34 44.89 41.01 34.61 37.65 46.09 FA FA / FA FA MA MA MA FA FA 43.91 44.15 41.70 39.60 36.33 40.91 38.25 33.96 34.37 FA FA FA MA MA FA FA / MA FA' MA FA MA MA 33.92 29.84 32.76 34.39 23.52 27.72 33.05 41.56 35.46 36.32 25.25 32.26 32.43 MA FA MA FA / MA MA FA FA FA 50.75 44.57 43.60 39.79 46.34 44.78 44.80 37.41 40.74 M = MALE F = FEMALE A = ALIVE E = EARLY RESORPTION L = LATE RESORPTION CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . DENOTES POSITION OF CERVIX PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 21 (PAGE 3) : FETAL S E X , V IT A L STATU S AND BODY W EIGHT - IN D IV ID U A L DATA 418-010: PAGE B-85 003985 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 DOSAGE GROUP II 0.1 MG/KG/DAY RABBIT # 8594 8595 8596 8597 8598 8599 8600 8601 8602 8603 8604 CLs 3/ 8 FA FA E / MA E FA MA E 51.81 50.44 53.16 50.79 52.50 3/ 4 MA FA FA / MA MA 53.84 52.62 45.20 42.19 54.46 5/ 7 FA MA MA / FA MA FA FA 41.24 39.09 42.15 45.46 42.63 38.59 36.84 5/ 4 MA FA MA FA MA / FA MA FA MA 40.80 44.99 26.59 32.16 37.79 43.76 41.54 40.26 39.52 4/ 3 / MA MA FA 52.37 49.06 49.07 5/ 6 FA FA MA FA / FA FA FA MA MA 38.27 38.66 42.15 40.74 38.85 36.72 43.38 35.19 36.10 5/ 8 FA MA FA E FA / FA MA FA ML FL FA MA 53.78 48.89 50.99 38.27 46.74 41.57 34.23 20.58 23.54 36.08 39.45 3/ 6 FA MA MA / FA FA FA FA MA MA' 47.44 46.88 45.46 35.75 42.16 38.11 41.86 35.18 44.78 3/ 7 / PA MA FA FA MA FA MA 44.17 43.13 42.87 39.54 28.66 25.30 34.45 7/ 4 FA FA MA MA MA MA FA / MA MA 54.44 49.57 47.59 46.87 39.59 30.92 38.97 58.13 52.04 NOT PREGNANT 8605 8606 9/ 6 4/ 6 MA MA MA MA MA FA MA FA ,/ FA FA 53.06 44.45 45.12 38.74 45.05 46.61 43.45 47.60 52.98 49.83 FA MA FA /' MA MA FA MA MA FA 48.63 54.94 50.24 55.13 48.58 50.38 48.18 52.08 48.92 M = MALE F - FEMALE A = ALIVE E = EARLY RESORPTION L = LATE RESORPTION C L s = CORPORA LUTEA/OVARY FETAL BODY W EIGHTS WERE RECORDED IN GRAMS (G) . "/" DENOTES POSITION OF CERVIX PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 21 (PAGE 4 ) : FETAL S E X , V IT A L STATUS AND BODY WEIGHT - IN D IV ID U A L DATA 418-010: PAGE B-86 003986 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 DOSAGE GROUP II 0.1 MG/KG/DAY RABBIT # CLs 8607 NOT PREGNANT 8608 8609 8610 8611 8612 8613 8614 8615 5/ 7 2/ 8 6/ 6 5/ 4 6/ 5 6/ 5 6/ 7 4/ 8 FA MA MA FA MA / MA MA FA FA FA MA 43.30 31.39 33.84 31.67 30.93 35.26 34.20 36.33 32.75 23.52 28.58 MA MA / FA MA FA MA FA MA FA 44.13 44.89 39.28 44.56 41.78 44.34 42.98 41.48 34.34 FA FA MA MA FA / MA MA FA *FA 36.34 42.52 27.21 40.71 42.69 47.04 45.35 45.61 46.26 FA MA FA MA FA / MA FA FA FA 40.66 43.12 40.79 35.11 35.66 43.40 28.02 27.52 36.19 MA MA FA FA FA / MA FA MA 51.69 50.94 49.90 44.28 53.91 4T. 29 51.55 47.76 MA MA MA MA FA / MA FA MA FA MA 42.83 44.11 40.54 37.12 41.99 43.20 44.29 38.29 36.84 37.57 MA FA MA MA /' FA FA MA MA MA' 40.11 47.24 46.33 33.10 45.92 46.89 50.85 40.71 43.63 FA MA FA / MA FA MA FA MA FA FA MA 53.71 51.10 47.25 49.38 50.56 44.52 48.24 39.77 34.76 33.95 39.83 MALE F -- FEMALE A = ALIVE E = EARLY RESORPTION L = LATE RESORPTION CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . '/" DENOTES POSITION OF CERVIX PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SPO N SO R' S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 21 (PAGE 5) : FETAL S E X , V IT A L STATUS AND BODY W EIGHT - IN D IV ID U A L DATA 418-010: PAGE B-87 003987 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 IS 16 17 18 19 DOSAGE GROUP III 1.0 MG/KG/DAY RABBIT # 8616 8617 8618 8619 8620 CLs 6/ 3 7/ 6 61 8 6/ 5 FA L MA MA L MA / FA L 48.33 1.92 45.61 38.05 10.57 36.49 47.16 4.50 FA FA MA FA E / MA FA FA MA 54.55 48.00 42.79 42.87 54.77 47.12 48.89 40.87 MA FA FA MA / MA FA FA FA MA MA 40.04 40.05 45.18 36.97 40.35 32.58 38.95 36.22 35.03 36.96 MA MA MA MA / FA FA FA 33.99 32.96 28.62 27.60 32.40 30.64 33.12 NOT PREGNANT 8621 8622 8623 4/ 6 4/ 3 FA FA MA / MA FA MA FA MA MA 42.88 48.02 44.46 46.03 42.56 35.43 37.84 41.41 43.07 MA FA MA / MA 44.17 45.02 46.73 44.70 NOT PREGNANT ' 8624 8625 8626 8627 8628 4/ 8 4/ 5 4/ 3 6/ 4 5/ 6 FA FA MA E / FA MA FA MA FA FA 37.03 43.12 47.31 43.84 47.81 41.56 44.99 48.09 43.80 FA MA MA /' MA MA MA FA 40.93 35.34 35.11 40.93 39.22 33.34 31.83 FA MA FA FA / MA MA MA 48.34 51.83 43.13 47.37 50.33 51.14 49.13 FA MA FA FA MA FA / MA MA FA FA 36.52 43.40 39.31 37.29 39.97 38.19 34.40 44.02 34.86 38.60 MA MA MA MA FA / MA FA MA FA 45.66 43.14 42.88 39.23 45.20 45.20 39.54 43.54 41.94 M = MALE F = FEMALE A = ALIVE E = EARLY RESORPTION L = LATE RESORPTION "/" DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G). PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 21 (PAGE 6) : FETAL S E X , V IT A L STATU S AND BODY W EIGHT - IN D IV ID U A L DATA 418-010:PAGE B-88 003988 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 DOSAGE GROUP III 1.0 MG/KG/DAY RABBIT # CLs 8629 5/ 6 8630 5/ 4 8631 8/ 3 8632 4/ 4 8633 4/ 5 8634 6/ 5 8635 6/ 5 8636 4/ 3 8637 12/ 4 FA MA MA MA / MA FA MA FA FA FA 38.26 40.62 39.71 34.07 42.91 32.68 40.37 37.01 32.04 37.10 MA MA FA FA FA / FA FA MA 54.05 48.56 47.43 39.21 42.17 45.38 47.48 46.03 FA FA FA FA FA FA FA / MA FA 35.24 43.84 44.36 47.44 43.31 40.76 34.09 50.67 45.15 MA FA FA MA / FA FA MA FA 43.79 43.37 41.80 38.67 45.68 41.58 45.68 41.90 FA MA MA MA / FA MA MA FA 51.73 52.61 49.99 49.08 44.96 43.98 37.95 43.48 FA FA MA FA FA /' MA MA FA FA 46.72 38.26 41.76 40.70 37.00 46.46 48.68 38.21 42.46 FA MA FA MA / MA MA FA MA 45.78 47.55 45.96 48.28 48.49 50.50 41.38 41.22 MA FA FA MA / FA FA FA ' 50.28 51.83 46.05 47.12 52.01 42.71 49.53 E FA MA FA FA MA FA FA FA MA / MA FA FA MA 45.74 42.00 36.06 44.82 41.26 34.68 25.38 24.35 38.22 50.86 37.05 41.21 44.37 M = MALE F S FEMALE A - ALIVE E = EARLY RESORPTION L = LATE RESORPTION "/" DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: G 3 1 6 .8 ) TABLE 21 (PAGE 7) : FETAL S E X , V IT A L STATUS AND BODY WEIGHT - IN D IV ID U A L DATA 418-010: PAGE B-89 003989 FETUS # 1 2 3 4 5 6 7 8 9 10 DOSAGE GROUP IV 2.5 MG/KG/DAY RABBIT # 8638 8639 8640 8641 8642 8643 8644 8645 8646 8647 CLs 2/ 5 FA FA / FA MA FA MA FA 40.28 32.90 38.25 46.95 43.41 31.64 51.17 6/ 5 FA FA L FA MA / MA FA L 23.26 24.69 5.15 18.43 29.94 26.65 26.53 16.40 1/ 6 / MA FA FA MA FA MA 44.53 33.60 38.80 34.42 38.36 37.55 4/ 6 MA FA FA / MA MA MA MA MA 39.77 42.81 46.04 39.08 33.05 37.62 36.19 38.17 6/ 4 FA MA FA MA MA / MA FA MA 35.34 30.14 30.91 27.71 28.84 29.20 15.63 31.16 5/ 4 MA FA MA MA MA / MA FA 50.36 45.62 42.69 45.99 37.18 45.32 48.50 3/ 6 FA FA MA / MA MA MA MA FA 42.26 39.28 41.03 35.48 31.24 29.67 29.85 35.59 4/ 5 MA MA MA / MA MA MA FA 48.81 46.23 43.18 48.91 47.45 46.30 46.20 3/ 3 FA FA MA / MA MA MA 41.73 40.94 47.24 48.25 43.29 38.67 ABORTED ON DAY 21 OF GESTATION FA MA MA 8648 8649 8650 9/14 3/ 3 2/ 4 FA FA FA FA MA FA FA / FA 31.21 36.66 30.62 35.19 35.13 29.89 38.65 39.35 FA MA MA / FA FA FA 45.80 48.91 52.20 50.56 46.91 48.16 MA MA / MA MA FA FA 40.62 34.76 47.05 34.78 36.42 41.06 FA ML M = MALE F - FEMALE A = ALIVE E = EARLY RESORPTION L = : C L s = CORPORA LUTEA/OVARY FETAL BODY W EIGHTS WERE RECORDED IN GRAMS ( G ) . 11 12 13 14 15 16 17 18 ML MA MA L L FA MA FA 0.57 3.81 28.46 25.93 26.72 "/" DENOTES POSITION OF CERVIX 19 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 21 (PAGE 8) : FETAL S E X , V IT A L STATUS AND BODY WEIGHT - IN D IV ID U A L DATA FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 DOSAGE GROUP IV 2.5 MG/KG/DAY RABBIT # 8651 8652 CLs 4/ 5 MA FA FA / MA MA MA MA 47.52 50.95 43.93 52.77 47.93 45.91 43.32 ABORTED ON1 DAY 26 OF GESTATION 8653 NOT PREGNANT 8654 8655 8656 8657 8658 8659 3/ 7 6/ 4 5/ 8 4/ 4 3/ 5 4/ 4 FA MA ! FA FA MA MA MA 51.69 50.86 50.69 50.28 50.69 43.80 44.66 FA /' FA FA 56.63 55.06 53.82 MA FA MA MA / FA MA MA FA MA FA 37.66 40.21 41.71 32.74 43.55 39.48 33.27 33.61 30.92 35.29 MA MA FA MA / FA FA MA FA 49.99 49.18 44.11 43.64 46.72 48.48 49.62 48.81 FA FA MA / MA MA MA FA FA 47.86 47.10 44.22 46.38 45.20 44.16 45.44 43.43 FA MA FA / MA FA MA 47.92 45.38 41.33 56.20 39.65 47.95 M = MALE F - FEMALE A = ALIVE E = EARLY RESORPTION L = LATE RESORPTION "/" DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . 418-010: PAGE B-90 003990 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 21 (PAGE 9) : FETAL S E X , V IT A L STATUS AND BODY W EIGHT - IN D IV ID U A L DATA 418-010: PAGE B-91 003991 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 DOSAGE GROUP V 3.75 MG/KG/DAY RABBIT # CLS 8660 ABORTED ON DAY 20 OF GESTATION 8661 ABORTED ON DAY 23 OF GESTATION 8662 3/ 5 L FA MA / L FA FA ML 14.24 18.19 19.01 17.85 14.21 14.92 21.94 8663 ABORTED ON DAY 26 OF GESTATION 8664 8665 8666 8667 4/ 9 6/ 5 9/ 3 MA FA / FA MA FA MA FA 48.71 42.52 18.62 44.75 27.39 0.66 0.64 0.67 38.68 31.83 FA FA FA FA FA MA / FA MA FA MA 30.36 32.81 37.90 33.12 30.14 33.64 36.87 36.62 39.80 33.57 MA FA FA FA FA MA MA MA / FA FA MA 48.23 42.22 44.74 42.32 45.72 40.93 38.45 41.81 47.19 41.82 45.10 ABORTED ON DAY 19 OF GESTATION 8668 5/ 6 MA FA L / FA L FA 49.75 49.19 2.11 52.64 4.54 46.18 8669 ABORTED ON DAY 29 OF GESTATION E FA MA 43.63 44.66 8670 2/ 8671 6/ 8672 3/ FA MA / FA FA MA 52.67 48.51 51.90 49.43 3.38 51.89 FA FA FA MA MA FA / MA MA MA 48.01 36.65 41.41 37.76 34.86 39.38 39.77 40.59 38.63 MA MA / MA E FA MA MA FA MA FA 35.46 24.22 29.95 36.85 30.08 32.11 0.42 29.92 24.17 35.43 M = MALE F = FEMALE A = ALIVE E = EARLY RESORPTION L = LATE RESORPTION "/" DENOTES POSITION OF CERVIX CLS = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G). PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 21 (PAGE 10) : FETAL S E X , V IT A L STATUS AND BODY W EIGHT - IN D IV ID U A L DATA 418-010:PAGE B-92 003992 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 DOSAGE GROUP V 3.75 MG/KG/DAY RABBIT # 8673 8674 8675 8676 8677 CLs 5/ 6 3/ 3 5/ 3 6/ 8 FA FA MA MA / MA MA FA FA 30.95 38.53 39.90 38.87 31.37 33.22 30.59 32.22 FA FA FA / MA FA MA 49.59 54.01 46.52 53.09 50.20 52.36 MA MA FA FA FA / MA FA MA 46.05 44.30 36.36 36.46 38.11 40.70 35.83 40.51 MA L MA MA MA / MA FA FA FA MA MA MA 50.42 20.57 43.22 39.04 34.96 50.88 37.16 42.56 37.34 31.27 28.67 35 .07 NOT PREGNANT 8678 8679 8680 8681 5/ 6 6/ 8 4/ 4 4/ 5 FA FA FA / FA FA MA FA MA 46.40 48.47 46.74 44.42 45.12 55.24 46.76 46.02 PA FA MA FA / MA MA MA FA MA MA MA 49.58 51.39 46.44 45.11 46.38 44.28 41.01 42.09 38.65 40.91 36.42 MA FA FA FA / MA MA FA FA 42.43 43.95 39.22 39.32 45.29 43.40 38.22 44.94 MA MA MA FA / MA MA FA FA 48.74 40.64 37.25 35.10 35.94 46.95 42.29 40.92 M = MALE F S FEMALE A = ALIVE E = EARLY RESORPTION L = LATE RESORPTION CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . 7 - DENOTES POSITION OF CERVIX PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 21 (PAGE 11) : FETAL S E X , V IT A L STATUS AND BODY W EIGHT - IN D IV ID U A L DATA 418-010: PAGE B-93 003993 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 SATELLITE DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RABBIT # CLs 8682 5/ 6 8683 3/ 5 8684 9/ 0 A 4.69 A 4.50 A 4.18 A 4.09 A 4.73 A 5.37 AA 4.36 4.52 A/ A 4.74 4.74 AA 3.72 4.35 A/ A 4.67 4.81 AA 4.50 4.27 AA 3.83 5.46 A 4.33 A 4.49 A 4.06 A 4.92 A 4.75 A 3.82 AA 5.01 4.87 A/ 4.88 A 4.90 SATELLITE DOSAGE GROUP II 0.1 MG/KG/DAY RABBIT # CLs 8685 9/ 4 8686 6/ 5 8687 6/ 3 8688 5/ 5 8689 6/ 7 A 5.07 A 4.69 A 4.75 A 4.98 A 5.10 A 4.86 A 4.83 A 4.55 A 5.59 A 4.52 A 5.30 A 4.95 A 4.69 A 5.05 A 4.90 A 5.67 A 4.86 A 4.36 A 5.26 L AAA 5.76 6.00 5.61 A A/ A 4.47 5.06 4.82 A A/ A 4.52 4.37 4.60 A/ A A 5.24 4.79 5.30 A/ A A 4.41 5.11 4.77 A 5.56 E A 4.53 A 5.36 A 4.81 A/ A 5.00 5.86 AA 4.84 4.79 4.30 AA 4.90 5.21 AA 4.33 4.64 A 5.76 A 5.05 A 5.47 A 5.55 SATELLITE DOSAGE GROUP III 1.0 MG/KG/DAY RABBIT # CLs 8690 7/ 6 8691 A A A A A A A/ A A A A A A 5.70 5.41 3.85 5.32 5.39 5.08 5.84 4.52 4.97 5.22 5.01 5.10 5.07 ABORTED ON DAY 18 OF GESTATION 8692 3/ 6 A A A / A A A A A 4.93 4.89 4.79 4.51 4.73 4.80 4.84 4.03 A = ALIVE E EARLY RESORPTION L LATE RESORPTION "/" DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 21 (PAGE 12) : FETAL S E X , V IT A L STATUS AND BODY W EIGHT - IN D IV ID U A L DATA 418-010:PAGE B-94 003994 FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 SATELLITE DOSAGE GROUP IV 2.5 MG/KG/DAY RABBIT # CLs 8693 NOT PREGNANT 8694 3/ 7 8695 6/ 4 A 5.54 A 5.30 A 4.57 A 5.59 A/ A 4.70 5.39 AA 5.70 6.23 AA 5.40 4.46 A/ A 4.71 5.52 A 5.18 A 5.21 A 4.60 A 5.65 A 3.59 A 5.17 A 4.66 SATELLITE DOSAGE GROUP V 3.75 MG/KG/DAY RABBIT # CLs 8696 6/ 5 8697 2/ 4 8698 5/ 3 8699 6/ 7 8700 A A A A A A/ A 5.34 4.62 4.39 4.43 3.60 5.22 5.12 A A/ A A 5.03 5.32 5.26 5.00 A A A A/ A A A 3.94 4.33 4.03 4.58 4.11 4.21 4.07 A A A A A/ A A 5.30 5.62 5.10 5.11 5.17 5.29 5.53 ABORTED ON DAY 19 OF GESTATION A 5.09 A 5.38 A 4.78 A 5.34 A 4.76 A 4.29 A 4 .67 A ALIVE E = EARLY RESORPTION L = LATE RESORPTION "/ DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: G 3 1 6 .8 ) TABLE 22 (PAGE 1) : FETAL ALTERATIONS - INDIVIDUAL DATA 418-010:PAGE B-95 003995 DOSAGE GROUP I RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8572 1( 14.3) 0 (VEHICLE) MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N 0/ 7 DESCRIPTION N/N 0/ 7 DESCRIPTION 8573 1( 14.3) 0/ 7 8574 8575 0( 0.0) 1( 10.0) 0/ 9 0/10 8576 8577 NOT PREGNANT 1( 14.3) 0/ 7 8578 8579 0( 0.0) 3( 42.8) 0/ 7 0/ 7 0/ 7 0/ 9 1/10 , FETUS 10 LUNGS: INTERMEDIATE LOBE ABSENT 0/ 7 0/ 7 1/ 7 FETUS 4 EYES: CIRCUMCORNEAL HEMORRHAGE, right eye N/N NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 1/ 7 1/ 7 0/ 9 0/10 DESCRIPTION FETUS 6 SKULL: FRONTALS, CONTAINED AN INTERFRONTAL, 0.5 mm X 1.0 mm FETUS 1 SKULL: NASALS, CONTAINED AN INTERNASAL, 0.4 mm X 1.0 mm 1/ 7 0/ 7 2/ 7 FETUS 1 HYOID: ALA, ANGULATED, bilateral FETUS 1 HYOID: ALA, ANGULATED, bilateral FETUS 2 HYOID: ALA, ANGULATED, bilateral PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SPO N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 2) : FETAL ALTERATION S - IN D IV ID U A L DATA 418-010:PAGE B-96 003996 DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) GROSS1 EXTERNAL EXAMINATION N/N DESCRIPTION SOFT TISSUE EXAMINATION N/N DESCRIPTION SKELETAL EXAMINATION N/N DESCRIPTION 8580 NOT PREGNANT 8581 ABORTED ON DAY 26 OF GESTATION a 8582 1( 33.3) 0/ 3 0/ 3 1/ 3 FETUS 8 THORACIC VERTEBRAE: ARCH, SMALL, left 10th; CENTRUM, UNILATERAL OSSIFICATION, left 10th RIBS: FUSED, 10th and 11th 8583 NOT PREGNANT 8584 NOT PREGNANT 8585 0( 0.0) 0/ 8 FETUS 3 LATE RESORPTION, autolysis precluded further evaluation 0/ 8 0/ 8 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED a. Doe 8581 aborted one late resorption and had eight late resorptions in utero on day 26 of gestation; autolysis precluded further evaluation. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R AB BITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 3): FETAL ALTERATIONS - INDIVIDUAL DATA 418-010: PAGE B-97 003997 DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) GROSS EXTERNAL EXAMINATION N/N DESCRIPTION SOFT TISSUE EXAMINATION N/N DESCRIPTION SKELETAL EXAMINATION N/N DESCRIPTION 8586 1( 10.0) 1/10 FETUS 8 TRUNK: SHORT TAIL: ABSENT 1/10 FETUS 8 KIDNEYS: FUSED, bilateral; DISPLACED, bilateral kidneys, caudally; SMALL, bilateral ABDOMEN: SITUS INVERSUS 1/10 FETUS 8 STERNAL CENTRA: FUSED, 1st - 4th XIPHOID: FUSED, to 4th sternal centra THORACIC VERTEBRAE : 6 PRESENT a CENTRUM, NOT OSSIFIED, 5th and 6th; ARCH, NOT OSSIFIED, bilateral 5th and 6th RIBS: FUSED, left 4th and 5th, bilateral 6th, to each other; EXTRA OSSIFICATION, attached to 6th ribs LUMBAR VERTEBRAE : 0 PRESENT a SACRAL VERTEBRAE : 0 PRESENT a CAUDAL VERTEBRAE : 0 PRESENT a 8587 FOUND DEAD ON DAY 13 OF GESTATION b 8588 0( 0.0) 0/ 7 0/ 7 0/ 7 8589 0( 0.0) 0/ 9 0/ 9 0/ 9 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED a. Excluded from ossification site group averages and statistical analyses. b. Doe 8587 was found dead on day 13 of gestation. Eight fetuses were present in utero; viability could not be determined because of their early developmental ages. All fetuses appeared normal for developmental ages at gross external examination. Soft tissue and skeletal examinations were not performed because of the early developmental ages of the fetuses. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S TABLE 22 (PAGE 4 ) : FETAL ALTERATIONS - IN D IVID U A L DATA (SPO N SO R'S STUDY NUMBER: 6 3 1 6 .8 ) 418-010: PAGE B-98 003998 DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) GROSS EXTERNAL EXAMINATION N/N DESCRIPTION SOFT TISSUE EXAMINATION N/N DESCRIPTION 8590 11(100.0) 0/11 11/11 FETUS 1 KIDNEYS: DISPLACED, left kidney, caudally FETUS 2 KIDNEYS: DISPLACED, left kidney, caudally FETUS 3 KIDNEYS: DISPLACED, left kidney, caudally FETUS 4 KIDNEYS: DISPLACED, left kidney, caudally FETUS 5 KIDNEYS: DISPLACED, left kidney, caudally FETUS 6 KIDNEYS: DISPLACED, left kidney, caudally FETUS 7 KIDNEYS: DISPLACED, left kidney, caudally FETUS 8 KIDNEYS: DISPLACED, left kidney, caudally N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 1/11 DESCRIPTION FETUS 8 SKULL: NASALS, CONTAINED AN INTERNASAL, 0.4 mm x 1.5 mm PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S TABLE 22 (PAGE 5) : FETAL ALTERATIONS - IN D IV ID U A L DATA (SPO N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) 418-010: PAGE B-99 003999 DOSAGE GROUP I RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8590 (Cont.) 8591 2( 22.2) 0 (VEHICLE) MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N DESCRIPTION 0/ 9 N/N 1/ 9 DESCRIPTION FETUS 9 KIDNEYS: DISPLACED, left kidney, caudally FETUS 10 KIDNEYS: DISPLACED, left kidney, caudally FETUS 11 KIDNEYS: DISPLACED, left kidney, caudally FETUS 9 LUNGS: INTERMEDIATE LOBE ABSENT 8592 8593 0( 0.0) 1( 11.1) 0/13 0/ 9 0/13 0/ 9 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION 1/ 9 0/13 1/ 9 FETUS 1 SKULL: FRONTALS, CONTAINED AN INTERFRONTAL, 1.0 mm X 2.5 mm FETUS 1 SKULL: NASALS, MIDLINE SUTURE DISPLACED, left PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N S O R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 6) : FETAL ALTERATIONS - IN D IV ID U A L DATA 00t00 DOSAGE GROUP II RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8594 3 ( 60.0) 0.1 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT' TISSUE EXAMINATION N/N 0/ 5 DESCRIPTION N/N 0/ 5 DESCRIPTION 8595 8596 0( 0.0) 1( 14.3) 0/ 5 0/ 7 0/ 5 0/ 7 8597 2( 22.2) 0/ 9 1/ 9 FETUS 8 EYES: CIRCUMCORNEAL HEMORRHAGE, right eye LUNGS: INTERMEDIATE LOBE ABSENT 8598 0( 0.0) 0/ 3 0/ 3 N/N = NUMBER OF SPE CIM EN S WITH ALTERATIONS/NUM BER OF SPECIM EN S EXAM INED SKELETAL EXAMINATION N/N 3/ 5 0/ 5 1/ 7 1/ 9 DESCRIPTION FETUS 4 CAUDAL VERTEBRAE: MISALIGNED, 15th FETUS 6 SKULL: FRONTALS, CONTAINED AN INTERFRONTAL, 2.0 mm X 4.5 mm FETUS 7 CAUDAL VERTEBRAE: MISALIGNED, 16th FETUS 1 HYOID: ALA, ANGULATED, bilateral STERNAL CENTRA: FUSED, 3rd and 4th FETUS 2 STERNAL CENTRA: FUSED, 3rd and 4th 0/ 3 418-010: PAGE B-100 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 7) : FETAL ALTERATIONS - IN D IVID U A L DATA DOSAGE GROUP II 0.1 MG/KG/DAY RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N(%) GROSS EXTERNAL EXAMINATION N/N DESCRIPTION SOFT TISSUE EXAMINATION N/N DESCRIPTION 8599 1< 11.1) 0/ 9 1/ 9 FETUS 3 LUNGS: INTERMEDIATE LOBE ABSENT 8600 3 ( 33.3) 1/ 9 FETUS 9 LATE RESORPTION, autolysis precluded further evaluation 0/ 9 FETUS 10 LATE RESORPTION, autolysis precluded further evaluation FETUS 11 ABDOMEN : DISTENDED N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 0/ 9 DESCRIPTION 2/ 9 FETUS 5 SKULL: NASALS, MIDLINE SUTURE DISPLACED, right FETUS 7 STERNAL CENTRA: FUSED, 3rd and 4th 418-010: PAGE B-101 004001 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 8 ) : FETAL ALTERATIONS - IN D IV ID U A L DATA 418-010: PAGE B-102 004002 DOSAGE GROUP II RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8601 2( 22.2) 0.1 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N 0/ 9 DESCRIPTION N/N 1/ 9 DESCRIPTION FETUS 8 KIDNEYS: DISPLACED, left kidney, caudally 8602 8603 0( 0.0) 1< 11.1) 0/ 7 0/ 9 0/ 7 0/ 9 8604 8605 8606 NOT PREGNANT 0( 0.0) 0/10 3( 33.3) 0/ 9 0/10 1/ 9 FETUS 4 LUNGS: INTERMEDIATE LOBE ABSENT 8607 NOT PREGNANT 8608 0( 0.0) 0/11 0/11 8609 0( 0.0) 0/ 9 0/ 9 8610 0( 0.0) 0/ 9 0/ 9 8611 0( 0.0) 0/ 9 0/ 9 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 1/ 9 0/ 7 1/ 9 DESCRIPTION FETUS 5 THORACIC VERTEBRAE: CENTRUM, UNILATERAL OSSIFICATION, right 13th FETUS 1 HYOID: ALA, ANGULATED, bilateral 0/10 2/ 9 FETUS 6 HYOID: ALA, ANGULATED, right FETUS 8 STERNAL CENTRA: FUSED, 3rd and 4th 0/11 0/ 9 0/ 9 0/ 9 PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RABBITS (SPONSOR'S STUDY NUMBER: 6316.8) TABLE 22 (PAGE 9) : FETAL ALTERATIONS - INDIVIDUAL DATA 418-010:PAGE B-103 004003 DOSAGE GROUP II RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8612 1( 12.5) 0.1 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N 0/ 8 DESCRIPTION N/N 0/ 8 DESCRIPTION 8613 8614 0( 0.0) 3 ( 33.3) 0/10 0/ 9 8615 2( 18.2) 0/11 0/10 2/ 9 0/11 FETUS 3 LUNGS : INTERMEDIATE LOBE ABSENT FETUS 8 LUNGS : INTERMEDIATE LOBE ABSENT N/N = NUMBER OF SPE CIM EN S WITH ALTERATIONS/NUM BER OF SPECIM EN S EXAMINED SKELETAL EXAMINATION N/N 1/ 8 0/10 1/ 9 DESCRIPTION FETUS 6 LUMBAR VERTEBRAE: HEMIVERTEBRA, right, between 6th and 7th, arch and centrum FETUS 4 HYOID: ALA, ANGULATED, left; ALA, SHORT, bilateral CAUDAL VERTEBRAE: MISALIGNED, 16th 2/11 FETUS 4 SKULL: NASALS, CONTAINED AN INTERNASAL, 1.5 mm x 4.5 mm; NASALS, MIDLINE SUTURE DISPLACED, right FETUS 10 SKULL: NASALS, MIDLINE SUTURE DISPLACED, right PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 10) : FETAL ALTERATIONS - IN D IVID U A L DATA DOSAGE GROUP III RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8616 0( 0.0) 1.0 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N 0/ S DESCRIPTION FETUS 2 LATE RESORPTION, autolysis precluded further evaluation FETUS 5 LATE RESORPTION, autolysis precluded further evaluation FETUS 8 LATE RESORPTION, autolysis precluded further evaluation N/N 0/ 5 DESCRIPTION SKELETAL EXAMINATION N/N 0/ 5 DESCRIPTION 004004 8617 1( 12.S) 0/ 8 0/ 8 8618 0( 0.0) 0/10 0/10 8619 O o o 0/ 7 0/ 7 8620 NOT PREGNANT N/N = NUMBER OF SPECIM EN S WITH ALTERATIONS/NUM BER OF SPECIM EN S EXAMINED 1/ 8 0/10 0/ 7 FETUS 7 SKULL: NASALS, MIDLINE SUTURE DISPLACED, right 418-010: PAGE B-104 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 1 1 ): FETAL ALTERATIONS - IN D IV ID U A L DATA so o fro o DOSAGE GROUP III RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N(%) 8621 1< 11.1) 1.0 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N 0/ 9 DESCRIPTION N/N 0/ 9 DESCRIPTION 8622 8623 8624 0( 0.0) 0/ 4 NOT PREGNANT l( ll.l) 0/ 9 8625 1( 14.3) 0/ 7 0/ 4 0/ 9 0/ 7 8626 8627 0( 0.0) 1( 10.0) 0/ 7 0/10 0/ 7 0/10 N/N = NUMBER OF SPE CIM EN S WITH ALTERATIONS/NUM BER OF SPECIM EN S EXAM INED SKELETAL EXAMINATION N/N 1/ 9 0/ 4 DESCRIPTION FETUS 2 SKULL: FRONTALS, CONTAINED AN INTERFRONTAL, 3.0 mm x 7.5 mm 1/ 9 1/ 7 0/ 7 1/10 FETUS 6 SKULL: NASALS, CONTAINED AN INTERNASAL, 1.5 mm X 4.0 mm FETUS 5 THORACIC VERTEBRAE: CENTRA, FUSED, 8th to right 9th; CENTRUM, BIFID, 9th RIBS: FUSED, right 8th and 9th, bases FETUS 9 HYOID: ALA, ANGULATED, left 418-010: PAGE B-105 PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RABBITS (SPONSOR'S STUDY NUMBER: 6316.8) TABLE 22 (PAGE 12) : FETAL ALTERATIONS - INDIVIDUAL DATA 9 0 0 fr0 DOSAGE GROUP III RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8628 2( 22.2) 1.0 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N 0/ 9 DESCRIPTION N/N 0/ 9 DESCRIPTION 8629 8630 8631 8632 0( 0.0) 0( 0.0) 0( 0.0) 2( 25.0) 0/10 0/ 8 0/ 9 0/ 8 0/10 0/ 8 0/ 9 1/ 8 FETUS 1 LUNGS: INTERMEDIATE LOBE ABSENT 8633 0( 0.0) 0/ 8 0/ 8 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 2/ 9 0/10 0/ 8 0/ 9 1/ 8 0/ 8 DESCRIPTION FETUS 6 THORACIC VERTEBRAE: CENTRA, FUSED, 12th to lumbar right 1st LUMBAR VERTEBRAE: CENTRUM, BIFID, 1st FETUS 8 THORACIC VERTEBRAE: PRESENT a RIBS: 11 PRESENT, bilateral a SPLIT, right 7th, distally, left 8th, medial - distal 11 FETUS 4 SKULL: NASALS, CONTAINED AN INTERNASAL, 2.0 mm X 4.0 mm 418-010: PAGE B-106 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 13) : FETAL ALTERATIONS - INDIVIDUAL DATA 418-010: PAGE B-107 004007 DOSAGE GROUP III 1.0 MG/KG/DAY RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) GROSS EXTERNAL EXAMINATION N/N DESCRIPTION SOFT TISSUE EXAMINATION N/N DESCRIPTION 8634 9(100.0) 0/ 9 9/ 9 FETUS 1 KIDNEYS: DISPLACED, left kidney, caudally FETUS 2 KIDNEYS: DISPLACED, left kidney, caudally FETUS 3 KIDNEYS: DISPLACED, left kidney, caudally FETUS 4 KIDNEYS: DISPLACED, left kidney, caudally FETUS 5 KIDNEYS: DISPLACED, left kidney, caudally FETUS 6 KIDNEYS: DISPLACED, left kidney, caudally FETUS 7 KIDNEYS: DISPLACED, left kidney, caudally FETUS 8 KIDNEYS: DISPLACED, left kidney, caudally N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 0/ 9 DESCRIPTION PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 14) : FETAL ALTERATIONS - INDIVIDUAL DATA 418-010: PAGE B-108 004008 DOSAGE GROUP III 1.0 MG/KG/DAY RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) GROSS EXTERNAL EXAMINATION N/N DESCRIPTION SOFT TISSUE EXAMINATION N/N DESCRIPTION 8634 (Cont.) FETUS 9 KIDNEYS: DISPLACED, left kidney, caudally 8635 8(100.0) 0/ 8 8/ 8 FETUS 1 KIDNEYS: DISPLACED, left kidney, caudally FETUS 2 KIDNEYS: DISPLACED, left kidney, caudally FETUS 3 KIDNEYS: DISPLACED, left kidney, caudally FETUS 4 KIDNEYS: DISPLACED, left kidney, caudally FETUS 5 KIDNEYS: DISPLACED, left kidney, caudally N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION 0/ 8 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S TABLE 22 (PAGE 15) : FETAL ALTERATIONS - IN D IVID U A L DATA (SPONSOR' S STUDY NUMBER: 6 3 1 6 .8 ) 418-010:PAGE B-109 004009 DOSAGE GROUP III RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N(%) 8635 (Cont.]I o o o 8636 8637 3( 23.1) 1.0 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N DESCRIPTION 0/ 7 0/13 N/N 0/7 0/13 DESCRIPTION FETUS 6 KIDNEYS: DISPLACED, left kidney, caudally FETUS 7 KIDNEYS: DISPLACED, left kidney, caudally FETUS 8 KIDNEYS: DISPLACED, left kidney, caudally N/N = NUMBER OF SPECIM EN S WITH ALTERATIONS/NUM BER OF SPECIM EN S EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION 0/ 7 3/13 FETUS 2 STERNAL CENTRA: FUSED, 2nd - 4th FETUS 4 STERNAL CENTRA: FUSED, 3rd and 4th FETUS 14 STERNAL CENTRA: FUSED, 3rd and 4th PROTOCOL 4 1 8 -0 X 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 1 6 ): FETAL ALTERATIONS - IN D IV ID U A L DATA 418-010:PAGE B-110 004010 DOSAGE GROUP IV RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N(%) 8638 0( 0.0) 8639 2( 28.6) 8640 2( 33.3) 2.5 MG/KG/DAY GROSS! EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N 0/ 7 0/ 7 0/ 6 DESCRIPTION FETUS 3 LATE RESORPTION, autolysis precluded further evaluation FETUS 8 LATE RESORPTION, autolysis precluded further evaluation N/N 0/ 7 0/ 7 DESCRIPTION 0/ 6 8641 8642 0( 0.0) 1( 12.5) 0/ 9 0/ 8 0/ 9 0/ 8 N/N = NUMBER OF SPECIM EN S WITH A LT ER A T IO N S/NUMBER OF SPECIM EN S EXAMINED SKELETAL EXAMINATION N/N 0/ 7 2/ 7 DESCRIPTION FETUS 4 PELVIS: PUBIS, NOT OSSIFIED, bilateral FETUS 9 PELVIS: PUBIS, NOT OSSIFIED, bilateral 2/ 6 0/ 9 1/ 8 FETUS 2 HYOID: ALA, ANGULATED, left FETUS 6 HYOID: ALA, ANGULATED, right FETUS 7 PELVIS: PUBIS, NOT OSSIFIED, bilateral PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 1 7 ): FETAL ALTERATIONS - IN D IV ID U A L DATA 418-010: PAGE B 004011 DOSAGE GROUP IV RABBIT HUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8643 1( 14.3) 2.5 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N 0/ 7 DESCRIPTION N/N 0/ 7 DESCRIPTION 8644 8645 K 11.1) 3 ( 42.8) 1/ 9 0/ 7 FETUS 5 SNOUT: SHORT, tongue protrudes 0/ 9 1/ 7 FETUS 6 LUNGS: INTERMEDIATE LOBE ABSENT 8646 3( 50.0) 0/ 6 3/ 6 FETUS 1 VESSELS: COMMON TRUNCUS ARTERIOSUS LUNGS: SMALL, all lobes; FUSED, all lobes N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 1/ 7 0/ 9 DESCRIPTION FETUS 7 SKULL: NASALS, CONTAINED AN INTERNASAL, 0.3 mm X 1.5 mm 2/ 7 0/ 6 FETUS 1 SKULL: NASALS, MIDLINE SUTURE DISPLACED, left FETUS 5 SKULL: NASALS, MIDLINE SUTURE DISPLACED, left PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 18) : FETAL ALTERATIONS - IN D IV ID U A L DATA 418-010:PAGE B-112 004012 DOSAGE GROUP IV 2.5 MG/KG/DAY RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) GROSS EXTERNAL EXAMINATION N/N DESCRIPTION SOFT TISSUE EXAMINATION N/N DESCRIPTION SKELETAL EXAMINATION N/N DESCRIPTION 8646 (Cont.)I FETUS 2 EYES : CIRCUMCORNEAL HEMORRHAGE, bilateral, FETUS 6 KIDNEYS: DISPLACED, left kidney, caudally 8647 ABORTED ON DAY 21 OF GESTATION a 8648 3( 21.4) 0/14 FETUS 10 LATE RESORPTION, autolysis precluded further evaluation FETUS 11 LATE RESORPTION, autolysis precluded further evaluation 0/14 3/14 FETUS 1 STERNAL CENTRA: FUSED, 2nd and 3rd FETUS 9 STERNAL CENTRA: FUSED, 3rd and 4th N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED a. Doe 8647 aborted one live fetus and one late resorption and had eight live fetuses, 2 dead fetuses and one late resorption in utero on day 21 of gestation. Autolysis precluded further evaluation of the late resorptions. All remaining fetuses appeared normal at gross external examination for developmental ages and appeared normal at soft tissue examination. Fetuses 1, 2, 4, 5, 6, 8, 9, 10, 11 and 12 had pelvis, pubis not ossified (bilateral) at skeletal examination. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B ITS (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 19) : FETAL ALTERATIONS - IN D IV ID U A L DATA 418-010: PAGE B-113 o o o 004013 DOSAGE GROUP IV 2.5 MG/KG/DAY RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) GROSS EXTERNAL EXAMINATION N/N DESCRIPTION SOFT TISSUE EXAMINATION N/N DESCRIPTION 8648 (Cont.) FETUS 14 LATE RESORPTION, autolysis precluded further evaluation FETUS 15 LATE RESORPTION, autolysis precluded futher evaluation 8649 8650 0( 0.0) 0/ 6 0/ 6 0/ 6 0/ 6 ' 8651 4( 57.1) 0/ 7 4/ 7 FETUS 1 KIDNEYS : DISPLACED, left kidney, caudally FETUS 2 KIDNEYS: DISPLACED, left kidney, caudally FETUS 5 KIDNEYS: DISPLACED, left kidney, caudally N/N = NUMBER OF SPE C IM EN S WITH ALTERATION S/N UM BER OF SPECIM EN S EXAM INED SKELETAL EXAMINATION N/N DESCRIPTION FETUS 18 SKULL: NASALS, MIDLINE SUTURE DISPLACED, left STERNAL CENTRA: FUSED, 1st - 4th 0/ 6 0/ 6 0/ 7 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 2 0 ): FETAL ALTERATIONS - IN D IV ID U A L DATA 418-010: PAGE B-114 004014 DOSAGE GROUP IV 2.5 MG/KG/DAY RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N(%) GROSS EXTERNAL EXAMINATION N/N DESCRIPTION SOFT TISSUE EXAMINATION N/N DESCRIPTION SKELETAL EXAMINATION N/N DESCRIPTION 8651 (Cont.) FETUS 7 KIDNEYS: DISPLACED, left kidney, caudally 8652 ABORTED ON DAY 26 OF GESTATION a 8653 NOT PREGNANT 8654 0( 0.0) 0/ 7 0/ 7 0/ 7 8655 8656 0( 0.0) 1( 10.0) 0/ 3 0/10 0/ 3 0/10 0/ 3 1/10 FETUS 1 SKULL: FRONTALS, CONTAINED AN INTERFRONTAL, 2.0 mm x 3.5 mm 8657 1( 12.5) 0/ 8 0/ 8 1/ 8 FETUS 7 STERNAL CENTRA: FUSED, 3rd and 4th 8658 1( 12.5) 0/ 8 0/ 8 1/ 8 FETUS 6 STERNAL CENTRA: FUSED, 3rd and 4th 8659 0( 0.0) 0/ 6 0/ 6 0/ 6 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED a. Doe 8652 aborted one dead fetus and had 2 live fetuses and one late resorption in utero on day 26 of gestation. All fetuses and the late resorption appeared normal at gross external examination for developmental ages. All fetuses appeared normal at soft tissue and skeletal examinations. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPM ENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 21) : FETAL ALTERATIONS - IN D IV ID U A L DATA 418-010:PAGE B-115 o o 004015 DOSAGE GROUP V 3.75 MG/KG/DAY RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) GROSS EXTERNAL EXAMINATION N/N DESCRIPTION SOFT TISSUE EXAMINATION N/N DESCRIPTION SKELETAL EXAMINATION N/N DESCRIPTION 8660 8661 8662 ABORTED ON DAY 20 OF GESTATION a ABORTED ON DAY 23 OF GESTATION b 1 0/ 4 FETUS 1 LATE RESORPTION, autolysis precluded further evaluation 0/ 4 0/ 4 FETUS 4 LATE RESORPTION, autolysis precluded further evaluation FETUS 7 LATE RESORPTION, autolysis precluded further evaluation 8663 ABORTED ON DAY 26 OF GESTATION c N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED a. Doe 8660 aborted three dead fetuses and had seven fetuses of undetermined viability in utero on day 20 of gestation. All fetuses appeared normal for their developmental ages at gross external examination. Soft tissue and skeletal examinations were not performed because of the early developmental ages of the fetuses. b. Doe 8661 aborted one dead fetus and had six live fetuses and two late resorptions in utero on day 23 of gestation. Autolysis precluded further evaluation of the late resorptions. Fetus 6 had edema (dorsal and ventral neck) at gross external examination. All remaining fetuses appeared normal at gross external examination for developmental age. All fetuses appeared normal at soft tissue examination. Fetuses 1, 2, 3, 5, 6, 7 and 9 had pelvis, pubis not ossified (bilateral) at skeletal examination. c. Doe 8663 aborted nine dead fetuses and one late resorption on day 26 of gestation. Autolysis precluded further evaluation of the late resorption. All fetuses were partially cannibalized. Fetuses 1, 2, 3, 4, 5, 6, 8 and 10 appeared normal at gross external examination for developmental age and appeared normal at soft tissue examination. Fetuses 2, 3, 4, 5, 6, 8 and 10 had pelvis, pubis not ossified (bilateral) and fetus 4 had ribs, split (right 12th, medial-distal) at skeletal examination. PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R AB BITS TABLE 22 (PAGE 2 2 ) : FETAL ALTERATIONS - IN D IV ID U A L DATA (SPO N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) 418-010: PAGE B-116 004016 DOSAGE GROUP V RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8664 3 ( 42.8) 8665 2( 20.0) 3.75 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N 0/ 7 1/10 DESCRIPTION FETUS 6 LATE RESORPTION, autolysis precluded further evaluation FETUS 7 LATE RESORPTION, autolysis precluded further evaluation FETUS 8 LATE RESORPTION, autolysis precluded further evaluation FETUS 8 BODY: EDEMA, neck SNOUT: SHORT, tongue protrudes EARS: SMALL, bilateral N/N 0/ 7 DESCRIPTION 0/10 8666 0( 0.0) 0/11 0/11 N/N = NUMBER OF SPE C IM EN S WITH ALTERATIONS/NUM BER OF SPECIM EN S EXAM INED SKELETAL EXAMINATION N/N 3/ 7 DESCRIPTION FETUS 3 HYOID : ALA , ANGULATED, left FETUS 5 HYOID: ALA , ANGULATED, right FETUS 10 HYOID : ALA , ANGULATED, bilateral 2/10 0/11 FETUS 7 STERNAL CENTRA: FUSED, 3rd .and 4th FETUS 8 STERNAL CENTRA: FUSED, 3rd and 4th HYOID: ALA , ANGULATED, bilateral PROTOCOL 4 X 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 23) : FETAL ALTERATIONS - IN D IVID U A L DATA TOfroO DOSAGE GROUP V 3.75 MG/KG/DAY RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) GROSS EXTERNAL EXAMINATION N/N DESCRIPTION 8667 ABORTED ON DAY 19 OF GESTATION a SOFT TISSUE EXAMINATION N/N DESCRIPTION SKELETAL EXAMINATION N/N DESCRIPTION 8668 2( 33.3) 0/ 6 FETUS 3 LATE RESORPTION, autolysis precluded further evaluation 1/ 6 FETUS 2 LUNGS : INTERMEDIATE LOBE ABSENT 1/ 6 FETUS 4 HYOID: ALA, ANGULATED, left FETUS 5 LATE RESORPTION, autolysis precluded further evaluation 8669 ABORTED ON DAY 29 OF GESTATION b 8670 1( 20.0) 0/ 5 FETUS 5 LATE RESORPTION, autolysis precluded further evaluation 8671 2( 22.2) 0/ 9 0/ 5 1/ 9 FETUS 5 LUNGS: INTERMEDIATE LOBE ABSENT 1/ 5 1/ 9 FETUS 1 THORACIC VERTEBRAE: HEMIVERTEBRA, right 12th, arch with attached rib RIBS: SPLIT, left 10th, medial - distal FETUS 3 SKULL: NASALS, MIDLINE SUTURE DISPLACED, right N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED a- Doe 8667 aborted two dead fetuses and had two fetuses of undetermined viability ijr utero on day 19 of gestation. All fetuses appeared normal for their developmental ages at gross external examination. Soft tissue and skeletal examinations were not performed because of the early developmental ages of the fetuses, b. Doe 8669 aborted five late resorptions and had five late resorptions in utero on day 29 of gestation; autolysis precluded further evaluation. 418-010: PAGE B-117 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: 6 3 1 6 .8 ) TABLE 22 (PAGE 24) : FETAL ALTERATIONS - IN D IV ID U A L DATA 8 * 0 to o DOSAGE GROUP V RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8672 1( 11.1) 3.75 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N 0/ 9 DESCRIPTION FETUS 8 LATE RESORPTION, autolysis precluded further evaluation N/N 1/ 9 DESCRIPTION FETUS 6 LUNGS: INTERMEDIATE LOBE ABSENT 8673 1( 12.5) 0/ 8 1/ 8 FETUS 3 HINDLIMB: SKIN CONSTRICTED, right 8674 0( 0.0) 0/ 6 0/ 6 8675 0( 0.0) 0/ 8 0/ 8 8676 0( 0.0) 0/11 FETUS 2 LATE RESORPTION, autolysis precluded further evaluation 0/11 8677 NOT PREGNANT N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 1/ 9 0/ 8 DESCRIPTION FETUS 6 SKULL: NASALS, CONTAINED AN INTERNASAL, 1.5 mm x 3.0 nun STERNAL CENTRA: FUSED, 2nd and 3rd CAUDAL VERTEBRAE: MISALIGNED, 12th and 15th 0/ 6 0/ 8 0/11 418-010: PAGE B-118 PROTOCOL 4 1 8 -0 1 0 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R AB BITS TABLE 22 (PAGE 25) : FETAL ALTERATIONS - IN D IV ID U A L DATA (SPO N SO R'S STUDY NUMBER: 6 3 1 6 .8 ) DOSAGE GROUP V RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8678 1( 12.5) 3.75 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N 0/ 8 DESCRIPTION N/N 0/ 8 DESCRIPTION 8679 0( 0.0) 0/11 0/11 8680 1( 12.5) 0/ 8 1/ 8 FETUS 6 LUNGS: INTERMEDIATE LOBE ABSENT 8681 0( 0.0) 0/ 8 0/ 8 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N 1/ 8 0/11 0/ 8 DESCRIPTION FETUS 7 HYOID: ALA, ANGULATED, right STERNAL CENTRA: FUSED, 3rd and 4th 0/ 8 6T 0 00 418-010:PAGE B-119 APPENDIX C PROTOCOL AND AMENDMENT 0 4 0 2 o 418-010:PAGE C-1 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 418-010 SPONSOR'S STUDY NUMBER: 6316.8 STUDY TITLE: PURPOSE: TESTING FACILITY: STUDY DIRECTOR: SPONSOR: STUDY MONITOR: ALTERNATIVE STUDY MONITOR: Oral (Stomach Tube) Developmental Toxicity Study of N-EtFOSE in Rabbits The purpose of this study is to detect adverse effects of N-EtFOSE on New Zealand White [Hra:(NZW)SPF] presumed pregnant female rabbits and development of the embryo and fetus consequent to exposure of the doe from implantation to closure of the hard palate. This study evaluates ICH Harmonised Tripartite Guideline stages C and D of the reproductive process in a nonrodent species. 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 004021 418-010:PAGE C-2 Protocol 418-010 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 for Safety Studies on Drugs, MHW Ordinance Number 21, March 26,1997. 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. 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. 00402 2 418-010: PAGE C-3 Protocol 418-010 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 W ater (R.O. Deionized Water). Supplier and lot identification of Tween 80 to 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. Room temperature (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. 004023 418-010: PAGE C-4 Protocol 418-010 Page 4 FORMULATION: Frequency o f P reparation: Formulations (suspensions) will be prepared daily at the Testing Facility. Detailed preparation procedures are attached to this protocol (ATTACHMENT 3). A djustm ent fo r P u ritv: The test article will be considered 100% pure for the purpose of dosage calculations. Testing F a cility Reserve Sam ples: The Testing Facility will reserve a sample (1 g) of each lot of bulk test article and a sample (5 mL) of each lot of vehicle 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. B ulk Test A rticle S am pling: 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 o f Prepared Form ulations: Homogeneity and stability of prepared formulations 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) w ill 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. 0 4 0 ;>4 418-010: PAGE C-5 Protocol 418-010 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. DISPOSITION: 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 upon completion of all work with the test article. TEST SYSTEM: Soecies/Strain and Reason for Selection: The New Zealand White [Hra:(NZW)SPF] rabbit was selected as the Test System because: 1) it is one non-rodent mammalian species accepted and widely used throughout the industry for nonclinical studies of developmental toxicity (embryo-fetal toxicity/teratogenicity); 2) this strain of rabbit 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 the species and strain. Number and Sex: Population evaluated: 110 timed-pregnant female rabbits (22 per dosage group). Population selected for toxicokinetic evaluation: 19 satellite female rabbits (five at the low and high dose levels plus three at the other dose levels). Body Weight and Age: The individual body weights of the female rabbits will range from 2.5 kg to 5.5 kg; the rabbits will be approximately five to seven months of age at the time of study assignment. Actual body weights recorded at receipt and at study assignment will be documented in the raw data, and the weight range will be included in the final report. 004025 418-010: PAGE C-6 Protocol 418-010 Page 6 Source: Covance Research Products, Inc. Swampbridge Road, Box 7200 Denver, Pennsylvania 17517 The rabbits will be shipped in filtered cartons by truck from Covance Research Products, Inc., Denver, Pennsylvania, to the Testing Facility. Identification: Rabbits are permanently identified using Monel self-piercing ear tags (Gey Band and Tag Co., Inc., No. MSPT 20103). Female rabbits are given unique permanent identification numbers when assigned to the study on the basis of day 0 o f presumed gestation body weights. ANIMAL HUSBANDRY: All cage sizes are in compliance with the Guide for the Care and Use of Laboratory Animals(4). Housing: The rabbits will be individually housed in units of six to eight stainless steel cages. No nesting materials will be supplied because the female rabbits will be sacrificed before parturition is expected. Room Air. Temperature and Humidity: 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. Room temperature will be maintained at 61 F (16C) to 72F (22C) 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. Diet: Approximately 150 g of Certified Rabbit Chow #5322 (PMI Nutrition International) will be available to each rabbit each day until the first day of dosage, at which time approximately 180 g of the same certified feed will be offered to each rabbit each day. The certified feed will be available from individual stainless steel "J-type" feeders attached to each cage. 0 4 0 2 G 418-010: PAGE C-7 Protocol 418-010 Page 7 Water: W ater 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. Contaminants: Neither the Sponsor nor the 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. MATING AND RANDOMIZATION: The female rabbits will be naturally bred at the Supplier by breeder male rabbits of the same source and strain before shipment to the Testing Facility. The day mating occurs will be designated day 0 of presumed gestation. The rabbits will be mated on five consecutive days and shipped to the Testing Facility after the last mating day to arrive on day 1,2, 3, 4 or 5 of presumed gestation. Before shipment of the rabbits, the Supplier will forward breeding records and day 0 of presumed gestation body weights. A computer-generated (weight-ordered) randomization procedure will be used to assign the rabbits to dosage groups based on this information. ADMINISTRATION: Route and Reason for Choice: The oral (stomach tube) 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 possible routes of human exposure. Method and Frequency: Female rabbits will be given the test article once daily on days 7 through 20 of presumed gestation. Dosages will be adjusted daily for body weight changes and given at approximately the same time each day. Rationale for Dosage Selection: Dosages were selected on the basis of a dosage-range study (Argus Research Laboratories, Inc., Protocol 418-01 OP). ^0 4 0 2 7 418-010:PAGE C-8 Protocol 418-010 Page 8 Dosage Levels. C oncentrations and V olum es: Dosage Group Number of Rabbits Dosage (mg/kg/day) Concentration (mg/mL) Dosage Volume (mUkg) Argus Batch Number I 22+3* 0 (Vehicle) 0 5 B-418-010-A(Day.Month.Year) II 22+5* 0.1 0.02 5 B-418-010-B(Day.Month.Year) III 22+3* 1.0 0.2 5 B-418-010-C(Dav.Month.Year) IV 22+3* 2.5 0.5 5 B-418-010-D(Dav.Month.Year) V 22+5* 3.75 0.75 5 B-418-01O-E(Day.Month.Year) a. Rabbits assigned to toxicokinetic evaluation. The test article will be considered 100% pure for the purpose of dosage calculations. TESTS. ANALYSES AND MEASUREMENTS: V ia b ility: All Periods: At least twice daily. C linical O bservations and/or General Appearance: Predosage Period: At least once. 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 W eights: Predosage Period: Day 0 of presumed gestation and on the day of arrival at the Testing Facility. Dosage Period: Daily. Postdosage Period: Daily. Feed C onsum ption Values: Predosage Period: Recorded daily after arrival at the Testing Facility (values not tabulated). Dosage Period: Recorded daily. 004028 418-010:PAGE C-9 Protocol 418-010 Page 9 Postdosage Period: Recorded daily. Feed consumption values during the dosing period will be tabulated for the same intervals as body weight evaluations. Caesarean-Sectioning Observations: Rabbits will be Caesarean-sectioned on day 29 of presumed gestation. The fetuses will be removed from the uterus and placed in individual containers. The rabbits 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 identified as an early resorption.) Fetal Observations: Body Weights and Identification: The body weight of each fetus will be recorded. Only body weights o f live fetuses will be used to determine litter fetal body weight averages. Fetuses will be tagged with identification noting study number, litter number and uterine distribution. Gross External Alterations: All fetuses will be examined for gross external alterations. Late resorptions and dead fetuses also will be examined for gross external alterations to the extent possible but such observations will not be included in either data summarization or statistical analyses. 04029 418-010:PAGE C-10 Protocol 418-010 Page 10 Soft Tissue Examination and Sex: All fetuses will be examined internally to determine sex. Cavitated organs will be evaluated in all fetuses by dissection(5>. A single cross-section will be made between the parietal and frontal bones, and the brain will be examined in situ. Skeletal Examination: All fetuses will be examined for skeletal alterations after staining with alizarin red S<6). 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: Beuthanasia-D Special (manufactured by Schering-Plough Health) will be used to sacrifice rabbits (via intravenous injection) and live fetuses (via intraperitoneal injection). NECROPSY: Gross lesions w ill be retained in neutral buffered 10% formalin for possible future evaluation (corresponding tissues will be retained from rabbits in the vehicle control group at the discretion of the Study Director). (Exception: Parovarian cysts will be discarded; these are common, spontaneous lesions in rabbits.) Unless specifically cited below, all other tissues will be discarded. Satellite Rabbits Assigned to Toxicokinetic Sample Collection: On day 21 of presumed gestation (the day following the last dosage), toxicokinetic samples will be collected from the rabbits assigned to the toxicokinetic evaluation. Following anesthesia of pentobarbital, blood samples (approximately 4 mL per rabbit) 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 w ill be excised, weighed, and a sample will be taken from the right lateral lobe, frozen and retained at -70C until shipment to the Sponsor for analysis. Rabbits will be Caesarean-sectioned and fetuses will be examined grossly to the extent possible as described above for rabbits assigned to the main study. Fetuses and placentae will be pooled per litter and retained frozen (-70C) until shipment to the Sponsor for analysis. After completion of sample collection, serum, liver sections, fetal and placental samples will be shipped (frozen on dry ice) to Kris J. Hansen, Ph.D., at the previously cited 004030 418-010: PAGE C-11 Protocol 418-010 Page 11 address for analysis. Both the recipient and the Study Monitor will be notified in advance of sample shipment. Scheduled Sacrifice: On day 29 of presumed gestation, female rabbits will be Caesarean-sectioned, and a gross necropsy of the thoracic, abdominal and pelvic viscera will be performed. Uteri of apparently nonpregnant does will be stained with 10% ammonium sulfide to confirm the absence of implantation sites*7*. Rabbits Found Dead or Moribund: Rabbits 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. Pregnancy status and uterine contents 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 does will be stained with 10% ammonium sulfide to confirm the absence of implantation sites(7). 004031 418-010: PAGE C-12 Protocol 418-010 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. NonDarametricb A. Bartlett's Test*" A. Kruskal-Wallis Test (75% ties) Significant at p<.0.05 Not Significant Significant at p<.0.05 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. 004032 418-010:PAGE C-13 Protocol 418-010 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. Veterinarian Examination. Mating History. Treatment (if prescribed by Staff Veterinarian). General Comments. Clinical Observations and/or General Appearance. Blood 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 W ater 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 004033 418-010: PAGE C-14 Protocol 418-010 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., Hoberman, A.M. and Smith, T.H.F. (1982). Dosage-range study of the teratogenic potential of suspensions of trinitrofluorenone (TNF) administered orally to New Zealand White rabbits. Toxicologist 2(1):40 (#143). 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. Feussner, E.L., Lightkep, G.E., Hennesy, R.A., Hoberman, A.M. and Christian, M.S. (1992). A decade of rabbit fertility data: Study of historical control animals. Teratology 46(4):349-365. 4. Institute of Laboratory Animal Resources (1996). Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C. 5. Staples, R.E. (1974). Detection o f visceral alterations in mammalian fetuses. Teratology 9(3):A37-38. 0 4 0 3 4 418-010: PAGE C-15 Protocol 418-010 Page 15 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). Nonparametric Statistics for the Behavioral Sciences, McGraw-Hill, New York, pp. 96-104. 004035 PROTOCOL APPROVAL: FOR THE TESTING FACILITY Gedrge E/Dearlove, Ph.D., DABT Associate Director of Research 418-010: PAGE C-16 Protocol 418-010 Page 16 Date Study Director Dena C. Lebo, V.M.D. Member, Institutional Animal Care and Use Committee ___ LLiC Lu Date / FOR THE SPONSOR u :4a,t t r \ Marvin T. Case, D.V.M., Ph.D. Study Monitor ^ Date rr 004036 418-010:PAGE C-17 ATTACHMENT 1 SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE 004037 ATTACHMENT 1 418-010: PAGE C-18 Protocol 418-010 Page 1 of 2 STUDY SCHEMATIC RABBIT DEVELOPMENTAL TO XICITY STUDY" Timed-Pregnant Rabbits Start of Dosage Day 0 of Presumed Gestation Day 7 of Presumed Gestation End of Dosage CaesareanSectioning6 Day 20 of Presumed Gestation Day 29 of Presumed Gestation mmmm Dosage Period a. For additional details, see 'Tests, Analyses and Measurements" section of the protocol. b. Fetal evaluations (external soft tissue and skeletal). 004038 ATTACHMENT 1 418-010:PAGE C-19 Protocol 418-010 Page 2 of 2 SCHEDULE8 28 AUG 98 30 AUG 9 8 -1 6 SEP 98 13 SEP 9 8 -1 7 SEP 98 21 SEP 98 - 25 SEP 98 22 DEC 98 Animals Arrive - Acclimation Begins. Dosage Period (Days 7 through 20 of presumed gestation). Toxicokinetic Sample Collection (Day 21 of presumed gestation). Caesarean-Sectioning Period (Day 29 of presumed gestation). Draft Final Report. a. The study initiation date is the date the Study Director signs the protocol. 004039 418-010: PAGE C-20 ATTACHMENT 2 MATERIAL SAFETY DATA SHEET 004040 material safety data SHEET 418-010: PAGE C-21 3m N-fc+Pobt 3M Canter St. Paul, Minnesota 55144-1000 1-800-364-3577 or (612) 737-6501 (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 Fluorochemical Alcohol ID NUMBER/U.P.C.: 98-0211-1113-7 00-51135-09495-2 98-0211-1183-0 98-0211-1575-7 00-51135-02145-3 98-0211-6620-6 2F-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 ALCOHOl---PERFLUOROBUTANESULFONAMIDO ALCOHOL.... PERFLUOROPENTANESULFONAMIDO ALCOHOl____ 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 BOILING POINT:..... VAPOR PRESSURE:.... VAPOR DENSITY:..... EVAPORATION RATE:... SOLUBILITY IN WATER: SPECIFIC GRAVITY:... PERCENT VOLATILE:... p H : .................... VISCOSITY:......... MELTING POINT:...... ca. 118 c 8 1 mm Hg < 1 0 mmHg Calc 8 20 C > 1 . 0 Air=1 Calc 8 20 C. < 1 . 0 BuOAc-1 neglig. ca. 1.7 Water=i (of melt) 0% N/A N/D N/D 004041 Abbreviations: N/D - Not Determined N/A Not Applicable CA * Approximately MSDS: FC-10 FLUORAD Brand Fluorochnical Alcohol January 29, 1998 2. PHYSICAL DATA (continued) 418-010: PAGE C-22 PAGE 2 APPEARANCE AND ODOR: Amber waxy solid 3. FIRE AND EXPLOSION HAZARD DATA FLASH POINT:.......... FLAMMABLE LIMITS - LEL: FLAMMABLE LIMITS - UEL: AUTOIGNITION TEMPERATURE:..... N/A EXTINGUISHING MEDIA: Mater, 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 604042physical and health hazards, respiratory protection, ventilation, an personal protective equipment. Collect spilled material. Clean up residue. Place in a U.S. DOT-approved container. Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately MSDS: FC-10 FLUORAD Brand Fluorochemical Alcohol January 29, 1998 5. ENVIRONMENTAL INFORMATION (continued) 418-010:PAGE C-23 PAGE 3 RECOMMENDED DISPOSAL: Incinerate in a permitted hazardous waste incinerator in the presence of a combustible material. Combustion products will include HP. 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, % 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. Wash 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 SWALLOWED: Call a physician IMMEDIATELY. If swallowed, induce vomiting immediately as directed by medical personnel. Never give anything by mouth to an unconscious person. 004043 Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately MSDS: FC-10 FLU0RA0 Brand Fluorochemical Alcohol January 29, 1998 7. PRECAUTIONARY INFORMATION 418-010: PAGE C-24 PAGE 4 EYE PROTECTION: Avoid eye contact. Near 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 material(s) 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 m s d s . 004044 HMIS HAZARD RATINGS: HEALTH: 1 FLAMMABILITY: 1 REACTIVITY: 0 PERSONAL PROTECTION: X (See precautions, section 7.) EXPOSURE LIMITS INGREDIENT VALUE UNIT TYPE AUTH SKIN* PERFLUOROOCTANESULFONAMIDO ALCOHOL... 0.1 MG/M3 . TWA 3M PERFLUOROHEXANESULFONAMIDO ALCOHOL... 0.1 MG/M3 TWA 3M PERFLUOROHEPTANESULFONAMIDO ALCOHOL............................ 0.1 MG/M3 TWA 3M Y Y Y Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 418-010:PAGE C-25 HSOS: FC-10 FLUORAD Brand Fluorochemical Alcohol January 29, 1998 EXPOSURE LIMITS (continued) PAGE 5 INGREDIENT VALUE UNIT TYPE AUTH SKIN PERFLUOROBUTANESULFONAMIDO ALCOHOL. PERFLUOROPENTANESULFONAMIDO ALCOHOL......................... 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. 00404S Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately MSOS: FC-10 FLUORAD Brand Fluoroeheaieal Alcohol January 29, 1998 418-010:PAGE C-26 PAGE 6 SECTION CHANGE DATES HEADING SECTION CHANGED SINCE November 05, 1997 ISSUE Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately The information in this Material Safety Data Sheet (MSOS) 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 the 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. 3M provides information in electronic form as a service to its customers. Due to the remote possibility that electronic transfer may have resulted in errors, omissions or alterations in this information, 3M makes no representations as to its completeness or accuracy. In addition, 004046 information obtained from a database may not be as current as the information in the MSDS available directly from 3M. 418-010:PAGE 0,-27 ATTACHMENT 3 TEST ARTICLE PREPARATION PROCEDURE 004047 418-010:PAGE C-28 ATTACHMENTS Protocol 418-010 ' Version: 4 1 8 -0 1 0 (09 AUG 981 Page 1 of 3 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE Test Article: N-EtFOSE Vehicle: 2% Tween 80 in R.O. Deionized Water A. Purpose: The purpose of this procedure is to provide a method for the preparation o f dosage suspensions of N-EtFOSE and the vehicle for oral administration to rabbits on Argus Study 418-010. 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: X Daily Weekly For days of use 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. 004048 418-010: PAGE C-29 ATTACHMENT 3 Protocol 418-010 Version: 418-010 (09 AUG 98) Page 2 of 3 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE NOTE: The 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 50C 5C, then add the required amount of Tween 80 and mix until uniform (See TEST ARTICLE CALCULATIONS). D. Test Article Suspension Preparation: 1. To prepare the 0.75 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 80C 5C for approximately 30 minutes or until the TA/S dissolves. 2. Once the test article has dissolved; spin over night while the suspension cools. (Be sure there is a visible vortex, this will achieve the desired emulsion.) 3. To prepare the 0.5 mg/mL, Group IV suspension, remove the required amount of stock suspension (Group V) (See TEST ARTICLE CALCULATIONS), QS ad with the vehicle and mix. 4. To prepare the 0.2 mg/mL, Group III suspension, remove the required amount of stock suspension (Group IV) (See TEST ARTICLE CALCULATIONS), QS ad with the vehicle and mix. 5. To prepare the 0.02 mg/mL, Group II suspension, remove the required amount of stock suspension (Group III) (See TEST ARTICLE CALCULATIONS), QS ad with the vehicle and mix. 004049 418-010: PAGE C-30 ATTACHMENT 3 Protocol 418-010 ' Version: 4 1 8 -0 1 0 (09 AUG 981 Page 3 of 3 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE 6 . To prepare the 0 mg/mL, Group I suspension, add the required amount of vehicle to an appropriately sized, labeled container (See TEST ARTICLE CALCULATIONS) and mix. Written by: ,'y U J L 0 , _____________ Approved by: Date: H -A tf-lA r Clarification: X No ___Yes (See attached clarification form.) Initials/Date : 004050 O P rim edica 418-010: PAGE C-31 Argus Research Laboratories, Inc. 905 Sheehy Drive, Building A Horsham, PA 19044 Telephone: (215) 443-B710 Telefax: (215) 443-8587 PROTOCOL 418-010 ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-ETFOSE IN RABBITS SPONSOR'S STUDY NUMBER: 6316.8 Amendment 1 - 2 2 December 1998 1. Sponsor (page 1 o f 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. G b rg e 't. Dearlove, Ph.D., DABT Date Raymcmf G. York, Ph.Dl Associate Director of Research Associate Director of Re Study Director z.2-ae.-9r Date Dena Gitysbo, V.M ./ Date Chairperson, Institutional Animal Care and Use Committee Marvin T. Case, D.V.M., Ph.D. Study Monitor Date 00405^ APPENDIX D DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY 04O52 418-010: PAGE D-1 DEVIATIONS FROM THE PROTOCOL AND STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY On 2 September 1998 (Day 11 of presumed gestation) one rabbit in Group V (3.75 mg/kg/day dosage group, rabbit 8675) was inadvertently not dosed. This deviation does not adversely affect the outcome of the study because this represents only a small loss of data and was a single event. All deviations are documented in the raw data. //-a fru -9 9 JD., DABT Associate Directotarf-Research and Study Director Date W 4053 APPENDIX E TEMPERATURE AND RELATIVE HUMIDITY REPORTS AND DEVIATIONS REPORT OG4054 ARGUS 418-010: PAGE E-1 Temperature and Relative Humidity Report Location: Room 07 Protocol Number: 418-010 Range of Dates: 28-Aug-1998 14:00 to 21-Sep-1998 13:53 Target Range: Species: RABBIT Total Number o f Days: Total Number of Hours: Total Number of Data Points: Temperature 61 *F to 72F 25 575.74 576 Relative Humidity 30% to 70% 25 575.74 576 Mean ( SD): Maximum: Median: Minimum: Number of Points in Range (%): Number of Points High (%): Number of Points Low (%): 67.4 ( 0.4) 60.4 ( 3.0) 68.6 68.7 67.4 60.5 66.3 53.1 576 (100.0) 576 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Report Generated: 28-Sep-1998 at 13:48 COMMENTS: REVIEWED BY: DATE: Cumulative by Location (v 0 4 .0 1 .97) 004055 ARGUS 418-010: PAGE E-2 Temperature and Relative Humidity Report Location: Room 08 Protocol Number 418-010 Range of Dates: 28-Aug-1998 14:00 to 25-Sep-1998 11:50 Target Range: Species: RABBIT Total Number o f Days: Total Number o f Hours: Total Number of Data Points: Temperature 61 *F to 72*F 29 669.75 670 Relative Humidity 30% to 70% 29 669.75 670 Mean ( SD): Maximum: Median: Minimum: Number of Points in Range (%): Number of Points High (%): Number of Points Low (%): 67.0 ( 0.7) 62.5 69.3 70.0 66.8 63.0 65.6 47.7 670 (100.0) 669 0 (0.0) 1 0 (0.0) 0 ( 3.6) (99.9) (0.1) (0.0) Report Generated: 28-Sep-1998 at 13:56 COMMENTS: ____________ REVIEWED BY: DATE: Cumulative by Location (v04.01.97) 4056 ARGUS 418-010: PAGE E-3 Temperature and Relative Humidity Report Location: Room 09 Protocol Number: 418-010 Range of Dates: 28-Aug-1998 14:00 to 25-Sep-1998 11:50 Target Range: Species: RABBIT Total Number of Days: Total Number of Hours: Total Number of Data Points: Temperature 6rF to 72-F 29 669.75 670 Relative Humidity 30% to 70% 29 669.75 S70 Mean ( 1 SD): Maximum: Median: Minimum: Number o f Points in Range (%): Number of Points High (%): Number of Points Low (%): 66.7 69.7 66.5 64.7 670 0 0 ( 0.9) (100.0) (0.0) (0.0) 63.7 73.7 64.1 44.8 640 30 0 ( 4 .2 ) (95.5) (4.5) (0.0) Report Generated: 28-Sep-1998 at 13:57 COMMENTS: REVIEWED BY: DATE: W A f / " Cum ulative by Location (v 0 4 .0 1 .97) 004057 ARGUS 418-010: PAGE E-4 Relative Humidity Deviations Report Location: Room 09 Protocol Number: 418-010 Range of Dates: 28-Aug-1998 14:00 to 25-Sep-1998 11:50 Humidity Target Range: Species: Rabbit Date 29-Aug-1998 30-Aug-1998 30-Aug-1998 30-Aug-1998 31-Aug-1998 31-Aug-1998 02-Sep-1998 02-Sep-1998 04-Sep-1998 14-Sep-1998 14-Sep-1998 15-Sep-1998 15-Sep-1998 15-Sep-1998 16-Sep-1998 16-Sep-1998 17-Sep-1998 17-Sep-1998 Time 09:00 00:00 01:00 22:00 08:00 19:00 01:00 20:00 20:00 11:00 13:00 16:00 19:00 21:00 09:00 21:00 00:00 14:00 R.H. 70.6 H 70.2 H 70.2 H 70.9 H 72.2 H 71.0 H 70.9 H 70.6 H 70.6 H 70.2 H 70.4 H 70.3 H 70.1 H 71.0 H 70.7 H 73.7 H 71.5 H 72.2 H 30% to 70% Date 17-Sep-1998 18-Sep-1998 18-Sep-1998 18-Sep-1998 19-Sep-1998 19-Sep-1998 20-Sep-1998 20-Sep-1998 21-Sep-1998 22-Sep-1998 Time 23:00 10:00 11:00 21:00 21:00 22:00 10:00 13:00 10:00 10:00 H = Value out of range - High L = Value out of range - Low R.H. = Relative Humidity (%) Report Generated: 03-Dec-1998 at 10:02 R.H. 70.2 H 73.1 H 70.9 H 70.1 H 70.2 H 71.3 H 70.4 H 70.4 H 72.8 H 70.4 H i^ T h e s e deviations did not adversely affect the outcome or interpretation of the study. __ The following deviation(s) impacted on the outcome of the study as described: Deviations by Location (v04.01.97) 04058 APPENDIX F PILOT REPORT 004059 418-010:PAGE F-1 FINAL PILOT REPORT Study Title Oral (Stomach Tube) Dosage-Range Developmental Toxicity Study of N-EtFOSE in Rabbits SPONSOR'S STUDY NUMBER: T-6316.8 Author Raymond G. York, Ph.D., DABT (Study Director) Study Completed On 6 January 1999 (Final Pilot Report) Performing Laboratory Argus Research Laboratories, Inc. 905 Sheehy Drive, Building A Horsham, Pennsylvania 19044-1297 Laboratory Project ID Argus Research Laboratories, Inc., Protocol Number: 418-01 OP 004060 418-010:PAGE F-2 PROTOCOL 418-01 OP 418-010P:PAGE 2 ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RABBITS SPONSOR'S STUDY NUMBER: T-6316.8 TABLE OF CONTENTS SUBJECT PAGE ABSTRACT 4 I. Purpose 6 II. Methods 6 III. Results 7 IV. Conclusion 12 Figure 1. Maternal Body W eights 13 Table 1. Clinical Observations - Summary 14 Table 2. Necropsy Observations - Summary 18 Table 3. Uterine Contents and Litter Data for the Individual Rabbits that were Found Dead, Moribund Sacrificed or Aborted 20 Table 4. Maternal Body W eights - Summary 23 Table 5. Maternal Body W eight Changes - Summary 26 Table 6. Maternal Absolute Feed Consumption Values (g/day) Summary 28 Table 7. Maternal Relative Feed Consumption Values(g/kg/day) Summary 30 Table 8. Caesarean-Sectioning Observations - Summary 32 004061 418-010: PAGE F-3 Table 9. 418-010P.PAGE 3 Litter Observations (Caesarean-Delivered Fetuses) Summary 34 Table 10. Fetal Gross External Alterations - Summary 36 Table 11. Clinical Observations - Individual Data 38 Table 12. Necropsy Observations - Individual Data 44 Table 13. Maternal Body W eights - Individual Data 48 Table 14. Maternal Feed Consumption Values - Individual Data 55 Table 15. Caesarean-Sectioning Observations - Individual Data 62 Table 16. Litter Observations (Caesarean-Delivered Fetuses) Individual Data 64 Table 17. Fetal Sex, Vital Status and Body Weight Individual Data 66 ATTACHMENT 1 - PROTOCOL AND AMENDMENT 69 004062 418-010: PAGE F-4 418-010P:PAGE4 TITLE: ORAL(STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RABBITS ARGUS RESEARCH LABORATORIES, INC., PROTOCOL NUMBER: 418-01 OP SPONSOR'S STUDY NUMBER: T-6316.8 ABSTRACT The purpose of this study was to provide information for the selection of dosages to be used in the developmental toxicity (embryo-fetal toxicity and teratogenic potential) study of N-EtFOSE administered orally via stomach tube to New Zealand White [Hra:(NZW)SPF] presumed pregnant female rabbits. Thirty-five presumed pregnant New Zealand White [Hra:(NZW)SPF] rabbits were randomly assigned to seven dosage groups, five per group. Suspensions of N-EtFOSE were administered orally once daily on days 7 through 20 of gestation (DGs 7 to 20) at dosages of 0 (Vehicle), 1, 5, 10, 25, 50 and 75 mg/kg/day. The vehicle was 2% Tween 80 in reverse osmosis membrane processed deionized Water. The dosage volume was 5 mL/kg, adjusted daily on the basis of the individual body weights. Checks for viability were made twice daily. Clinical observations were recorded twice daily during the dosage period (once prior to dosage administration and once approximately one hour after dosage administration) and once daily during the postdosage period. Body weights and feed consumption values were recorded daily during the dosage and postdosage periods. All surviving rabbits were sacrificed on DG 29 of presumed gestation and examined for the number and distribution of corpora lutea, implantation sites and uterine contents. A gross necropsy of the thoracic, abdominal and pelvic viscera was performed. Fetuses were weighed and examined for gross external alterations and sex. Severe maternal body weight loss occurred in the 10, 25, 50 and 75 mg/kg/day dosage groups; there were no surviving rabbits in these groups. Abortions occurred in 5 and 10 mg/kg/day dosage groups. Caesarean-section 004063 418-010:PAGE F-5 418-010P:PAGE 5 observations revealed increasing late resorptions and reduced fetal body weights at 5 mg/kg/day. Increases in early resorptions were found at 1 mg/kg/day; however, there was no decrease in mean litter size. Based on the results of this dosage-range finding study, dosages of 0, 0.1, 1.0, 2.5 and 3.75 mg/kg/day were recommended for the full developmental toxicity study of N-EtFOSE in rabbits. 004064 418-010:PAGE F-6 I. Purpose: 418-010P:PAGE 6 The purpose of this study was to provide information for the selection of dosages to be used in the developmental toxicity (embryo-fetal toxicity and teratogenic potential) study of N- EtFOSE administered orally via stomach tube to New Zealand White [Hra:(NZW)SPF] presumed pregnant female rabbits. II. Methods8: The test article, N-EtFOSE (lot FM-3932), an off-white wax, was received on 20 May 1998, and stored at room temperature. The vehicle, 2% Tween 80 (lot 3H05), a clear viscous liquid, was received on 22 May 1998, and stored at room temperature. The vehicle diluent, reverse osmosis membrane processed deionized water (R.O. Deionized Water) is available from a continuous source at the Testing Facility and is maintained at room temperature. Thirty-five presumed pregnant New Zealand White [Hra:(NZW)SPF] rabbits were randomly assigned to seven dosage groups [five per group (Groups I through VII)]. Suspensions of N-EtFOSE were administered orally (stomach tube) once daily to these timed-pregnant rabbits on days 7 through 20 of gestation (DGs 7 to 20) at dosages of 0 (Vehicle), 1,5, 10, 25, 50 and 75 mg/kg/day. The vehicle was 2% Tween 80 in reverse osmosis membrane processed deionized W ater (R.O. Deionized Water). The dosage volume was 5 mL/kg, adjusted daily on the basis of the individual body weights recorded immediately before intubation of the test article. Checks for viability were made twice daily. Clinical observations were recorded twice daily during the dosage period (once prior to dosage administration and once approximately one hour after dosage administration) and once daily during the postdosage period. Body weights and feed consumption values were recorded daily during the dosage and postdosage periods. All surviving rabbits were sacrificed on DG 29 of presumed gestation and examined for the number and distribution of corpora lutea, implantation sites and uterine contents. A gross necropsy of the thoracic, abdominal and pelvic viscera was performed. Fetuses were weighed and examined for gross external alterations and sex. a. Detailed descriptions of all procedures used in the conduct of this study are provided in the appropriate sections of this report and in the attached protocol and amendments. Deviations from the Protocol and Standard Operating Procedures of the Testing Facility are available in the raw data. U4065 418-010: PAGE F-7 III. Results: 418-010P:PAGE 7 A. Mortality. Moribund Sacrifices. Abortions. Clinical and Necropsy Observations (Summaries - Tables 1 and 2: Individual Data - Tables 11.12 and 31 A.1. Mortality One, two and one rabbits were found dead in the 1, 50 and 75 mg/kg/day dosage groups, respectively. The remaining rabbits in the 50 and 75 mg/kg/day dosage groups and all five rabbits in the 25 mg/kg/day dosage group were moribund sacrificed. 1 mq/ka/dav Dosage Group Doe 8206 was found dead on DG 16, within an hour following dosage administration, after 10 dosages of the test article. The rabbit had no adverse clinical signs during the dosing period. The rabbit gained weight during the dosage period, but feed consumption values were reduced on DGs 12 through 15. The uterus contained eight fetuses, which appeared normal for their developmental ages. Viability of the fetuses could not be determined because of the death of the dam. All tissues appeared normal at necropsy. 50 mq/ka/dav Dosage Group Doe 8226 was found dead on DG 14, within three hours following dosage administration, after nine dosages of the test article. The rabbit had soft or liquid feces and scant or no feces between DGs 9 and 14 and lost weight and had reduced feed consumption during the dosage period. The uterus contained six fetuses and one early resorption. Viability of the fetuses could not be determined because of the death of the dam. Necropsy revealed the stomach mucosa contained black viscous material; all other tissues appeared normal. Doe 8229 was found dead before dosage administration on DG 12, after five dosages of the test article. The rabbit had soft or liquid feces or scant feces on DGs 9 to 12 and lost weight and had reduced feed consumption during the dosage period. The uterus contained 13 fetuses. Viability of the fetuses could not be determined because of the death of the dam. Necropsy revealed greenish-gray areas on all lobes of the liver and 30 mL of fluid in the thoracic cavity. All other tissues appeared normal for the slight degree of autolysis. 004066 418-010: PAGE F-8 iv Dosage Group 418-010P:PAGE 8 as found dead before dosage administration on DG15, after nine he test article. The rabbit had soft or liquid feces or scant feces on decreased motor activity on DGs 13 and 14 and excess salivation he rabbit lost weight and had reduced feed consumption during the )d. The uterus contained nine fetuses and one early resorption, e fetuses could not be determined because of the death of the dam. nal cavity contained approximately 18 mL of thin, brown fluid and mucosa contained a viscous, brown material. All other tissues rmal. und Sacrificed the 25, 50 and 75 mg/kg/day dosage groups were moribund DG 15. Clinical observations in these rabbits included decreased /, impaired righting reflex, cold to touch, emaciation, red substance an, perioral substance, excess salivation, ungroomed coat, and :es (scant, soft or liquid, absent). ed and S a crifice d 5 in the 5 mg/kg/day dosages group and all five rabbits in the / dosages group aborted and were sacrificed. Dosage Group orted on DG 26. The rabbit had scant feces, soft or liquid feces or DGs 10 through 25. There was a red substance in the cage pan on rabbit lost weight and had reduced feed consumption during the d. There were one aborted late resorption and five late resorptions Issues appeared normal at necropsy. orted on DG 24. The rabbit had scant feces or soft or liquid feces >23. There was a red substance in the cage pan on DG 20. The iight and had reduced feed consumption during the dosage period. ie aborted late resorption. There three live fetuses and eight late i utero. All tissues appeared normal at necropsy. orted on DG 26. The rabbit had scant feces or no feces on DGs 17 was a red substance in the cage pan on DG 26. The rabbit lost ) the dosage period and had reduced feed consumption on DGs 10 004067 418-010: PAGE F-9 418-010P:PAGE 9 to 26. There were four implantations and three aborted dead fetuses. The fourth conceptus was presumed cannibalized. All tissues appeared normal at necropsy. 10 ma/ka/dav Dosage Group Doe 8216 aborted on DG 26. The rabbit had scant feces, soft or liquid feces or no feces on DGs 10 through 25 and dark orange urine on DG 24. There was a red substance in the cage pan on DG 26. The rabbit lost w eight and had reduced feed consumption during the dosage period. There were eight aborted late resorptions. The liver had pale, tan areas on all lobes, ranging in size from 1.5 cm x 1.0 cm to 4.0 cm x 1.6 cm. All other tissues appeared normal at necropsy. Doe 8217 aborted DG 22. The rabbit had scant feces or no feces on DGs 9 to 21 and a red substance in the cage pan on DG 21. The rabbit lost w eight and had reduced feed consumption during the dosage period. There were two aborted late resorptions and four early and four late resorptions in utero. All tissues appeared normal at necropsy. Doe 8218 aborted on DG 24. The rabbit had scant feces, soft or liquid feces or no feces on DGs 9 to 23. The rabbit lost weight and had reduced feed consumption during the dosage period. There were eight aborted late resorptions and two late resorptions in utero. All tissues appeared normal at necropsy. Doe 8219 aborted on DG 22. The rabbit had scant feces or no feces on DGs 9 through 21 and a red substance in the cage pan and dark orange urine on DG 21. The rabbit lost weight and had reduced feed consumption during the dosage period. There were eight aborted early resorptions, four aborted late resorptions and one early resorption in utero. Necropsy revealed that all lobes of the liver were pale. All other tissues appeared normal. Doe 8220 aborted on DG 23. The rabbit had scant feces or soft or liquid feces on DGs 9 to 22. The rabbit lost weight and had reduced feed consumption during the dosage period. There were three aborted late resorptions and seven live fetuses in utero. All tissues appeared normal at necropsy. A.4. Clinical Observations Clinical observations considered to be test article related included scant feces, soft or liquid feces or no feces in 5, 10, 25, 50 and/or 75 mg/kg/day dosage 004068 418-010: PAGE F-10 418-010P:PAGE 10 groups, and dark urine in the 10 mg/kg/day dosage group. Ungroomed coat, decreased motor activity, impaired righting reflex, cold to touch, lost righting reflex, emaciation, perioral substance and excess salivation occurred in rabbits that were found dead or moribund sacrificed in the 25, 50 and/or 75 mg/kg/day dosage groups. Red substance in cage pan was correlated with abortion and/or moribund condition in the 5 , 1 0 and 75 mg/kg/day dosage groups. All other clinical observations were considered unrelated to the test article because: 1) the incidences were not dosage-dependent; and/or 2) they occurred in only one rat. These observations included abrasion and localized alopecia on the limbs and/or back. A. 5. Necropsy Necropsy observations from all unscheduled deaths or sacrifices have been previously described. One 5 mg/kg/day dosage group doe (7385) had pale liver lobes. The only other necropsy observations were confirmation of clinical observations of localized alopecia. B. Maternal Body Weights and Body Weight Changes fFigure 1: Summaries - Tables 4 and 5: Individual Data - Table 131 Severe maternal body weight losses occurred in the 10, 25, 50 and 75 mg/kg/day dosage groups; there were no surviving rabbits in these groups after DGs 26, 15, 15 and 15, respectively. Maternal body weight losses occurred for the 5 mg/kg/day dosage group for the entire the dosage period (calculated as DGs 7 to 21), the postdosage period (DGs 21 to 29) and the entire gestation period (DGs 0 to 29). Maternal body weights and body weight gains for the 1 mg/kg/day dosage group were generally comparable to control values during the dosage and postdosage periods (DGs 7 to 21). C. Absolute (q/davl and Relative fa/ka/davl Feed Consumption Values (Summaries - Tables 6 and 7: Individual Data - Table 141 Absolute and relative feed consumption values were severely reduced in the 10, 25, 50 and 75 mg/kg/day dosage groups; there were no surviving rabbits in these groups after DGs 26, 15, 15 and 15, respectively. 004069 418-010: PAGE F-11 418-01 OP:PAGE 11 Absolute and relative feed consumption values for the 5 mg/kg/day dosage group were severely reduced, compared to the control group, during the dosage and postdosage periods. Absolute and relative feed consumption values for the 1 mg/kg/day dosage group were generally comparable to control values over each interval tabulated. D. Caesarean-Sectioning and Litter Observations /Summaries - Tables 8 through 10: Individual Data - Tables 15 through 171 Caesarean-sectioning observations were based on 5, 4 and 2 pregnant rabbits with live litters in the 0 (Vehicle), 1 and 5 mg/kg/day dosage groups. There were no surviving does in the 10, 25, 50 or 75 mg/kg/day dosage groups. An increase in early resorptions occurred in the 1 mg/kg/day dosage group, relative to the control group. This observation was considered an effect of the test article because it was outside the historical control range for the Testing Facility. An increase in late resorptions (and a concomitant decrease in litter size) and reduced fetal body weights occurred at the 5 mg/kg/day dosage, relative to the control group. These observations were also considered an effect of the test article because they were dosage-dependent and occurred at maternally toxic dosages (decreased body weight and feed consumption values). No dams had all resorbed conceptuses and there were no dead fetuses. Totals of 36, 34 and 13 live fetuses were evaluated for external gross alterations in the three respective dosage groups with litters. One fetus (8207-7) in the 1 mg/kg/day dosage group had a distended abdomen. One fetus (7385-1) in the 5 mg/kg/day dosage group had open eyelids and protruding tongue and another in the same litter (7385-4) had downward flexed forepaws, cleft snout, absent incisors and a large right eye. This litter also contained three late resorptions and three normal fetuses. No fetal gross external alterations were observed in the vehicle control group fetuses. 004070 418-010: PAGE F-12 IV. Conclusion: 418-01 OP:PAGE 12 Based on the results of this study, dosages o f 0 (Vehicle), 0.1, 1.0, 2.5 and 3.75 mg/kg/day of N-EtFOSE were recommended for the developmental toxicity study in rabbits (418-010). The 0.1 m g/kg/day dosage is expected to be a no-observable-effect-level (NOEL) for both maternal and embryo-fetal toxicity, and the 3.75 mg/kg/day dosage is expected to produce maternal toxicity (decreased maternal body weight and feed consumption values) and may produce minimal developmental toxicity (decreased fetal body weight and delayed ossification). Cl*- Alan M. Hoberman, Ph.D., DABT D ire c to r^ Research / Date Rmend G. York, Associate Director and Study Director ofe-'Sft'O- c)9 , DABT search Date 004071 MATERNAL BODY WEIGHT FIGURE 1 418-010: PAGE F-13 004072 DAY OF GESTATION 0 (VEHICLE) MG/KG/DAY -1 MG/KG/DAY V 5 MG/KG/DAY X 10 MG/KG/DAY v 25 MG/KG/DAY i 50 MG/KG/DAY C*3 75 MG/KG/DAY ? O o Tl 5 Q m 03 418-010P:PAGE 14 004073 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N E tF O SE IN R A B B IT S (SP O N SO R 'S STUDY NUMBER: T 6 3 1 6 .8 ) TABLE 1 (PAGE 1): CLINICAL OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I II 0 (VEHICLE) 1 III 5 IV 10 MAXIMUM POSSIBLE INCIDENCE 115/ 5 102/ 5 104/ 5 87/ 5 MORTALITY MORIBUND SACRIFICED ABORTED AND SACRIFICED FOUND DEAD 0 135 0 00 0 0 0 3b 5b 0 lb 0 0 SCANT FECES 0/ 0 0/ 0 62/ 5 59/ 5 DECREASED MOTOR ACTIVITY 0/ 0 0/ 0 0/ 0 0/ b UNGROOMED COAT 0/ 0 0/ 0 11/ 1 0/ 0 SOFT OR LIQUID FECES 0/ 0 0/ 0 4/ 3 1/ 3 DRIED YELLOW, BROWN OR YELLOW-BROWN PERIORAL SUBSTANCE 0/ 0 0/ 0 0/ 0 0/ 0 NO FECES 0/ 0 0/ 0 10/ 3 10/ 4 RED SUBSTANCE IN CAGE PAN 0/ 0 1/ 1 3/ 3 3/ 3 IMPAIRED RIGHTING REFLEX 0/ 0 0/ 0 0/ 0 0/ 0 COLD TO TOUCH 0/ 0 0/ 0 0/ 0 0/ 0 EMACIATION 0/ 0 0/ 0 0/ 0 0/ 0 EXCESS SALIVATION 0/ 0 0/ 0 0/ 0 0/ 0 LOST RIGHTING REFLEX 0/ 0 0/ 0 0/ 0 0/ 0 DARK URINE 0/ 0 0/ 0 0/ 0 2/ 2 MAXIMUM POSSIBLE INCIDENCE = (DAYS X RABBITS)/NUMBER OF RABBITS EXAMINED PER GROUP ON DAYS 7 THROUGH 29 OF PRESUMED GESTATION. N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RABBITS WITH OBSERVATION. a. Dosage occurred on days 7 through 20 of presumed gestation. b. Refer to the individual clinical observations table (Table 11) for observations for rabbits that died or aborted. -{V 00 418-010P:PAGE 15 004074 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R ABBITS (SP O N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE I (PAGE 2): CLINICAL OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a V VI VII 25 50 75 MAXIMUM POSSIBLE INCIDENCE 45/ 5 41/ 5 45/ 5 MORTALITY MORIBUND SACRIFICED ABORTED AND SACRIFICED FOUND DEAD 555 5b 3b 4b 000 0 2b lb SCANT FECES 25/ 5 20/ 5 22/ 5 DECREASED MOTOR ACTIVITY 1/ 1 4/ 4 13/ 5 UNGROOMED COAT 5/ 2 0/ 0 15/ 4 SOFT OR LIQUID FECES 0/ 0 10/ 3 13/ 4 DRIED YELLOW, BROWN OR YELLOW-BROWN PERIORAL SUBSTANCE 0/ 0 3/ 3 5/ 2 NO FECES 2/ 1 2/ 2 4/ 2 RED SUBSTANCE IN CAGE PAN 0/ 0 0/ 0 2/ 2 IMPAIRED RIGHTING REFLEX 1/ 1 0/ 0 3/ 1 COLD TO TOUCH 0/ 0 0/ 0 1/ i EMACIATION 0/ 0 0/ 0 2/ 1 EXCESS SALIVATION 0/ 0 0/ 0 1/ i LOST RIGHTING REFLEX 0/ 0 1/ 1 0/ 0 DARK URINE 0/ 0 0/ 0 0/ 0 MAXIMUM POSSIBLE INCIDENCE = (DAYS x RABBITS)/NUMBER OF RABBITS EXAMINED PER GROUP ON DAYS 7 THROUGH 29 OF PRESUMED GESTATION. N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RABBITS WITH OBSERVATION. a. Dosage occurred on days 7 through 20 of presumed gestation. b. Refer to the individual clinical observations table (Table 11) for observations for rabbits that died or were moribund sacrificed. -_r 00 418-010P:PAGE 16 004075 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O SE IN RABBITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 1 (PAGE 3): CLINICAL OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I II 0 iVEHICLE) 1 hi 5 IV 10 MAXIMUM POSSIBLE INCIDENCE 115/ 5 102/ 5 104/ 5 87/ 5 MORTALITY MORIBUND SACRIFICED ABORTED AND SACRIFICED FOUND DEAD 0135 0000 0 0 3b 5b 0 lb 0 0 ABRASION C 0/ 0 0/ 0 17/ 2 0/ 0 LOCALIZED ALOPECIA: TOTAL LIMBS BACK 1/ 1 0/ 0 1/ 1 2/ i 2/ i 1/ 1 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 MAXIMUM POSSIBLE INCIDENCE (DAYS X RABBITS) /NUMBER OF RABBITS EXAMINED PER GROUP ON DAYS 7 THROUGH 29 OF PRESUMED GESTATION. N/N = TOTAL NUMBER OP OBSERVATIONS/NUMBER OF RABBITS HITH OBSERVATION. a. Dosage occurred on days 7 through 20 of presumed gestation. b. Refer to the individual clinical observations table (Table 11) for observations for rabbits that died or aborted. c. Located on the left forepaw or left hindpaw. A 00 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RABBITS (SP O N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE I (PAGE 4): CLINICAL OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY) a V VI VII 25 50 75 MAXIMUM POSSIBLE INCIDENCE 45/ 5 41/ 5 45/ 5 MORTALITY MORIBUND SACRIFICED ABORTED AMD SACRIFICED FOUND DEAD 555 5b 3b 4b 000 0 2b lb ABRASION 0/ 0 0/ 0 0/ 0 LOCALIZED ALOPECIA: TOTAL LIMBS BACK 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 MAXIMUM POSSIBLE INCIDENCE > (DAYS X RABBITS)/NUMBER OF RABBITS EXAMINED PER GROUP ON DAYS 7 THROUGH 29 OF PRESUMED GESTATION. N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RABBITS WITH OBSERVATION. a. Dosage occurred on days 7 through 20 of presumed gestation. b. Refer to the individual clinical observations table (Table 11) for observations for rabbits that died or were moribund sacrificed. 418-010:PAGE F-17 004076 * 9 o o TJ Om -j 004077 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R ABBITS (SPO N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 2 (PAGE 1) : NECROPSY OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a 1 0 (VEHICLE) II 1 hi 5 IV 10 RABBITS EXAMINED b N5 5 S s MORTALITY MORIBUND SACRIFICED ABORTED FOUND DEAD N0 N0 N0 N0 135 000 0 3c 5c lc 0 0 APPEARED NORMAL N5 5 4 3 STOMACH: MUCOSA, BLACK OR BROWN VISCOUS MATERIAL N0 0 0 0 FRIABLE N0 9 0 0 ABDOMINAL CAVITY: THIN BROWN FLUID N0 0 0 0 LIVER: ALL LOBES, GREEN-GREY AREAS N 0 0 0 0 ALL LOBES, PALE OR PALE TAN AREAS N0 0 1 2 THORACIC CAVITY: TAN-GREY FLUID N0 0 0 0 LUNGS: ALL LOBES, TAN-GREY N0 0 0 0 a. Dosage occurred on days 7 through 20 of presumed gestation. b. Refer to the individual clinical observations table (Table 11) for external observations confirmed at necropsy. c. Refer to the individual necropsy observations table (Table 12) for observations for rabbits that died or aborted. 4^ 00 i O o o9 TJ o> T) o m 5 mO n oo oo 418-010P-.PAGE 19 004078 PROTOCOL 4 1 6 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RABBITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 2 (PAGE 2) : NECROPSY OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a V VI VII 25 so 75 RABBITS EXAMINED b N5 5 5 MORTALITY N5 5 5 MORIBUND SACRIFICED N Sc 3c 4c ABORTED N0 0 0 FOUND DEAD N0 2c lc APPEARED NORMAL N5 3 3 STOMACH: MUCOSA, BLACK OR BROWN VISCOUS MATERIAL N0 1 2 FRIABLE N0 0 1 ABDOMINAL CAVITY: THIN BROHN FLUID N0 0 1 LIVER: ALL LOBES, GREEN-GREY AREAS N 0 1 0 ALL LOBES, PALE OR PALE TAN AREAS N0 0 0 THORACIC CAVITY: TAN-GREY FLUID N0 1 0 LUNGS: ALL LOBES, TAN-GREY N0 1 0 a. Dosage occurred on days 7 through 20 of presumed gestation. b. Refer to the individual clinical observations table (Table 11) for external observations confirmed at necropsy. c. Refer to the individual necropsy observations table (Table 12) for observations for rabbits that died or were moribund sacrificed. 00 004079 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE- RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B BIT S (SPO N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 3 (PAGE 1): UTERINE CONTENTS AND LITTER DATA FOR RABBITS THAT WERE FOUND DEAD, MORIBUND SACRIFICED OR ABORTED DOSAGE GROUP RABBIT DOSAGE (MG/KG/DAY) c NUMBER DAY OF DEATH CORPORA LUTEA RLT IMPLANTATIONS RLT I 0 (VEHICLE) - - *- - -- - II 1 6206 FOUND DEAD ON DAY 45 9 35 8 16 OF GESTATION III 5 8211 ABORTED ON DAY 26 6 4 10 33 6 OF GESTATION 8212 ABORTED ON DAY 24 OF GESTATION 6 7 13 6 6 12 8214 ABORTED ON DAY 26 OF GESTATION 44 6 22 4 IV 10 8216 ABORTED ON DAY 26 5 7 12 44 8 OF GESTATION 8217 ABORTED ON DAY 22 OF GESTATION 5 6 11 5 5 10 8218 ABORTED ON DAY 24 OF GESTATION 5 6 11 5 5 10 8219 ABORTED ON DAY 22 OF GESTATION 6 7 13 6 7 13 8220 ABORTED ON DAY 23 OF GESTATION 6 5 11 4 10 R = RIGHT L = LEFT T = TOTAL A <= ABORTED a. Conceptuaes appeared normal for developmental ages. b. Early resorptions, unless noted otherwise. c. Dosage occurred on days 7 through 20 of presumed gestation. d. Unable to determine viability of conceptuses because of death of doe. e. Autolysis precluded further evaluation. f. One conceptus was presumed cannibalized. g. Dead fetuses. EMBRYOS/FETUSES a RLAT RESORPTIONS b RLAT - - - - `- - - - 350 8d 000 0 000 120 003 0 231 6 (LR) 3 441 9e (LR) 3f,g 0 0 0 0 000 0 008 8e (LR) 000 0 4 4 2 10e (1LR)(3LR) (LR) 000 0 0 2 a 10e (LR) 000 0 0 1 12 13e 4LR) 520 7 003 3 (LR) . o9 o u TJ > mo too o010 o no > O m T1 oNi 418-010P.PAGE 004080 PROTOCOL 418 0 1 0 P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R AB BITS (SP O N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 3 (PAGE 2): UTERINE CONTENTS AND LITTER DATA FOR RABBITS THAT WERE FOUND DEAD, MORIBUND SACRIFICED OR ABORTED DOSAGE GROUP RABBIT DOSAGE (MG/KG/DAY) c NUMBER DAY OF DEATH CORPORA LUTEA RLT IMPLANTATIONS RLT EMBRYOS/FETUSES a RLAT RESORPTIONS b RLAT 7371 MORIBUND SACRIFICED 3 ON DAY 15 OF GESTATION 5 8 8222 MORIBUND SACRIFICED 6 4 10 ON DAY 15 OF GESTATION 8223 MORIBUND SACRIFICED 5 5 10 ON DAY 15 OF GESTATION 8224 MORIBUND SACRIFICED 5 5 10 ON DAY 15 OF GESTATION 8225 MORIBUND SACRIFICED 5 6 11 ON DAY 15 OF GESTATION 25 7 e 4 10 43 7 5 5 10 5 6 11 230 5 6 4 0 10 430 7 5 5 0 10 5 6 0 11 020 000 000 000 000 2 0 0 0 0 8226 FOUND DEAD ON DAY 14 OF GESTATION 7 4 11 34 8227 MORIBUND SACRIFICED S ON DAY 15 OF GESTATION 6 11 5 8228 MORIBUND SACRIFICED 2 ON DAY 15 OF GESTATION 1 3 11 8229 FOUND DEAD ON DAY 12 OF GESTATION 7 6 13 76 8230 MORIBUND SACRIFICED 7 5 12 ON DAY 15 OF GESTATION 32 R = RIGHT L = LEFT T = TOTAL A = ABORTED a. Conceptusea appeared normal for developmental ages. b. Early resorptions, unless noted otherwise. c. Dosage occurred on days 7 through 20 of presumed gestation. d. Unable to determine viability of conceptuses because of death of doe. 7 11 2 13 5 330 6d 5 6 0 11 110 2 7 6 0 13d 32 0 5 0 10 000 000 000 000 1 0 0 0 0 N) PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R AB BITS (SP O N SO R 'S STUDY NUMBER: T - 6 3 1 6 .8 ) TABLE 3 (PAGE 3) : UTERINE CONTENTS AND LITTER DATA FOR RABBITS THAT WERE FOUND DEAD, MORIBUND SACRIFICED OR ABORTED DOSAGE GROUP RABBIT DOSAGE (MG/KG/DAY)c NUMBER DAY OF DEATH CORPORA LUTEA RL T IMPLANTATIONS Rh T VII 75 8231 MORIBUND SACRIFICED 0 4 4 04 4 ON DAY 15 OF GESTATION 8232 MORIBUND SACRIFICED 0 0 0 ON DAY IS OF PRESUMED GESTATION 00 0 8233 FOUND DEAD ON DAY IS OF GESTATION 2 9 11 1 9 10 8234 MORIBUND SACRIFICED 4 ON DAY IS OF GESTATION 3 7 33 6 8235 MORIBUND SACRIFICED 6 5 11 ON DAY 15 OF GESTATION 6 4 10 R RIGHT L = LEFT T - TOTAL A = ABORTED a . Conceptusea appeared normal for developmental ages. b. Early reaorptions, unless noted otherwise. c. Dosage occurred on days 7 through 20 of presumed gestation. d. Unable to determine viability of conceptusea because of death of doe. EMBRYOS/FETUSES a RLA T 000 0 000 0 180 9d 330 6 6 4 0 10 RESORPTIONS b R LA 040 4 000 0 0 10 1 000 0 000 0 004081 oo <b o 9o* *u op > O m T| mO I 418-010: PAGE F-23 004082 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O SE IN RABBITS (SP O N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 4 (PAGE I) : MATERNAL BODY WEIGHTS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a RABBITS TESTED N PREGNANT N MATERNAL BODY WEIGHT (KG) DAY 0 MEAN*S.D. DAY 7 MEAN+S.D . DAY a MEAN+S.D . DAY 9 MEAN+S.D. DAY 10 MEAN+S.D . DAY 11 MEAN+S.D. DAY 12 MEAN+S.D. DAY 13 MEAN+S.D . DAY 14 MEAN+S.D . DAY IS MEAN+S.D . DAY IS MEAN+S.D . DAY 17 MEAN+S.D. DAY 18 MEAN+S.D. DAY 19 MEAN+S.D. DAY 20 MEAN+S.D. i 0 (VEHICLE) 5 5 1.80 + 0.36 3.76 + 0.17 3.77 0.18 3.82 + 0.19 3.83 + 0.17 3.81 + 0.16 3.83 + 0.16 3.86 + 0.1S 3.90 + 0.17 3.92 + 0.18 3.92 0.16 3.94 + 0.16 3.96 + 0.17 3.98 + 0.16 3.99 + 0.15 DAY = DAY OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for a rabbit that was found dead. II 1 5 5 3.84 + 0.24 3.97 + 0.18 4.00 + 0.17 4.02 + 0.17 4.05 + 0.18 4.05 + 0.15 4.07 + 0.14 4.09 + 0.13 4.13 + 0.12 4.17 + 0.14 4.21 + 0.10 4.22 + 0.10 i 4]lb 4.20 + 0.10 I 4]b 4.22 + 0.10 ( 4)b 4.24 0.12 t 4]b hi 5 5 5 3.95 0.28 4.10 0.30 4.06 + 0.30 4.06 0.33 3.98 0.30 3.93 + 0.30 3.88 + 0.24 3.83 + 0.28 3.85 + 0.24 3.86 + 0.23 3.76 0.24 3.78 0.18 3.76 + 0.12 3.77 + 0.16 3.75 + 0.14 IV 10 5 5 3.79 +_ 0.28 3.98 + 0.29 3.88 + 0.28 3.81 + 0.25 3.70 + 0.25 3.61 0.21 3.54 0.23 3.51 + 0.20 3.46 + 0.21 3.45 + 0.22 3.42 + 0.19 3.42 + 0.20 3.40 + 0.18 3.37 + Q .19 3.36 0.19 0I0 o o T3 5 a m K) G> CSOfrOO PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RABBITS (SP O N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 4 (PAGE 2) : MATERNAL BODY WEIGHTS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a RABBITS TESTED N PREGNANT N INCLUDED IN ANALYSES N MATERNAL BODY WEIGHT (KG) DAY 21 MEAN+S.D. DAY 22 MEAN+S.D. DAY 23 MEAN+S.D. DAY 24 MEAN+S.D. DAY 25 MEAN+S.D. DAY 26 MEAN+S.D. DAY 27 MEAN+S.D. DAY 28 MEAN+S.D. DAY 29 MEAN+S.D. I 0 (VEHICLE) S 5 5 4.02 0.15 4.03 0.14 4.03 4 0.13 4.02 0.14 4.01 0.14 4.03 4 0.16 4.04 + 0.17 4.06 0.19 4.07 0.24 DAY = DAY OF GESTATION ( ) c NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation b. Excludes values for rabbits that died or aborted. II 1 5 s 4b 4.27 + 0.13 4.28 + 0.11 4-34 + 0.10 4.35 ,4 0.10 4.38 + 0.10 4.41 + o.oa 4.42 + 0.07 4.40 + 0.03 4.42 4 0.05 hi 5 5 5 5 3.72 0.15 3.69 + 0.19 3.63 + 0.20 3.69 0.11 I 4]b 3.68 + 0.15 l 41b 3.70 + 0.16 I 2)b 3.70 + 0.23 i 21b 3.70 + 0.29 I 2]b 3.70 + 0.36 l 21b IV 10 5 5 5 3.29 4 0 1 8 3.18 + 0.21 [ 31b 3.22 0.19 I 21b 3.28 4 0.00 ( lib 3.25 4 0.00 l lib b 418-010P:PAGE 24 -Cn 00 1 004084 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SPO N SO R 'S STUDY NUMBER: T 6 3 1 6 .8 ) TABLE 4 (PAGE 3) : MATERNAL BODY HEIGHTS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a V VI 25 50 RABBITS TESTED N 5 5 PREGNANT N5 5 MATERNAL BODY HEIGHT (KG) DAY 0 MEAN+S.D . 3.49 + 0.25 3.81 + 0.31 DAY 7 MEAN+S.D . 3.60 + 0.18 3.89 + 0.25 DAY 8 MEAN+S.D. 3.50 + 0.17 3.78 + 0.27 DAY 9 MEAN+S.D. 3.41 + 0.13 3.65 0.24 DAY 10 MEAN+S.D. 3.33 + 0.16 3.56 + 0.25 DAY 11 MEAN+S.D. 3.26 + 0.16 3.46 + 0.22 DAY 12 MEAN+S.D. 3.20 + 0.13 3.39 + 0.23 DAY 13 DAY 14 DAY 15 MEAN+S.D. MEAN+S.D. MEAN+S.D. 3.15 + 0.14 3.09 + 0.14 b 3.26 + 0.22 i 41b 3.17 0.24 [ 4]b 1D DAY = DAY OF GESTATION I ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or were moribund sacrificed. VII 75 5 4 3.65 + 0.39 3.76 +_ 0.34 3.70 + 0.29 3.63 + 0.32 3.48 + 0.40 3.34 + 0.38 3.28 + 0.37 3.17 + 0.34 3.12 0.31 b 00 . o_IL ? o O a o> "O o ij m > O n m to ro cn tn 418-010:PAGE F-26 CD o o +1 004085 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RABBITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 5 (PAGE 1): MATERNAL BODY WEIGHT CHANGES - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY) a RABBITS TESTED PREGNANT MATERNAL BODY HEIGHT CHANGE (KG) DAYS 0 - 7 DAYS 7 - 10 DAYS 10 - 13 DAYS 13 - 16 DAYS 16 - 19 DAYS 19 - 21 DAYS 21 - 25 DAYS 25 - 29 DAYS 7 - 21 DAYS 7 - 29 DAYS 0 - 29 N N MEAN+S.P . MEAN+S.D . MEAN+S.D. MEAN+S.D . MEAN+S.D. MEAN+S.0. MEAN+S.D . MEAN+S.D. MEAN+S.D . MEAN+S.D. MEAN+S.D. I 0 (VEHICLE) 5 5 -0.04 0.36 +0.07 + 0.02 +0.03 + 0.03 +0.06 0.04 +0.05 + 0.02 +0.04 + 0.02 -0.01 0.08 +0.06 +_ 0.12 +0.26 + 0.08 +0.31 _+ 0.11 0.27 + 0.38 DAYS = DAYS OF GESTATION ( ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or aborted. II 1 5 5 +0.14 +0.08 + 0.04 +0.04 + 0.08 +0.12 + 0.04 +0.04 + 0.03 I 4]b +0.04 + 0.04 l 4)b +0.12 + 0.05 C 4)b +0.04 0.06 l 4]b +0.34 + 0.07 4]b +0.51 + 0.14 ( 4]b +0.66 + 0.18 4]b hi 5 s 5 +0.16 + 0.09 -0.13 + 0.08 -0.14 0.05 -0.07 + 0.12 +0.01 + 0.12 -0.05 + 0.04 -0.09 + 0.14 I 4]b +0.00 + 0.25 I 2)b -0.38 0.21 -0.58 + 0.74 r 21b -0.36 + 0.74 I 2)b IV 10 5 5 +0.19 + 0.08 -0.28 + 0.06 -0.19 + 0.12 -0.09 0.02 -0.04 + 0.07 -0.09 + 0.03 -0.22 + 0.00 [ lib b -0.69 + 0.20 to ? O O p O m &o> PROTOCOL 4 1 S -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O SE IN RABBITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 5 (PAGE 2) : MATERNAL BODY WEIGHT CHANGES - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a V VI 25 50 RABBITS TESTED N 5 5 PREGNANT N5 5 MATERNAL BODY HEIGHT CHANGE (KG) DAYS 0 - 7 MEAN+S.D. +0.11 + 0.07 +0.09 + 0.10 DAYS 7 - 10 MEAN+S.D . -0.27 + 0.04 -0.33 + 0.04 DAYS 10 - 13 DAYS 13 - 16 MEAN+S.D. MEAN+S.D. -0.18 + 0.12 b -0.27 + 0.05 l 41b b DAYS = DAYS OF GESTATION [ ] - NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation, b. Excludes values for rabbits that died or were moribund sacrificed. VII 75 5 4 0.11 + 0.06 -0.28 + 0.07 -0.32 + 0.07 b 418-010:PAGE F-27 0040S6 o9 o p Om ro -i 418-010:PAGE F-28 004087 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RAB BITS (SPONSOR' S STUDY NUMBER: T -6 3 1 G .8 ) TABLE 6 (PAGE 1) - MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a RABBITS TESTED PREGNANT MATERNAL FEED CONSUMPTION (G/DAY) DAYS 7 - 10 DAYS 10 - 13 DAYS 13 - 16 DAYS 16 - 19 DAYS 19 - 21 DAYS 21 - 25 DAYS 2S - 29 DAYS 7 - 21 DAYS 7 - 29 N N MEAN+S.D . MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. i 0 (VEHICLE) S 5 165.2 20.2 165.9 + 21.1 169.2 + 21.6 167.2 + 17.2 156.6 + 25.4 114.1 58.5 101.9 + 47.2 165.4 + 17.9 144.5 24.5 DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or aborted. ii 1 s 5 167.6 + 14.1 158.9 + 17.7 163.6 + 20.8 1 4]b 155.5 + 40.1 [ 4]b 161.4 + 25.0 ( 4]b 164.6 + 8.7 t 4]b 123.4 + 26.0 i 4]b 162.0 + 21.9 [ 4]b 155.4 + 11.8 ( 4)b III 5 s s 111.9 + 47.8 21.1 + 29.0 9.1 + 15.8 2.6 1.1 1.9 + 1.3 25.5 + 46.6 ( 4]b 79.6 +110.1 i 2)b 31.3 + 17.7 46.2 + 40.6 [ 2Jb IV 10 5 s 19.5 6.1 0.7 + 0.2 7.2 + 9.5 9.1 + 14.5 1.4 + 1.5 1.0 + 0.0 [ lib b 8.0 + 5.6 b . 9o o "0 TJ > O m to oo PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE- RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SPO N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 6 (PAGE 2): MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a V VI 25 50 RABBITS TESTED N 5 5 PREGNANT Ns 5 MATERNAL FEED CONSUMPTION (G/DAY) DAYS 7 - 10 MEAN+S.D. 12.1 + 6.7 5.4 + 3 4 DAYS 10 - 13 DAYS 13 - 16 MEAN+S.D. MEAN+S.D . 1.4 + 1.9 b 0.8 + 0.2 [ 4)b b DAYS - DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or were moribund sacrificed. VII 75 5 4 4.5 + 2.6 0.1 0.2 b 418-010: PAGE F-29 004088 o9 > o 13 5 o m to <0 418-010:PAGE F-30 004089 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RABBITS (SPO N SO R'S STUDY NUMBER: T 6 3 1 6 .8 ) TABLE 7 (PAGE 1) : MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY) a RABBITS TESTED PREGNANT MATERNAL PEED CONSUMPTION (G/KG/DAY) DAYS 7 - 10 DAYS 10 - 13 DAYS 13 - 16 DAYS 16 - 18 DAYS 16 - 19 DAYS 19 - 21 DAYS 21 - 25 DAYS 25 - 29 DAYS 7 - 21 DAYS 7 - 29 N N MEAN+S .D . MEANtS.D . MEAN+S.D . MEAN+S.D . MEAN+S.D . MEAN+S.D . MEAN+S.D . MEAN+S.D . MEAN+S.D. MEAN+S.D. I 0 (VEHICLE) 5 5 43.5 +_ 4.8 43.2 + 4.8 43.3 + 5.1 42.2 + 4.6 42.3 4.3 39.2 4 6.4 28.3 + 14.2 24.9 + 10.4 42.5 + 4.2 36.6 4 5.5 DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or aborted. II 1 5 5 41.9 4.6 39.1 4.9 39.6 + 4.7 l 4]b 36.5 + 9.0 I 4Jb 36.9 + 9.4 l 4]b 38.0 5.4 l 4]b 38.0 + 1.1 I 4]b 28.0 + 6.1 1 4)b 39.4 5.2 ( 4]b 37.0 + 2.7 [ 4]b III 5 5 5 27.4 + 11.4 5.3 + 7.3 2.4 4.0 0.8 0.5 0.7 _+ 0.3 0.5 0.3 7.0 + 12.7 [ 4)b 20.6 28.4 2]b 8.0 + 4.4 12.0 + 10.7 ( 2]b IV 10 5 S 5.1 4 1.5 0.2 4 0.1 2.2 + 3.1 3.0 4 4.4 2.8 + 4.6 0.4 4 0.5 0.3 + 0.0 ( lib b 2.3 + 1.8 b o9 op 5 mO ow PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R ABBITS (SP O N SO R 'S STUDY NUMBER: T -6 3 1 6 -8) TABLE 7 (PAGE 2) : MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a V VI 25 50 RABBITS TESTED N 5 5 PREGNANT Ns 5 MATERNAL FEED CONSUMPTION (G/KG/DAY) DAYS 7 - 1 0 MEAN+S.D. 3.5 + 1.9 1.5 + 1.0 DAYS 10 - 13 DAYS 13 - IS MEAN.S .D . MEAN+S.D . 0.4 + 0.6 b 0.2 + 0.0 ( 4]b b DAYS = DAYS OF GESTATION ( ) - NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Excludes values for rabbits that died or were moribund sacrificed. VII 75 5 4 1.3 + 0.9 0.0 * 0.0 b 418-010:PAGE F-31 004090 9o 0 TJ 1 m O) PROTOCOL 418 - 0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SPO N SO R 'S STUDY NUMBER: T 6 3 1 6 .8 ) TABLE 8 (PAGE 1) : CAESAREAN-SECTIONING OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) RABBITS TESTED N 5 PREGNANT FOUND DEAD ABORTED MORIBUND SACRIFICED Nit) N(t) N (%) Nil) 5(100.0) 0( 0.0) 0( 0.0) 0( 0.0) RABBITS PREGNANT AND CAESAREAN -SECTIONED ON DAY 29 OF GESTATION N 5 CORPORA LUTEA MEAN+S.D. 10.8 + 2.6 IMPLANTATIONS MEAN+S.D. 8.2 + 3.8 LITTER SIZES MEAN+S.D. 7.0 + 3.4 LIVE FETUSES N MEAN+S.D. 35 7.0 + 3.4 DEAD FETUSES N 0 RESORPTIONS MEAN+S.D. 1.2 + 0.8 EARLY RESORPTIONS N MEAN+S.D. 4 0.8 0.8 LATE RESORPTIONS N MEAN+S.D . 2 0.4 + 0.5 DOES WITH ANY RESORPTIONS N(%) 4( 80.0) DOES WITH ALL CONCEPTUSES RESORBED N 0 DOES WITH VIABLE FETUSES N(t) 5(100.0) PLACENTAE APPEARED NORMAL N<%) 5(100.0) a. Dosage occurred on days 7 through 20 of gestation. II 1 5 5(100.0) 1( 20.0) 0( 0.0) 0( 0.0) 4 11.2 + 1.5 10.2 + 1.0 8.5 + 3.1 34 8.5 + 3.1 0 1.8 + 2.9 7 1.8 + 2.9 0 0.0 + 0.0 2< 50.0) 0 4 (100.0) 4 (100.0) III 5 5 5(100.0) 0( 0.0) 3 ( 60.0) 0( 0.0) 2 11.0 + 2.8 10.0 + 2.8 6.5 + 2.1 13 6.5 4 2.1 0 3.5 + 0.7 0 0.0 + 0.0 7 3.S + 0.7 2(100.0) 0 2(100.0) 2(100.0) IV 10 5 5(100.0) 0( 0.0) 5(100.0) 0( 0.0) 0 9o o "0 Tl > O m 418-010: PAGE F-32 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N E tF O SE IN R AB BITS (SP O N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 8 (PAGE 2): CAESAREAN-SECTIONING OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a V 25 RABBITS TESTED N 5 PREGNANT POUND DEAD ABORTED MORIBUND SACRIFICED N(%) N(t) N (%) N (4) 5(100.0) 0( 0.0) 0( 0.0) 5(100.0) RABBITS PREGNANT AND CAESAREAN-SECTIONED ON DAY 29 OP GESTATION N 0 a. Dosage occurred on days 7 through 20 of gestation. VI so s 5(100.0) 2( 40.0) 0( 0.0) 3( eo.o) 0 VII 75 5 4 ( 80.0) 1( 20.0) 0 ( 0.0) 3( 60.0) 0 418-010: PAGE F-33 004092 9o o p O m w b> 418-010:PAGE F-34 004093 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R AB BITS (SP O N SO R 'S STUDY NUMBER: T 6 3 1 6 .8 ) TABLE 9 (PAGE 1): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) LITTERS WITH ONE OR MORE LIVE FETUSES N 5 IMPLANTATIONS MEAN+S.O . 8.2 + 3.8 LIVE FETUSES N MEAN+S.D . 35 7.0 + 3.4 LIVE MALE FETUSES N 24 % LIVE MALE FETUSES/LITTER MEAN+S.D . 73.1 + 20.3 LIVE FETAL BODY HEIGHTS (GRAMS) /LITTER MEAN+S.D. 45.66 + 5.70 MALE FETUSES MEAN+S.D. 46.30 + 5.33 FEMALE FETUSES % RESORBED CONCEPTUSES/LITTER MEAN+S. D. MEAN+S.D. 44.74 + 7.45 { 4)b 15.0 + 10.9 ( ] = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of gestation. b. Litter 8201 had no female fetuses. II 1 4 10.2 + 34 8.5 + 15 1.0 3.1 45.0 + 4.1 46.50 '* 6.26 46.75 + 4.85 46.44 + 7.60 17.3 + 28.8 III 5 2 10.0 2.8 13 6.5 2.1 5 38.8 + 1.8 23.80 + 6.68 25.51 + 3.55 22.64 + 8.73 35.4 + 3.0 9o o TJ TJ > mo PROTOCOL 4 1 8 -0 1 0 P ; ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RABBITS (SP O N SO R 'S STUDY NUMBER: T -6 3 1 6 .B ) TABLE 9 (PAGE 2) : LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY) a V 25 LITTERS WITH ONE OR MORE LIVE FETUSES NO a. Dosage occurred on days 7 through 17 of gestation. VI 50 0 VII 75 0 418-010: PAGE F-35 004094 9o> o TJ T) > O m o tn 418-010: PAGE F-36 004095 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R ABBITS (SP O N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) 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 N N s 35 35 BODY: ABDOMINAL DISTENTION LITTER INCIDENCE FETAL INCIDENCE N (%) NI) 0< 0.0) 0( 0.0) TONGUE: PROTRUDED LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) 0 ( 0.0) 0( 0.0) EYELIDS: OPENED LITTER INCIDENCE FETAL INCIDENCE N (%) N(%) 0< 0.0) 0( 0.0) FORE AND/OR HINDLIMBS: FLEXED DOWNWARD LITTER INCIDENCE N(%) FETAL INCIDENCE N (%) 0( 0.0) 0( 0.0) INCISORS: ABSENT LITTER INCIDENCE FETAL INCIDENCE N (%) N(%) 0( 0.0) Ot 0.0) SNOUT: CLEFT LITTER INCIDENCE PETAL INCIDENCE N (% N (%) 0( 0.0) 0( 0.0) EYES: LARGE LITTER INCIDENCE FETAL INCIDENCE N (%) N (%} 0( 0.0) 0( 0.0) a. Dosage occurred on days 7 through 20 of gestation. b. Fetus 7385-1 had other gross external alterations. c. Fetus 7385-4 had other gross external alterations. II 1 4 34 34 1( 25.0) 1< 2.9) 0( 0.0) 0( 0.0) 0( 0.0) 0! '0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) III 5 2 13 13 0( 0.0) 0( 0.0) 1< 50.0) 1( 7.7) b 1( 50.0) 1< 7.7) b 1( 50.0) 1( 7.7) c 1( 50.0) It 7.7) c 1< 50.0) 1 ( 7.7 )c 1( 50.0) 1( 7.7 )c IV 10 0 0 0 4k. ? O O "P 5 m0 u o> PROTOCOL 4 1 8 -0 1 0 P ; ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R ABBITS (SPO N SO R 'S STUDY NUMBER-. T - 6 3 1 6 .8 ) TABLE 10 (PAGE 2) : FETAL GROSS EXTERNAL ALTERATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY) a V 25 LITTERS EVALUATED FETUSES EVALUATED LIVE N0 N0 N0 a. Dosage occurred on days 7 through 20 of gestation. VI 50 0 0 0 VII 75 0 0 0 9&OfrOO 418-010: PAGE F-37 4k ? O w-v l PROTOCOL 4 1 B -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R ABBITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 11 (PAGE 1) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA RABBIT DESCRIPTION DOSAGE GROUP I 0 (VEHICLE)MG/KG/DAY 8201 8202 8203 8204 8205 DG ( 29 ) NO ADVERSE FINDINGS LOCALIZED ALOPECIA: NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS BACK a DOSAGE GROUP II 1 MG/KG/DAY 820C 8207 8208 8209 8210 DG ( 16 ) DG( 19 ) DG ( 28- 29) DG ( 29 ) FOUND DEAD RED SUBSTANCE IN CAGE PAN NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS a LOCALIZED ALOPECIA: BACK a NO ADVERSE FINDINGS DG = DAY OP PRESUMED GESTATION a. Observation confirmed at necropsy. 004097 00 6 --X Vo O "T> o> o m 5 *n mG) > O) oo oo 418-010: PAGE F-39 004098 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O SE IN RAB BITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 11 (PAGE 2): CLINICAL OBSERVATIONS - INDIVIDUAL DATA RABBIT DOSAGE GROUP III 8211 8212 8213 8214 7385 DG ( 10- 25) DG ( 17 ) DG ( 22 ) DG ( 26 ) DG ( 26 ) DG ( 10- 23) DG ( 20 ) DG ( 20- 21) DG ( 22 ) DG ( 22 ) DG ( 24 ) DG ( 13- 25) DG ( 17- 19) DG ( 20- 25) DG ( 26 ) DG ( 26 ) DG ( 7- 21) DG ( 22 ) DG ( 10- 20) DG ( 12- 13) DG ( 12- 22) DG ( 21- 24) DG ( 26 ) DG ( 27 ) DG ( 28 ) DG ( 29 ) DG = DAY OF PRESUMED GESTATION DESCRIPTION 5 MG/KG/DAY SCANT FECES NO FECES SOFT OR LIQUID FECES RED SUBSTANCE IN CAGE PAN ABORTED AND SACRIFICED SCANT FECES RED SUBSTANCE IN CAGE PAN LEFT FOREPAW : ABRASION ABRASION NO LONGER APPARENT SOFT OR LIQUID FECES ABORTED AND SACRIFICED SCANT FECES NO FECES SCANT FECES RED SUBSTANCE IN CAGE PAN ABORTED AND SACRIFICED LEFT HINDPAW: ABRASION (DID NOT EXCEED 0.5 CM IN DIAMETER) ABRASION NO LONGER APPARENT SCANT FECES SOFT OR LIQUID FECES UNGROOMED COAT NO FECES SCANT FECES NO FECES SCANT FECES NO FECES o9 o TJ ^0 > mO CO CO PROTOCOL 4 1 8 -0 1 0 P : ORAL ISTOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O SE IN RABBITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 . B) TABLE 11 (PAGE 3): CLINICAL OBSERVATIONS INDIVIDUAL DATA 418-01 OP:PAGE 40 004099 RABBIT * DOSAGE GROUP IV 8216 8217 8218 8219 8220 DG ( 10 ) DG ( 11- IS) DG ( 17- 19) DG ( 20 ) DG ( 21 ) DG ( 22 ) DG ( 23- 25) DG ( 24 ) DG ( 25 ) DG ( 26 ) DG ( 26 ) DG ( 9- 18) DG ( 19- 20) DG ( 21 ) DG ( 21 ) DG ( 22 ) DG ( 9- 11) DG ( 10- 21) DG ( 22 ) DG ( 23 ) DG ( 24 ) DG ( 9- 16) DG ( 17- 20) DG ( 21 ) DG ( 21 ) DG ( 21 ) DG ( 22 ) DG ( 9- 22) DG ( 11- 13) DG ( 23 ) DG = DAY OF PRESUMED GESTATION DESCRIPTION 10 MG/KG/DAY NO FECES SCANT FECES SCANT FECES NO FECES SCANT FECES NO FECES SCANT FECES DARK URINE SOFT OR LIQUID FECES RED SUBSTANCE IN CAGE PAN ABORTED AND SACRIFICED SCANT FECES NO FECES RED SUBSTANCE IN CAGE PAN SCANT FECES ABORTED AND SACRIFICED SOFT OR LIQUID FECES SCANT FECES NO FECES SCANT FECES ABORTED AND SACRIFICED SCANT FECES NO FECES RED SUBSTANCE IN CAGE PAN SCANT FECES DARK URINE ABORTED AND SACRIFICED SCANT FECES SOFT OR LIQUID FECES ABORTED AND SACRIFICED PROTOCOL 4 1 8 0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OP N -E tF O SE IN RABBITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 -8 ) TABLE 11 (PAGE 4) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA RABBIT DOSAGE GROUP V 7371 B222 8223 8224 8225 DG ( 9- 11) DG ( 12- 13) DG ( 14 ) DG ( 15 ) DG ( 9- 14) DG ( 15 ) DG ( 10- 14) DG ( 15 ) DG ( 10- 14) DG ( 11 ) DG ( 11 ) DG ( 13- 14) DG ( 15 ) DG( 10- 14) DG ( 12- 14) DG ( 15 ) DG = DAY OP PRESUMED GESTATION DESCRIPTION 25 MG/KG/DAY SCANT FECES NO FECES SCANT FECES MORIBUND SACRIFICED SCANT FECES MORIBUND SACRIFICED SCANT FECES MORIBUND SACRIFICED SCANT FECES DECREASED MOTOR ACTIVITY IMPAIRED RIGHTING REFLEX UNGROOMED COAT MORIBUND SACRIFICED SCANT FECES UNGROOMED COAT MORIBUND SACRIFICED OTf.Oo 418-010:PAGE F-41 o9 o mO -u 418-010: PAGE F-42 004101 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RABBITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 11 (PAGE 5) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA RABBIT * DOSAGE GROUP VI 8226 8227 8228 8229 8230 DG( 9- 13) DG( 10- 13) DG( 14 ) DG ( 14 ) DG( 14 ) DG ( 14 ) DG ( 10- 14) DG ( 14 ) DG ( 14 ) DG ( IS ) DG ( 10- 14) DG ( 14 I DG( 14 ) DG( 15 ) DG ( 9 ) DG ( 10- 11) DG( 12 ) DG ( 10- 13) DG ( 10- 13) DG ( 14 ) DG ( 14 ) DG( 14 ) DG ( 15 ) DG = DAY OF PRESUMED GESTATION DESCRIPTION 50 MG/KG/DAY SOFT OR LIQUID FECES SCANT FECES DECREASED MOTOR ACTIVITY LOST RIGHTING REFLEX NO FECES FOUND DEAD SCANT FECES DECREASED MOTOR ACTIVITY DRIED YELLOW BROWN PERIORAL SUBSTANCE MORIBUND SACRIFICED SCANT FECES DECREASED MOTOR ACTIVITY DRIED YELLOW PERIORAL SUBSTANCE MORIBUND SACRIFICED SOFT OR LIQUID FECES SCANT FECES FOUND DEAD SCANT FECES SOFT OR LIQUID FECES DECREASED MOTOR ACTIVITY DRIED YELLOW PERIORAL SUBSTANCE NO FECES MORIBUND SACRIFICED 9 o o TJ ti > mo .fc. W PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O SE IN RAB BITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 11 (PAGE 6) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA 418-010:PAGE F ^3 004102 RABBIT * DESCRIPTION DOSAGE GROUP VII 75 MG/KG/DAY 8231 8232 8233 8234 B235 DG ( 9- 14) DG ( 12- 14) DG ( 13- 14) DG ( 13- 14) DG ( IS ) DG ( 9- 14) DG ( 13 ) DG ( 13- 14) DG ( 13- 15) DG ( 13- 14) DG ( IS ) DG( 15 ) DG ( 9- 13) DG ( 9- 13) DG ( 13- 14) DG ( 14 ) DG ( 14 ) DG ( IS ) DG ( 9- 14) DG ( 9- 14) DG ( 12- 14) DG ( 13- 14) DG ( 15 ) DG ( 9 ) DG ( 10 ) DG ( 10- 11) DG ( 10- 14) DG ( 12- 15) DG ( 12- 14) DG ( 13- 14) DG< 14 ) DG ( 14- 15) DG ( 15 ) DG ( 15 ) SCANT FECES UNGROOMED COAT a DECREASED MOTOR ACTIVITY DRIED BROWN PERIORAL SUBSTANCE a MORIBUND SACRIFICED SCANT FECES SOFT OR LIQUID FECES DECREASED MOTOR ACTIVITY DRIED YELLOW PERIORAL SUBSTANCE UNGROOMED COAT RED SUBSTANCE IN CAGE PAN MORIBUND SACRIFICED SCANT FECES SOFT OR LIQUID FECES DECREASED MOTOR ACTIVITY EXCESS SALIVATION NO FECES FOUND DEAD UNGROOMED COAT SOFT OR LIQUID FECES SCANT FECES DECREASED MOTOR ACTIVITY MORIBUND SACRIFICED SOFT OR LIQUID FECES IMPAIRED RIGHTING REFLEX SCANT FECES DECREASED MOTOR ACTIVITY UNGROOMED COAT NO FECES IMPAIRED RIGHTING REFLEX COLD TO TOUCH EMACIATION RED SUBSTANCE IN CAGE PAN MORIBUND SACRIFICED DG = DAY OF PRESUMED GESTATION a. Observation confirmed at necropsy. POT&00 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B BIT S (SPO N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 12 (PAGE 1) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a I 0 (VEHICLE) 8201 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8202 DG 29 p 14 ALL TISSUES APPEARED NORMAL. 8203 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8204 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8205 DG 29 P 14 ALL TISSUES APPEARED NORMAL. II 1 8206 DG 16 P 10 FOUND DEAD ON DAY 16 OF GESTATION (DEATH OCCURRED 13 MINUTES AFTER DOSAGE). ALL TISSUES APPEARED NORMAL. 8207 DG 29 p 14 ALL TISSUES APPEARED NORMAL. 8208 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8209 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8210 DG 29 p 14 ALL TISSUES APPEARED NORMAL. III s 8211 DG 26 P 14 ABORTED ON DAY 26 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8212 DG 24 P 14 ABORTED ON DAY 24 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8213 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8214 DG 26 p 14 ABORTED ON DAY 26 OF GESTATION. ALL TISSUES APPEARED NORMAL. 7385 DG 29 P 14 LIVER: ALL LOBES, PALE. ALL OTHER TISSUES APPEARED NORMAL. P - PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 11) for external observations confirmed at necropsy. A 9o op mO 418-010: PAGE F-44 418-010: PAGE F-45 004104 PROTOCOL 418 - 0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R ABBITS (SPO N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 12 (PAGE 2) : NECROPSY OBSERVATIONS INDIVIDUAL DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a IV 10 8216 DG 26 P 14 ABORTED ON DAY 26 OF GESTATION. LIVER: ALL LOBES. PALE TAN AREAS (1.5 CM X 1.0 CM TO 4.0 CM X 1.6 CM) . ALL OTHER TISSUES APPEARED NORMAL. 8217 DG 22 P 14 ABORTED ON DAY 22 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8218 DG 24 P 14 ABORTED ON DAY 24 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8219 DG 22 P 14 ABORTED ON DAY 22 OF GESTATION. LIVER: ALL LOBES, PALE. ALL OTHER TISSUES APPEARED NORMAL. 8220 DG 23 P 14 ABORTED ON DAY 23 OF GESTATION. ALL TISSUES APPEARED NORMAL. V 25 7371 DG 15 P 9 MORIBUND SACRIFICED ON DAY 15 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8222 DG 15 P 9 MORIBUND SACRIFICED ON DAY 15 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8223 DG 15 P 9 MORIBUND SACRIFICED ON DAY 15 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8224 DG 15 P 9 MORIBUND SACRIFICED ON DAY 15 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8225 DG 15 P 9 MORIBUND SACRIFICED ON DAY 15 OF GESTATION. ALL TISSUES APPEARED NORMAL. P = PREGNANT NP NOT PREGNANT DG DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 11) for external observations confirmed at necropsy. -t*. 9* o o TJ TO > mO cn 418-010P:PAGE 46 004105 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R AB BITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 12 (PAGE 3): NECROPSY OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a VI 50 8226 DG 14 P 8 FOUND DEAD ON DAY 14 OF GESTATION (DEATH OCCURRED 1 HOUR AND 33 MINUTES AFTER DOSAGE). STOMACH: MUCOSA, BLACK VISCOUS MATERIAL. ALL OTHER TISSUES APPEARED NORMAL. 8227 DG 15 P 9 MORIBUND SACRIFICED ON DAY 15 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8228 DG 15 P 9 MORIBUND SACRIFICED ON DAY 15 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8229 DG 12 P 6 FOUND DEAD ON DAY 12 OF GESTATION (DEATH OCCURRED 11 HOURS AND 53 MINUTES AFTER DOSAGE). LIVER: ALL LOBES, GREEN-GREY AREAS. THORACIC CAVITY: TAN-GREY FLUID (APPROXIMATELY 30 ML). LUNGS: ALL LOBES, TAN-GREY. ALL OTHER TISSUES APPEARED NORMAL FOR THE SLIGHT DEGREE OF AUTOLYSIS. 8230 DG 15 P 9 MORIBUND SACRIFICED ON DAY 15 OF GESTATION. ALL TISSUES APPEARED NORMAL. P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 11) for external observations confirmed at necropsy. 00 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R AB BITS (SPO N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 12 (PAGE 4) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a VII 8231 DG 15 P 9 MORIBUND SACRIFICED ON DAY 15 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8232 DG 15 NP 9 MORIBUND SACRIFICED ON DAY 15 OF PRESUMED GESTATION. ALL TISSUES APPEARED NORMAL. 8233 DG 15 P 9 FOUND DEAD ON DAY 15 OF GESTATION (DEATH OCCURRED OVERNIGHT). ABDOMINAL CAVITY: THIN BROWN FLUID (APPROXIMATELY 18 ML) STOMACH: FRIABLE; MUCOSA, VISCOUS BROWN MATERIAL. ALL OTHER TISSUES APPEARED NORMAL. 8234 DG 15 P 9 MORIBUND SACRIFICED ON DAY 15 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8235 DG 15 P 9 MORIBUND SACRIFICED ON DAY 15 OF GESTATION. STOMACH; MUCOSA, BLACK VISCOUS MATERIAL. ALL OTHER TISSUES APPEARED NORMAL. P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. Refer to the individual clinical observations table (Table 11) for external observations confirmed at necropsy. 418-010:PAGE F-47 004106 o9 PROTOCOL 4 1 B -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RAB BITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 13 (PAGE 1) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA RABBIT t DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 8201 P 8202 P 8203 P 8204 P 8205 P 4.40 3.69 3.86 3.53 3.51 3.72 3.82 4.02 3.58 3.67 3.67 3.84 4.06 3.60 3.67 3.72 1.92 4.11 3.64 3.70 3.75 3.90 4.09 3.67 3.73 3.74 3.92 4.05 3.68 3.68 3.78 3.95 4.05 3.70 3.69 3.80 3.97 4.07 3.72 3.74 3.78 4.01 4.15 3.75 3.83 3.79 4.03 4.18 3.76 3.86 pH OD 4.07 4.11 376 3.86 DAY 19 20 2 1 2 2 23 24 25 26 27 28 29 8201 P 8202 P 8203 P 8204 P 8205 P 3.85 4.11 4.18 3.80 3.94 3.87 4.10 4.19 3.82 3.99 3.88 4.12 4.22 3.86 4.01 3.93 4.13 4.19 3.86 4.03 3.92 4.11 4.21 3.89 4.01 3.93 4.05 4.25 3.90 3.97 3.94 3.99 4.26 3.89 3.99 3.95 4.04 4.29 3.87 3.98 3.93 4.09 4.30 3.87 4.02 3.97 4.14 4.34 3.83 4.04 4.03 4.10 4.41 373 4.09 P PREGNANT NP * NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 17 3.82 4.08 4.14 3.77 3.90 18 3.84 4.11 4.16 3.78 3.91 OTOO -N 00 9o* o TJ > o m T| Ja 00 oo PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RABBITS (SPO N SO R'S STUDY NUMBER: T - 6 3 1 6 .8 ) TABLE 13 (PAGE 2) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA RABBIT * DOSAGE GROUP II 1 MG/KG/DAY PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 IS 16 8206 P 8207 P 8208 P 8209 P 8210 P 4.13 3.73 3.83 3.98 3. SI 4.17 3.84 4.04 4.08 3.72 4.19 3.89 4.04 4.10 3.76 4.19 3.96 4.06 4.14 3.77 4.24 3.99 4.09 4.IS 3.78 4.22 4.00 4.10 4.12 3.83 4.26 4.00 4.12 4.10 3.89 4.24 4.01 4.20 4.10 3.92 4.23 4.08 4.24 4.16 3.94 4.30 4.06 4.31 4.18 4.01 4.32 4.17 4.28 4.23 4.06 DAY 19 20 21 22 23 24 25 26 27 28 29 8206 P 8207 P 8208 P 8209 P 8210 P FOUND DEAD ON DAY 16 OF GESTATION 4.17 4.13 4.16 4.17 4.34 4.36 4.39 4.38 4.28 4.32 4.37 4.36 4.11 4.13 4.16 4.20 4.26 4.43 4.42 4.24 4.26 4.47 4.41 4.27 4.32 4.50 4.^2 4.29 4.36 4.49 4.46 4.32 4.38 4.50 4.45 4.34 4.38 4.45 4.41 4.38 4.36 4.47 4.46 4.41 P = PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE, a. Doe 8206 was found dead on day 16 of gestation. 17 a 4.20 4.33 4.26 4.08 18 4.18 4.30 4.26 4.08 418-010:PAGE F-49 004108 A o9 <0 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B BIT S (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 13 (PAGE 3) : MATERNAL BODY HEIGHTS - INDIVIDUAL DATA Lv coPa* RABBIT DOSAGE GROUP III S MG/KG/DAY PREGNANCY STATUS DAY 0 7 8 9 10 ii 12 13 14 15 16 8211 P 8212 P 8213 P 8214 P 7385 P 4.09 3.61 3.80 3.92 4.33 4.11 3.72 4.02 4.10 4.56 4.13 3.64 4.00 4.06 4.49 4.01 3.61 4.06 4.07 4.53 3.92 3.56 4.03 3.99 4.40 3.80 3.51 4.02 3.98 4.34 3.76 3.54 3.94 3.97 4.18 3.74 3.43 3.88 3.92 4.20 3.86 3.44 3.93 3.94 4.07 3.90 3.49 3.84 3.95 4.11 3.79 3.38 369 3.94 3-99 DAY 19 20 21 22 23 24 25 26 27 28 29 8211 P 8212 P 8213 P 8214 P 7385 P 3.66 3.54 3.81 3.90 3.92 3.70 3.57 3.70 3.87 3.90 3.64 3.52 3.70 3.89 3.86 3.64 3.41 3.66 3.92 3.80 3.56 3.40 3.55 3.91 3.73 3.57 3.48 ABORTED ON DAY 26 OF GESTATION ABORTED ON DAY 24 OF GESTATION 3.68 3.79 3.81 3.87 3.91 3.96 3.84 3.81 ABORTED ON DAY 26 OF GESTATION 3.68 3.63 3.58 3.54 3.50 3.45 P PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS HERE RECORDED IN GRAMS (G), ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG). ALL CALCULATIONS EXCEPT BODY HEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 17 3.75 3.49 3.78 3.90 3.96 18 3.75 3.56 3.76 3.85 3.88 - a. U 0oI0 o9 o T> o> TJ o ij m O m otn 0o3 418-010P.PAGE 51 004110 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 13 (PAGE 4) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA RABBIT N DOSAGE GROUP IV 10 MG/KG/DAY PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 8216 P 8217 P 8218 P 8219 P 8220 P 4.08 3.75 3.81 3.96 3.35 4.26 4.02 4.09 4.05 3.48 4.16 3.93 3.88 4.00 3.42 4.13 3.82 3.74 3.90 3.44 3.98 3.71 3.75 3.78 3.29 3.90 3.65 3.55 3.65 3.32 3.82 3.60 3.48 3.61 3.19 3.75 3.64 3.41 3.53 3.24 3.69 355 3.42 3.52 3.12 3.71 3.58 3.40 3.46 3.11 3.65 3.53 3.34 3.44 3.14 DAY 19 20 21 22 23 24 25 26 27 28 29 8216 P 8217 P 8218 P 8219 P 8220 P 3.54 3.55 3.20 3.44 3.14 3.47 3.56 3.23 3.45 3.11 3.47 3.44 3.16 3.32 3.06 3.40 3.36 3.28 3.25 ABORTED ON DAY 26 OF GESTATION ABORTED ON DAY 22 OF GESTATION 3.17 3.09 ABORTED ON DAY 24 OF GESTATION ABORTED ON DAY 22 OF GESTATION 2.98 ABORTED ON DAY 23 OF GESTATION P PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OP PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WBIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 17 3.60 3.58 3.28 3.51 3.15 18 3.54 3.55 3.28 3.46 3.15 --k 0I0 004111 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R ABBITS (SP O N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 13 (PAGE S) : MATERNAL BODY HEIGHTS - INDIVIDUAL DATA RABBIT * DOSAGE GROUP V 2S MG/KG/DAY PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 7371 P 8222 P 8223 P 8224 P 822S P 3.14 3.63 3.79 3.S2 3.39 3.34 3.70 3.82 3.61 3.55 3.26 3.56 3.72 3.50 3.47 3.28 3.46 3.60 3.38 3.31 3.11 3.42 3.53 3.28 3.31 3.06 3.30 3.49 3.24 3.19 3.10 3.23 3.41 3.14 3.11 3.14 3.18 3.38 3.04 3.03 2.98 3.15 3.30 2.99 3.02 a b c d e DAY 19 20 21 22 23 24 25 26 27 28 29 7371 P 8222 P 8223 P 8224 P 8225 P MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION P PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS HERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) . ALL CALCULATIONS EXCEPT BODY HEIGHT AVERAGES ARE PERFORMED HITH THE UNROUNDED GRAM (G) VALUE. BODY HEIGHT AVERAGES ARE CALCULATED HITH THE ROUNDED KILOGRAM (KG) VALUE. a . Doe 7371 was moribund sacrificed on day 15 of gestation b. Doe 8222 was moribund sacrificed on day 15 of gestation c. Doe 8223 was moribund sacrificed on day 15 of gestation d. Doe 8224 was moribund sacrificed on day 15 of gestation e. Doe 8225 was moribund sacrificed on day IS of gestation 17 18 -b. 0oi0 o O 0 O T3 m > oi m cn tcon NO tHo Hr* 004112 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O SE IN RABBITS (SPO N SO R'S STUDY NUMBER: T -S 3 1 6 .8 ) TABLE 13 (PAGE 6) : MATERNAL BODY HEIGHTS - INDIVIDUAL DATA RABBIT DOSAGE GROUP VI 50 MG/KG/DAY PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 8226 P 8227 P 8228 P 8229 P 8230 P 4.21 3.76 3.83 3.89 3.34 4.17 3.89 3.84 4.05 3.51 4.07 3.70 383 3-95 3.36 3.90 3-63 3.63 3.80 3.28 3.84 3.51 3.57 3.72 3.17 3.70 3.40 3.45 3.64 3.13 3.61 3.36 3.35 3.60 3.05 3.52 3.43 a 3.26 3.18 b 3.27 3.23 c FOUND DEAD ON DAY 12 OF GESTATION 2.97 2.85 d DAY 19 20 21 22 23 24 25 26 27 28 29 8226 P 822? P 8228 P 8229 P 8230 P FOUND DEAD ON DAY 14 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION FOUND DEAD ON DAY 12 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION P - PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL HEIGHTS HERB RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY HEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. a. Doe 8226 was found dead on day 14 O: gestation b. Doe 8227 was moribund sacrificed on day 15 of gestation c. Doe 8228 was moribund sacrificed on day 15 of gestation d. Doe 8230 was moribund sacrificed on day IS of gestation oo -ft 6 9o o TJ o> "D 0 TJ m > o "Tl m cn co PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R ABBITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 13 (PAGE 7): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA RABBIT # DOSAGE GROUP VII 75 MG/KG/DAY PREGNANCY STATUS DAY 0 7 a 9 10 11 12 13 14 15 16 8231 P 8232 NP 8233 P 8234 P 8235 P 4.10 3.50 3.80 3.54 3.17 4.11 3.65 3.92 3.69 3.32 4.00 3.52 3.85 3.64 3.33 3.97 3.42 3.82 3.44 3.29 3.85 3.33 3.73 3.41 2.95 3.72 3.22 3.53 3.25 2.85 3.66 3.14 3.40 3.26 2.78 3.52 3.00 3.32 3.14 2.71 3.41 2.93 3.24 3.14 2.68 a b c d e DAY 19 20 21 22 23 24 25 26 27 28 29 8231 P 8232 NP 8233 P 8234 P 8235 P MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF PRESUMED GESTATION FOUND DEAD ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION P = PREGNANT NP * NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS HERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGNIFICANT DIGITS AND REPORTED IN KILOGRAMS (KG) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED HITH THE ROUNDED KILOGRAM (KG) VALUE. a. Doe 8231 was moribund sacrificed on day IS of gestation. b. Rabbit 8232 was moribund sacrificed on day 15 of presumed gestation. c. Doe 8233 was found dead on day 15 of gestation. d. Doe 8234 was moribund sacrificed on day 15 of gestation. e. Doe 8235 was moribund sacrificed on day 15 of gestation. 17 18 418-010: PAGE F-54 004113 o o TJ 3> mO PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RAB BITS (SPO N SO R'S STUDY NUMBER: T - 6 3 1 6 .8 ) TABLE 14 (PAGE I) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA RABBIT 8 DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 > 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 8201 P 8202 P 8203 P 8204 P 8205 P 124. 181. 180. 185. 173. 135. 181. 182. 173. 150. 143. 164. 185. 177. 145. 144 . 185. 180. 173. 135. 157. 180. 183. 180. 158. 128. 185. 181. 184. 135. 129. 175. 185. 167. 175. 121. 174 . 184. 173. 181. 143 . 184. 180. 182. 185. 127. 154. 180. 167. 181. 148. 164. 183 . 180. ISO. 148. 159. 180. 176. 181. 144. 140. 183. 180. 166. DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 8201 P 8202 P 8203 P 8204 P 8205 P 115. 126. 183. 182. 147. 148. 105. 184. 173. 119. 105. 61. 183. 181. 76. 112. 3. 184. 141. 40. 97. 1. 183. 136. 50. 82. 37. 182. 113. 73. 96. 81. 183. 79. 68. 108. 92. 185. 74. 81. 123. 68. 184. 52. 78. P PREGNANT NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OP PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 418-010:PAGE F-55 o9 o Tl o m in in PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R ABBITS (SP O N SO R 'S STUDY NUMBER: T -6 3 1 6 .B ) TABLE 14 (PAGE 2) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA RABBIT 8 DOSAGE GROUP II 1 MG/KG/DAY PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 8206 P 8207 P 8208 P 8209 P 8210 P 166. 143. 185. 171. 182. 156. 171, 185. 163. 181. 160. 148. 183. 139. 181. 159. 165. 183. 138. 185. 176. 157. 180. 150. 171. 132. 114. 181. 131. 162. 102. 140 . 177. 171. 149. 133. 114. 177. 172. 170. a 146. 181. 184. 183. 74 . 181. 169. 156. 119. 180. 174. 175. 94 . 181. 182. 181. 115. 184. 169. 165. DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 8206 P 8207 P 8208 P 8209 P 8210 P FOUND DEAD ON DAY 16 OF GESTATION 136. 135. 181. 154. 183. 182. 183. 174. 166. 173. 182. 159. 173. 168. 168. 149. 156. 163. 157. 150. 152. 105. 161. 137. 170. 85. 151. 138. 135. 79. 137. 121. 115. 75. 108. 106. P PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G) . a. Doe 8206 was found dead on day 16 of gestation. STTfrOO -tw 00 oI o s TJ o> u 0 " m > am -1n 8 418-010P:PAGE 57 004116 PROTOCOL 4 1 B -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RABBITS (SPO N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 14 (PAGE 3) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA RABBIT M DOSAGE GROUP III S MG/KG/DAY PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 8211 P 8212 P 8213 P 8214 P 7385 P 181. 14. 0. 2. 0. 0- 1. 0 . 2. 1. 1. 2. 0. 126. 59. 2. l. 1. 0. 4. 0. 10. 10. 2. 1. 0. 180. 183. 149. 96. 1. 14 . 0. 1. 3. 0. 6. 1. 0. 172. 156. 102. 113. 0. 82. 44. 46. 22. 0. 5. 3. 0. 184. 160. 10. 1. 2. 3. 2. 0. 2. 0. 6. 1. 1. DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 8211 P 8212 P 8213 P 8214 P 7385 P 4 . 2. 3. 2. 3. 17. 8. 4. 0. l. 3. 2. 1. ABORTED OH DAY 26 OF GESTATION 2. ABORTED ON DAY 24 OF GESTATION 98. 114. 153. 149. 168. 153. 160. 0. 3. 4. ABORTED ON DAY 26 OF GESTATION 2. 3. 1. 2. , 2. 1. 2. P = PREGNANT NP * NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G). A 00 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RABBITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 1 TABLE 14 (PAGE 4) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA RABBIT N DOSAGE GROUP IV 10 MG/KG/DAY PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 8216 P 8217 P 8218 P 8219 P 8220 P 82. 2. 1. 2. 0 . 0. 1. 1. 3. 5. 0. 1. 2. 39. 1. 0. 1. 1. 0. 3. 0. 0. 10. 2. 1. 1. 65. 0. 0. 1. 1. 0. 11 . 3 . 1. 4 . 3. 0. 1. 42. 0. 0. l. 0. 0. 5, 7. 1. 1. 4. 0. 2. 49. 9. 2. 2. 1. 0. 7. 29. 36. 26. 42. 37. 7. DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 8216 P 8217 P 8218 P 8219 P 8220 P 0. 2. 0. 1. 1. ABORTED ON DAY1 26 OF iGESTATION 0. ABORTED ON DAY 22 OF GESTATION 0. 2. 0. ABORTED ON DAY 24 OF GESTATION 0. ABORTED ON DAY 22 OF GESTATION 1. 1. ABORTED AND SACRIFICED ON DAY 23 OF'GESTATION P - PREGNANT NP > NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G) . 004117 00 6 --V Vo O o5 -0 G) TJ > m O m cn oo cn oo PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R ABBITS (SPO N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 14 (PAGE S): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA RABBIT # DOSAGE GROUP V 2S MG/KG/DAY PREGNANCY STATUS DAYS 7 - B 8 - 9 9 - 1 0 1 0 - 1 1 11 - 12 12 - 13 13 - 14 14 IS 15 - 16 16 7371 P 8222 P 8223 P 8224 P 8225 P 14. 1. o. 11. 0. 3. 0 . 1. a 25. 3. 0. 2. 1. 0. 0. 1. b 36. 1 . 0. 1. 1. 0. 1. 0. c 31. 0. 2. 0. 0. 0. 0. 0. d 64. 4 . l. 1. 0. 1. 0. 0. e DAYS 20 - 21 21 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 2 8 - 2 9 7371 P 8222 P 8223 P 8224 P 8225 P MORIBUND SACRIFICED ON DAY IS OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION P = PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G) . a. Doe 7371 was moribund sacrificed on day 15 of gestation b. Doe 8222 was moribund sacrificed on day 15 of gestation c. Doe 8223 waB moribund sacrificed on day 15 of gestation d. Doe 8224 was moribund sacrificed on day 15 of gestation e. Doe 8225 was moribund sacrificed on day 15 of gestation 17 17 - 18 18 - 19 19 - 20 004118 00 6 ?o O O T3 V > > O m On m <o0n cn CO 004119 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R A B B IT S (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 14 (PAGE 6): MATERNAL FEED CONSUMPTION VALUES INDIVIDUAL DATA RABBIT 8 DOSAGE GROUP VI 50 MG/KG/DAY PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 14 14 - 15 IS - 16 16 - 17 17 - 18 18 - 19 19 - 20 8226 P 8227 P 8228 P 8229 P 8230 P 4. 2. 14. 1. 30. 2. 6. 2. S. 12. 0. 2. 0. 0. 1. FOUND DEAD ON DAY 14 OF GESTATION 0 . 1. 1. 1. 2. 0. a 0. 1. 2. 0- 0. 0. b 1. 0. FOUNDDEAD ON DAY 12 iOF GESTATION 2. 1. 1. 0. 0. 0- c DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 8226 P 8227 P 8228 P 6229 P 8230 P FOUND DEAD ON DAY 14 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION FOUND DEAD ON DAY 12 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION P PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS . DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G) . a. Doe 8227 was moribund sacrificed on day 15 of gestation b. Doe 8226 was moribund sacrificed on day 15 Qf gestation c. Doe 8230 was moribund sacrificed on day 15 Of gestation --k 00 <b --Ifsc o 9 o 3 o> "0 T Q m > T| mo o0> oo> PROTOCOL 410 -O XO P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RAB BITS (SPO N SO R'S STUDY NUMBER: T 6 3 1 6 .8 ) TABLE 14 (PAGE 7) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA RABBIT DOSAGE GROUP VII 75 MG/KG/DAY PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 1 0 1 0 - 1 1 1 1 - 1 2 1 2 - 1 3 1 3 - 1 4 1 4 - 1 5 1 5 - 1 6 1 6 - 1 7 17 - 18 18 - 19 19 - 20 8231 P 8232 NP 8233 P 8234 P 8235 P 9. 1. 2. 0. 0. 0. 0. 0. a 2. 2. l. 0. 0. 0. 0. 0. b 2. 2. l. 0. 0. 0. 0. c 10. 2. l. 1. 0. 0. 1. 0. d 22. 2. 0. 0. 0. 0. 1. 0. e DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 8231 P 8232 NP 8233 P 8234 P 8235 P MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF PRESUMED GESTATION FOUND DEAD ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION P PREGNANT NP > NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS * DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G) . a. Doe 8231 was moribund sacrificed on day 15 of gestation. b. Rabbit 8232 was moribund sacrificed on day 15 of presumed gestation. c. Doe 8233 was found dead on day 15 of gestation. d. Doe 8234 was moribund sacrificed on day 15 of gestation. e. Doe 8235 was moribund sacrificed on day 15 of gestation. OZTfroo 418-010:PAGE F-61 ? O m o> 418-010: PAGE F-62 004121 PROTOCOL 4 1 8 -O lO P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RAB BITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .B ) TABLE 15 (PAGE 1): 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 RABBIT M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TOTAL DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8201 5 0 1 4 5 0 0 0 0 0 0 0 0 0 1 4 5 5 5 10 9202 7 3 6 A 10 0 0 0 i 0 i 1 0 i 8 4 12 9 5 14 8203 2 1 1 2 3 0 0 0 1 0 1 0 0 0 2 2 4 5 4 9 8204 5 1 1 5 6 0 0 0 0 2 2 0 0 0 1 7 8 i 7 8 8205 S 6 5 6 ii 0 0 0 0 0 0 1 0 1 6 6 12 7 6 13 DOSAGE GROUP II 1 MG/KG/DAY 8206 FOUND DEAD ON DAY 16 OF GESTATION 8207 4 6 S s 10 0 0 0 1 0 1 0 0 0 6 5 11 8 5 13 8208 4 S 5 4 9 0 0 0 0 0 0 0 0 0 5 4 9 S 5 10 B209 2 2 2 2 4 0 0 0 0 6 6 0 0 0 2 8 10 2 8 10 8210 s e 6 5 ii 0 0 0 0 0 0 0 0 0 6 5 11 6 6 12 DOSAGE GROUP III 5 MG/KG/DAY 8211 ABORTED ON DAY 26 OF GESTATION 8212 ABORTED ON DAY 24 OF GESTATION 8213 3 5 4 4 8 0 0 0 0 0 0 1 3 4 5 7 12 6 7 13 8214 ABORTED ON DAY 26 OF GESTATION 7385 2 3 2 3 5 0 0 0 0 0 0 2 1 3 4 4 8 4 5 9 DOSAGE GROUP IV 10 MG/KG/DAY 8216 8217 8218 8219 8220 ABORTED ON DAY 26 OF GESTATION ABORTED ON DAY 22 OF GESTATION ABORTED ON DAY 24 OF GESTATION ABORTED ON DAY 22 OF GESTATION ABORTED ON DAY 23 OF GESTATION M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 9o" op 5 Q m CD M 004122 PROTOCOL 418- 0 10P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O SE IN R A B B IT S (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .B ) TABLE IS (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 RABBIT # M F HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL HORN TOTAL OVARY TOTAL DOSAGE GROUP V 25 MG/KG/DAY 7371 8222 8223 8224 8225 MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION DOSAGE GROUP VI 50 MG/KG/DAY 8226 8227 8228 8229 8230 FOUND DEAD ON DAY 14 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OP GESTATION FOUND DEAD ON DAY 12 OF GESTATION MORIBUND SACRIFICED ON DAY IS OF GESTATION ' DOSAGE GROUP VII 75 MG/KG/DAY 8231 8232 8233 8234 8235 MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF PRESUMED GESTATION FOUND DEAD ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. A 0oI0 o ? O--k D o> Tl o m 5 O m 6i o> co to PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R AB BITS (SPO N SO R 'S STUDY NUMBER: T 6 3 1 6 .B) TABLE 16 (PAGE I): LITTER OBSERVATIONS (CAESAREAN DELIVERED FETUSES) - INDIVIDUAL DATA 418-010P:PAGE 64 004123 NUMBER OF LIVE FETUSES AVERAGE FETAL BODY HEIGHT (G) RABBIT 0 MALE FEMALE TOTAL MALE FEMALE TOTAL a 8201 8202 8203 8204 8205 DOSAGE GROUP I 50 73 21 S1 56 0 (VEHICLE) MG/KG/DAY 5 49.35 ___ 49.35 10 37.55 37.81 37.63 3 51.50 51.48 51.50 6 47.19 50.88 47.80 11 45.92 38.79 42.03 DOSAGE GROUP II 1 MG/KG/DAY 8206 8207 8208 8209 8210 FOUND DEAD ON DAY 16 OF GESTATION 4 6 10 45.56 4 5 9 44.68 2 2 4 53.84 5 6 11 42.93 42.93 45.10 57.44 40.28 43.98 44.91 55.64 41.49 DOSAGE GROUP III 5 MG/KG/DAY 8211 8212 8213 8214 7385 ABORTED ON DAY 26 OF GESTATION ABORTED ON DAY 24 OF GESTATION 3 5 8 28.02 ABORTED ON DAY 26 OF GESTATION 2 3 5 23.00 28.82 16.47 28.52 19.08 DOSAGE GROUP IV 10 MG/KG/DAY 8216 8217 8218 8219 8220 ABORTED ON DAY 26 OF GESTATION ABORTED ON DAY 22 OF GESTATION ABORTED ON DAY 24 OF GESTATION ABORTED ON DAY 22 OF GESTATION ABORTED ON DAY 23 OF GESTATION a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. --- CONCEPTUSES --RESORBED N N% 5 0 0.0 12 2 16.7 4 1 25.0 B 2 25.0 12 1 . 8.3 11 1 9.1 9 0 0.0 10 6 60.0 11 0 0.0 12 4 33.3 8 3 37.5 418-010: PAGE F-65 004124 PROTOCOL 418 010P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R ABBITS (SP O N SO R 'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 16 (PAGE 2) : LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) RABBIT MALE FEMALE TOTAL MALE FEMALE TOTAL a DOSAGE GROUP V 25 MG/KG/DAY 7371 8222 8223 8224 8225 MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION DOSAGE GROUP VI 50 MG/KG/DAY 8226 8227 8228 8229 8230 FOUND DEAD ON DAY 14 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION FOUND DEAD ON DAY 12 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION DOSAGE GROUP VII 75 MG/KG/DAY 8231 8232 8233 8234 8235 MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF PRESUMED GESTATION FOUND DEAD ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION MORIBUND SACRIFICED ON DAY 15 OF GESTATION a. TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIVE FETUSES. CONCEPTUSES --RESORBED N N% o9* o 2 O m CD Ui 418-010: PAGE F-66 004125 PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN RABBITS (SPO N SO R'S STUDY NUMBER: T 6 3 1 6 .B) TABLE 17 (PAGE 1) : FETAL SEX. VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS tf 10 11 12 13 14 15 16 17 18 19 DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RABBIT 6201 8202 8203 8204 8205 CLs 5/ 5 9/ 5 5/ 4 1/ 7 7/ 6 MA / HA MA MA MA 57.56 41.35 47.67 48.21 51.98 L MA FA E FA MA MA FA / MA MA MA MA 39.86 42.07 34.09 29.66 38.33 37.27 44.39 38.89 34.11 37.61 E MA / MA FA 52.60 50.41 51.48 MA / FA MA E MA E MA MA 48.96 50.88 46.06 46.18 49.74 45.01 FA MA FA FA L FA / MA MA FA MA MA FA 43.95 44.94 40.84 43.58 40.44 53.54 51.38 34.22 37.03 42.72 29.69 DOSAGE GROUP II 1 MG/KG/DAY 8206 FOUND DEAD ON DAY 16 OP GESTATION , 8207 8208 8209 8210 8/ 5 5/ 5 2/ 8 6/ 6 FA MA E FA MA MA / MA FA FA FA FA 49.48 48.31 45.78 39.00 45.12 49.82 42.07 37.73 40.76 41.74 FA MA MA MA FA / FA MA FA FA 41.55 50.39 43.05 42.27 45.86 52.04 43.03 40.77 45.27 MA FA / E E E E E E MA FA 55.77 58.25 51.91 56.63 MA MA FA FA FA MA / MA MA FA FA FA 45.50 41.96 34.82 37.56 41.80 41.67 42.70 42.84 44.01 41.20 42.32 DOSAGE GROUP III 5 MG/KG/DAY 8211 ABORTED ON DAY 26 OF GESTATION 8212 ABORTED ON DAY 24 OF GESTATION 8213 6/ 7 FA MA FA L MA / MA 38.65 27.40 29.39 26.21 30.46 8214 ABORTED ON DAY 26 OF GESTATION L FA FA 27.18 22.78 FA 26.11 7385 4/ 5 FA 18.86 L FA / MA 13.20 24.97 FA MA 17.36 21.03 M = MALE F * FEMALE A = ALIVE E = EARLY RESORPTION L = LATE RESORPTION '/" DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . ? --Ok o -0 > mQ oo>> PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O S E IN R ABBITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 17 (PAGE 2) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA 418-010: PAGE F-67 004126 FETUS * 1 2 3 4 5 10 12 13 14 15 16 17 18 19 DOSAGE GROUP IV 10 MG/KG/DAY RABBIT 8 CLs 8216 ABORTED ON DAY 26 OF GESTATION 8217 ABORTED ON DAY 22 OP GESTATION h 8218 ABORTED ON DAY 24 OF GESTATION 8219 ABORTED ON DAY 22 OF GESTATION 8220 ABORTED ON DAY 23 OF GESTATION DOSAGE GROUP V 25 MG/KG/DAY 7371 MORIBUND SACRIFICED ON DAY 15 OF GESTATION 8222 MORIBUND SACRIFICED ON DAY 15 OF GESTATION 8223 MORIBUND SACRIFICED ON DAY 15 OF GESTATION 8224 MORIBUND SACRIFICED ON DAY 15 OF GESTATION 8225 MORIBUND SACRIFICED ON DAY 15 OF GESTATION DOSAGE GROUP VI 50 MG/KG/DAY 8225 FOUND DEAD ON DAY 14 OF GESTATION 8227 MORIBUND SACRIFICED ON DAY 15 OF GESTATION 8228 MORIBUND SACRIFICED ON DAY 15 OF GESTATION 8229 FOUND DEAD ON DAY 12 OF GESTATION 8230 MORIBUND SACRIFICED ON DAY 15 OF GESTATION M = MALE F FEMALE A = ALIVE E = EARLY RESORPTION L = LATE RESORPTION CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G). "/" DENOTES POSITION OF CERVIX g O U a m o> PROTOCOL 4 1 8 -0 1 0 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL T O X IC IT Y STUDY OF N -E tF O SE IN RABBITS (SPO N SO R'S STUDY NUMBER: T -6 3 1 6 .8 ) TABLE 17 (PAGE 3) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS It 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 DOSAGE GROUP VIX 75 MG/KG/DAY RABBIT 8 CLs 8231 MORIBUND SACRIFICED ON DAY 15 OF GESTATION 8232 MORIBUND SACRIFICED ON DAY 15 OF PRESUMED GESTATION 8233 FOUND DEAD ON DAY IS OF GESTATION 8234 MORIBUND SACRIFICED ON DAY 15 OF GESTATION 8235 MORIBUND SACRIFICED ON DAY IS OF GESTATION M - MALE F - FEMALE A - ALIVE E - EARLY RESORPTION L = LATE RESORPTION /* DENOTES POSITION OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . 418-010:PAG E F-68 004127 tw --a 9o" o TJ TJ > mG) O) oo 418-010:PAGE F-69 418-010P.PAGE 69 ATTACHMENT 1 PROTOCOL AND AMENDMENT 004128 418-010:PAGE F-70 418-010P:PAGE 70 Argus Research Laboratories, Inc. 90S Sheehy Drive, Building A Horsham, Pennsylvania 19044 T: (215)443-5710 F: (215)443-5587 PROTOCOL 418-01 OP R'S STUDY NUMBER: T-6316.8 STUDY TITLE: PURPOSE: TESTING FACILITY: STUDY DIRECTOR: SPONSOR: STUDY MONITOR: ALTERNATIVE STUDY MONITOR: Oral (Stomach Tube) Dosage-Range Developmental Toxicity Study of N-EtFOSE in Rabbits The purpose of this study is to provide information for the selection of dosages to be used in the developmental toxicity (embryo-fetal toxicity and teratogenic potential) study of N-EtFOSE administered orally via stomach tube to New Zealand White [Hra:(NZW)SPF] presumed pregnant female rabbits. 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: (612)733-5180 Telefax: (612) 733-1773 Andrew M. Seacat, Ph.D. Telephone: (612) 575-3161 Telefax: (612) 733-1773 ^04129 418-010:PAGE F-71 418-010P.PAGE 71 Protocol 418-01OP 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 for Safety Studies on Drugs, MHW Ordinance Number 21, March 26,1997. 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. REGULATORY COMPLIANCE: This study will be conducted in the spirit of the Good Laboratory Practice (GLP) regulations cited above in that the Testing Facility personnel will adhere to the Standard Operating Procedures for laboratory operations and data collection. The Testing Facility Quality Assurance Unit (QAU) will not audit the protocol, the raw data, the reports or the critical phases of the study. All changes or revisions of this protocol shall be documented, signed by the Study Director and the Sponsor, dated and maintained with the protocol. STUDY SCHEDULE: See ATTACHMENT 1 to the protocol. 004130 418-010: PAGE F-72 418-010P:PAGE 72 Protocol 418-01 OP 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 to 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 (ATTACHMENT 2). Storage: Bulk Test Article: Vehicle Components: Prepared Vehicle: Prepared Formulations: Room temperature. Room temperature. Room temperature. Frozen (-20C). 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. 004131 418-010:PAGE F-73 418-01 OP:PAGE 73 Protocol 418-01 OP Page 4 FORMULATION: Frequency of Preparation: Formulations (suspensions) will be prepared daily at the Testing Facility. Vehicle 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 Sponsor will reserve a sample (1 g) of each lot of the bulk test article used during the course of this study. The Testing Facility will reserve a sample (5 mL) of each lot of the vehicle components used during the course of this 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. However, records will be maintained to document how the test article formulations were prepared. DISPOSITION: 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. 00413 2 418-010:PAGE F-74 418-010P.PAGE 74 Protocol 418-01 OP Page 5 TEST SYSTEM: Species/Strain and Reason for Selection: The New Zealand White [Hra:(NZW)SPF] rabbit was selected as the Test System because: 1) it is one non-rodent mammalian species accepted and widely used throughout the industry for nonclinical studies of developmental toxicity (embryo-fetal toxicity/teratogenicity); 2) this strain of rabbit has been demonstrated to be sensitive to developmental toxins; 3) historical data and experience exist at the Testing Facility'1'3'; and 4) the test article is pharmacologically active in the species and strain. Number and Sex: Population evaluated: 35 timed-pregnant female rabbits (5 per dosage group). Body Weight and Aae: The individual body weights of the female rabbits will range from 2.5 kg to 5.5 kg; the rabbits will be approximately five to seven months of age at the time of study assignment. Actual body weights recorded at receipt and at study assignment will be documented in the raw data. Source: Covance Research Products, Inc. Swampbridge Road, Box 7200 Denver, Pennsylvania 17517 The rabbits will be shipped in filtered cartons by truck from Covance Research Products, Inc., Denver, Pennsylvania, to the Testing Facility. Identification: Rabbits are permanently identified using Monel self-piercing ear tags (Gey Band and Tag Co., Inc., No. MSPT 20103). Female rabbits are 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 are in compliance with the Guide for the Care and Use of Laboratory Animals(4). 004133 418-010: PAGE F-75 418-010P.PAGE 75 Protocol 418-010P Page 6 Housing: The rabbits will be individually housed in units of six to eight stainless steel cages. No nesting materials will be supplied because the female rabbits will be sacrificed before parturition is expected. Room Air. Temperature and Humidity: 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. Room temperature will be maintained at 61 F (16C) to 72F (22C) 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. Diet: Approximately 150 g of Certified Rabbit Chow #5322 (PMI Nutrition International) will be available to each rabbit each day until the first day of dosage, at which time approximately 180 g of the same certified feed will be offered to each rabbit each day. The certified feed will be available from individual, stainless steel, "J-type" feeders attached to each cage. 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. Contaminants: Neither the Sponsor nor the 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. 004134 418-010: PAGE F-76 418-010P.PAGE 76 Protocol 418-01 OP Page 7 MATING AND RANDOMIZATION: The female rabbits will be naturally bred at the Supplier by breeder male rabbits of the same source and strain before shipment to the Testing Facility. The day mating occurs will be designated day 0 of presumed gestation. The rabbits will be shipped to the Testing Facility after mating, to arrive on day 2 of presumed gestation. Before shipment of the rabbits, the Supplier will forward breeding records and day 0 of presumed gestation body weights. A computer-generated (weight-ordered) randomization procedure will be used to assign the rabbits to dosage groups based on this information. ADMINISTRATION: Route and Reason for Choice: The oral (stomach tube) 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 possible routes of human exposure. Method and Frequency: Female rabbits will be given the test article once daily on days 7 through 20 of presumed gestation. Dosages will be adjusted for the most recently recorded body weight and given at approximately the same time each day. Rationale for Dosaoe Selection: Dosages will be selected by the Sponsor on the basis of previous studies conducted with the test article. 004135 418-010: PAGE F-77 418-010P:PAGE 77 Protocol 418-01 OP Page 8 Dosage Levels. Concentrations and Volumes: Dosage Group Number of Rabbits Dosage Concentration Volume (mg/kg/day) (mg/mL) (mL/kg) Argus Batch Number 1 5 0 (Vehicle) 0 II 5 1 0.2 III 5 5 1 IV 5 10 2 V5 25 5 VI 5 50 10 5 B-418-010P-A(Day.Month.Year) 5 B-418-010P-B(Day:Month.Year) 5 B-418-010P-C(Day.Month.Year) 5 B-418-010P-D(Day. Month. Year) 5 B-418-010P-E(Day.Month Year) 5 B-418-010P-F(Day.Month.Year) VII 5 75 15 5 B-418-010P-G( Day.Month.Year) The test article will be considered 100% pure for the purpose of dosage calculations. TESTS. ANALYSES AND MEASUREMENTS: . Viability: All Periods: At least twice daily. Clinical Observations and/or General Appearance: Predosage Period: At least once. Dosage Period: Twice daily. Prior to dosage administration and once approximately on 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: Predosage Period: Day 0 of presumed gestation and on the day of arrival at the Testing Facility. Dosage Period: Daily. Postdosage Period: Daily. 004136 418-010.PAGE F-78 418-010P:PAGE 78 Protocol 418-010P Page 9 Feed Consumption Values: Predosage Period: Recorded daily after arrival at the Testing Facility (values not tabulated). Dosage Period: Recorded daily. Postdosage Period: Recorded daily. Feed consumption values during the dosage period will be tabulated for the same intervals as body weight evaluations. Caesarean-Sectionino Observations: Rabbits will be Caesarean-sectioned on day 29 of presumed gestation. The fetuses will be removed from the uterus and placed in individual containers. The rabbits will be examined for number and distribution of: Corpora Ltea. Implantation Sites. [Placentae that appear abnormal (size, color or shape) 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 identified as an early resorption.) Fetal Observations: Body Weights: 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. 004137 418-010: PAGE F-79 418-010P:PAGE 79 Protocol418-010P Page 10 Gross External Alterations: All fetuses will be examined for gross external alterations. Late resorptions and dead fetuses also will be examined for gross external alterations to the extent possible but such observations will not be included in either data summarization or statistical analyses. Fetuses with gross external alterations will be preserved in neutral buffered 10% formalin. All other fetuses will be discarded. Representative photographs of fetal gross alterations will be taken. Sex: All fetuses will be examined internally to determine sex. METHOD OF SACRIFICE: Beuthanasia-D Special, manufactured by Schering-Plough Animal Health, will be used to sacrifice rabbits (via intravenous injection) and live fetuses (via intraperitoneal injection). NECROPSY: Gross lesions will be retained in neutral buffered 10% formalin for possible future evaluation (corresponding tissues will be retained from rabbits in the vehicle control group at the discretion of the Study Director). (Exception: Parovarian cysts will be discarded; these are common, spontaneous lesions in rabbits.) Unless specifically cited below, all other tissues will be discarded. Scheduled Sacrifice: On day 29 of presumed gestation, female rabbits will be Caesarean-sectioned, and a gross necropsy of the thoracic, abdominal and pelvic viscera will be performed. Uteri of apparently nonpregnant does will be stained with 10% ammonium sulfide to confirm the absence of implantation sites(5). Rabbits Found Dead or Moribund: Rabbits 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. Pregnancy status and uterine contents 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 does will be stained with 10% ammonium sulfide to confirm the absence of implantation sites'5'. 004138 418-010.PAGE F-80 418-010P:PAGE 80 Protocol 418-01OP Page 11 STATISTICAL EVALUATION: Averages and percentages will be calculated. Litter values will be used where appropriate. Additional procedures and/or analyses may be performed if deemed appropriate. 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. Veterinarian Examination. Mating History. Treatment (if prescribed by Staff Veterinarian). General Comments. Clinical Observations and/or General Appearance. Body Weights. Feed Consumption Values. Caesarean-Sectioning and Fetal Observations. Gross Necropsy Observations. Organ Weights (if required). Photographs (if required). Study Maintenance (room and environmental records). Feed and Water Analyses. Packing and/or Shipment Lists. 004139 418-010: PAGE F-81 418-010P:PAGE 81 Protocol 418-01 OP Page 12 KEY PERSONNEL: Executive Director of Research: Mildred S. Christian, Ph.D., 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 REPORT: A letter report for the purpose of dosage selection for the full study will be prepared immediately following completion of the in-life phase. A summary report will be prepared including: abstract, summaries of the methods, results and conclusion: table of contents: copy of the protocol; amendments; summary and individual tables; and reports of supporting data (if appropriate). The report will be included as an appendix to the full study report. The Sponsor will receive one copy of the draft report and two copies of the final report. 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. 004140 418-010:PAGE F-82 418-01 OP:PAGE 82 Protocol 418-01 OP Page 13 REFERENCES: 1. Christian, M.S., Hoberman, A.M. and Smith, T.H.F. (1982). Dosage-range study of the teratogenic potential of suspensions of trinitrofiuorenone (TNF) administered orally to New Zealand White rabbits. Toxicologist 2(1):40 (#143). 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. Feussner, E.L., Lightkep, G.E., Hennesy, R.A., Hoberman, A.M. and Christian, M.S. (1992). A decade of rabbit fertility data: Study of historical control animals. Teratology 46(4):349-365. 4. Institute of Laboratory Animal Resources (1996). Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C. 5. Salewski, E. (1964). Farbemethode zum makroskopischen Nachweis von Implantationsstellen am Uterus der Ratte.- Arch. Pathol. Exp. Pharmakol. 247:367. 004141 418-010: PAGE F-83 418-010P:PAGE 83 Protocol 418-01 OP Page 14 PROTOCOL APPROVAL: FOR THE TESTING FACILITY George Ej/Deariove, Ph.D., DABT Associate Director of Research uDate Date C - _____________ Dena C. Lebo, V.M.D. Member, Institutional Animal Care and Use Committee /(s Date ( / 9F FOR THE SPONSOR 7 Marvin T. Case, D.V.M., Ph.D. Study Monitor M tffr Date 04142 418-010: PAGE F-84 418-010P.PAGE 84 ATTACHMENT 1 SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE 04143 ATTACHMENT 1 418-010.PAGE F-85 418-010P:PAGE 85 Protocol 418-01 OP Page 1 of 2 STUDY SCHEMATIC DOSAGE-RANGE DEVELOPMENTAL TO XICITY STUDY* TimedPregnant Rabbits Start of Dosage CaesareanSectioning End of Dosage Day 0 of Presumed Gestation Day 7 of Presumed Gestation Day 20 of Presumed Gestation Day 29 of Presumed Gestation H i Dosage Period. a. For additional details see "Tests, Analyses and Measurements" section of the protocol. b. Fetal evaluations (all fetuses - external examinations). 004144 ATTACHMENT 1 418-010: PAGE F-86 418-010P:PAGE 86 Protocol 418-01 OP Page 2 of 2 SCHEDULE* 26 JUN 98 01 JU L9 8- 14 JUL98 23 JUL 98 30 JUL 98 06 OCT 98 Animals Arrive - Acclimation Begins. Dosage Period (Days 7 through 20 of presumed gestation). Caesarean-Sectioning Period (Day 29 of presumed gestation). Letter Report. Summary Report. a. The study initiation date is the date the Study Director signs the protocol. 004145 418-010:PAGE F-87 418-010P:PAGE 87 ATTACHMENT 2 MATERIAL SAFETY DATA SHEET 004146 418-010.PAGE F-88 MATERIAL SAFETY DATA SHEET 3M 3M Center St. Paul, Minnesota 55144-1000 1-800-364-3577 or (612) 737-6501 N - + F 0 5 r 418-010P:PAGE 88 (24 hours) Copyright, 1998, Minnesota Mining end 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 u n l e s s 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 Fluorochemical Alcohol ID NUMBER/U.P.C.: 98-0211-1113-7 00-51135-09495-2 98-0211-1183-0 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 ALCOHOL PERFLUOROBUTANESULFONAMIDO ALCOHOL. PERFLUOROPENTANESULFONAMIDO ALCOHOL 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 BOILING POINT:..... VAPOR PRESSURE:.... VAPOR DENSITY:..... EVAPORATION RATE:... SOLUBILITY IN WATER: SPECIFIC GRAVITY:... PERCENT VOLATILE:... P H : ................ VISCOSITY:......... MELTING POINT:..... ca. 118 C 9 1 mm Hg < 10 mmHg Calc 9 2 0 C > 1 . 0 Air=1 Calc 9 20 C. < 1 . 0 BuOAc=1 neglig. ca. 1.7 Water=l (of melt) 0h N/A N/D N/D 004147 Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 418-010: PAGE F-89 MSDS: FC-10 FLUORAD Brand Fluorochraieal Alcohol January 29, 1996 41&-010P:PAGE 89 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: ....... N/A AUTOIGNITION TEMPERATURE:..... N/A EXTINGUISHING MEDIA: Mater, 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 personal protective equipment. Collect spilled material. Clean up residue. Place in a U.S. DOT-approved container. 4 l4 8 Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 418-010: PAGE F-90 MSDS: FC-10 FLUORAD Brand Fluorochaaical Alcohol January 29, 1998 5. ENVIRONMENTAL INFORMATION (continued) 418-010P:PAGE 90 PAGE 3 RECOMMENDED DISPOSAL: Incinerate in a permitted hazardous waste incinerator in the presence of 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, % 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. Wash 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 SWALLOWED: Call a physician IMMEDIATELY. If swallowed, induce vomiting immediately as directed by medical personnel. Never give anything by mouth to an unconscious person. 004149 Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 418-010: PAGE F-91 USDS: FC-10 FLUORAD Brand Fluorochemical Alcohol January 29, 1998 418-010P:PAGE 91 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. Nash exposed areas thoroughly with soap and water. Nash 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.) EXPOSURE LIMITS INGREDIENT VALUE UNIT TYPE AUTH SKIN* PERFLUOROOCTANESULFONAMIDO ALCOHOI___ 0.1 MG/M3 . TWA 3M PERFLUOROHEXANESULFONAMIDO ALCOHOL... 0.1 MG/M3 TNA 3M PERFLUOROHEPTANESULFONAMIDO ALCOHOL........................... 0.1 MG/M3 TWA 3M Y Y Y Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 418-010:PAGE F-92 NSOS: FC-10 FLUORAD Brand Fluorochraical Alcohol January 29, 1998 EXPOSURE LIMITS (continued) 418-010P:PAGE 92 PAGE 5 INGREDIENT VALUE UNIT TYPE AUTH SKIN PERFLUOROBUTANESULFONAMIDO ALCOHOI--PERFLUOROPENTANESULFONAMIDO ALCOHOL.......................... 0.1 MG/M3 0.1 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 nucous 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. 004151 Abbreviations: N/D Not Determined N/A - Not Applicable CA Approximately 418-010:PAGE F-93 USDS: FC-10 FLUORAD Brand Fluorochemical Alcohol January 29, 1998 418-010P:PAGE 93 PAGE 6 SECTION CHANGE DATES HEADING SECTION CHANGED SINCE November 05, 1997 ISSUE Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately The 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 the 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. 3M provides information in electronic form as a service to its customers. Due to the remote possibility that electronic transfer may have resulted in 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 information in the MSDS available directly from 3M. 418-010:PAGE F-94 418-010P:PAGE 94 ATTACHMENT 3 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE 004153 418-010: PAGE F-95 418-010P:PAGE 95 ATTACHMENT 3 Protocol418-01OP Version:418-01OP (12 JUN 981 Page 1of3 TEST ARTICLE AND VEHICLE 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 vehicle for oral administration to rabbits on Argus Study 418-01 OP. 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: X Daily __ 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 solutions 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. 004154 418-010:PAGE F-96 418-01 OP:PAGE 96 ATTACHMENT 3 Protocol418-010P Version: 418-010P M2 JUN 98) Page 2 of3 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE NOTE: The 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 50C, 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 15-mg/mL, Group VII 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 80C, 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 10-mg/mL, Group VI suspension, remove the required amount of stock suspension (Group VII) (See TEST ARTICLE CALCULATIONS), add the required amount of vehicle and mix. 4. To prepare the 5-mg/mL, Group V suspension, remove the required amount of stock suspension (Group VI) (See TEST ARTICLE CALCULATIONS), add the required amount of vehicle and mix. 5. To prepare the 2-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. 004155 418-010: PAGE F-97 418-010P:PAGE 97 ATTACHMENT 3 Protocol418-01OP Version: 418-01OP (12 JUN 98) Page 3 of3 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE 6 . To prepare the 1-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. 7. 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 Date: -% Clarification: No M res (See attached clarification form.) Initials/Date : 004156 418-010: PAGE F-98 418-010P.PAGE 98 Argus Research Laboratories, Inc. 905 Sheehy Drive, Building A Horsham, Pennsylvania 19044 T: (215)443-8710 F: (215)4434587 PROTOCOL 418-01 OP ORAL (STOMACH TUBE)DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RABBITS SPONSOR'S STUDY NUMBER: T-6316.8 Amendment 1 - June 25, 1998 1. Clinical Observations and/or General Appearance (page 8 of the protocol): The postdosage observation will be made approximately one hour postdosage. Reason for Change: This change corrects a typographical error. riove, Ph.D., DABT Date Raymond/G. York, Ph. Associate Director of Research Associate Director of R and Study Director 2S.Zu*.-.yY jfiftaiUJL Dena C. Lebo, V.M.D. Date Member, Institutional Animal Care and Use Committee U d L r.. Marvin T. Case, D.V.M., Ph.D. Date Study Monitor 004157 APPENDIX G HISTORICAL CONTROL DATA 004158 418-010:PAGE G-1 SUMMARY OF REPRODUCTIVE INDICES NZW RABBIT PERIOD: JANUARY 1996 - JANUARY 1998 NUMBER OF STUDIES: 66 NUMBER OF RABBITS: TESTED PREGNANT FOUND DEAD ABORTED DELIVERED PREMATURELY 901 861 6* 22 4 NUMBER OF RABBITS PREGNANT AT CAESAREAN-SECTIONING ON DAY 29 OF GESTATION: 825 NUMBER OF RABBITS WITH SINGLE CONCEPTUS LITTER: LIVE RESORBED ABORTED 1 1 2 MEAN or % % PREGNANT 96.0 AVERAGE # CORPORA LUTEA 9.7 AVERAGE # IMPLANTATIONS 8.9 AVERAGE LITTER SIZE AVERAGE # LIVE FETUSES 8.4 AVERAGE # DEAD FETUSES 0.0 AVERAGE # RESORPTIONS 0.4 AVERAGE # EARLY RESORPTIONS 0.3 AVERAGE # LATE RESORPTIONS 0.1 * Three were moribund sacrifices, one was attributed to an intubation accident RANGE/STUDY MEAN or % (75.0-100) (7.8-11.7) (3.8-10.6) (3.2-10.4) (0-0.1) (0-3.2) (0-2.8) (0-1.2) 0041S9 418-010:PAGE G-2 SUMMARY OF REPRODUCTIVE INDICES NZW RABBIT MEAN or % RANGE/STUDY MEAN or % AVERAGE % DOES WITH ANY RESORPTIONS 26.8 (0-100) AVERAGE % DOES WITH ALL CONCEPTUSES RESORBED 0.6 (0-20.0) AVERAGE % DOES WITH ONE OR MORE LIVE FETUSES 99.4 (80.0-100) AVERAGE SEX RATIO, (% MALES/LITTER) 51.2 (31.4-61.0) AVERAGE FETAL BODY WEIGHT (G) 43.74 (31.85-55.74) AVERAGE FOR MALES (G) 44.26 (29.55-56.97) AVERAGE FOR FEMALES (G) 43.08 (32.25-53.76) AVERAGE % DEAD OR RESORBED CONCEPTUSES/LITTER 4.4 (0-18.8) 04160 418-010: PAGE G-3 SUMMARY OF MATERNAL NECROPSY OBSERVATIONS NZW RABBITS PERIOD JANUARY 1996 - JANUARY 1998 TOTAL# STUDIES 67 TOTAL# DOES 921 # PREGNANT 876 # DIED 6* # ABORTED 22 # DELIVERED PREMATURELY 4 # DOES WITH 100% RESORPTIONS 5 % OF PRE 0.6 2.4 0.4 0.5 EXTERNAL OBSERVATIONS RANGE /STUDY N %N % Fecal material in perianal region Localized alopecia Left ear, tom 1 0.11 0-1 (0-5.0) 2 0.22 0-1 (0-5.0) 1 0.11 0-1 (0-5.0) GROSS LESIONS THYMUS Small 1 0.11 0-1 (0-5.0) LUNGS Discolored Tear in right dia phragmatic lobe Multiple lesions 6 0.65 0-4 (0-20.0) 1 0.11 0-1 (0-4.0) 1 0.11 0-1 (0-4.2) THORACIC CAVITY Contained red fluid 1 0.11 0-1 (0-4.0) LIVER Pale and/or discolored 7 0.76 0-4 (0-16.0) Accentuated lobular pattern on lobe(s) 1 0.11 0-1 (0-5.0) BACK Break present in lumbar region of spine 1 0.11 0-1 (0-5.0) * Three were moribund sacrifices, one was attributed to an intubation accident 004161 418-010:PAGE G-4 SUMMARY OF MATERNAL NECROPSY OBSERVATIONS NZW RABBITS GROSS LESIONS BACK (CONT.) Dorsal muscles, three hemorrhagic areas in lumbar region N 1 STOMACH Trichobezoar Mucosa, eroded in areas 2 1 SPLEEN Small Large 3 1 KIDNEY(S) Small Right, displaced caudally 1 1 ADRENAL GLAND Right, absent 1 UTERUS Right horn contained dark brown fluid Homs contained a viscous, green-brown substance Vascularization Placentae surrounded by a thick, yellow substance 1 1 1 1 OVARIES Parovarian cyst(s) 30 RANGE / STUDY %N % 0.11 0-1 (0-12.5) 0.22 0-1 (0-4.3) 0.11 0-1 (0-4.2) 0.32 0-1 (0-20.0) 0.11 0-1 (0-4.0) 0.11 0-1 (0-20.0) 0.11 0-1 (0-5.0) 0.11 0-1 (0-5.0) 0.11 0-1 (0-16.7) 0.11 0-1 (0-4.0) 0.11 0-1 (0-4.3) 0.11 0-1 (0-5.0) 3.26 0-5 (0-25.0) 004162 418-010: PAGE G-5 SUMMARY OF FETAL GROSS EXTERNAL ALTERATIONS NZW RABBITS PERIOD JANUARY 1996 - JANUARY 1998 # OF STUDIES 65 # LITTERS EXAMINED 816 # LIVE FETUSES EXAMINED (DAY 29) 6929 SKIN ALTERATION Absent area HEAD Meningocele Cyclops U pperjaw intw o segments Nares absent Fleshy protrusion EYES Bulge depressed Eyelids open SNOUT Short TONGUE Protrudes BODY Umbilical Hernia Edema L: LITTER INCIDENCE F: FETAL INCIDENCE RANGE/STUDY N% N % L 1 0.12 0-1 (0-5.3) F 1 0.01 0-1 (0-0.6) L 2 0.24 0-1 (0-16.7) F 3 0.04 0-2 (0-3.7) L 1 0.12 0-1 (0-5.9) F 1 0.01 0-1 (0-0.7) L 1 0.12 0-1 (0-5.9) F 1 0.01 0-1 (0-0.7) L 1 0.12 0-1 (0-5.3) F 1 0.01 0-1 (0-0.6) L 1 0.12 0-1 (0-5.3) F 1 0.01 0-1 (0-0.6) L 3 0.37 0-1 (0-5.3) F 3 0.04 0-1 (0-0.6) L 1 0.12 0-1 (0-5.9) F 1 0.01 0-1 (0-0.7) L 2 0.24 0-1 (0-5.9) F 2 0.03 0-1 (0-0.7) L 1 0.12 0-1 (0-5.3) F 1 0.01 0-1 (0-0.6) L 9 1.10 0-2 (0-50.0) F 10 0.14 0-3 (0-12.0) L 1 0.12 0-1 (0-5.3) F 1 0.01 0-1 (0-0.6) 004163 418-010: PAGE G-6 SUMMARY OF FETAL GROSS EXTERNAL ALTERATIONS NZW RABBITS ALTERATION BODY (CONT.) Skin discolored purple Spina bifida Hemorrhagic area(s) Meningocele Hematoma Dark red areas L F L F L F L F L F L F FORELIMBS AND/OR HINDLIMBS Paw(s): Flexed/ L Rotated F Paw: Short digits L F Limb(s): Rotated L F Limb(s): Absent L F TAIL Short L F RANGE/ STUDY N% N % 1 0.12 0-1 3 0.04 0-3 2 0.24 0-1 2 0.03 0-1 2 0.24 0-1 2 0.03 0-1 2 0.24 0-1 2 0.03 0-1 1 0.12 0-1 1 0.01 0-1 1 0.12 0-1 1 0.01 0-1 (0-5.3) (0-1.9) (0-20.0) (0-1.9) (0-5.0) (0-0.6) (0-16.7) (0-2.0) (0-5.9) (0-0.8) (0-5.6) (0-0.6) 2 0.24 0-1 2 0.03 0-1 1 0.12 0-1 1 0.01 0-1 2 0.24 0-1 2 0.03 0-1 1 0.12 0-1 1 0.01 0-1 (0-5.6) (0-0.6) (0-5.6). (0-0.7) (0-16.7) (0-1.9) (0-5.3) (0-0.6) 7 0.86 0-1 10 0.14 0-4 (0-20.0) (0-2.3) L: LITTER INCIDENCE F: FETAL INCIDENCE 004164 418-010: PAGE G-7 SUMMARY OF FETAL SOFT TISSUE ALTERATIONS N2W RABBITS PERIOD JANUARY 1996 - JANUARY 1998 # STUDIES 38 # LITTERS EXAMINED 674 # FETUSES EXAMINED 5739 ALTERATION BRAIN Dilated lateral ventricles (Moderate) (Grade 2) L F EYE(S) Circumcomeal hemorrhage L F Microphthalmia L F HEART Large Three ventricles L F L F VESSELS Persistent truncus arteriosis Innominate, absent Two pulmonary arteries L F L F L F LUNGS One or more lobes, partial or complete agenesis Right apical and cardiac lobes fused L F L F DIAPHRAGM Hernia L F RANGE/STUDY N% N % 2 0.30 0-1 (0-5.0) 2 0.03 0-1 (0-0.6) 20 2.97 0-2 (0-16.7) 21 0.36 0-3 (0-1.9) 1 0.15 0-1 (0-5.0) 1 0.02 0-1 (0-0.6) 1 0.15 0-1 (0-5.9) 1 0.02 0-1 (0-0.6) 1 0.15 0-1 (0-5.9) 1 0.02 0-1 (0-0.6) 1 0.15 0-1 (0-5.0) 1 0.02 0-1 (0-0.6) 1 0.15 0-1 (0-5.3) 1 0.02 0-1 (0-0.7) 1 0.15 0-1 (0-5.9) 1 0.02 0-1 (0-0.6) 69 10.24 0-5 (0-27.8) 90 1.57 0-9 (0-5.0) 1 0.15 0-1 (0-5.3) 1 0.02 0-1 (0-0.6) 1 0.15 0-1 (0-5.0) 1 0.02 0-1 (0-0.6) L: LITTER INCIDENCE F: FETAL INCIDENCE 4l65 418-010: PAGE G-8 SUMMARY OF FETAL SOFT TISSUE ALTERATIONS NZW RABBITS ALTERATION KIDNEY(S) Absent Displaced caudally SPLEEN Pale GONADS Right testis displaced caudally * L F L F L F L F RANGE/STUDY N% N % 1 0.15 0-1 (0-5.6) 1 0.02 0-1 (0-0.6) 1 0.15 0-1 (0-4.3) 1 0.02 0-1 (0-0.5) 1 0.15 0-1 (0-7.1) 1 0.02 0-1 (0-0.9) 1 0.15 0-1 (0-5.9) 1 0.02 0-1 (0-0.6) L: LITTER INCIDENCE F: FETAL INCIDENCE 4 l6 6 SUMMARY OF FETAL SKELETAL ALTERATIONS N Z W RABBITS 418-010: PAGE G-9 PERIOD JANUARY 1996 -JANUARY 1998 # STUDIES 37 # UTTERS EXAMINED 668 # FETUSES EXAMINED 5684 # OF STUDIES ALTERATIONS RANGE/STUDY WITH SKULL N% N % ALTERATION Summarization ofallirregular L ossificationofskull F 185 27.69 0-11 (0-66.7) 237 4.17 0-17 (0-9.8) 35 AnteriorFontanelle :Irregularlyshaped L 1 0.15 0-1 (0-5.3) F 1 0.02 0-1 (0-0.5) 1 Posterior Fontanelle :Enlarged (Slight) (Grade 1) L 1 0.15 0-1 (0-5.3) F 1 0.02 0-1 (0-0.6) 1 Frontals :Irregularsuture :Interfrontalspresent :Fused :Two segments :Suture large ;S m all L 18 2.69 0-3 (0-16.7) F 20 0.35 0-3 (0-1.8) L 17 2.54 0-3 (0-15.0) F 17 0.30 0-3 (0-1.7) L 5 0.75 0-2 (0-10.5) F 5 0.09 0-2 (0-1.1) L 1 0.15 0-1 (0-5.9) F 1 0.02 0-1 (0-0.7) L 1 0.15 0-1 (0-5.0) F 1 0.02 0-1 (0-0.6) L 1 0.15 0-1 (0-5.3) F 1 0.02 0-1 (0-0.6) 13 13 4 1 1 1 Parietali) :Contain holes :Fused and small :Interparietals irregularlyshaped :Interparietals incom pletely ossified L F L F L F L F 3 0.45 3 0.05 1 0.15 1 0.02 1 0.15 1 0.02 1 0.15 1 0.02 0-1 (0-5.6) 0-1 (0-0.6) 0-1 (0-5.3) 0-1 (0-0.6) 0-1 (0-5.3) 0-1 (0-0.5) 0-1 (0-16.7) 0-1 (0-1.9) L:LITTER INCIDENCE F:FETAL INCIDENCE 004167 3 1 1 1 418-010: PAGE G-10 SUMMARY OF FETAL SKELETAL ALTERATIONS N Z W RABBITS # OF STUDIES ALTERATIONS RANGE/STUDY WITH SKULL (CONT.) N% N % ALTERATION Nasals :Irregularsuture L 4 0.60 0-2 (0-10.0) 3 F 4 0.07 0-2 (0-1.2) :Intemasals L 26 3.89 0-3 (0-15.8) 18 F 29 0.51 0-4 (0-2.3) :Intranasals L 16 2.40 0-2 (0-16.7) 13 F 16 0.28 0-2 (0-1.9) :Displaced suture L 116 17.36 0-8 (0-40.0) 34 F 129 2 2 7 0-9 (0-5.2) :Fused L 10 1.50 0-2 (0-10.0) 9 F 11 0.19 0-2 (0-1.3) :Small L 1 0.15 0-1 (0-5.0) 1 F 1 0.02 0-1 (0-0.6) Nasal/Frontal sutures: L irregularand/ormisaligned F 12 1.80 13 0.23 0-2 (0-11.1) 0-3 (0-1.9) 9 Premaxillae: fused Premaxillae: notossified Maxillae:fused Supraoccipitals: irregularly shaped Eye socket small Skull: extra ossification L F L F L F L F L F L F 1 0.15 1 0.02 1 0.15 1 0.02 1 0.15 1 0.02 1 0.15 1 0.02 2 0.30 2 0.04 1 0.15 1 0.02 0-1 (0-5.9) 0-1 (0-0.7) 0-1 (0-5.0) 0-1 (0-0.6) 0-1 (0-5.3) 0-1 (0-0.6) 0-1 (0-5.3) 0-1 (0-0.5) 0-1 (0-5.0) 0-1 (0-0.6) 0-1 (0-5.6) 0-1 (0-0.6) 1 1 1 1 2 1 HYOID A1a(e), angulated Small Irregularlyshaped L:LITTER INCIDENCE F:FETAL INCIDENCE L 108 16.17 0-8 (0-40.0) F 137 2.41 0-18 (0-9.9) L 1 0.15 0-1 (0-5.3) F 4 0.07 0-4 (0-2.4) L 1 0.15 0-1 (0-5.3) F 1 0.02 0-1 (0-0.6) 34 1 1 04168 418-010: PAGE G-11 SUMMARY OF FETAL SKELETAL ALTERATIONS N Z W RABBITS #OF STUDIES RANGE/STUDY WITH ALTERATIONS N% N % ALTERATION VERTEBRAE Cervical :Centrum, unilateral L 2 0.30 0-1 (0-5.6) 2 ossification F 2 0.04 0-1 (0-0.7) :Arches and/orCentra, L 3 0.45 0-1 (0-5.6) 3 fused F 3 0.05 0-1 (0-0.7) :Hemivertebra L 3 0.45 0-1 (0-5.9) 3 F 3 0.05 0-1 (0-0.6) :Centrum, asymmetric L 1 0.15 0-1 (0-5.6) 1 F 1 0.02 0-1 (0-0.7) :Centra, bifid L 1 0.15 0-1 (0-5.3) 1 F 1 0.02 0-1 (0-0.6) Thoracic :Hemivertebra :Arches and/orCentra, fused :Centrum, unilateral ossification :Centra, one ormore asymmetric :Centrum, bifid :Centra, notossified :Arch, absent :Arch, small L F L F L F L F L F L F L F L F 10 1.50 11 0.19 5 0.75 6 0.10 5 0.75 5 0.09 1 0.15 1 0.02 4 0.60 4 0.07 1 0.15 1 0.02 1 0.15 1 0.02 3 0.45 3 0.05 0-1 (0-5.9) 0-2 (0-1.1) 0-2 (0-10.5) 0-2 (0-1.2) 0-1 (0-5.3) 0-1 (0-0.6) 0-1 (0-5.6) 0-1 (0-0.6) 0-2 (0-10.5) 0-2 (0-1.2) 0-1 (0-4.5) 0-1 (0-0.6) 0-1 (0-5.6) 0-1 (0-0.6) 0-1 (0-5.9) 0-1 (0-0.6) 10 4 5 1 3 1 1 3 Lumbar :Hemivertebra :Centrum, unilateral ossification :Arch, small :Centrum, notossified L:LITTER INCIDENCE F:FETAL INCIDENCE L F L F L F L F 2 0.30 2 0.04 1 0.15 1 0.02 2 0.30 2 0.04 1 0.15 1 0.02 0-1 (0-5.9) 0-1 (0-0.8) 0-1 (0-5.0) 0-1 (0-0.6) 0-1 (0-5.0) 0-1 (0-0.6) 0-1 (0-5.0) 0-1 (0-0.6) 2 1 2 1 04169 418-010: PAGE G-12 SUMMARY OF FETAL SKELETAL ALTERATIONS NZWRABBrTS #OF STUDIES RANGE/STUDY WITH ALTERATIONS N% N % ALTERATION VERTEBRAE (CONT.) Sacral :Arches open L 1 0.15 0-1 (0-5.3) 1 F 1 0.02 0-1 (0-0.5) Caudal :One ormore misaligned :Fused :11 present :12 present :13 to 14 present :15 present :Irregularlyshaped L 30 4.49 0-3 (0-16.7) F 31 0.54 0-3 (0-2.0) L 8 1.20 0-1 (0-5.6) F 10 0.18 0-3 (0-1.6) L 1 0.15 0-1 (04.3) F 1 0.02 0-1 (0-0.5) L 1 0.15 0-1 (04.3) F 2 0.04 0-2 (0-1.0) L 3 0.45 0-1 (05.6) F 3 0.05 01 (0-0.6) L 1 0.15 01 (04.3) F 1 0j02 01 (0-0.5) L 1 0.15 01 (05.0) F 1 0.02 01 (00.6) 24 8 1 1 3 1 1 VERTEBRAE/RIB InterrelatedVertebral/Rib malformations L F 3 0.45 3 0.05 03 (015.8) 03 (01.6) 1 RIBS Cervical Rib present Two ormore, fused Bases proximate One ormore, split One ormore, thickened areas Flat L F L F L F L F L F L F 2 0.30 2 0.04 6 0.90 6 0.10 10 1.50 10 0.18 8 1.20 8 0.14 27 4.04 29 0.51 2 0.30 2 0.04 01 (05.6) 01 (00.6) 02 (010.5) 02 (01.2) 0-2 (09.1) 02 (01.1) 01 (05.6) OI (00.6) 03 (016.7) 03 (02.2) 01 (05.6) 01 (0-0.6) 2 5 9 8 19 2 L:LITTER INCIDENCE F:FETAL INCIDENCE 04170 418-010: PAGE G-13 SUMMARY OF FETAL SKELETAL ALTERATIONS N Z W RABBITS #OF STUDIES RANGE/STUDY WITH ALTERATIONS N% N % ALTERATION RIBS (CONT.) Extra rib L 1 0.15 0-1 (0-4.3) 1 F 1 0.02 0-1 (0-0.5) Small L 2 0.30 0-1 (0-5.9) 2 F 2 0.04 0-1 (0-0.6) Bread L 1 0.15 0-1 (0-5.9) 1 F 1 0.02 0-1 (0-0.8) Bent L 1 0.15 0-1 (0-4.5) 1 F 1 0.02 0-1 (0-0.6) MANUBRIUM Duplicated Fused L 1 0.15 0-1 (0-5.9) 1 F 1 0.02 0-1 (0-0.7) L 3 0.45 0-2 (0-10.5) 2 F 3 0.05 0-2 (0-1.1) STERNEBRAE Two ormore,fused One ormore, asymmetric One ormore, incompletely or not ossified Duplicated L F L F L F L F - 64 9.58 78 1.37 6 0.90 6 0.10 11 1.65 11 0.19 1 0.15 1 0.02 0-5 (0-27.8) 0-7 (0-3.9) 0-2 (0-10.5) 0-2 (0-1.2) 0-2 (0-10.5) 0-2 (0-1.2) 0-1 (0-5.9) 0-1 (0-0.7) 31 5 9 1 PELVIS Pubis(es): incompletely or notossified L 4 0.60 0-1 (0-5.9) F 5 0.09 0-2 (0-1.1) 4 SCAPULAE Ala(e): irregularly shaped Ala(e):wavy L 4 0.60 0-2 (0-10.5) 3 F 4 0.07 0-2 (0-1.2) L 1 0.15 0-1 (0-5.3) 1 F 1 0.02 0-1 (0-0.6) L:LITTER INCIDENCE F: FETAL INCIDENCE 004171 418-010: PAGE G-14 SUMMARY OF FETAL SKELETAL ALTERATIONS N Z W RABBITS # OF STUDIES RANGE/STUDY WITH ALTERATIONS N% N % ALTERATION SCAPULAE (CONT.) Misaligned Bent L 5 0.75 0-2 (0-10.5) 4 F 5 0.09 0-2 <0-1.2) L 1 0.15 0-1 (0-5.0) 1 F 1 0.02 0-1 (0-0.6) FORELIMB(S) 1 Phalanx present 0 Phalanges present Humerus, Radius, Ulna, Carpals, Metacarpals, Fore digitsand Forephalanges absent L F L F L F 1 0.15 1 0.02 1 0.15 1 0.02 0-1 (0-5.6) 0-1 (0-0.7) 0-1 (0-5.6) 0-1 (0-0.7) 1 0.15 1 0.02 0-1 (0-5.3) 0-1 (0-0.6) 1 1 1 L: U T T E R INCIDENCE F: FETAL INCIDENCE 2 418-010: PAGE G-15 SUMMARY OF FETALOSSIFICATIONSITES NZW RABBITS PERIOD JANUARY 1996 - JANUARY 1998 # STUDIES 37 # LITTERS EXAMINED 667 # FETUSES EXAMINED 5682 FETUS / LITTER SKELETAL AVERAGES MEAN RANGE/STUDY HYOID 1.00 (0.98-1.00) VERTEBRAE CERVICAL THORACIC LUMBAR SACRAL CAUDAL 7.00 12.58 6.41 3.00 16.96 (12.44-12.72) (6.27-6.57) (16.75-17.13) RIBS (Pairs) 12.51 (12.36-12.67) STERNUM MANUBRIUM STERNAL CENTERS XIPHOID 1.00 3.92 (3.83-3.99) 0.98 (0.92-1.00) FOREPAWS (Calculated as average per limb) CARPALS METACARPALS DIGITS PHALANGES 0.00 4.99 5.00 13.91 (4.96-5.00) (13.80-13.99) HINDPAWS (Calculated as average per limb) TARSALS METATARSALS DIGITS PHALANGES 2.00 4.00 4.00 12.00 (1.98-2.00) -- -- (11.97-12.00) 004173 APPENDIX H STATEMENT OF THE STUDY DIRECTOR 004174 418-010:PAGE H-1 Argus Research Laboratories, Inc. 905 Sheehy Drive, Building A Horsham, P A 19044 Telephone: (215) 443-8710 Telefax: (215)443-8587 PROTOCOL 418-010: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF N-EtFOSE IN RABBITS SPONSOR'S STUDY NUMBER: 6316-8 STATEMENT OF THE STUDY DIRECTOR This final report accurately reflects the raw data obtained during the performance of the study. No significant deviations from the U.S. Food and Drug Adm inistration (FDA) Good Laboratory Practice Regulations; Final Rule3, the Japanese Ministry of Health and W elfare (MHW) Good Laboratory Practice Standard for Safety Studies on Drugsband the European Economic Comm unity (EEC) Council decision on 28 July 1989 on the acceptance by the European Economic Community of an OECD decision/recommendation on compliance with principles o f good laboratory practicec occurred that affected the quality or integrity of the study. 'id * ----// Raymond G. York^E^ .D ,, DABT Associate Director of Research and Study Director 50 Date a. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58. b. Japanese Ministry of Health and Welfare (1988). Good Laboratory Practice Standard for Safety Studies on Drugs, MHW O rdinance Number 21, March 26, 1997. c. European Economic Community (1989). Council decision on 28 July 1989 on the acceptance by the European Economic Community o f an OECD decision/recommendation on compliance with principles o f good laboratory practice. Official Journal of the European Communities: Legislation. 32(No. L 315; 28 October): 1-17. 004175 APPENDIX I QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT 4176 O P rimedica 418-010:PAGE 1-1 Argus Research Laboratories, Inc. 905 Sheehy Drive, Building A Horsham, PA 19044 Telephone: (215) 443-8710 Telefax: (215) 443-8587 QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT Study Director: Raymond G. York, Ph.D., DABT Executive Director o f Research: Mildred S. Christian, Ph.D., Fellow, ATS Protocol 418-010: Oral (Stomach Tube) Developmental Toxicity Study of N-EtFOSE in Rabbits Sponsor's Study Number: 6316.8 The draft protocol for this study was audited for adherence to U.S. Food and Drug Administration (FDA) Good Laboratory Practice Regulations, Japanese Ministry of Health and Welfare (MHW); Good Laboratory Practice Standard for Safety Studies on Drugs, and 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 on 10 AUG 98. Critical phases of this study were inspected four times; study information and raw data were audited twice (see tables 1 and 2 for dates and phases/data). The draft final report and the raw data for this study were compared and audited for accuracy, for adherence to protocol requirements, and for adherence to U.S. Food and Drug Administration (FDA) Good Laboratory Practice Regulations, Japanese Ministry of Health and Welfare (MHW); Good Laboratory Practice Standard for Safety Studies on Drugs, and 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 between 14 DEC 98 and 23 DEC 98, for revisions requested by the Sponsor 07 JAN 99, and for finalization on 11 JAN 99. 004177 418-010:PAGE I-2 This study was conducted according to U.S. Food and Drug Administration (FDA) Good Laboratory Practice Regulations, Japanese Ministry of Health and Welfare (MHW); Good Laboratory Practice Standard for Safety Studies on Drugs, and 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. Barbara J. P&jfterson, B.A. Director of Operations and Compliance Date Heather L. Rabuttino, M.S. Quality Assurance Supervisor and Principal Auditor ___ Date 004178 TABLE 1 CRITICAL PHASES INSPECTED 418-010:PAGE I-3 Test Article Preparation Date of inspection: 31 AUG 98 Date results reported to the Study Director and Management: 31 AUG 98 Test Article Administration - Gavaae Date o f inspection: 01 SEP 98 Date results reported to the Study Director and Management: 02 SEP 98 Blood Collection Date o f inspection: 17 SEP 98 Date results reported to the Study Director and Management: 18 SEP 98 Caesarean-Sectioning Date o f inspection: 21 SEP 98 Date results reported to the Study Director and Management: 24 SEP 98 004179 TABLE 2 418-010:PAGE I-4 RAW DATA AUDIT(S) The following study information and raw data were audited on 11 OCT 98, 13 OCT 98 to 17 OCT 98: Protocol. List of personnel and computer operator codes. Error codes and codes for clinical sign observations. Animal receipt, randomization, and acclimation. Veterinary examination. In-life transaction record. Feed consumption. Caesarean-sectioning. Maternal gross observations. Fetal gross observations. Fetal fixative assignment. Fetal visceral examination. Fetal skeletal examination. Tissue packing lists. General comments. Study maintenance records. Temperature and relative humidity reports. Feed and water analyses. Edit requests. Dosage volumes. Data review page. Blood collection data and packing lists. Liver weights. Deviations. The results of this audit were reported to the Study Director and Management on 19 OCT 98. The following study information and raw data were audited on 27 OCT 98: Vehicle receipt, preparation and use. Test article receipt, preparation and use. Test article packing lists. The results of this audit were reported to the Study Director and Management on 29 OCT 98. 004180
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CUNY - The Graduate CenterColumbia University Mailman School of Public Health - Sociomedical Sciences