Document 8RQaD7281Mjp0R58x1YmrqXrB

/\R-I26-0%5 Summary PFOS Rabbit Teratology v Study Numbers: 3M T-6295.10, Argus 418-012 Compound & Lot: PFOS (Perfluorooctanesulfonate) - Lot 217, 98.4% pure (SMD Analytical Request c^? 53030) Analytical Documentation filed along with final report. Note - same lot as used in two-year rat od PFOS carcinogenicity study (T-6295, Covance 6329-183). \ ,v Studv Title: Oral (Stomach Tube) Developmental Toxicity Study of PFOS in Rabbits ^ '_ Report Date: 11 January 1999 "C - Study Monitor Summary: (written by Marvin T. Case) Pregnant rabbit females, 22 per group, were given t daily oral (intubation) of PFOS at dose levels of 0, 0.1, 1.0, 2.5, and 3.75 mg/kg/day on days 7 through 20 of gestation. The rabbit fetuses which had been exposed in utero during organogensis were collected at day 29 of gestation. All of the fetuses were examined for soft tissue (visceral) changes using a dissection microscope and then all fetuses were examined for skeletal changes. A dose related body weight effect occurred in the 1.0, 2.5, and 3.75 mg/kg dose groups. The difference in mean body weights was statistically significant at the 3.75 mg/kg dose. A significant reduction in food consumption was also present at the 2.5 and 3.75 mg/kg doses. No compound related deaths occurred at Aanbyordtoiosensleovceclu.rred in one 2.5 mg/kg doe, and in ten 3.75 mg/kg does. The abortions at the high dose were cTohnesirdeedruecdedtofoboedcocmonpsouumnpdtiroenlaatendd. aMdveearnsepbuopdwyewigehigtshtweefrfeecdtetchraetasoecdcuirnrethdea2t.t5heantdwo3.h75ighmegst/kdgogseroluepvse.ls were indicative of dam toxicity. The increased number of abortions and reduced pup weights were pInrcorbeaabsleydsnecuomnbdearryoftodetlhaeyeddamostsoifxiiccaittyio.n sites were found in the 2.5 and 3.75 mg/kg fetuses which is another reflection of maternal toxicity at these dose levels. No compound-related soft tissue or skeletal malformations were found at any dose level. Thus, the compound was not found to be teratogenic in the rabbit. The maternal toxic NOEL was 0.1 mg/kg. The fetal toxic NOEL was 1.0 mg/kg. TNeOraTtEog:enDicosNeOpEreLpainratthioenrsaabmbipt lwesasw>er3e.7c5ollmecgt/ekdg.twice during the study and these samples were sent to 3M Evirornmental Analytical laboratory in Bldg 2. Likewise, samples were collected from extra females assigned as toxicokinetic satellite animals (3/group except low and high dose 5/group). These animals were killed on gestation day 21 (day after last dose) and the following samples were collected: serum and liver from pregnant dams, fetuses and placentas (pooled by litter) from uterus. These samples were frozen and sent to 3M Evirornmental Analytical laboratory in Bldg 2. At time of this summary, March 1999, analysis of these samples had not been done; therefore, these analytical results were not included in the final report nor in this summary. A ,O RECEIVED OPPT HCSC 2000DEC~6 PH 2: 29 .0 Hi Wy 12 309 00 GGAlDJJd < p" 'j 'a^ 000650 & EP A -O T8 000811786V oaiiTstv FINAL REPORT PROTOCOL 418-012 ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS SPONSOR'S STUDY NUMBER: 6295.10 FINAL REPORT DATE: 11 JANUARY 1999 000651 PROTOCOL 418-012 ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS SPONSOR'S STUDY NUMBER: 6295.10 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 i 000652 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 SUBJECT A.7. Regulatory Compliance A.8. Ownership of the Study A.9. Study Monitor A.10. Alternate Study Monitor A.11 Study Director A.12. Technical Performance A.13. Report Preparation A.14. Report Review A. 15. Date Protocol Signed A.16. Dates of Technical Performance A.17. Records Maintained B. Test Article Information B.1. Description B.2. Lot Number B.3. Date Received and Storage Conditions B.4. Special Handling Instructions B.5. Analysis of Activity C. Vehicle Information C.1. Description C.2. Lot Number C.3. Date Received and Storage Conditions C.4. Special Handling Instructions 000653 PAGE 11-1 II-2 II-2 II-2 II-2 II-2 II-2 II-2 II-2 II-3 II-3 II-3 II-3 II-3 II-3 II-3 II-3 II-4 II-4 II-4 II-4 II-4 SUBJECT C.5. Analysis of Purity D. Test Article Preparation D.1. Sample Information 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 000654 PAGE II-4 II-4 II-5 II-5 II-5 II-5 II-5 II-5 II-5 II-6 II-6 II-6 II-6 II-7 II-7 II-7 II-7 II-7 II-7 II-7 II-8 II-8 SUBJECT F.9. Water Analysis G. Methods G.1. Dosage Administration G.2. Rationale for Dosage Selection G.3. Route of Administration G.4. Rationale for Route of Administration G.5. Frequency of Administration G.6. Length of Study G.7. Method of Study Performance G.8. Gross Necropsy G.9 Statistical Analyses III. RESULTS A. Mortality, Abortions, Clinical and Necropsy Observations A.1. Abortions A.2. Clinical Observations A.3. Necropsy Observations B. Maternal Body Weights and Body Weight Changes C. Maternal Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values D. Caesarean-Sectioning and Litter Observations E. Fetal Alterations E.1. Summary of Fetal Alterations E.2. Fetal Gross External Alterations IV 000655 PAGE II-8 II-9 II-9 II-9 II-9 II-9 II-9 II-9 11-10 11-10 11-12 111-1 111-1 MI-1 III-3 III-3 MI-3 MI-4 MI-4 MI-5 MI-5 MI-6 SUBJECT E.3. Fetal Soft Tissue Alterations E. 4. Fetal Skeletal Alterations F. Satellite Rabbits REFERENCES APPENDIX A - REPORT FIGURE Figure 1. Maternal Body Weights APPENDIX B - REPORT TABLES Table 1. Clinical Observations and Necropsy Observations Summary Table 2. Uterine Contents and Litter Data for Individual Rabbits That Aborted Table 3. Maternal Body Weights - Summary Table 4. Maternal Body Weight Changes - Summary Table 5. Maternal Absolute Feed Consumption Values (g/day) - Summary Table 6. Maternal Relative Feed Consumption Values (g/kg/day) - Summary Table 7. Caesarean-Sectioning Observations - Summary Table 8. Litter Observations (Caesarean-Delivered Fetuses) Summary Table 9. Fetal Alterations - Summary Table 10. Fetal Gross External Alterations - Summary Table 11. Fetal Soft Tissue Alterations - Summary Table 12. Fetal Skeletal Alterations - Summary PAGE 111-6 111-7 111-10 111-12 A-1 B-1 B-2 B-4 B-6 B-7 B-8 B-9 B-10 B-11 B-12 B-13 B-14 V 000656 SUBJECT PAGE Table 13. Fetal Ossification Sites - Caesarean-Delivered Live Fetuses (Day 29 of Gestation) - Summary B-19 Table 14. Clinical Observations - Individual Data B-20 Table 15. Necropsy Observations - Individual Data B-26 Table 16. Maternal Body Weights - Individual Data B-33 Table 17. Maternal Feed Consumption Values Individual Data B-48 Table 18. Caesarean-Sectioning Observations - Individual Data B-63 Table 19. Litter Observations (Caesarean-Delivered Fetuses) Individual Data B-69 Table 20. Fetal Sex, Vital Status and Body Weight Individual Data B-75 Table 21. Fetal Alterations - Individual Data B-87 APPENDXC - PROTOCOL AND AMENDMENT C-1 to C-32 APPENDIX D - PILOT REPORT D-1 to D-94 APPENDIX E - HISTORICAL CONTROL DATA E-1 to E-14 APPENDIX F - STATEMENT OF THE STUDY DIRECTOR F-1 APPENDIX G - QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT G-1 to G-4 000657 VI 418-012:PAGE 1-1 TITLE: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS ARGUS RESEARCH LABORATORIES, INC. PROTOCOL NUMBER: 418-012 SPONSOR'S STUDY NUMBER: 6295.10 I. SUMMARY AND CONCLUSION A. Methods3 One hundred ten New Zealand White [Hra(NZW)SPF] rabbits were assigned to each of five dosage groups (Groups I through V) for the main portion of the study. 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, PFOS, or vehicle, 0.5% Tween 80 in Reverse Osmosis Membrane Processed Deionized Water (R.O. Deionized Water), was administered orally (via stomach tube) once daily to female 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 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 each daily intubation during the dosage period, and once daily during the postdosage period. Body weights were recorded on DGs 0 and 6 through 29. Feed consumption values were recorded daily throughout the study. All surviving rabbits were sacrificed by intravenous administration of Beuthanasia-D Special euthanasia solution on DG 29 and a gross necropsy of the thoracic, abdominal and pelvic viscera was performed. The number of corpora lutea in each ovary was recorded. The uterus of each rabbit was a. Detailed descriptions of all procedures used in the conduct of this study are provided in the appropriate sections of this report and in APPENDIX C (PROTOCOL AND AMENDMENT). 000858 418-012:PAGE I-2 examined for pregnancy, number and distribution of implantations, live and dead fetuses and early and late resorptions. The fetuses were weighed, examined for gross external alterations and sex. Visceral alterations and cavitated organs were evaluated by dissection. The brains of approximately one half of the fetuses in each litter were free-hand cross-sectioned and examined in situ. All fetuses were eviscerated, stained with alizarin red S and evaluated for skeletal alterations. Rabbits in the satellite study were sacrificed on DG 21. Blood samples were collected and centrifuged. The liver was excised, weighed and sectioned. Fetuses were examined grossly to the extent possible as described for rabbits assigned to the main study. Fetuses and placentae were pooled per litter. After completion of sample collection, serum, liver section, fetal and placental samples were shipped to the Sponsor for analysis. B. Results Administration of the 2.5 and 3.75 mg/kg/day dosages of the test article resulted in ten abortions (one in the 2.5 mg/kg/day dosage group and nine in the 3.75 mg/kg/day dosage group). These abortions occurred after the completion of the dosing period (on DGs 22, 24, 25 or 28). All other does survived to scheduled sacrifice. Increased numbers of does in the 3.75 mg/kg/day dosage group had observations of scant or no feces. Scant feces also occurred in one and three rabbits in the 1.0 and 2.5 mg/kg/day dosage groups, respectively. The 1.0 mg/kg/day dosage group rabbit also had soft or liquid feces on one day. One doe in the 3.75 mg/kg/day dosage group had red substance in the cage pan associated with impending abortion. No other clinical or necropsy observations related to the test article occurred. Dosage-dependent, significant body weight reductions or body weight losses occurred in the 1.0, 2.5 and 3.75 mg/kg/day dosage groups for the entire dosage period (calculated as DGs 7 to 21). Dosage-dependent reductions in body weight gains occurred in the 2.5 and 3.75 mg/kg/day dosage groups for the entire gestation period (DGs 0 to 29) and for the gestation period after the initiation of dosing (DGs 7 to 29). Average body weights were significantly reduced on DGs 17 through 24 in the 3.75 mg/kg/day dosage group. Absolute (g/day) and relative (g/kg/day) feed consumption values were reduced in the 2.5 and 3.75 mg/kg/day dosage groups for the entire dosage period (DGs 7 to 21), and the entire period after the initiation of dosage (DGs 7 to 29). Fetal body weights (total, male and female) were significantly reduced in the 2.5 and 3.75 mg/kg/day dosage groups. Delays in fetal ossification associated with 000659 418-012:PAGE I-3 the significantly reduced fetal body weights in the 2.5 and 3.75 mg/kg/day dosage groups were evident as significant reductions in the litter averages for ossified sternal centers in the 2.5 and 3.75 mg/kg/day dosage groups and significant reductions in the litter averages for ossified hyoid and metacarpals and significant reductions in the litter and fetal incidences of incompletely ossified pubes in the 3.75 mg/kg/day dosage group. C. Conclusion Based on these data, the maternal no-observable -effect-level (NOEL) for PFOS is 0.1 mg/kg/day. The 1.0 mg/kg/day and higher dosages reduced maternal body weight gain. Dosages of 2.5 and 3.75 mg/kg/day caused abortions and reduced feed consumption. The developmental NOEL is 1.0 mg/kg/day. Dosages of 2.5 and 3.75 mg/kg/day caused reductions in fetal body weights and delays in ossification. Based on these data, PFOS should not be identified as a selective developmental toxicant; the compound was not found to be teratogenic in the rabbit. ___ L//TTPtv/ Mildred S. Christian, Ph.D., Fellow, ATS Date Executive Director of Research Alan M. Hoberman, Ph.D., DABT Director of Research Date Associate Director o Study Director U '^f L : 22 Date 000660 418-012: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: 418-012 A.4. Sponsor's Study Number: 6295.10 A.5. Purpose of the Study: The purpose of this study was designed to detect adverse effects of PFOS 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 Guideline(1) were used as the basis for study design. A.7. Regulatory Compliance: The study was conducted in compliance with the Good Laboratory Practice (GLP) regulations of the U.S. Food and Drug Administration (FDA)(2), the Japanese Ministry of Health and Welfare (MHW)(3) and the European Economic Community (EEC)(4). There were no significant deviations from the GLP regulations that affected the quality or integrity of the study. Quality Assurance 000661 418-012P A G E II-2 Unit findings derived from the 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) Kristen landola Sherer, B.S. (Research Associate/Fetal Evaluation) Matthew J. Vaneman, B.S. (Laboratory Technician) A.13. Report Preparation: Raymond G. York, Ph.D., DABT Michelle R. Rzaca, B.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 000662 418-012:PAGE II-3 A.16. Dates of Technical Performance: 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) 21 AUG 98 23 AUG 98 - 09 SEP 98 06 SEP 9 8 - 1 0 SEP 98 14 SEP 9 8 - 1 8 SEP 98 A. 17. Records Maintained: The original report, raw data and reserve samples of the test article and vehicle components are retained in the archives of Argus Research Laboratories, Inc. Any preserved tissues are retained in the archives of the Testing Facility for one year after the mailing of the draft final report, after which time the Sponsor will decide their final disposition. All unused test article suspensions were discarded at the Testing Facility. Unused bulk test article will remain at the Testing Facility until its disposition is decided by the Sponsor. B. Test Article Information: B.1. Description: PFOS - an off-white powder B.2. Lot Number: 217 (Expiration date: May 2000) B.3. Date Received and Storage Conditions: The test article was received on 20 May 1998, and stored at room temperature. Prepared formulations were stored refrigerated. B.4. Special Handling Instructions: Standard safety precautions (use of protective clothing, gloves, dust-mist respirator, safety goggles or safety glasses and a face-shield) were taken when handling the bulk test article and prepared suspensions. B.5. Analysis of Purity: Information regarding the purity, identity, strength and composition of the test article is on file with the Sponsor. 000663 418-012:PAGE II-4 C. Vehicle Information: C.1. Description: 0.5% Tween 80 prepared using 2% Tween 80, a clear viscous to yellow liquid, in Reverse Osmosis Membrane Processed Deionized Water (R.O. Deionized Water). C.2. Lot Number: M03H05 C.3. Date Received and Storage Conditions: The 2% Tween 80 was received on 8 July 1998, and stored at room temperature. R.O. deionized water is available from a continuous source at the Testing Facility and is maintained at room temperature. C.4. Special Handling Instructions: Standard safety precautions (use of protective clothing, gloves, dust-mist respirator, safety goggles or safety glasses and a face-shield) were taken when handling the vehicle. C. 5. Analysis of Purity: 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 PFOS were prepared daily at concentrations of 0, 0.02, 0.2, 0.5 and 0.75 mg/mL. The test article was considered 100% pure for the purpose of dosage calculations. 000664 418-012P A G E II-5 D.1. Sample Information: Sample Type Concentration (all levels) Bulk Test Article Reserve Vehicle Reserve Components N/A N/A Tween 80 R.O. deionized water Size 2mLa 19 5 mL 5 mL Date Retained 23 AUG 98b 09 SEP 98c 25 AUG 98 25 AUG 98 25 AUG 98 Storage Conditions Frozen Room temperature Room temperature Room temperature Shipped To Sponsor Testing Facility Archives Testing Facility Archives Testing Facility Archives Date Shipped 23 AUG 98 09 SEP 98 Not available Not available Not available a. Duplicate samples were taken from each concentration. One set of samples was sent for analysis; the remaining samples were retained at the Testing Facility as backups. b. First day of preparation. c. Last day of preparation. Homogeneity and stability of prepared formulations are on file with the Sponsor. D. 2. Analytical Results: Concentration samples (2 mL) were taken on the first and last days of preparation for analyses by 3M Environmental Technology and Safety Services. The results of these analyses were not available at the time of this report. E. Test System: E.1. Species: Rabbit E.2. Strain: New Zealand White [Hra:(NZW)SPF] E.3. Supplier (Source): Covance Research Products, Inc., Denver, Pennsylvania E.4. Sex: Timed-pregnant female 000665 418-012:PAGE II-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*5'7'; and 4) the test article is biologically 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 133 21 MAR 98 5 months 2.77-4.20 2.84-4.21 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: Cage tags were marked with the study number, permanent rabbit number, sex, test article identification and dosage level. 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. 000666 418-012:PAGE II-7 F. Husbandry: F.1. Research Facility Registration: USDA Registration No. 23-R-099 under the Animal Welfare Act, 7 U.S.C. 2131 et seq. F.2. Study Rooms: The study rooms were maintained under conditions of positive airflow relative to a hallway and independently supplied with a minimum often 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%. F.3. Housing: Rabbits were individually housed. All cage sizes and housing conditions are in compliance with the Guide for the Care and Use of Laboratory Animals{8). F.4. Lighting: An automatically-controlled fluorescent light cycle was maintained at 12-hours light: 12-hours dark, with each dark period beginning at 1900 hours EST. F.5. Sanitization: Cage pan liners were changed approximately three times each week. Cages were changed approximately every other week. F.6. Feed: 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. 000867 418-012:PAGE II-8 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 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 individual water bottles and/or from an automatic watering system (individual sipper tubes). Chlorine was added to the processed water as a bacteriostat. F.9. Water Analysis: The processed water is analyzed twice annually for possible chemical contamination (Lancaster Laboratories, Lancaster, Pennsylvania) and monthly for possible bacterial contamination (Analytical Laboratories, Inc., Chalfont, Pennsylvania). Copies of the results of the water analyses are available in the raw data. Neither the 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. 000668 418-012:PAGE II-9 G. Methods: G.1. Dosage Administration: Dosage Group I II III IV V Number of Rabbits 22+3 a 22+53 22+33 22+3a 22+53' Dosage (mg/kg/day) 0 (Vehicle) 0.1 1.0 2.5 3.75 Concentration (mg/mL) 0 0.02 0.2 0.5 0.75 Dosage Volume (mL/kg) 5 5 5 5 5 Assigned Rabbit Numbers Main Satellite3 8443-8464 8553-8555 8465-8486 8556-8560 8487-8508 8561-8563 8509-8530 8564-8566 8531-8552 8567-8571 The test article was considered 100% pure for the purpose of dosage calculations, a. Rabbits assigned to the toxicokinetic evaluation. G.2. Rationale for Dosage Selection: Dosages were selected on the basis of a dosage-range study (Argus Research Laboratories, Inc., Protocol 418-012P). 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 comparison 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 were administered orally (via stomach tube) once daily to naturally-bred rabbits on DGs 7 through 20. 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 of 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 0C0SS9 418-012: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 several times during acclimation and on DG 0. Additional examinations for clinical observations of effects of the test article, abortions, premature deliveries and deaths were made at least once during the predosage period, once before each daily intubation and approximately 60 minutes after intubation during the dosage period. These observations were also made once daily during the postdosage period (DGs 21 through 29). Body weights were recorded on DGs 0 and 6 through 29. Feed consumption values were recorded daily throughout the study. G.8. Gross Necropsy: G.8.a. Satellite Rabbits Assigned to Toxicokinetic Sample Collection: On day 21 of presumed gestation (the day following the last dosage), toxicokinetic samples were collected from the rabbits assigned to the toxicokinetic evaluation. Following anesthesia of 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 furthest extent. Fetuses and placentae were pooled per litter and retained frozen (-70C) until shipment to the Sponsor for analysis. After completion of sample collection, serum, liver sections, fetal and placental samples were shipped (frozen on dry ice) to 3M Environmental Technology and Safety Services, St. Paul, Minnesota. 000670 418-012: PAGE 11-11 G.8.b. Scheduled Sacrifice: All surviving rabbits were sacrificed by intravenous administration of Beuthanasia-D Special euthanasia solution on DG 29. The thoracic, abdominal and pelvic viscera of each rabbit were examined for gross lesions. 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, including the brain, were evaluated by dissection(10); and the brain was free-hand crosssectioned (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 eviscerated, stained with alizarin red S(11) and evaluated for skeletal alterations. All skeletal preparations were stored in 80% glycerin with thymol crystals added to retard fungal growth. Late resorptions were examined to the extent possible. Representative photographs of fetal alterations are available in the raw data. Rabbits that aborted were examined on the day the observation was made. Pregnancy status and uterine contents were recorded. Aborted fetuses were examined to the extent possible, using the same methods described for fetuses. Uteri of apparently nonpregnant does were stained with 10% ammonium sulfide to confirm the absence of implantation sites<9). 000671 418-012:PAGE 11-12 G.9. Statistical Analyses: The following schematic represents the statistical analyses of the data: Type of Tesf I. Parametric13 Nonparametric0 A. Bartlett's Testd A. Kruskal-Wallis Test (<75% ties) Significant at p<0.05 Nonparametric Not Significant Analysis of Variance Significant at p<0.05 Dunn's Test Not Significant Significant at p<0.05 Not Significant B. Fisher's Exact Test (>75% ties) Dunnett's Test III. Test for Proportion Data Variance Test for Homogeneity of the Binomial Distribution a. Statistically significant probabilities are reported as either at 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. 000672 418-012:PAGE 11-13 Clinical observation and other proportion data were analyzed using the Variance Test for Homogeneity of the Binomial Distribution02'. 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 of 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 of the individual groups. If the Analysis of Variance was not appropriate [i.e., Bartlett's Test was significant (p<0.05)], the Kruskal-Wallis Test06' was used, when less than or equal to 75% ties were present; when more than 75% ties were present, Fisher's Exact Test07' was used. In cases in which the Kruskal-Wallis Test was statistically significant (p<0.05), Dunn's Method of Multiple Comparisons08' 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'. Group I rabbit 8481 had a litter consisting often dead fetuses. Because such occurrences can abnormally skew the distribution of the data, statistical analyses were made with and without the values for this rabbit and litter. Data for this litter were excluded from summarization and statistical analyses; values are presented on the individual tables. 000673 418-012:PAGE 111-1 III. RESULTS A. Mortality. Abortions. Clinical and Necropsy Observations (Summary Table 1: Individual Data - Tables 3.14 and 15) A.1 Abortions A total often rabbits aborted; one in the 2.5 mg/kg/day dosage group and nine** in the 3.75 mg/kg/day dosage group. These abortions occurred after the completion of the dosing period [on days 22, 24, 25 or 28 of gestation (DGs 22, 24, 25 or 28)] and were considered related to the test article because they occurred at dosage-dependent incidences in the two highest dosage groups. All other rabbits survived to scheduled sacrifice. 2.5 mq/kq/dav Doe 8517 aborted eight late resorptions on DG 25 and was sacrificed. There were no adverse clinical observations before aborting. This doe lost body weight and feed consumption was severely reduced after DG 13. Necropsy revealed eight implantation sites and all tissues appeared normal. Autolysis precluded further evaluation of the eight late resorptions. 3.75 mq/kq/day Doe 8534 aborted one dead fetus on DG 22 and was sacrificed. There were no adverse clinical observations before aborting. This doe generally lost weight and had severely reduced feed consumption values throughout the study. Necropsy revealed seven live fetuses in the uterus and all tissues appeared normal. All fetuses appeared normal for their developmental ages at gross external and soft tissue examination. Fetuses 1,2, 3, 4, 5, 6, 7 and 8 had not ossified pubes at skeletal examination. Doe 8537 aborted five late resorptions on DG 25 and was sacrificed. The only adverse clinical observation before abortion was absent feces (DG 24). This doe generally lost weight and had severely reduced feed consumption values throughout the study. Necropsy revealed five implantation sites and all tissues appeared normal. Autolysis precluded further evaluation of the five late resorptions. Doe 8538 aborted eight late resorptions on DG 24 and was sacrificed. There were no adverse clinical observations before aborting. This doe generally lost weight and had severely reduced feed consumption values throughout the study. Necropsy revealed nine implantation sites and all tissues appeared normal. One conceptus was presumed cannibalized and autolysis precluded further evaluation of the eight late resorptions. Significantly different from the vehicle control group value (p<0.01). 000674 418-012:PAGE III-2 Doe 8539 aborted seven live fetuses on DG 24 and was sacrificed. The only adverse clinical observation before abortion was scant feces (DGs 22 and 23). This doe generally lost weight and had severely reduced feed consumption values throughout the study. Necropsy revealed seven implantation sites and all tissues appeared normal. All fetuses appeared normal for their developmental ages at gross external and soft tissue examination. Fetuses 1,2,3, 4, 5, 6 and 7 had not ossified pubes and fetuses 2 and 3 had not ossified sternal centra at skeletal examination. Doe 8540 aborted four dead fetuses on DG 25 and was sacrificed. There were no adverse clinical observations before aborting. This doe lost weight and feed consumption values were severely reduced after DG 15. Necropsy revealed three live fetuses, one dead fetuses and six late resorptions in the uterus. All tissues appeared normal at necropsy. All fetuses appeared normal for their developmental ages at gross external and soft tissue examination. Autolysis precluded further evaluation of the six late resorptions. Fetuses 1, 2, 3, 5, 7, 8, 9, and 10 had not ossified pubes and fetus 2 had incompletely ossified nasal bones and short maxillae at skeletal examination. Doe 8542 aborted six dead fetuses on DG 28 and was sacrificed. The only adverse clinical observation before abortion was scant feces (DGs 21 to 23 and 27). This doe lost weight and had severely reduced feed consumption after DG 18. Necropsy revealed eight implantation sites and all tissues appeared normal. Two conceptuses were presumed cannibalized and all six aborted fetuses were partially cannibalized. All fetuses appeared normal at soft tissue examination. Doe 8544 aborted nine dead fetuses on DG 25 and was sacrificed. The only adverse clinical observation before abortion was scant feces (DGs 19 to 20 and 22 to 24). After DG 12, this doe lost weight and had severely reduced feed consumption until sacrifice. Necropsy revealed nine implantation sites and all tissues appeared normal. All fetuses appeared normal at gross external and soft tissue examination. Fetuses 1, 2, 3, 4, 5, 6, 7, 8 and 9 had not ossified pubes and fetus 3 had not ossified sternal centra at skeletal examination. Doe 8547 aborted eight late resorptions on DG 22 and was sacrificed. The only adverse clinical observations before abortion were scant feces (DG 18) and a red substance in the cage pan (DG 21). Body weights and feed consumption values were reduced DGs 11 to 21. Necropsy revealed eight implantation sites and all tissues appeared normal. Autolysis precluded evaluation of the eight late resorptions. Doe 8548 aborted one dead fetus on DG 25 and was sacrificed. The only adverse clinical observation before abortion was scant feces (DGs 21 and 23 to 24). This doe lost weight after DG 15 and feed consumption was severely reduced after DG 17. Necropsy revealed seven live fetuses, one dead fetus and 000675 418-012:PAGE III-3 two late resorptions in the uterus. All tissues appeared normal at necropsy. All fetuses appeared normal for their developmental ages at gross external and soft tissue examination. The late resorptions appeared normal at gross external examination; autolysis precluded further evaluation. Fetuses 1, 2, 3, 4, 5, 6, 7, 8 and 11 had not ossified pubes at skeletal examination. A.2. Clinical Observations Increased numbers of does in the 3.75 mg/kg/day dosage group had observations of scant or no feces; the incidence of scant feces was significant (p<0.01). Scant feces also occurred in one and three rabbits in the 1.0 and 2.5 mg/kg/day dosage groups respectively. The 1.0 mg/kg/day dosage group rabbit also had soft or liquid feces on one day. One doe in the 3.75 mg/kg/day dosage group had red substance in the cage pan associated with impending abortion. All other adverse clinical observations, and any statistically significant (p<0.01) increases in the incidences of these observations, were considered unrelated to the test article because the incidences were not dosage-dependent. These observations included localized alopecia on the limbs, back and/or underside and ungroomed coat. A. 3. Necropsy Observations With the exception of persistent adverse clinical observations, no additional gross lesions were identified at necropsy. B. Maternal Body Weights and Body Weight Changes (Figure 1: Summaries - Tables 3 and 4: Individual Data - Table 16) Maternal body weight gains were reduced or body weight losses occurred in the 1.0, 2.5 and 3.75 mg/kg/day dosage groups at most tabulated intervals during the dosage period; these reductions or body weight losses were statistically significant (p<0.05 orp<0.01) in the 3.75 mg/kg/day dosage group on DGs 10 to 13, 13 to 16 and 16 to 19. During the first three days of the postdosage period (DGs 21 to 24), body weight gains continued to be reduced in the 1.0 and 2.5 mg/kg/day dosage groups; significant (p<0.05) body weight loss occurred in the 3.75 mg/kg/day dosage group during this period. As a result of these reductions, dosage-dependent, significant body weight reductions or body weight losses (p<0.05 or p<0.01) occurred in the 1.0, 2.5 and 3.75 mg/kg/day dosage groups for the entire dosage period (calculated as DGs 7 to 21). Dosage-dependent reductions in body weight gains occurred in the 2.5 and 3.75 mg/kg/day dosage groups for the entire gestation period (DGs 0 to 29) and for the gestation period after the initiation of dosing (DGs 7 to 29; significant at 00GS76 418-012:PAGE III-4 p<0.01 in the 2.5 mg/kg/day dosage group). Average body weights were significantly reduced (p<0.05 orp<0.01) on DGs 17 through 24 in the 3.75 mg/kg/day dosage group, as compared with the vehicle control group values. Body weights and body weight gains were unaffected by the 0.1 mg/kg/day dosage of PFOS. The significant reduction (p<0.05) in body weight gain in the 0.1 mg/kg/day dosage group on DGs 10 to 13 was not considered treatmentrelated because it was transient and not dosage-dependent. C. Maternal Absolute (q/dav) and Relative (q/ka/dav) Feed Consumption Values (Summaries - Tables 5 and 6: Individual Data - Table 17) Absolute (g/day) and relative (g/kg/day) feed consumption values were reduced during the dosage period (after DG 10) in the 2.5 and 3.75 mg/kg/day dosage groups; these reductions were statistically significant (p<0.05 or p<0.01) in one or both of these groups on DGs 13 to 16 (relative only), 16 to 19 and 19 to 21. Absolute and relative feed consumption values continued to be reduced in these two groups during the postdosage period; the reductions were generally statistically significant (p<0.05 or p<0.01) on DGs 21 to 24. Reflecting these effects of the test article, absolute and relative feed consumption values were reduced or significantly reduced (p<0.05 or p<0.01) in the 2.5 and 3.75 mg/kg/day dosage groups for the entire dosage period (DGs 7 to 21), and the entire period after the initiation of dosage (DGs 7 to 29). Absolute and relative feed consumption values were unaffected by the 1.0 mg/kg/day dosage of PFOS. D. Caesarean-Sectioning and Litter Observations (Summaries - Tables 7 and 8: Individual Data - Tables 18 through 201 Pregnancy occurred in 20 (90.9%), 19 (86.4%), 19 (86.4%), 17 (77.3%) and 21 (95.4%) rabbits in each dosage group. Caesarean-sectioning observations on DG 29 were based on 20, 18, 19, 16 and 12 pregnant rabbits in each of the five respective dosage groups. One and nine does aborted in the 2.5 and 3.75 mg/kg/day dosage groups, respectively. Values for one 0.1 mg/kg/day dosage group doe (8481) that had a litter consisting of ten dead fetuses were excluded from data tabulation and statistical analyses; this total litter death was considered to be a non test article related, spontaneous event. Fetal body weights (total, male and female) were significantly reduced (p<0.05 and p<0.01, respectively) in the 2.5 and 3.75 mg/kg/day dosage groups, as compared to the vehicle control group values. There were no other biologically important or statistically significant differences in the litter averages for corpora lutea, implantations, live fetuses and early or late resorptions. There were no does with all conceptuses resorbed and all placentae appeared normal. 000677 418-012:PAGE III-5 E. Fetal Alterations (Summaries - Tables 9 through 13: Individual Data Table 21) 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 175, 162, 152, 130 and 108 DG 29 Caesarean delivered live fetuses in 20, 18, 19, 16 and 12 litters in the 0 (Vehicle), 0.1, 1.0, 2.5 and 3.75 mg/kg/day dosage groups, respectively. All fetuses were examined for gross external, soft tissue and skeletal alterations and fetal ossification site averages. It was also possible to examine the ten dead fetuses from litter 8481 in the 2.5 mg/kg/day dosage group for gross external, soft tissue and skeletal alterations. The embryonic sacs of all of these fetuses contained a dark red substance. One fetus had downward flexion of the forelimbs, an observation associated with in utero compression (skeletal ossification not affected); another fetus had angulated hyoid alae, and two fetuses had only ten or six caudal vertebrae. The remaining six fetuses appeared normal. E.1. Summary of Fetal Alterations (Summary - Table 10: Individual Data Table 221 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 mg/kg/day dosage groups, respectively, 14 (70.0%), 11 (61.1%), 9 (47.3%), 4 (25.0%) and 8 (66.7%) 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 25 (14.3%), 25 (15.4%), 14 (9.2%), 5 (3.8%)** and 19 (17.6%). One or more alterations occurred in averages of 14.1%, 17.0%, 9.5%, 3.6% and 17.4% of the fetuses per litter in the five respective dosage groups. The significant reduction (p<0.05) in the total number of fetuses with identified alterations in the 2.5 mg/kg/day dosage group was not considered treatmentrelated because the expected response to a toxicant would be an increase, rather than a decrease, in the number of alterations. Delays in fetal ossification associated with the significantly reduced (p<0.05 or p<0.01) fetal body weights in the 2.5 and 3.75 mg/kg/day dosage groups were evident as significant reductions (p<0.05 or p<0.01) in the litter averages for ossified sternal centers in the 2.5 and 3.75 mg/kg/day dosage groups and significant reductions (p<0.05 or p<0.01) in the litter averages for ossified hyoid and metacarpals and significant reductions (p<0.01) in the litter and fetal incidences of incompletely ossified pubes in the 3.75 mg/kg/day dosage group. Significantly different from the vehicle control group value (p<0.01). 000678 418-012:PAGE III-6 All other fetal gross external, soft tissue and skeletal alterations (malformations and variations) were considered unrelated to the test article because: 1) the incidences were not dosage-dependent; and/or 2) the incidences were within ranges observed historically at the Testing Facility3. E.2. Fetal Gross External Alterations (Summary - Table 10: Individual Data - Table 211 E.2.a. Malformations The first digit was absent on both forelimbs for vehicle control group fetus 8448-1. Skeletal examination of this fetus revealed absent 1st medial and distal phalanges and 1st metacarpal on both forelimbs. No additional alterations occurred in this fetus. E.2.b. Variations One fetus (8473-6) in a 0.1 mg/kg/day dosage group litter and another fetus (8543-3) in a 3.75 mg/kg/day dosage group litter had downward flexed forepaws, an observation associated with in utero compression. Skeletal examination of fetus 8543-3 revealed a variation in skull ossification (hole in the parietal bone). Fetus 8473-6 had no additional alterations. E.3. Fetal Soft Tissue Alterations (Summary - Table 11: Individual Data Table 211 E.3.a. Malformations No soft tissue malformations were observed. E.3.b. Variations E.3.b.1. Eves One control dosage group fetus (8449-6) had a circumcorneal hemorrhage of the left eye, a variation generally attributable to trauma during processing. Skeletal evaluation of this fetus revealed variations in ossification of the skull and hyoid (irregular nasal-frontal suture and angulated alae). a. See APPENDIX E (HISTORICAL CONTROL DATA). 000679 418-012:PAGE III-7 E.3.b.2. Lunas The intermediate lobe of the lungs was absent in 2, 7**, 1, 0 and 1 fetuses from 2, 4, 1, 0 and 1 litters in the 0 (Vehicle), 0.1, 1.0, 2.5 ad 3.75 mg/kg/day dosage groups, respectively. Two of the 0.1 mg/kg/day dosage group fetuses (8476-8, 8483-4) also had fused 3rd and 4th sternal centra. The significant increase (p<0.01) in the fetal incidence of this observation in the 0.1 mg/kg/day dosage group was not considered related to the test article because: 1) this variation in lung development is frequent in this rabbit strain09), 2) the fetal and litter incidences are within the historical ranges of the Testing Facility, 3) it was not dosage-dependent; and 4) it was not significantly increased for the unit of measurement, the litter. E.4. Fetal Skeletal Alterations (Summaries - Tables 12 and 13: Individual Data - Table 21) E.4.a. Malformations E.4.a.1. Thoracic Vertebrae/Ribs Interrelated vertebral/rib malformations or malformations of only the ribs occurred in one, three and one fetuses in the 0 (Vehicle), 0.1 and 1.0 mg/kg/day dosage groups, respectively. These types of vertebral/rib malformations are relatively common at maternally toxic dosages in rabbits and generally considered to be secondary to maternal stress(20). Fetus 8452-1 in the vehicle control group had a left hemivertebra present as the 3rd thoracic vertebra and a split 2nd left rib. This fetus also had asymmetric 1st to 3rd sternal centra and an angulated hyoid ala. Fetus 8476-1 in the 0.1 mg/kg/day dosage group had fused centra of the 11th and 12th thoracic vertebrae and a bifid centrum of the 12th thoracic vertebra, and its littermate, fetus 8476-7, had fused 5th and 6th ribs as the only alteration. Fetus 8485-2 in the 0.1 mg/kg/day dosage group had a small left arch of the 11th thoracic vertebra, fused left centra of the 11th and 12th thoracic vertebrae and proximate bases of the 10th and 11th left ribs. Fetus 8500-3 in the 1.0 mg/kg/day dosage group had split 8th right and 7th left ribs as the only alteration. E.4.a.2. Lumbar Vertebrae Fetus 8500-8 had a left hemivertebra present as the 1st lumbar vertebra and a bifid centrum of the 2nd lumbar vertebra. Significantly different from the vehicle control group value (p<0.01). 000680 418-012:PAGE III-8 E.4.a.3. Metacarpals/Phalanaes The 1st medial and distal phalanges and 1st metacarpal on both forelimbs were absent for vehicle control group fetus 8448-1 that had missing first digits at external examination. E.4.b. Variations E.4.b.1. Skull Common small irregularities in ossification of the skull(19) [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 7, 9, 3, 1* and 10** fetuses in 6, 7, 3, 1 and 3 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 (irregular nasal-frontal suture, fused, internasal, midline suture displaced and intranasal) were the most common of these small irregularities in skull ossification, occurring in 6, 9, 3, 1 and 1 fetuses in 5, 7, 3, 1 and 1 litters in the five respective dosage groups. The significant reduction (p<0.05) in the fetal incidence of variations in skull ossification in the 2.5 mg/kg/day dosage group was considered unrelated to the test article because the expected effect of a toxicant would be an increase in delayed skull ossification, rather than a decrease. The significant increase (p<0.01) in the fetal incidence of variations in skull ossification in the 3.75 mg/kg/day dosage group was considered to reflect the significantly increased (p<0.01) fetal incidence of hole(s) in the parietal and unrelated to the test article, as discussed below. The fetal incidence of nasal midline suture displaced was significantly increased (p<0.01) in the 0.1 mg/kg/day dosage group but was considered unrelated to the test article because: 1) it was not dosage-dependent; and 2) the litter incidence was not significantly increased. The fetal incidence of a hole in the parietal was significantly increased (p<0.01) in the 3.75 mg/kg/day dosage group. This increase was considered unrelated to the test article because the observation occurred in seven fetuses from only one high dosage group litter (8543-1, -3, -4, -5, -6, -8 and -10), so the litter incidence, the more relevant parameter(1), was not significant. Two of the fetuses in this litter also had not ossified pubes; all other fetuses had no additional alterations One 0.1 mg/kg/day dosage group fetus (8471-1) had unossified premaxillae as the only alteration. Significantly different from the vehicle control group value (p<0.05). Significantly different from the vehicle control group value (p<0.01). 000681 418-012:PAGE III-9 E.4.b.2. Hvoid One or both alae of the hyoid were angulated in 10, 4, 7, 3 and 5 fetuses in 6, 3, 3, 2 and 3 litters in the 0 (Vehicle), 0.1, 1.0, 2.5 and 3.75 mg/kg/day dosage groups, respectively. One fetus (8452-1) in the vehicle control group also had vertebral/rib malformations and asymmetric 1st to 3rd sternal centra, as previously described. E.4.b.3. Vertebrae E.4.b.3.a. Cervical One 0.1 mg/kg/day dosage group fetus had unilateral ossification of the centrum of the 2nd cervical vertebrae as the only alteration. E.4.b.3.b. Thoracic One vehicle control group fetus had unilateral ossification of the centrum of the 5th thoracic vertebrae as the only alteration. E.4.b.3.c. Lumbar Bifid centrum of a lumbar vertebra occurred in one fetus in the 1.0 and 3.75 mg/kg/day dosage groups, respectively. Fetus 8500-8 in the 1.0 mg/kg/day dosage group also had a hemivertebra present as a lumbar vertebra, as previously described. The fetus in the 3.75 mg/kg/day dosage group had no additional alterations. E.4.b.3.d. Caudal A misaligned 17th caudal vertebra occurred in one vehicle control group fetus as the only alteration. E.4.b.4. Ribs Cervical ribs were present at the 7th cervical vertebra for one fetus in each of the 0 (Vehicle) and 2.5 mg/kg/day dosage groups. No additional alterations occurred in these fetuses. Thickened areas in two or three ribs occurred in one vehicle control group fetus (8456-4) and one 1.0 mg/kg/day dosage group fetus (8493-7). No other alterations occurred in these fetuses. OOOS8 2 418-012:PAGE 111-10 E.4.b.5. Sternum Fused 3rd and 4th sternal centra occurred as the only skeletal alteration in 2 and 3 fetuses from different litters in the 0 (Vehicle) and 0.1 mg/kg/day dosage groups, respectively. Fetus 8452-1 in the vehicle control group had asymmetric 1st to 3rd sternal centra. This fetus also had vertebral/rib malformations and an angulated hyoid ala, as previously described. E.4.b.6. Pelvis Four** fetuses from two** 3.75 mg/kg/day dosage group litters had incompletely ossified pubes. Two of these fetuses also had a variation in skull ossification (hole in parietal), as described previously. The significant increase (p<0.01) in the fetal and litter incidences of this observation was considered a test article related delay in ossification and to reflect the significantly reduced (p<0.01) fetal body weights in this dosage group. E. 4.b.7. Fetal Ossification Site Averages The average numbers of ossification sites per fetus were significantly reduced (p<0.05 or p<0.01) in the 3.75 mg/kg/day dosage group for hyoid, sternal centers and metacarpals. The average numbers of ossified sternal centers were also significantly reduced (p<0.01) in the 2.5 mg/kg/day dosage group, as compared with the vehicle control group value. The values were below the ranges observed historically at the Testing Facility. These delays in ossification were considered effects of the test article associated with the significantly reduced (p<0.05 or p<0.01) fetal body weights in these dosage groups. The average numbers of ossification sites in the vertebrae (cervical, thoracic, lumbar, sacral and caudal), ribs, sternum (manubrium and xiphoid), forelimbs (carpals 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 14 through 20) All rabbits in the satellite dosage groups survived to scheduled sacrifice. There were no adverse clinical observations in these does. Patterns of body weight gain and feed consumption were comparable to the rabbits in the main study at the same dosage levels. Only one rabbit in the 3.75 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. There was not a reduction in fetal body weights at the 2.5 and 3.75 mg/kg/day dosages as Significantly different from the vehicle control group value (p<0.01). 000S83 418-012: PAGE 111-11 was observed for the main study rabbits. All does appeared normal at necropsy. Average liver weights for pregnant does were 140.5 29.2, 127.1 15.2, 123.9 33.2, 115.7 5.7 and 90.7 22.2 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. 000684 418-012:PAGE 111-12 REFERENCES: 1. U.S. Food and Drug Administration (1994). 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Snedecor, G.W. and Cochran, W.G. (1967). Variance test for homogeneity of the binomial distribution. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 240-241. 13. Sokal, R.R. and Rohlf, F.J. (1969). Bartlett's test of homogeneity of variances. Biometry, W.H. Freeman and Co., San Francisco, pp. 370-371. 14. Snedecor, G.W. and Cochran, W.G. (1967). Analysis of Variance. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 258-275. 15. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1129. 16. Sokal, R.R. and Rohlf, F.J. (1969). Kruskal-Wallis Test. Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389. 17. 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. 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 White rabbits. J. Amer. Col. Toxicol. 6(4):562 (#126). 20. 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. 000688 APPENDIX A REPORT FIGURE 000687 8890ao MATERNAL BODY WEIGHTS Figure 1 0 (VEHICLE) MG/KG/DAY 0.1 MG/KG/DAY 1.0 MG/KG/DAY 2.5 MG/KG/DAY 3.75 MG/KG/DAY *p<0.05 **p<0.01 418-012: PAGE A-1 APPENDIX B REPORT TABLES 000689 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 1 (PAGE 1) : CLINICAL AND NECROPSY OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I I I I I I IV V 0 (VEHICLE) 0 .1 1.0 2.5 3.75 MAXIMUM P O SSIB L E INCIDENCE 506/ 22 506/ 22 506/ 22 502/ 22 465/ 22 ABORTED 0 0 0 lb 9**c-k SCANT FECES 0/ 0 0/ 0 2/ 1 5/ 3 24/ 7**f,h-k NO FECES 0/ 0 0/ 0 0/ 0 0/ 0 2/ 2d RED SUBSTANCE IN CAGE PAN LOCALIZED ALOPECIA: TOTAL LIMBS BACK UNDERSIDE 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 11/ 3** 8/ 2 3/ 1 0/ 0 0/ 0 14/ 5** 7/ 2 6/ 2 1/ 1 0/ 0 4/ 2 3/ 2 1/ 0/ 1 0 1/ lj 0/ 0 0/ 0 0/ 0 0/ 0 UNGROOMED COAT 0/ 0 4/ 2 3/ 1 5/ 1 0/ 0 SOFT OR LIQUID FECES 0/ 0 0/ 0 1/ 1 0/ 0 0/ 0 WITH THE EXCEPTION OF P E R SIST EN T ADVERSE C LIN IC A L OBSERVATIONS, NO ADDITIONAL GROSS L ESIO N S WERE ID E N T IF IE D AT NECROPSY STA TISTIC A L ANALYSES OF C LIN ICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RABBITS WITH OBSERVATIONS. MAXIMUM P O S S IB L E INC IDENC E = (DAYS X R A B BIT S)/N U M BE R OF R A B BITS EXAMINED PER GROUP ON DAYS 7 THROUGH 29 OF PRESUMED G ESTA T IO N . N /N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RABBITS WITH OBSERVATION. a . Dosage o cc u rre d on days 7 th ro u g h 20 o f presum ed g e s ta tio n . b. Doe 8517 a b o rte d on day 25 o f g e s t a t i o n . c . Doe 8534 a b o rte d on day 22 o f g e s ta tio n . d. Doe 8537 a b o rte d on day 25 o f g e s ta tio n . e . Doe 8538 a b o rte d on day 24 o f g e s t a t i o n . f . Doe 8539 a b o rte d on day 24 o f g e s t a t i o n . 9h -. Doe 8540 a b o rte d on day 25 o f g e s ta tio n . Doe 8542 a b o rte d on day 28 o f g e s ta tio n . i . Doe 8544 a b o rte d on day 25 o f g e s ta tio n . kj* . Doe 8547 a b o rte d on day 22 o f g e s t a t i o n . Doe 8548 a b o rte d on day 25 o f g e s ta tio n . S ig n ific a n tly d iff e re n t from th e v e h ic le c o n tro l group v a lu e (pcO.Ol) 069000 418-012: PAGE B- PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PROS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 2 (PAGE 1) : UTERINE CONTENTS AND LITTER DATA FOR INDIVIDUAL RABBITS THAT ABORTED DOSAGE GROUP RABBIT DOSAGE (MG/KG/DAY) a NUMBER I 0 (VEHICLE) - DAY OF DEATH - CORPORA LUTEA R LT -- - 0.I 1I - - -- - I1I. 0I - - - IV 2 .5 8 5 1 7 ABORTED ON DAY 2 5 639 OF GESTATION R = RIGHT L = LEFT A = ABORTED T = TOTAL a. Dosage o cc u rre d on days 7 th ro u g h 20 o f g e s ta tio n . b. C onceptuses appeared norm al fo r developm ental ages. c. Late reso rp tio n u nless otherw ise noted. IMPLANTATIONS R LT FETUSES b RESORPTIONS C RLATRL AT ----------- --------------------- 538 000000 88 418-012:PAGE B-2 000691 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 2 (PAGE 2): UTERINE CONTENTS AND LITTER DATA FOR INDIVIDUAL RABBITS THAT ABORTED DOSAGE GROUP RABBIT DOSAGE (MG/KG/DAY) a NUMBER DAY OF DEATH CORPORA LUTEA RL T IMPLANTATIONS RL T V 3.75 8 5 3 4 ABORTED ON DAY 22 54 9 53 8 OF GESTATION 8 5 3 7 ABORTED ON DAY 2 5 OF GESTATION 42 6 32 5 8 5 3 8 ABORTED ON DAY 24 OF GESTATION 5 5 10 54 9 8 5 3 9 ABORTED ON DAY 24 OF GESTATION 43 7 43 7 8 5 4 0 ABORTED ON DAY 2 5 OF GESTATION 6 8 14 6 8 14 8 5 4 2 ABORTED ON DAY 28 OF GESTATION 45 9 44 8 8 5 4 4 ABORTED ON DAY 25 OF GESTATION 45 9 45 9 8 5 4 7 ABORTED ON DAY 22 OF GESTATION 53 8 53 8 8 5 4 8 ABORTED ON DAY 2 5 OF GESTATION 5 7 12 4 7 11 R = RIGHT L = LEFT A = ABORTED T = TOTAL a. Dosage o ccu rred on days 7 th ro u g h 20 o f g e s ta tio n . b. C onceptuses appeared norm al fo r developm ental ages. c. Late reso rp tio n s u n less otherw ise noted. d. One a b o rte d c o n c ep tu s was presum ed to have b een c a n n ib a liz e d . e . Two a b o r te d c o n c e p tu s e s w ere p resu m ed to h av e b e e n c a n n ib a liz e d . FETUSES b RL AT 52 18 00 00 00 00 00 77 04 48 00 6 6e 00 99 00 00 35 19 RESORPTIONS C Rh AT 00 00 00 55 00 8 8d 00 00 24 06 00 00 00 00 00 88 02 02 418-012:PAGE B-3 000692 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 3 (PAGE 1) : MATERNAL BODY WEIGHTS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1 III 1.0 RABBITS TESTED N 22 22 22 PREGNANT N 20 19 19 INCLUDED IN ANALYSES N 20 18b 19 MATERNAL BODY WEIGHT (KG) DAY 0 MEAN+S.D . 3.34 + 0.26 3.33 + 0.27 3.36 + 0.27 DAY 7 MEAN+S. D . 3.38 + 0.29 3.43 + 0.22 3.47 + 0.23 DAY 8 MEAN+S.D . 3.42 + 0.30 3.48 + 0.23 3.50 + 0.22 DAY 9 MEAN+S. D . 3.43 + 0.30 3.50 + 0.23 3.49 + 0.22 DAY 1 0 MEAN+S.D . 3.45 + 0.27 3.52 + 0.23 3.50 + 0.24 DAY 11 MEAN+S. D . 3.50 + 0.27 3.52 + 0.25 3.53 + 0.24 DAY 12 MEAN+S.D. 3.53 + 0.29 3.54 + 0.28 3.56 + 0.24 DAY 13 MEAN+S.D . 3.54 + 0.29 3.55 + 0.25 3.60 + 0.24 DAY 14 MEAN+S.D . 3.59 + 0.30 3.60 + 0.25 3.64 + 0.26 DAY 15 MEAN+S.D . 3.62 + 0.29 3 .6 2 + 0 . 25 3.66 + 0.26 DAY 16 MEAN+S.D . 3.65 + 0.26 3.64 + 0.27 3.69 + 0.25 DAY 17 MEAN+S. D . 3.66 + 0.27 3.65 + 0.24 3.69 + 0.25 DAY 18 MEAN+S.D . 3.69 + 0.28 3.69 + 0.24 3.71 + 0.25 DAY 19 MEAN+S. D. 3.72 + 0.28 3.69 + 0.25 3.72 + 0.24 DAY 20 MEAN+S.D. 3.74 + 0.28 3.73 + 0.24 3.75 + 0.24 DAY = DAY OF GESTATION a. Dosage occurred on days 7 th ro u gh 20 of g e s ta tio n . b. Excludes valu es fo r doe 8481, which had a l i t t e r th a t c o n siste d of ten dead fe tu se s * S ig n ific a n tly d iffe re n t from th e v e h ic le c o n tro l group v alu e (p<0.05). ** S i g n i f ic a n t l y d i f f e r e n t from th e v e h ic le c o n tr o l g ro u p v a lu e (p < 0 .0 1 ). IV 2 .5 22 17 17 3.38 + 0.23 3.51 + 0.23 3.54 + 0.25 3.56 + 0.24 3.56 + 0.25 3.56 + 0.24 3.58 + 0.28 3.61 + 0.27 3.63 + 0.26 3.67 + 0.28 3.67 + 0.29 3.65 + 0.28 3.66 + 0.29 3.67 + 0.29 3.69 + 0.31 V 3 . '75 22 21 21 3.32 + 0.23 3.41 + 0.20 3.44 + 0.20 3.46 + 0.22 3.47 + 0.23 3.49 + 0.24 3.51 + 0.24 3.51 + 0.24 3.52 + 0.26 3.52 + 0.29 3.48 + 0.30 3.45 + 0.31* 3.44 + 0.32* 3.42 + 0.34** 3.41 + 0 . 36** 418-012:PAGE B-4 000693 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 3 (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 2 9 MEAN+S.D. I 0 (VEHICLE) 22 20 20 3.77 + 0.28 3.79 + 0.29 3.82 + 0.30 3.85 + 0.31 3.88 + 0.32 3.91 + 0.34 3.91 + 0.35 3.91 + 0.35 3.94 + 0.36 II 0 .1 22 19 18b 3.76 + 0.24 3.79 + 0.25 3.82 + 0.25 3.85 + 0.28 3.86 + 0.28 3.88 + 0.29 3.89 + 0.30 3.93 + 0.30 3.93 + 0.30 III 1.0 22 19 19 3.77 + 0.24 3.80 + 0.25 3.82 + 0.24 3.84 + 0.26 3.88 + 0.26 3.88 + 0.26 3.88 + 0.25 3.90 + 0.26 3.92 + 0.26 DAY = DAY OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Dosage o ccurred on days 7 through 20 of g e s ta tio n . b. Excludes valu es fo r doe 8481, which had a l i t t e r th a t c o n siste d of te n dead fe tu se s. c. Excludes values fo r ra b b its th a t abo rted . ** S i g n i f ic a n t l y d i f f e r e n t from th e v e h ic le c o n t r o l g ro u p v a lu e ( p < 0 .0 1 ). IV 2.5 22 17 17 3.71 + 0.31 3.71 + 0.33 3.72 + 0.33 3.74 + 0.35 3.81 + 0.29 [ 1 6 ]1c 3.80 + 0.29 [ 16] c 3.80 + 0.29 [ 16] c 3.82 + 0.28 [ 16 ] c 3.86 + 0.28 [ 16]c V 3.75 22 21 21 3.41 + 0.38** 3.43 + 0.37** [ 19] c 3.42 + 0.38** [ 19] c 3.45 + 0.41** [ 18] c 3.64 + 0.20 [ 13 ] C 3.65 + 0.23 [ 13 ] c 3.64 + 0.22 ( 13 ] c 3.67 + 0.25 t 12] c 3.72 + 0.26 [ 12]c 418-012:PAGE B-5 000694 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: G295.10) TABLE 4 (PAGE 1 ) : MATERNAL BODY WEIGHT CHANGES - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a RABBITS TESTED PREGNANT INCLUDED IN ANALYSES MATERNAL BODY WEIGHT CHANGE (KG) DAYS 0 - 7 DAYS 7 - 10 DAYS 10 - 13 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 N 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 . MEAN+S. D. MEAN+S.D. MEAN+S.D. i 0 (VEHICLE) 22 20 20 +0.04 + 0.13 +0.07 + 0.07 +0.09 + 0.08 +0.11 + 0.09 +0.06 + 0.09 +0.05 + 0.03 +0.09 + 0.05 +0.08 + 0.11 +0.38 + 0.10 +0.17 + 0.13 +0.SS + 0.18 +0.59 + 0.21 II III 0 .1 1 .0 22 22 19 19 18b 19 +0.10 + 0.13 +0.08 + 0.06 +0.03 + 0.07* +0.09 + 0.07 +0.05 + 0.08 +0.07 + 0.07 +0.09 + 0.06 +0.08 + 0.09 +0.33 + 0.09 +0.17 + 0.12 +0 .5 0 + 0 .1 6 +0.60 + 0.13 +0.11 + 0.08 +0.03 + 0.06 +0.10 + 0.05 +0.08 + 0.05 +0.03 + 0.06 +0.05 + 0.04 +0.07 + 0.05 +0.08 + 0.08 +0.30 + 0.08* +0.15 + 0.07 +0.45 + 0.12 +0.56 + 0.13 DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Dosage o ccu rred on days 7 through 20 o f g e s ta tio n . b. Excludes v alu es fo r doe 8481, which had a l i t t e r th a t c o n siste d of te n dead fe tu se s. c. Excludes values fo r rab b its th a t abo rted . * S ig n ific a n tly d iffe re n t from th e v e h ic le c o n tro l group v alu e (p<0.05). ** S i g n i f ic a n t l y d i f f e r e n t from th e v e h ic le c o n t r o l g ro u p v a lu e (p < 0 .0 1 ). IV V 2.5 3.75 22 22 17 21 17 21 +0.12 + 0.08 +0.05 + 0.06 +0.06 + 0.07 +0.05 + 0.09 +0.00 + 0.06 +0.04 + 0.03 +0.04 + 0.08 +0.06 + 0.14 ( 16] C +0.20 + 0.17** +0.11 + 0.15 [ 16]c +0.34 + 0.16** [ 16] c +0.46 + 0.14 [ 16] c +0.09 + 0.11 +0.06 + 0.12 +0.04 + 0.08* -0.03 + 0.11** -0.07 + 0.10** -0.01 + 0.08 -0.03 + 0.13* [ 18] c +0.08 + 0.10 [ 12 ) c -0.01 + 0.35** +0.11 + 0.20 ( 12] c +0.30 + 0.38 t 12] c +0.39 + 0.38 [ 12] c 418-012: PAGE B-6 000695 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 5 (PAGE 1) : MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) -- SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a RABBITS TESTED PREGNANT INCLUDED IN ANALYSES MATERNAL FEED CONSUMPTION (G/DAY) DAYS 7 - 10 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 - 29 N 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. MEAN+S.D. I 0 (VEHICLE) 22 20 20 142.6 + 50.4 149.7 + 35.7 162.3 + 24.5 177.5 + 11.8 173.6 + 19.9 160.9 + 32.5 124.5 + 40.5 160.2 + 20.5 138.4 + 34.8 152.4 + 21.7 II 0 .1 22 19 18b 171.3 + 19.1 142.0 + 47.8 158.1 + 35.7 175.2 + 12.8 [ 17] c 180.1 + 7.0 [ 17] c 165.2 + 20.7 135.5 + 38.7 163.3 + 20.8 [ 17] C 146.9 + 29.2 157.8 + 21.2 III 1 .0 22 19 19 161.2 + 22.8 [ 18] c 158.8 + 24.0 162.8 + 36.6 163.0 + 33.7 170.2 + 20.5 160.2 + 25.3 131.3 + 33.6 162.9 + 20.7 142.1 + 24.8 155.3 + 16.6 DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Dosage o ccu rred on days 7 th ro u g h 20 o f g e s ta tio n . b. Excludes values fo r doe 8481, which had a l i t t e r th a t c o n siste d of ten dead fe tu se s. c. Excludes values th a t were a sso c ia te d w ith sp illa g e or wet feed. d. Excludes values fo r ra b b its th a t aborted. ** S i g n i f i c a n t l y d i f f e r e n t fro m t h e v e h i c l e c o n t r o l g ro u p v a lu e ( p 0 .0 1 ). IV V 2.5 3.75 22 22 17 21 17 21 161.2 + 18.9 142.6 + 35.9 143.0 + 45.8 145.6 + 43.4** 146.1 + 45.5 130.4 + 41.0 112.8 + 37.2 t 16] d 147.8 + 28.8 120.7 + 29.3 [ 16] d 141.0 + 20.5 [ 16] d 151.5 + 41.0 129.6 + 53.7 95.8 + 75.0 77.1 + 76.7** 69.7 + 72.9** 80.5 + 72.0** [ 17] d 114.6 + 51.1 t 12] d 107.2 + 54.6** 112.7 + 50.9 l 12] d 127.7 + 39.0 [ 12 ]d 969000 418-012: PAGE B-7 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 6 (PAGE 1 ) : MATERNAL R ELATIVE FEED CONSUMPTION VALUES (G /K G /D A Y ) - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a RABBITS TESTED PREGNANT INCLUDED IN ANALYSES MATERNAL FEED CONSUMPTION (G/KG/DAY) DAYS 7 - 10 DAYS 10 - 13 DAYS 13 - 16 DAYS 16 - 19 DAYS 19 - 21 DAYS 21 - 24 DAYS 24 - 29 DAYS 7 - 21 DAYS 21 - 29 DAYS 7 - 29 N 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. MEAN+S.D. i 0 (VEHICLE) 22 20 20 41.4 + 14.5 42.5 + 9.1 45.1 + 6.5 48.4 + 3.9 46.6 + 5.8 42.3 + 8.0 31.7 + 9.0 44.8 + 5.1 35.7 + 7.8 41.4 + 4.9 ii 0.1 22 19 18b 4 9 .1 + 4.2 39.9 + 12.8 43.7 + 9.1 47.8 + 3.7 [ 17]c 48.5 + 3.4 [ 17] c 43.3 + 4.2 34.5 + 8.6 45.4 + 4.6 [ 17] c 37.9 + 6.0 4 2 .7 + 4.1 III 1.0 22 19 19 46.0 + 6.5 [ 18] c 44.8 + 6.9 44.5 + 9.7 44.1 + 9.4 45.5 + 5.7 42.1 + 6.6 33.9 + 8.9 45.1 + 5.8 36.9 + 6.6 42.0 + 4.6 DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Dosage o ccu rred on days 7 th ro u g h 20 o f g e s ta tio n . b. Excludes values fo r doe 8481, which had a l i t t e r th a t c o n siste d of ten dead fe tu se s. c. Excludes values th a t were a sso c ia te d w ith sp illa g e o r wet feed. d. Excludes values for ra b b its th a t aborted. * S ig n ific a n tly d iffe re n t from th e v eh ic le c o n tro l group valu e (p0.05). ** S i g n i f ic a n t l y d i f f e r e n t from th e v e h ic le c o n tr o l g ro u p v a lu e (p < 0 .0 1 ). IV V 2.5 3.75 22 22 17 21 17 21 45.5 + 4.5 39.6 + 8.7 39.0 + 11.8 39.3 + 11.2** 39.1 + 11.6* 34.6 + 9.3* 29.5 + 9.3 [ 16] d 40.6 + 6.4 31.7 + 6.8 [ 16] d 3 8 .1 + 4.0* [ 16] d 43.7 + 11.9 36.7 + 14.8 26.4 + 20.7* 21.2 + 20.9** 19.1 + 19.6** 22.0 + 19.4** [ 17] d 30.8 + 13.6 [ 12] d 30.4 + 14.9* 30.5 + 13.6 [ 12] d 35.4 + 10.4 [ 12] d 418-012: PAGE B-8 00069 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 7 (PAGE 1): CAESAREAN-SECTIONING OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1 III 1.0 RABBITS TESTED N 22 22 22 PREGNANT ABORTED N (%) 2 0 ( 9 0 . 9 ) N (%) 0 ( 0 . 0 ) 19( 86.4) 0( 0.0) 19( 86.4) 0( 0.0) RABBITS PREGNANT AND CAESAREAN-SECTIONED ON DAY 29 OF GESTATION N 20 19 19 INCLUDED IN ANALYSES N 20 18b 19 CORPORA LUTEA MEAN+S.D . 10.8 + 2.5 10.9 + 2.5 10.5 + 2.3 IMPLANTATIONS MEAN+S.D . 9.0 + 2.2 9.1 + 1.9 8.4 + 1.8 LITTER SIZES MEAN+S. D . 8.8 + 2.2 9.0 + 2.0 8.0 + 1.9 LIVE FETUSES N MEAN+S. D . 175 8.8 + 2.2 162 9.0 + 2.0 152 8.0 + 1.9 DEAD FETUSES N 0 0 0 RESORPTIONS MEAN+S.D . 0.2 + 0.4 0.1 + 0.3 0.4 + 0.8 EARLY RESORPTIONS N MEAN+S.D . 3 0.2 + 0.4 2 0.1 + 0.3 2 0.1 + 0.3 LATE RESORPTIONS N MEAN+S. D . 1 0.0 + 0.2 0 0.0 + 0.0 5 0.3 + 0.7 DOES WITH ANY RESORPTIONS: N (%) 4 ( 20.0) 2( 11.1) 5{ 26.3) DOES WITH ALL CONCEPTUSES RESORBED N (%) 0 0 0 DOES WITH VIABLE FETUSES N ( %) 20 (100.0) 18 (100.0) 19(100.0) PLACENTAE APPEARED NORMAL N(%) 20(100.0) 18(100.0) 19(100.0) a. Dosage o cc u rre d on days 7 th ro u g h 20 o f g e s ta tio n . b. Excludes values fo r doe 8481, which had a l i t t e r th a t c o n siste d of ten dead fe tu se s. IV 2.5 22 17( 77.3) 1( 5.9) 16 16 10.4 + 2.2 8.4 + 1.8 8.1 + 1.8 130 8.1 + 1.8 0 0.2 + 0.4 2 0.1 + 0.3 2 0.1 + 0.3 4 ( 25.0) 0 16(100.0) 16(100.0) V 3.75 22 21( 95.4) 9( 42.8) 12 12 11.1 + 1.7 9.2 + 1.9 9.0 + 2.0 108 9.0 + 2.0 0 0.2 + 0.4 1 0.1 + 0.3 1 0.1 + 0.3 2 ( 16.7) 0 12(100.0) 12 (100.0) 418-012: PAGE B-9 000698 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 8 (PAGE 1): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1 LITTER S WITH ONE OR MORE LIV E FETUSES N 20 18 IMPLANTATIONS MEAN+S.D . 9.0 + 2.2 9.1 + 1.9 LIVE FETUSES N MEAN+S.D . 175 8.8 + 2.2 162 9.0 + 2.0 LIVE MALE FETUSES N 87 74 % L IV E MALE FETUSES/LITTER MEAN+S.D . 50.4 + 15.1 45.8 + 19.2 LIV E FETAL BODY WEIGHTS (GRAMS)/LITTER MEAN+S.D . 44.15 + 4.50 41.67 + 3.28 MALE FETUSES MEAN+S.D. 44.50 + 4.90 41.82 + 2.77 FEMALE FETUSES MEAN+S. D. 43.86 + 4.84 41.36 + 4.09 % RESORBED CONCEPTUSES/LITTER MEAN+S.D. 2.1 + 4.4 1.4 + 4.1 ( ] = NUMBER OF VALUES AVERAGED a. Dosage o cc u rre d on days 7 th ro u g h 20 o f g e s ta tio n . b. L itte r 8546 had no m ale fe tu se s. * S ig n ific a n tly d iffe re n t from th e v e h ic le c o n tro l group value (p< 0.05). ** S i g n i f ic a n t l y d i f f e r e n t from th e v e h ic le c o n tr o l g ro u p v a lu e (p ^ O .O l). III 1.0 19 8.4 + 152 8.0 + 71 1.8 1 .9 45.6 + 18.0 42.37 + 4.34 43.12 + 5.13 41.94 + 4.90 4.4 + 9.4 IV 2 .5 16 8.4 + 130 8.1 + 66 1.8 1.8 50.2 + 14.1 39.89 + 4.33* 40.56 + 4.52* 38.98 + 5.28* 3.1 + 5.7 V 3.75 12 9.2 + 108 9.0 + 50 1 .9 2 .0 44.1 + 21.7 33.41 + 7.61** 34.10 + 7.36** t ii] b 32.31 + 8.27** 1.8 + 4.1 418-012: PAGE B-10 000699 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 9 (PAGE 1) : FETAL ALTERATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I I I I I I IV 0 (VEHICLE) 0.1 1 .0 2.5 LITTERS EVALUATED FETUSES EVALUATED LIVE DEAD N N N N 20 175 175 0 19b 19 172 152 162 152 10b 0 16 130 130 0 LITTERS WITH FETUSES WITH ANY ALTERATION OBSERVED N(%) 14( 70.0) 11 ( 61.1) 9 ( 47.4) 4 ( 25.0) FETUSES WITH ANY ALTERATION OBSERVED N (%) 25( 14.3) 25( 15.4) 14( 9.2) 5 ( 3.8)** % FETUSES WITH ANY ALTERATION/LITTER MEAN+S. D. 14.1 + 12.9 17.0 + 18.2 9.5 + 11.7 3.6 + 7.0 a. Dosage o cc u rre d on days 7 th ro u g h 20 o f g e s ta tio n . b. L itte r 8481 c o n siste d of te n dead fe tu s e s ; v alu es were excluded from group av erag es and s t a t i s t ic a l an a ly se s, observations fo r th is l i t t e r are c ite d on Table 21. ** S i g n i f i c a n t l y d i f f e r e n t from th e v e h ic le c o n tr o l g ro u p v a lu e (p < 0 .0 1 ). V 3.75 12 108 108 0 8( 66.7) 19( 17.6) 17.4 + 22.2 A dverse PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 10 (PAGE 1) : FETAL GROSS EXTERNAL ALTERATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1 I I I IV 1.0 2.5 LITTERS EVALUATED FETUSES EVALUATED LIVE DEAD N 20 N 175 N 175 N0 19b 19 162 152 162 152 10b 0 16 130 130 0 FORELIMBS: . FLEXED DOWNWARD LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0( 0.0) 0( 0.0) 1( 5.3) 1( 0.6) 0( 0.0) 0( 0.0) 0 ( 0.0) 0 ( 0.0) FORELIMB: POLLEX ABSENT LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) 1( 5.0) 1( 0.6) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 0 ( 0.0) a. Dosage o cc u rre d on days 7 th ro u g h 20 o f g e s ta tio n . b. L itte r 8481 c o n siste d of te n dead fe tu s e s ; v alu e s were excluded from group averag es and s t a t i s t i c a l an a ly se s, observations fo r th is l i t t e r are c ite d on Table 21. V 3.75 12 108 108 0 1( 8.3) 1( 0.9) 0( 0.0) 0( 0.0) A dverse PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 11 (PAGE 1) : FETAL SOFT TISSUE ALTERATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I II I I I IV 0 (VEHICLE) 0 .1 1.0 2 .5 LITTERS EVALUATED FETUSES EVALUATED LIVE DEAD N 20 N 175 N 175 N0 19b 19 172 152 162 152 10b 0 16 130 130 0 E Y ES: CIRCUMCORNEAL HEMORRHAGE LITTER INCIDENCE N {%) FETAL INCIDENCE N (%) 1( 5.0) 1( 0.6) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) LUNGS: INTERMEDIATE LOBE ABSENT LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 2( 10.0) 2( 1.1) 4 ( 22.2) 7 ( 4.3)** 1( 5.3) 1( 0.6) 0( 0.0) 0( 0.0) a. Dosage o cc u rre d on days 7 th ro u g h 20 o f g e s ta tio n . b. L itte r 8481 c o n siste d of te n dead fe tu s e s ; v alu e s were excluded from group av erag es and s t a t i s t i c a l a n a ly se s. observations for th is l i t t e r are c ite d on Table 21. ** S i g n i f ic a n t l y d i f f e r e n t from th e v e h ic le c o n tr o l g ro u p v a lu e (p < 0 .0 1 ). V 3.75 12 108 108 0 0( 0.0) 0( 0.0) 1( 8.3) 1( 0.9) A dverse PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 12 (PAGE 1) : FETAL SKELETAL OBSERVATIONS - SUMMARY (See fo o tn o tes on the la s t page of th is ta b le .) 6295.10) DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 10 . 1 LITTERS EVALUATED FETUSES EVALUATED LIVE DEAD N 20 N 175 N 175 N0 19b 172 162 10b SKULL - IRREGULAR OSSIFICA TION : C (SUMMARIZATION OF ALL IRREGULAR OSSIFICATION OF THE SKULL d ; INDIVIDUAL SUBCATEGORIES CITED BELOW) LITTER INCIDENCE N(%) 6 ( 3 0 .0 ) FETAL INCIDENCE N (%) 7 ( 4 . 0 ) 7 ( 38.9) 9 ( 5.6) SKULL: NASAL(S), IRREGULAR OSSIFICATION (SUMMARIZATION OF F U SE D ; :IRREGULAR SUTURE; MIDLINE SUTURE DISPLACED ; INTRANASAL; INTERNASAL) LITTER INCIDENCE N (%) 5 ( 2 5 . 0 ) FETAL INCIDENCE N (%) 6 ( 3 . 4 ) 7 ( 38.9) 9( 5.6) SKULL: NASAL - FRONTAL, IRREGULAR SUTURE LITTER INCIDENCE N (%) 1 ( 5 . 0 ) FETAL INCIDENCE N (%) 1 ( 0 . 6 ) f o SKULL: NASALS, FUSED o LITTER INCIDENCE N (%) H 5 . 0 ) ovj FETAL INCIDENCE N (%) K 0 . 6 ) o SKULL: NASALS, CONTAINED AN INTERNASAL CO LITTER INCIDENCE FETAL INCIDENCE N (%) 1 ( 5 . 0 ) N ( %) 1 ( 0 . 6 ) 2 ( 11.1) 2 ( 1.2) 0 ( 0.0) 0 ( 0.0) 2 ( 11.1) 3 ( 1.8) SKULL: NASALS, MIDLINE SUTURE DISPLACED LITTER INCIDENCE N (%> 0 ( 0 . 0 ) FETAL INCIDENCE N(%) 0 ( 0 .0 ) 3 ( 16.7) 4 ( 2.5)** SKULL: NASAL, CONTAINED AN INTRANASAL LITTER INCIDENCE N (%) 3 ( 1 5 . 0 ) FETAL INCIDENCE N (%> 3 ( 1 . 7 ) 0 ( 0.0) 0 ( 0.0) III 1 .0 19 152 152 0 3 ( 15.8) 3 ( 2.0) 3 ( 15.8) 3 ( 2.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0< 0 .0 ) 0 ( 0.0) K 5.3) K 0.6) 2 ( 10.5) 2 ( 1.3) IV 2.5 16 130 130 0 1( 6.2) M 0.8)* 1( 6.2) 1( 0.8) 0 ( 0.0) 0( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 6.2) 1 ( 0.8) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) V 3 . 75 12 108 108 0 3 ( 25.0) 10< 9 .2 )* * 1( 8.3) K 0.9) 0 ( 0.0) 0 ( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 0 ( 0.0) 0( 0.0) 0( 0.0) 1 ( 8.3) 1( 0.9) 418-012: PAGE B-14 PROTOCOL 41B-012 : ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 12 (PAGE 2 ) : FETAL SKELETAL OBSERVATIONS - SUMMARY (See fo o tn o te s on th e l a s t page o f th is t a b l e .) 6295.10) DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1 LITTERS EVALUATED FETUSES EVALUATED LIVE DEAD N 20 N 175 N 175 N0 19b 172 162 10b SKULL: FRONTALS, CONTAINED AN INTERFRONTAL LITTER INCIDENCE N ( %) K 5 . 0 ) FETAL INCIDENCE N (%) 1 ( 0 . 6 ) 0 ( 0.0) 0 ( 0.0) SKULL: PARIETAL, CONTAINED A HOLE LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0 ( 0.0) 0 ( 0.0) 0( 0.0) 0 ( 0.0) SKULL - OTHER ALTERATIONS:b HYOID: ALA, ANGULATED LITTER INCIDENCE N (%) 6 ( 3 0 . 0 ) FETAL INCIDENCE N (%) 1 0 ( 5 . 7 ) f , g 3 ( 16.7) 4 ( 2.5) SKULL: PREMAXILLAE, NOT O SSIFIED LITTER INCIDENCE N (%) FETAL INCIDENCE N ( %) 0( 0.0) 0 ( 0.0) 1 ( 5.6) M 0.6) CERVICAL VERTEBRAE: CERVICAL RIB PRESENT AT 7TH CERVICAL VERTEBRA LITTER INCIDENCE N(%) 1( 5 . 0 ) 0( 0.0) FETAL INCIDENCE N {%) 1 ( 0 . 6 ) 0 ( 0.0) CERVICAL VERTEBRAE: CENTRUM, UNILATERAL O SSIFIC A TIO N LITTER INCIDENCE N (%) 0 ( 0 . 0 ) FETAL INCIDENCE N ( %) 0 ( 0 . 0 ) 1< 5 . 6 ) M 0.6) THORACIC VERTEBRAE: CENTRUM, B IF ID LITTER INCIDENCE N (%) FETAL INCIDENCE N ( %) 0 ( 0.0) 0 ( 0.0) 1 ( 5.6) M 0 .6)h THORACIC VERTEBRAE: CENTRA, 1FUSED LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0< 0. 0) 0 ( 0.0) 2 ( 11.1) 2( 1.2)h, i III 1.0 19 152 152 0 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 3 ( 15.8) 7 ( 4.6) 0( 0.0) 0( 0.0) 0 ( 0.0) 0 ( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0( 0.0) IV 2.5 16 130 130 0 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 2 ( 12.5) 3 ( 2.3) 0 ( 0.0) 0( 0.0) M 1< 6.2) 0.8) 0( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0( 0.0) V 3 .7 5 12 108 108 0 K 8.3) 2( 1.8) 1< 8 .3 ) 7 ( 6 .5 )k ,l 3 ( 25.0) 5 ( 4.6) 0 ( 0.0) 0< 0 . 0 ) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 0 ( 0.0) 0< 0 . 0 ) 418-012: PAGE B-15 000704 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 12 (PAGE 3) : FETAL SKELETAL OBSERVATIONS - SUMMARY (See fo o tn o te s on th e la s t page o f th is ta b le .) 6295.10) DOSAGE GROUP DOSAGE (MG/KG/DAY)a i 0 (VEHICLE) LITTERS EVALUATED FETUSES EVALUATED LIVE DEAD N 20 N 175 N 175 N0 THORACIC VERTEBRAE: HEMIVERTEBRA LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 1( 5.0) 1( 0.6) g THORACIC VERTEBRAE: ARCH, SMALL LITTER INCIDENCE N (%) FETAL INCIDENCE N(%) 0 ( 0.0) 0 ( 0.0) THORACIC VERTEBRAE: CENTRUM, UNILATERAL OSSIFICATION LITTER INCIDENCE N (%) 1 ( 5 . 0 ) FETAL INCIDENCE N ( %) 1 ( 0 . 6 ) LUMBAR VERTEBRAE: CENTRUM, B IF I D LITTER INCIDENCE N (%) FETAL INCIDENCE N ( %) 0 ( 0.0) 0 ( 0.0) LUMBAR VERTEBRAE: HEMIVERTEBRA LITTER INCIDENCE N <%) FETAL INCIDENCE N (%) 0 ( 0.0) 0( 0.0) CAUDAL VERTEBRAE: MISALIGNED LITTER INCIDENCE N (%) FETAL INCIDENCE N ( %) 1( 5.0) 1( 0.6) R IB S : FUSED LITTER INCIDENCE FETAL INCIDENCE N (%) 0 ( 0 . 0 ) N(%) 0( 0 . 0 ) RIBS: SPLIT LITTER INCIDENCE FETAL INCIDENCE N (%) 1 ( 5 . 0 ) N ( %) 1 ( 0 . 6 ) g II 0.1 19b 172 162 10b 0 ( 0.0) 0 ( 0.0) K 5.6) M 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) 1 ( 5.6) M 0.6) 0 ( 0.0) 0 ( 0.0) III 1 .0 19 152 152 0 0 ( 0.0) 0 ( 0.0) 0( 0.0) 0< 0 . 0 ) 0 ( 0.0) 0 ( 0.0) 1< 5 . 3 ) 1( 0.6) j 1 ( 5.3) K 0.6) j 0( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 1 ( 5.3) 1 ( 0.6) IV 2.5 16 130 130 0 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0( 0.0) 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 12 108 108 0 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0( 0.0) 0 ( 0.0) 1( 8.3) 1( 0.9) 0 ( 0.0) 0 ( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 418-012: PAGE B-16 000705 PROTOCOL 4X8-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 1 2 (PAGE 4 ) : FETAL SKELETAL OBSERVATIONS - SUMMARY (See fo o tn o te s on th e la s t page of th is ta b le .) 6295.10) DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0 .1 LITTERS EVALUATED FETUSES EVALUATED LIVE DEAD N 20 N 175 N 175 N0 19b 172 162 10b RIBS: THICKENED LITTER INCIDENCE FETAL INCIDENCE N ( %) K 5 . 0 ) N ( %) 1 ( 0 . 6 ) 0 ( 0.0) 0 ( 0.0) R IB S: PROXIMATE LITTER INCIDENCE FETAL INCIDENCE N (%) 0 ( 0 . 0 ) N (%) 0 ( 0 . 0 ) K 5.6) M 0.6) STERNAL CENTRA : FUSED LITTER INCIDENCE FETAL INCIDENCE N (%) 2 ( 1 0 . 0 ) N (%) 2 ( 1 . 1 ) 3 ( 16.7) 3 ( 1.8) STERNAL CENTRA : ASYMMETRIC LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) 1 ( 5.0) 1 ( 0.6) g 0 ( 0.0) 0 ( 0.0) METACARPALS: FORELIMB, 4 METACARPALS PRESENT LITTER INCIDENCE N (%) K 5 . 0 ) FETAL INCIDENCE N ( %) 1 ( 0 . 6 ) e 0 ( 0.0) 0 ( 0.0) FOREDIGITS: FORELIMB, 4 DIGITS PRESENT LITTER INCIDENCE N (%) K 5 . 0 ) FETAL INCIDENCE N ( %) 1 ( 0 . 6 ) e 0 ( 0.0) 0 ( 0.0) FOREPHALANGES: FORELIMB, 1ST MEDIAL AND D ISTA L PHALANGES ABSENT < LITTER INCIDENCE FETAL INCIDENCE N (%) M 5 . 0 ) N ( %) M 0 . 6 ) e 0 ( 0.0) 0( 0.0) PELV IS: PU B IS, NOT O SS IF IE D LITTER INCIDENCE N ( %) FETAL INCIDENCE N ( %) 0 ( 0.0) 0< 0 . 0 ) 0 ( 0.0) 0 ( 0.0) III 1 .0 19 152 152 0 K 5.3) 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) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) IV 2.5 16 130 130 0 0 ( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 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 12 108 108 0 0 ( 0 .0) 0( 0.0) 0 ( 0 .0) 0 ( 0.0) 0 ( 0 .0) 0 ( 0 .0) 0< 0 .0) 0 ( 0.0) 0 ( 0.0) 0 ( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 0 ( 0.0) 2 ( 16.7)** 4 ( 3 . 7 ) k , 1** 418-012: PAGE B-17 000 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 12 (PAGE 5) : FETAL SKELETAL OBSERVATIONS - SUMMARY 6295.10) FOOTNOTES: a. Dosage o ccu rred on days 7 th ro u g h 20 o f g e s ta tio n . b. L itte r 8481 c o n siste d of te n dead fe tu s e s ; v alu e s w ere excluded from group av erag es and s t a t i s t ic a l a n a ly se s. A dverse observations for th is l i t te r are c ite d on Table 21. c. F etu ses w ith a lte r a tio n s o f th e s k u ll a n d /o r h yo id a re n ot s e p a ra te ly id e n tif ie d in th is summary ta b le , ex cep t when a lte ra tio n s of o th e r o s s ific a tio n s ite s were also p resen t. d. Includes a ll a lte ra tio n s noted for the sk u ll except hyoid, ala, angulated and sk u ll, prem axillae, not o ssifie d . These c ate g o rie s are excluded because th ese a lte ra tio n s do not re s u lt from ir re g u la r o s s ific a tio n . e. Fetus 8448-1 had o th e r s k e le ta l a lte ra tio n s . f. Fetus 8449-6 had o th e r s k e le ta l a lte ra tio n s . g. Fetus 8452-1 had o th e r s k e le ta l a lte ra tio n s . h. Fetus 8476-1 had o th e r s k e le ta l a lte ra tio n s . i. Fetus 8485-2 had o th e r s k e le ta l a lte ra tio n s . j. Fetus 8500-8 had o th e r s k e le ta l a lte ra tio n s . k. Fetus 8543-4 had o th e r s k e le ta l a lte ra tio n s . l. Fetus 8543-6 had o th e r s k e le ta l a lte ra tio n s . * S ig n ific a n tly d iffe re n t from th e v eh ic le c o n tro l group value (p<0.05). ** S ig n if ic a n tly d i f f e r e n t from th e v e h ic le c o n tr o l g ro u p v a lu e ( p<0. 01). PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 13 (PAGE 1 ) : FETA L O S S IF IC A T IO N S IT E S - CAESAREAN--D ELIV ER ED L IV E FE T U SE S (DAY 2 9 OF G ESTA TIO N ) - SUMMARY DOSAGE GROUP DOSAGE (M G/KG/DAY)a I 0 (VEHICLE) L ITTER S EXAMINED N 20 FETUSES EXAMINED N 1 75 LIVE N 175 DEAD N 0 OSSIFICATION SITES PER FETUS PER LITTER II 0 .1 19b 172 162 10b III 1 .0 19 152 152 0 IV V 2 .5 3 .7 5 16 12 130 108 130 108 00 HYOID MEAN+S.D . 1.00 + 0.00 1.00 + 0.00 1.00 + 0.00 1.00 + 0.00 0.92 + 0.20' VERTEBRAE CERVICAL THORACIC LUMBAR SACRAL CAUDAL MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D . 7.00 + 12.72 + 6.26 + 3.00 + 16.90 + 0.00 0.23 0.23 0.00 0.24 7.00 + 12.58 + 6.42 + 3.00 + 17.03 + 0.00 0.28 0.28 0.00 0.30 7.00 + 12.70 + 6.29 + 3.00 + 16.95 + 0.00 0.29 0.29 0.00 0.38 7.00 + 12.49 + 6.51 + 3.00 + 16.86 + 0.00 0.33 0.33 0.00 0.28 7.00 + 12.52 + 6.47 + 3.00 + 16.92 + 0.00 0.32 0.31 0.00 0.50 RIBS (PAIRS) MEAN+S.D . 12.66 + 0.26 12.50 + 0.26 12.60 + 0.29 12.42 + 0.28 12.47 + 0.34 STERNUM MANUBRIUM STERNAL CENTERS XIPHOID MEAN+S.D. MEAN+S.D. MEAN+S.D . 1.00 + 0.00 3.98 + 0.05 0.98 + 0.04 1.00 + 0.00 3.92 + 0.11 0.99 + 0.05 1.00 + 0.00 3.95 + 0.12 0.97 + 0.06 1.00 + 0.00 3.81 + 0.17** 0.94 + 0.10 1.00 + 0.00 3.82 + 0.22 0.95 + 0.10 FORELIMB c CARPALS METACARPALS DIGITS PHALANGES MEAN+S.D. MEAN+S.D. MEAN+S.D . MEAN+S.D . 0.00 + 4.98 + 5.00 + 13.92 + 0.00 0.05 0.00 0.12 0.00 + 4.97 + 5.00 + 13.92 + 0.00 0.06 0.00 0.17 0.00 + 4.99 + 5.00 + 13.90 + 0.00 0.04 0.00 0.17 0.00 + 4.97 + 5.00 + 13.96 + 0.00 0.07 0.00 0.07 0.00 + 4.82 + 5.00 + 13.92 + 0.00 0.31 0.00 0.15 HINDLIMB c 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 2.00 + 4.00 + 4.00 + 12.00 + 0.00 0.00 0.00 0.00 2.00 + 4.00 + 4.00 + 12.00 + 0.00 0.00 0.00 0.00 2.00 + 4.00 + 4.00 + 12.00 + 0.00 0.00 0.00 0.00 1.92 + 4.00 + 4.00 + 11.92 + 0.23 0.00 0.00 0.23 a. D osage o ccu rred on days 7 th ro u g h 20 o f g e s ta tio n . b . L itte r 8481 c o n s is te d o f te n dead fe tu s e s ; v a lu e s e x c lu d e d from g ro u p a v e ra g e s and s t a t i s t ic a l a n a ly se s . o b se rv a tio n s fo r th is l i t t e r a re c ite d on T able 21. c. C alc u la te d as av erag e p e r lim b. * S ig n ific a n tly d if f e r e n t from th e v e h ic le c o n tro l g ro u p v a lu e (p^O .0 5 ). ** S ig n if ic a n tly d if f e r e n t fro m th e v e h ic le c o n tro l g ro u p v a lu e (p < 0 .0 1 ). A dverse 418-012: PAGE B-19 000708 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 14 (PAGE 1) : C LIN IC A L OBSERVATIONS - IND IVIDU A L DATA RABBIT # D E SC R IPT IO N DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8 4 4 3 NO ADVERSE F IN D IN G S 8 4 4 4 NO ADVERSE F IN D IN G S 8 4 4 5 NO ADVERSE FIN D IN G S 8 4 4 6 NO ADVERSE F IN D IN G S 8 4 4 7 NO ADVERSE F IN D IN G S 8 4 4 8 NO ADVERSE F IN D IN G S 8 4 4 9 NO ADVERSE F IN D IN G S 8 4 5 0 NO ADVERSE F IN D IN G S 8 45 1 NO ADVERSE FIN D IN G S 8 4 5 2 NO ADVERSE F IN D IN G S 8 4 5 3 NO ADVERSE F IN D IN G S 8 4 5 4 NO ADVERSE F IN D IN G S 8 4 5 5 NO ADVERSE F IN D IN G S 8 4 5 6 NO ADVERSE F IN D IN G S 8 4 5 7 NO ADVERSE F IN D IN G S 8 4 5 8 NO ADVERSE F IN D IN G S 8 4 5 9 NO ADVERSE FIN D IN G S 8 4 6 0 NO ADVERSE F IN D IN G S 8 4 6 1 NO ADVERSE F IN D IN G S 8 4 6 2 NO ADVERSE F IN D IN G S 8 4 6 3 NO ADVERSE F IN D IN G S 8 4 6 4 NO ADVERSE F IN D IN G S DG = DAY OF PRESUMED GESTATION oo o cr 418-012: PAGE B-20 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 14 (PAGE 2): CLINICAL OBSERVATIONS - INDIVIDUAL DATA RABBIT # D E S C R IP T IO N DOSAGE GROUP I I 0 .1 MG/KG/DAY 8 4 6 5 DG ( 2 8 - 2 9 ) 8466 8467 8468 8469 8470 8471 8472 8473 DG ( 2 7 - 2 9 ) 8474 8475 8476 8477 8 4 7 8 DG ( 28 ) 8479 8480 8481 8 4 8 2 DG ( 2 4 - 2 9 ) 8483 8484 8485 8 4 8 6 DG ( 2 7 - 2 9 ) LOCALIZED ALOPECIA: NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE F IN D IN G S NO ADVERSE F IN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S LOCALIZED ALOPECIA: NO ADVERSE F IN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S UNGROOMED COAT NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FINDINGS LOCALIZED ALOPECIA: NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S UNGROOMED COAT LIMBS a BACK a LIMBS a DG = DAY OF PRESUMED G ESTA TIO N a. O bserv ation confirm ed a t n ecro p sy . 418-012:PAGE B-: 000710 M PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 14 (PAGE 3) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA RABBIT # D E S C R IP T IO N DOSAGE GROUP I I I 1 .0 MG/KG/DAY 8487 8488 8489 DG( 29 ) 8490 8491 8 4 9 2 DG ( 9 ) DG ( 9 - 1 1 ) DG( 10- 11) 8493 DG( 27- 29) 8494 8495 8496 DG( 26- 29) 8497 8498 8499 8500 8501 8502 8503 8504 8505 8506 DG( 26- 29) 8507 DG( 28- 29) 8508 NO ADVERSE FIN D IN G S NO ADVERSE F IN D IN G S LOCALIZED ALOPECIA: UNDERSIDE a NO ADVERSE F IN D IN G S NO ADVERSE F IN D IN G S SOFT OR LIQ UID FECES UNGROOMED COAT SCANT FECES LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S LOCALIZED ALOPECIA: BACK a NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE F IN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S LOCALIZED ALOPECIA: LIMBS a LOCALIZED ALOPECIA: BACK a NO ADVERSE FIN D IN G S DG = DAY OF PRESUMED GESTATION a. O b serv atio n confirm ed a t n ecro p sy . 418-012:PAGE B-22 000711 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 14 (PAGE 4 ) : C LIN IC A L OBSERVATIONS - INDIVIDUAL DATA RABBIT # D E S C R IP T IO N DOSAGE GROUP IV 2 .5 MG/KG/DAY 8509 8510 8511 8512 8513 8514 8515 8 5 1 6 DG ( 2 8 - 2 9 ) 8 5 1 7 DG ( 2 5 ) 8 5 1 8 DG ( 2 8 - 2 9 ) 8519 8520 852 1 DG ( 28 ) DG ( 29 ) DG ( 2 9 ) 8522 8523 852 4 DG ( 2 4 - 2 5) 8 52 5 DG ( 26 ) 8526 8 52 7 DG ( 2 4 - 2 8 ) 8528 8529 8530 NO ADVERSE FIN D IN G S NO ADVERSE FIND IN GS NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S LOCALIZED ALOPECIA: LIMBS a ABORTED AND SA C R IFIC ED SCANT FECES NO ADVERSE FIND IN GS NO ADVERSE FIND IN GS LOCALIZED ALOPECIA: LIMBS A LO PEC IA NO LONGER APPARENT LOCALIZED ALOPECIA: BACK a NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S SCANT FECES SCANT FECES NO ADVERSE FIN D IN G S UNGROOMED COAT NO ADVERSE FIND IN GS NO ADVERSE FIND IN GS NO ADVERSE FIN D IN G S DG = DAY OF PRESUMED G ESTA TIO N a. O b serv atio n confirm ed a t n ecro p sy . e 418-012: PAGE B-23 00712 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 14 (PAGE 5) CLIN ICAL OBSERVATIONS - INDIVIDUAL DATA RABBIT # DOSAGE GROUP V 8531 8532 8533 8 53 4 DG ( 22 ) 8 5 3 5 DG ( 2 6 - 2 7 ) 8536 8 5 3 7 DG ( 24 ) DG ( 25 ) 8 5 3 8 DG ( 24 ) 8 5 3 9 DG ( 2 2 - 2 3 ) DG ( 24 ) 8 5 4 0 DG ( 25 ) 8541 8 5 4 2 DG ( 2 1 - 2 3 ) DG ( 2 7 ) DG ( 28 ) 8 54 3 DG ( 1 9 - 2 0 ) DG ( 2 2 - 2 3 ) DG ( 24 ) DG ( 2 5 - 2 7 ) 854 4 DG ( 1 9 - 2 0) DG ( 2 2 - 2 4 ) DG ( 25 ) 8545 8546 8 5 4 7 DG ( 18 ) DG ( 21 ) DG ( 22 ) 8 5 4 8 DG { 21 ) DG ( 2 3 - 2 4 ) DG ( 25 ) 8549 8550 8551 8552 DG = DAY OF PRESUMED G ESTA TIO N D E S C R IP T IO N 3 .7 5 MG/KG/DAY NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S ABORTED AND SA C R IFICED SCANT FECES NO ADVERSE FIN D IN G S NO FECES ABORTED AND SA CRIFICED ABORTED AND SA C R IFICED SCANT FECES ABORTED AND SA C R IFICED ABORTED AND SA CRIFICED NO ADVERSE FIN D IN G S SCANT FECES SCANT FECES ABORTED AND SA CRIFICED SCANT FECES SCANT FECES NO FECES SCANT FECES SCANT FECES SCANT FECES ABORTED AND SA CRIFICED NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S SCANT FECES RED SUBSTANCE IN CAGE PAN ABORTED AND SA C R IFICED SCANT FECES SCANT FECES ABORTED AND SA C R IFICED NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S NO ADVERSE FIN D IN G S 418-012: PAGE B-24 000713 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 14 (PAGE 6) : C LIN IC A L OBSERVATIONS - IND IV ID U A L DATA RABBIT # D E S C R IP T IO N SATELLITE DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8 5 5 3 NO ADVERSE FIN D IN G S 8 5 5 4 NO ADVERSE FIN D IN G S 8 5 5 5 NO ADVERSE FIN D IN G S SATELLITE DOSAGE GROUP I I 0 .1 MG/KG/DAY 8 5 5 6 NO ADVERSE F IN D IN G S 8 5 5 7 NO ADVERSE FIN D IN G S 8 5 5 8 NO ADVERSE F IN D IN G S 8 5 5 9 NO ADVERSE F IN D IN G S 8 5 6 0 NO ADVERSE F IN D IN G S SATELLITE DOSAGE GROUP I I I 1 .0 MG/KG/DAY 8 5 6 1 NO ADVERSE FIN D IN G S 8 5 6 2 NO ADVERSE FIN D IN G S 8 5 6 3 NO ADVERSE FIN D IN G S SATELLITE DOSAGE GROUP IV 2 .5 MG/KG/DAY 8 5 6 4 NO ADVERSE F IN D IN G S 8 5 6 5 NO ADVERSE F IN D IN G S 8 5 6 6 NO ADVERSE F IN D IN G S SATELLITE DOSAGE GROUP V 3 .7 5 MG/KG/DAY ooo 8567 8568 8569 8570 p 8571 NO ADVERSE F IN D IN G S NO ADVERSE F IN D IN G S NO ADVERSE F IN D IN G S NO ADVERSE F IN D IN G S NO ADVERSE F IN D IN G S DG = DAY OF PRESUMED G ESTA TIO N 418-012:PAGE B-25 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 15 (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) 8443 DG 2 9 NP 14 ALL T IS S U E S APPEARED NORMAL 8444 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8445 DG 2 9 NP 14 ALL T IS S U E S APPEARED NORMAL 8446 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8447 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8448 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8449 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8450 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8451 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8452 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8453 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8454 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8455 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8456 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8457 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8458 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8459 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8460 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8461 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8462 DG 29 P 14 ALL T IS S U E S APPEARED NORMAL 8463 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8464 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED G ESTA TIO N a. R efer to th e in d iv id u a l c lin ic a l o b se rv a tio n s ta b le (T able 14) fo r e x te rn a l o b se rv a tio n s con firm ed a t n ecro p sy . 418-012:PAGE B-26 000715 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 15 (PAGE 2) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a II 0 .1 8465 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8466 DG 2 9 NP 14 ALL TISSU ES APPEARED NORMAL. 8467 DG 2 9 NP 14 ALL TISSU ES APPEARED NORMAL. 8468 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8469 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8470 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8471 DG 29 P 14 ALL TISSU ES APPEARED NORMAL. 8472 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8473 DG 29 P 14 ALL TISSU ES APPEARED NORMAL. 8474 DG 29 P 14 ALL TISSU ES APPEARED NORMAL. 8475 DG 29 P 14 ALL TISSU ES APPEARED NORMAL. 8476 DG 29 P 14 ALL TISSU ES APPEARED NORMAL. 8477 DG 2 9 NP 14 ALL TISSU ES APPEARED NORMAL. 8478 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8479 DG 29 P 14 ALL TISSU ES APPEARED NORMAL. 8480 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8481 DG 29 P 14 ALL TISSU ES APPEARED NORMAL. 8482 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8483 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8484 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8485 DG 29 P 14 ALL TISSU ES APPEARED NORMAL. 8486 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a . R efer to th e in d iv id u a l c lin ic a l o b se rv a tio n s ta b le (T able 14) fo r e x te rn a l o b se rv a tio n s con firm ed a t n ecro p sy . PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 629S.10) TABLE 15 (PAGE 3) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a III 8487 DG 2 9 P 14 ALL T ISSU E S APPEARED NORMAL 8488 DG 2 9 P 14 ALL T ISSU E S APPEARED NORMAL 8489 DG 2 9 P 14 ALL T ISSU E S APPEARED NORMAL 8490 DG 2 9 P 14 ALL T ISSU E S APPEARED NORMAL 8491 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8492 DG 29 P 14 ALL T ISSU E S APPEARED NORMAL 8493 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8494 DG 2 9 P 14 ALL T ISSU E S APPEARED NORMAL 8495 DG 2 9 P 14 ALL T ISSU E S APPEARED NORMAL 8496 DG 2 9 P 14 ALL T ISSU E S APPEARED NORMAL 8497 DG 29 P 14 ALL T ISSU E S APPEARED NORMAL 8498 DG 2 9 P 14 ALL T ISSU E S APPEARED NORMAL 8499 DG 2 9 P 14 ALL T ISSU E S APPEARED NORMAL 8500 DG 29 P 14 ALL T IS S U E S APPEARED NORMAL 8501 DG 29 P 14 ALL T IS S U E S APPEARED NORMAL 8502 DG 2 9 NP 14 ALL T IS S U E S APPEARED NORMAL 8503 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8504 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8505 DG 2 9 NP 14 ALL T IS S U E S APPEARED NORMAL 8506 DG 2 9 P 14 ALL T ISSU E S APPEARED NORMAL 8507 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL 8508 DG 2 9 P 14 ALL T IS S U E S APPEARED NORMAL P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. R efer to th e in d iv id u a l c lin ic a l o b se rv a tio n s ta b le (T able 14) fo r e x te rn a l o b se rv a tio n s co n firm ed a t n ecro p sy . PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 15 (PAGE 4 ) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a 8509 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8510 DG 29 P 14 ALL TISSU ES APPEARED NORMAL. 8511 DG 2 9 NP 14 ALL TISSU ES APPEARED NORMAL. 8512 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8513 DG 2 9 NP 14 ALL TISSU ES APPEARED NORMAL. 8514 DG 2 9 P 14 ALL TISSUES APPEARED NORMAL. 8515 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8516 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8517 DG 25 P 14 ABORTED ON DAY 2 5 OF GESTATION ALL TISSU ES APPEARED NORMAL. 8518 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8519 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8520 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8521 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8522 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8523 DG 29 NP 14 ALL TISSU ES APPEARED NORMAL. 8524 DG 29 NP 14 ALL TISSU ES APPEARED NORMAL. 8525 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8526 DG 29 NP 14 ALL TISSU ES APPEARED NORMAL. 8527 DG 29 P 14 ALL TISSU ES APPEARED NORMAL. 8528 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8529 DG 29 P 14 ALL TISSU ES APPEARED NORMAL. 8530 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. R efer to th e in d iv id u a l c lin ic a l o b se rv a tio n s ta b le (T able 14) fo r e x te rn a l o b se rv a tio n s co n firm ed a t n ecro p sy . 418-012: PAGE B-29 000718 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: G295.10) TABLE 15 (PAGE 5): NECROPSY OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a V 3 .7 5 8531 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8532 DG 2 9 p 14 ALL T ISSU ES APPEARED NORMAL. 8533 DG 2 9 p 14 ALL T ISSU ES APPEARED NORMAL. 8534 DG 2 2 P 14 ABORTED ON DAY 22 OF G ESTA TIO N . ALL TISSU ES APPEARED NORMAL. 8535 DG 2 9 p 14 ALL TISSU ES APPEARED NORMAL. 8536 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8537 DG 2 5 p 14 ABORTED ON DAY 25 OF G ESTA TIO N . ALL TISSU ES APPEARED NORMAL. 8538 DG 2 4 p 14 ABORTED ON DAY 24 OF G ESTA TIO N. ALL T ISSU ES APPEARED NORMAL. 8539 DG 24 P 14 ABORTED ON DAY 24 OF G ESTA TIO N. ALL TISSU ES APPEARED NORMAL. 8540 DG 25 p 14 ABORTED ON DAY 25 OF G ESTA TIO N . ALL TISSU ES APPEARED NORMAL. 8541 DG 2 9 p 14 ALL T ISSU ES APPEARED NORMAL. 8542 DG 28 P 14 ABORTED ON DAY 28 OF G ESTA TIO N . ALL TISSU ES APPEARED NORMAL. 8543 DG 2 9 p 14 ALL TISSU ES APPEARED NORMAL. 8544 DG 2 5 p 14 ABORTED ON DAY 25 OF G ESTA TIO N . ALL TISSU ES APPEARED NORMAL. 8545 DG 2 9 p 14 ALL TISSU ES APPEARED NORMAL. 8546 DG 2 9 p 14 ALL TISSU ES APPEARED NORMAL. P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a . R efer to th e in d iv id u a l c lin ic a l o b se rv a tio n s ta b le (T able 14) fo r e x te rn a l o b se rv a tio n s co n firm ed a t n ecro p sy . 418-012: PAGE B-30 000719 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 15 (PAGE 6 ) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a V 3 .7 5 (c o n t.) 8547 DG 22 P 14 ABORTED ON DAY 22 OF G ESTA TIO N . ALL T ISSU E S APPEARED NORMAL. 8548 DG 2 5 P 14 ABORTED ON DAY 25 OF G ESTA TIO N . ALL TISSU E S APPEARED NORMAL. 8549 DG 2 9 P 14 ALL T ISSU ES APPEARED NORMAL. 8550 DG 29 P 14 ALL T ISSU ES APPEARED NORMAL. 8551 DG 29 P 14 ALL T ISSU ES APPEARED NORMAL. 8552 DG 29 NP 14 ALL TISSU E S APPEARED NORMAL. P = PREGNANT NP = NOT PREGNANT DG - DAY OF PRESUMED GESTATION a . R efer to th e in d iv id u a l c lin ic a l o b se rv a tio n s ta b le (T able 14) fo r e x te rn a l o b se rv a tio n s con firm ed a t n ecro p sy . 418-012: PAGE B-: oo o fO co PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 15 (PAGE 7) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA SATELLITE DOSAGE GROUP DOSAGE (MG/KG/DAY) RABBIT NUMBER DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a L IV E R WEIGHT (G) I 0 (VEHICLE) 8553 DG 2 1 P 14 ALL T ISSU E S APPEARED NORMAL. 8554 DG 2 1 P 14 ALL T ISSU E S APPEARED NORMAL. 8555 DG 2 1 P 14 ALL T ISSU E S APPEARED NORMAL. 1 5 4 .4 1 6 0 .1 1 0 7 .0 II 0 .1 8556 DG 2 1 P 14 ALL T ISSU E S APPEARED NORMAL. 1 3 8 .0 8557 DG 2 1 P 14 ALL T ISSU E S APPEARED NORMAL. 1 3 4 .9 8558 DG 2 1 P 14 ALL T ISSU E S APPEARED NORMAL. 1 3 6 .7 8559 DG 2 1 P 14 ALL T ISSU E S APPEARED NORMAL. 1 2 4 .1 8560 DG 2 1 P 14 ALL T ISSU E S APPEARED NORMAL. 1 0 1 .6 III 1 .0 8561 DG 2 1 P 14 ALL TISSU ES APPEARED NORMAL. 1 5 9 .0 8562 DG 2 1 P 14 ALL TISSU ES APPEARED NORMAL. 1 1 9 .9 8563 DG 2 1 P 14 ALL T ISSU E S APPEARED NORMAL. 9 2.9 IV 2 .5 8564 DG 21 P 14 ALL TISSU ES APPEARED NORMAL. 1 1 6 .7 8565 DG 2 1 P 14 ALL TISSU ES APPEARED NORMAL. 1 0 9 .6 8566 DG 2 1 P 14 ALL TISSU ES APPEARED NORMAL. 1 2 0 .9 V 3 .7 5 8567 DG 2 1 P 14 ALL TISSU ES APPEARED NORMAL. 7 7.9 8568 DG 2 1 P 14 ALL TISSU ES APPEARED NORMAL. 9 7 .7 8569 DG 21 NP 14 ALL TISSU ES APPEARED NORMAL. 7 7 .6 8570 DG 21 P 14 ALL TISSU ES APPEARED NORMAL. 1 1 8 .6 8571 DG 21 P 14 ALL TISSU ES APPEARED NORMAL. 6 8 .5 P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED G ESTATION a. R efer to th e in d iv id u a l c lin ic a l o b se rv a tio n s ta b le (T able 14) fo r e x te rn a l o b se rv a tio n s con firm ed a t n ecro p sy . 418-012: PAGE B-32 000721 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 16 (PAGE 1) : MATERNAL BODY W EIGHTS - IND IV ID U A L DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 17 18 RABBIT # DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8443 NP 8444 P 8 44 5 NP 8446 P 8447 P 8448 p 8449 P 8450 P 8451 P 8452 P 8453 P 8454 P 8455 p 8456 P 8457 P 8458 p 8459 p 8460 P 8461 p 8462 P 8463 P 8464 p 3.22 3.35 3.42 3.38 3.41 3.36 3.43 3.46 3.53 3.53 3.63 3.55 3.60 3.40 3.42 3.51 3.52 3.48 3.48 3.46 3.48 3.52 3.53 3.52 3.53 3.56 3.58 3.76 3.81 3.91 3.89 3.87 3.94 3.94 3.92 3.93 4.01 3.91 3.95 3.24 3.38 3.45 3.40 3.29 3.31 3.41 3.50 3.56 3.63 3.68 3.59 3.62 3.44 3.79 3.82 3.82 3.85 3.94 3.97 3.96 4.00 4.05 4.01 4.04 4.10 3.44 3.44 3.54 3.54 3.62 3.61 3.63 3.67 3.74 3.84 3.78 3.81 3.84 3.55 3.50 3.41 3.34 3.40 3.55 3.54 3.66 3.66 3.66 3.66 3.69 3.77 3.07 3.24 3.29 3.32 3.37 3.34 3.39 3.36 3.40 3.43 3.50 3.55 3.55 3.34 3.41 3.43 3.47 3.50 3.51 3.58 3.65 3.80 3.77 3.74 3.77 3.74 3.17 2.86 2.83 2.80 2.97 3.15 3.12 3 .1 1 3.16 3.25 3.31 3.40 3.42 3.66 3.63 3.70 3.73 3.72 3.80 3.82 3.82 3.92 3.86 3.90 3.98 3.98 3.56 3.58 3.58 3.66 3.64 3.73 3.74 3.77 3.77 3.80 3.75 3.78 3.89 3.37 3.44 3.49 3.51 3.56 3.58 3.66 3.67 3.75 3.67 3.72 3.72 3.78 3.31 3.20 3.16 3.13 3.24 3.34 3.37 3.36 3.41 3.44 3.54 3.58 3.57 3.01 3.13 3.19 3.24 3.23 3.24 3.26 3.22 3.26 3.30 3.32 3.38 3.42 3.80 3.89 3.91 3.90 3.85 3.87 3.88 3.98 4.04 4.06 4.08 4.10 4.15 3.76 3.82 3.89 3.86 3.90 3.94 4.08 4.03 4.07 4.11 4.11 4.09 4.12 3.53 3.64 3.64 3.66 3.66 3.74 3.84 3.77 3.81 3.84 3.86 3.91 3.91 2.99 3.06 3.14 3.14 3.17 3.16 3.12 3.15 3.15 3.20 3.55 3.24 3.26 3.18 3.22 3.29 3.34 3.34 3.35 3.34 3.35 3.40 3.41 3.45 3.45 3.47 3.12 3.12 3.21 3.28 3.28 3.34 3.35 3.30 3.32 3.39 3.45 3.48 3.48 2.88 2.93 2.90 2.95 3.01 3.05 3.08 3.10 3.14 3.17 3.16 3.17 3.20 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED G ESTA TIO N ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIG N IF IC A N T D IG IT S AND REPORTED IN KILOGRAMS (KG) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED W ITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED W ITH THE ROUNDED KILOGRAM (KG) VALUE. c o 0 l\5 418-012:PAGE B-33 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 16 (PAGE 2) : MATERNAL BODY WEIGHTS - IN D IV ID U A L DATA PREGNANCY STATUS DAY 19 20 21 22 23 24 25 26 2 7 28 2 9 RABBIT # DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8443 NP 8444 P 8445 NP 8446 p 8447 p 8448 P 8449 P 8450 p 8451 P 8452 P 8453 p 8454 P 8455 P 8456 P 8457 P 8458 P 8459 P 8460 p 8461 P 8462 p 8463 P 8464 P 3.60 3.64 3.70 3.68 3.73 3.70 3.74 3.75 3.80 3.80 3.84 3.61 3.61 3.64 3.65 3.65 3.67 3.68 3.70 3.68 3.71 3.76 4.06 4.14 4.17 4.16 4.13 4.16 4.20 4.23 4.20 4.38 4.27 3.67 3.67 3.72 3.77 3.80 3.85 3.84 3.78 3.69 3.70 3.74 4.13 4.18 4.18 4.27 4.31 4.36 4.44 4.52 4.52 4.61 4.64 3.85 3.90 3.93 3.98 4.00 4.04 4.13 4.17 4.21 4.24 4.25 3.79 3.83 3.83 3.92 3.93 3.97 4.06 4.09 4.14 4.12 4.12 3.57 3.60 3.63 3.62 3.66 3.67 3.73 3.73 3.81 3.81 3.88 3.78 3.81 3.82 3.83 3.87 3.92 3.97 3.93 3.91 3.88 3.89 3.46 3.49 3.50 3.50 3.51 3.57 3.60 3.67 3.65 3.64 3.66 3.99 4.04 4.07 4.07 4.12 4.15 4.18 4.23 4.29 4.28 4.37 3.89 3.92 3.95 4.00 4.06 4.09 4.11 4.16 4.16 4.12 4.15 3.82 3.86 3.90 3.91 3.95 3.98 4.00 4.05 4.07 4.05 4.10 3.62 3.61 3.66 3.70 3.69 3.72 3.72 3.74 3.71 3.72 3.72 3.47 3.50 3.54 3.55 3.61 3.62 3.64 3.66 3.60 3.61 3.58 4.10 4.14 4.16 4.17 4.18 4.21 4.23 4.25 4.24 4.16 4.10 4.18 4.15 4.18 4.20 4.29 4.33 4.32 4.42 4.39 4.40 4.52 3.98 3.96 3.99 3.98 3.99 4.11 4.15 4.23 4.22 4.24 4.26 3.26 3.30 3.29 3.30 3.33 3.33 3.32 3.31 3.34 3.34 3.35 3.51 3.52 3.50 3.53 3.49 3.55 3.44 3.58 3.50 3.57 3.49 3.65 3.53 3.68 3.53 3.68 3.55 3.66 3.58 3.67 3.61 3.66 3.23 3.24 3.29 3.29 3.33 3.35 3.37 3.36 3.37 3.37 3.39 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED G ESTA TIO N ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) , ROUNDED TO THREE SIG N IF IC A N T D IG IT S AND REPORTED IN KILOGRAMS ( K G ) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. o BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. o *>1 Co 418-012: PAGE B-34 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 16 (PAGE 3) : MATERNAL BODY WEIGHTS - IND IVIDU A L DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 17 18 RABBIT # DOSAGE GROUP I I 0 .1 MG/KG/DAY 8465 P 3.58 3.88 3.94 3.91 3.94 3.97 4.02 4.02 4.09 4.07 4.11 4.04 4.08 8466 NP 3.53 3.63 3.63 3.64 3.57 3.64 3.63 3.66 3.63 3.64 3.68 3.72 3.78 8467 NP 3.43 3.63 3.66 3.66 3.68 3.77 3.73 3.77 3.87 3.80 3.92 3.85 3.85 8468 P 3.23 3.53 3.55 3.57 3.52 3.53 3.60 3.64 3.68 3.72 3.73 3.68 3.77 8469 P 3.17 3.39 3.45 3.46 3.49 3.47 3.50 3.56 3.62 3.65 3.84 3.60 3.65 8470 P 3.00 3.17 3.28 3.22 3.17 3.18 3.17 3.16 3.21 3.27 3.24 3.31 3.33 8471 P 3.10 3.30 3.37 3.40 3.39 3.38 3.30 3.34 3.34 3.40 3.40 3.43 3.46 8472 P 3.40 3.40 3.47 3.55 3.64 3.64 3.63 3.66 3.69 3.75 3.68 3.71 3.78 8473 P 2.95 3.15 3.11 3.11 3.25 3.28 3.25 3.30 3.32 3.30 3.27 3.35 3.37 8474 P 3.28 3.34 3.36 3.41 3.40 3.40 3.42 3.44 3.48 3.54 3.59 3.60 3.58 8475 P 3.51 3.47 3.54 3.54 3.49 3.56 3.63 3.67 3.77 3.72 3.77 3.79 3.83 8476 P 3.58 3.46 3.51 3.52 3.64 3.68 3.59 3.61 3.70 3.64 3.64 3.68 3.71 8477 NP 3.47 3.54 3.58 3.64 3.59 3.57 3.64 3.74 3.78 3.73 3.68 3.70 3.67 8478 P 2.95 3.21 3.24 3.25 3.22 3.05 2.96 3.15 3.28 3.26 3.26 3.26 3.32 8479 P 3.11 3.31 3.39 3.39 3.34 3.34 3.34 3.32 3.33 3.27 3.32 3.39 3.46 8480 p 3.74 3.69 3.76 3.78 3.78 3.84 3.96 3.90 3.94 3.99 4.01 4.04 4.03 8481 P a 3.32 3.43 3.45 3.42 3.35 3.37 3.38 3.46 3.52 3.60 3.57 3.53 3.57 8482 P 3.25 3.30 3.41 3.37 3.36 3.39 3.41 3.44 3.50 3.57 3.56 3.57 3.65 8483 p 3.60 3.57 3.61 3.67 3.72 3.71 3.84 3.74 3.80 3.88 3.92 3.93 3.99 8484 P 3.18 3.25 3.24 3.29 3.34 3.39 3.46 3.39 3.48 3.53 3.58 3.58 3.58 8485 P 3.47 3.49 3.54 3.60 3.63 3.64 3.64 3.68 3.72 3.74 3.75 3.76 3.78 8486 p 3.87 3.90 3.96 3.99 3.97 3.96 3.91 3.89 3.89 3.94 3.95 3.98 4.04 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED G ESTA TIO N ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE S IG N IF IC A N T D IG IT S 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 8481 had a l i t t e r w hich c o n s is te d on 10 d ead f e t u s e s ; v a lu e s e x c lu d e d from g ro u p a v e ra g e s and s t a t i s t i c a l a n a ly se s . ooo w 418-012: PAGE B-35 PROTOCOL 418012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 16 (PAGE 4) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 19 20 21 22 23 24 25 26 27 28 29 RABBIT # DOSAGE GROUP I I 0 .1 MG/KG/DAY 8465 P 4.12 4.15 4.15 4.25 4.23 4.26 4.25 4.32 4.33 4.34 4.34 8466 NP 3.82 3.87 3.89 3.92 3.95 3.94 3.96 4.01 4.03' 3.99 4.01 8467 NP 3.90 3.94 3.98 3.99 4.01 3.98 4.05 4.08 4.07 4.13 4.20 8468 P 3.77 3.83 3.89 3.88 3.89 3.92 3.98 3.94 3.97 3.94 3.91 8469 P 3.66 3.69 3.70 3.75 3.83 3.82 3.88 3.87 3.87 3.96 4.03 8470 P 3.37 3.34 3.36 3.32 3.30 3.28 3.31 3.35 3.37 3.38 3.40 8471 P 3.40 3.50 3.58 3.61 3.64 3.67 3.62 3.63 3.66 3.70 3.73 8472 P 3.82 3.84 3.87 3.93 3.95 3.98 4.03 4.05 4.10 4.12 4.12 8473 P 3.36 3.45 3.48 3.50 3.49 3.51 3.48 3.46 3.46 3.42 3.43 8474 P 3.60 3.65 3.64 3.71 3.74 3.75 3.73 3.77 3.79 4.15 3.81 8475 P 3.85 3.85 3.85 3.87 3.90 3.96 3.99 4.03 4.04 4.11 4.13 8476 P 3.74 3.81 3.91 3.91 3.91 3.97 4.01 4.05 4.10 4.13 4.18 8477 NP 3.74 3.78 3.80 3.82 3.82 3.87 3.88 3.93 3.93 3.97 4.06 8478 P 3.34 3.35 3.42 3.44 3.44 3.48 3.48 3.47 3.40 3.55 3.53 8479 P 3.53 3.57 3.59 3.64 3.72 3.74 3.74 3.80 3.78 3.78 3.77 8480 P 4.03 4.06 4.11 4.18 4.20 4.29 4.26 4.25 4.29 4.29 4.30 8481 P a 3.64 3.65 3.72 3.74 3.78 3.86 3.88 3.93 3.92 3.88 3.82 8482 P 3.51 3.65 3.70 3.70 3.77 3.78 3.81 3.87 3.86 3.89 3.91 8483 P 3.99 3.96 4.02 4.02 4.06 4.13 4.15 4.22 4.21 4.22 4.26 8484 P 3.58 3.62 3.64 3.66 3.71 3.67 3.69 3.62 3.63 3.58 3.58 8485 P 3.80 3.79 3.74 3.80 3.80 3.95 3.88 3.97 4.00 4.02 4.13 8486 P 3.99 4.02 4.07 4.11 4.15 4.20 4.25 4.24 4.15 4.16 4.21 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED G ESTA TIO N ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) , ROUNDED TO THREE S IG N IF IC A N T D IG IT S AND REPORTED IN KILOGRAMS ( K G ) . ALL CALCULATIONS EXCEPT BODY W EIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. a . Doe 8481 had a l i t t e r w hich c o n s is te d on 10 d ead f e t u s e s ; v a lu e s e x c lu d e d from g ro u p a v e ra g e s and s t a t i s t i c a l a n a ly se s . 418-012: PAGE B-36 000725 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 16 (PAGE 5) : MATERNAL BODY WEIGHTS - IND IVIDU A L DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 17 18 RABBIT # DOSAGE GROUP I I I 1 .0 MG/KG/DAY 8487 P 8488 P 8489 P 8490 P 8491 P 8492 P 8493 P 8494 P 8495 P 8496 P 8497 P 8498 P 8499 P 8500 P 8501 P 8502 NP 8503 P 8504 P 8505 NP 8506 p 8507 P 8508 NP 3.37 3.47 3.50 3.49 3.50 3.57 3.60 3.64 3.69 3.68 3.72 3.71 3.77 3.18 3.28 3.33 3.33 3.32 3.35 3.40 3.43 3.38 3.44 3.48 3.44 3.49 3.09 3.23 3.31 3.34 3.36 3.38 3.40 3.43 3.48 3.50 3.58 3.51 3.56 3.58 3.69 3.68 3.59 3.63 3.69 3.77 3.79 3.87 3.88 3.90 3.90 3.94 3.65 3.61 3.62 3.66 3.72 3.72 3.76 3.83 3.86 3.92 3.82 3.83 3.89 3.16 3.37 3.35 3.29 3.28 3.26 3.29 3.27 3.28 3.34 3.36 3.41 3.43 3.71 3.72 3.78 3.74 3.74 3.81 3.84 3.90 3.94 4.00 4.01 4.03 4.03 3.33 3.38 3.40 3.40 3.39 3.47 3.52 3.57 3.66 3.64 3.64 3.67 3.65 3.43 3.57 3.60 3.66 3.67 3.70 3.64 3.74 3.84 3.82 3.83 3.78 3.78 3.52 3.55 3.60 3.45 3.57 3.62 3.65 3.71 3.74 3.76 3.78 3.75 3.82 3.25 3.40 3.37 3.35 3.37 3.41 3.44 3.45 3.40 3.28 3.49 3.52 3.46 2.87 2.99 3.04 3.06 3.04 3.07 3.11 3.16 3.17 3.19 3.22 3.25 3.28 3.56 3.60 3.60 3.63 3.67 3.69 3.73 3.78 3.76 3.80 3.85 3.86 3.90 3.17 3.30 3.37 3.34 3.30 3.38 3.44 3.46 3.52 3.53 3.56 3.61 3.59 2.96 3.23 3.17 3.24 3.16 3.15 3.17 3.25 3.34 3.44 3.44 3.44 3.48 3.02 3.31 3.33 3.31 3.21 3.29 3.28 3.24 3.22 3.20 3.28 3.32 3.40 3.91 4.04 4.03 4.08 4.12 4.10 4.09 4.15 4.20 4.26 4.29 4.33 4.31 3.38 3.48 3.53 3.57 3.60 3.62 3.60 3.61 3.64 3.61 3.61 3.59 3.58 3.22 3.28 3.37 3.33 3.38 3.42 3.44 3.43 3.49 3.53 3.54 3.59 3.61 3.26 3.50 3.58 3.58 3.53 3.56 3.58 3.64 3.69 3.75 3.79 3.80 3.80 3.57 3.56 3.62 3.58 3.57 3.60 3.65 3.66 3.69 3.70 3.71 3.75 3.76 3.49 3.58 3.60 3.57 3.63 3.66 3.72 3.71 3.74 3.81 3.84 3.83 3.87 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED G ESTA TIO N ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) , ROUNDED TO THREE SIG N IF IC A N T D IG IT S AND REPORTED IN KILOGRAMS ( K G ) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. O BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. o o i0 Ci 418-012:PAGE B-37 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 16 (PAGE 6) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 1 9 2 0 2 1 22 2 3 2 4 2 5 2 6 2 7 28 2 9 RABBIT # DOSAGE GROUP I I I 1 .0 MG/KG/DAY 8487 P 8488 P 8489 P 8490 P 8491 P 8492 P 8493 P 8494 P 8495 P 8496 P 8497 P 8498 P 8499 P 8500 P 8501 P 8502 NP 8503 P 8504 P 8505 NP 8506 P 8507 P 8508 NP 3.76 3.80 3.81 3.86 3.89 3.92 3.94 3.92 3.88 3.88 3.90 3.56 3.56 3.59 3.64 3.66 3.69 3.70 3.75 3.75' 3.72 3.83 3.59 3.61 3.64 3.68 3.73 3.73 3.78 3.77 3.82 3.82 3.86 3.92 3.97 4.02 4.08 4.06 4.09 4.09 4.12 4.12 4.13 4.15 3.89 3.91 3.98 4.02 4.04 4.13 4.15 4.17 4.15 4.18 4.20 3.46 3.49 3.54 3.57 3.58 3.61 3.61 3.59 3.62 3.68 3.71 3.95 3.96 3.95 3.99 3.88 3.98 4.01 4.03 4.03 4.08 4.13 3.67 3.70 3.70 3.72 3.75 3.73 3.77 3.76 3.78 3.78 3.81 3.82 3.86 3.90 3.96 3.97 3.96 3.96 3.92 3.93 3.93 3.92 3.89 3.86 3.92 3.92 3.90 3.88 3.96 3.96 3.96 4.04 4.08 3.40 3.50 3.53 3.51 3.58 3.59 3.68 3.66 3.65 3.67 3.65 3.33 3.33 3.31 3.33 3.36 3.34 3.37 3.38 3.36 3.37 3.37 3.96 3.97 3.97 4.02 4.02 4.05 4.14 4.16 4.24 4.26 4.26 3.52 3.64 3.66 3.72 3.73 3.72 3.80 3.82 3.80 3.80 3.79 3.46 3.48 3.48 3.46 3.49 3.49 3.51 3.56 3.60 3.65 3.65 3.46 3.44 3.44 3.47 3.48 3.48 3.45 3.42 3.45 3.49 3.51 4.31 4.37 4.34 4.38 4.43 4.46 4.48 4.51 4.42 4.45 4.47 3.60 3.61 3.62 3.72 3.73 3.78 3.77 3.80 3.72 3.65 3.69 3.54 3.62 3.64 3.69 3.69 3.74 3.76 3 -77 3.78 3.86 3.84 3.78 3.81 3.84 3.84 3.89 3.94 3.99 4.01 3.99 4.03 4.08 3.76 3.81 3.83 3.88 3.89 3.91 3.93 3.91 3.90 3.91 3.98 3.85 3.86 3.86 3.84 3.90 3.99 4.00 3.99 3.88 3.90 3.97 PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) , ROUNDED TO THREE SIG N IF IC A N T D IG IT S AND REPORTED IN KILOGRAMS ( K G ) . ALL CALCULATIONS EXCEPT BODY W EIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 418-012: PAGE B-38 000727 418-012: PAGE B-39 000728 PROTOCOL 4 1 8 - 0 1 2 : ORAL (STOMACH TUBE) DEVELOPMENTAL TO X IC ITY STUDY OF PFOS IN RABBITS (SPONSOR' S STUDY NUMBER: 6 2 9 5 . 1 0 ) TABLE 16 (PAGE 7 ) : MATERNAL BODY WEIGHTS - IND IVIDU A L DATA PREGNANCY STATUS DAY 0 7 8 9 1 0 11 12 13 14 15 1 6 RABBIT # DOSAGE GROUP IV 2 .5 MG/KG/DAY 8509 P 8510 P 8511 NP 8512 p 8513 NP 8514 P 8515 P 8516 P 8517 P 8518 p 8519 P 8520 P 8521 P 8522 P 8523 NP 8524 NP 8525 P 8526 NP 8527 p 8528 P 8529 P 8530 P 3.00 3.11 3.13 3.13 3.09 3.11 3.13 3.20 3.23 3.24 3.25 3.40 3.53 3.53 3.58 3.61 3.60 3.68 3.78 3.80' 3.81 3.78 3.17 3.33 3.47 3.47 3.50 3.54 3.56 3.60 3.55 3.54 3.51 3.37 3.54 3.51 3.60 3.60 3.60 3.59 3.62 3.68 3.73 3.78 3.43 3.56 3.57 3.63 3.61 3.59 3.58 3.66 3.67 3.63 3.64 3.32 3.57 3.64 3.65 3.60 3.56 3.61 3.68 3.72 3.74 3.72 3.58 3.59 3.71 3.71 3.74 3.71 3.74 3.84 3.85 3.93 3.87 3.55 3.63 3.67 3.68 3.64 3.62 3.61 3.59 3.68 3.70 3.69 3.14 3.44 3.38 3.37 3.41 3.45 3.49 3.49 3.43 3.32 3.24 3.50 3.70 3.69 3.74 3.74 3.78 3.88 3.82 3.88 3.91 3.91 3.27 3.32 3.29 3.36 3.41 3.47 3.44 3.46 3.50 3.55 3.56 3.08 3.14 3.16 3.18 3.14 3.15 3.17 3.20 3.26 3.28 3.32 3.23 3.44 3.48 3.49 3.47 3.47 3.44 3.45 3.51 3.59 3.57 3.74 3.81 3.85 3.91 3.93 3.93 3.96 4.11 4.02 4.10 4.18 3.62 3.83 3.82 3.86 3.90 3.88 3.96 3.96 3.93 3.94 3.80 2.88 3.10 3.14 3.14 3.13 3.10 3.12 3.14 3.20 3.24 3.26 3.57 3.66 3.73 3.70 3.68 3.68 3.65 3.68 3.56 3.64 3.67 2.83 2.98 2.95 2.93 2.96 2.99 3.00 3.01 3.01 3.00 3.01 3.51 3.53 3.62 3.71 3.69 3.61 3.62 3.64 3.63 3.68 3.61 3.17 3.29 3.28 3.29 3.29 3.26 3.25 3.25 3.28 3.37 3.39 3.26 3.33 3.41 3.40 3.41 3.41 3.45 3.50 3.53 3.56 3.55 3.85 4.01 4.07 4.02 4.00 4.03 4.22 4.11 4.19 4.24 4.24 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED G ESTA TIO N ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE S IG N IFIC A N T D IG IT S AND REPORTED IN KILOGRAMS (KG) . ALL CALCULATIONS EXCEPT BODY W EIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 17 3.23 3.77 3.53 3.71 3.66 3.70 3.86 3.71 3.20 3.91 3.55 3.32 3.52 4.11 3.73 3.26 3.68 3.04 3.63 3.37 3.57 4.24 18 3.25 3.76 3.56 3.77 3.63 3.72 3.89 3.73 3.16 3.85 3.56 3.30 3.54 4.10 3.66 3.24 3.71 3.08 3.77 3.39 3.58 4.24 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 16 (PAGE 8) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 1 9 20 2 1 22 23 24 25 2 6 2 7 2 8 2 9 RABBIT # DOSAGE GROUP IV 2 .5 MG/KG/DAY 8509 P 8510 P 8511 NP 8512 P 8513 NP 8514 p 8515 p 8516 P 8517 P 8518 p 8519 p 8520 P 8521 p 8522 P 8523 NP 8524 NP 8525 P 8526 NP 8527 p 8528 P 8529 p 8530 p 3.24 3.29 3.31 3.32 3.34 3.29 3.33 3.34 3.34 3.39 3.42 3.75 3.76 3.81 3.80 3.84 3.83 3.89 3.91 3.92' 3.94 3.98 3.58 3.62 3.63 3.64 3.65 3.62 3.63 3.68 3.68 3.73 3.72 3.82 3.79 3.83 3.85 3.87 3.91 3.93 3.86 3.88 3.86 3.92 3.65 3.64 3.65 3.68 3.65 3.66 3.70 3.71 3.75 3.77 3.76 3.72 3.73 3.77 3.70 3.70 3.80 3.82 3.82 3.83 3.86 3.86 3.90 3.94 4.00 4.01 4.03 4.04 4.04 4.07 4.07 4.01 3.95 3.70 3.71 3.76 3.77 3.81 3.89 3.86 3.86 3.89 3.90 3.98 3 . 1 1 3 . 1 0 3 . 0 9 3 . 0 3 3 . 0 3 2 . 9 8 ABORTED ON DAY 2 5 OF GESTATION 3.92 3.92 3.94 3.96 3.96 3.93 3.86 3.74 3.62 3.56 3.57 3.60 3.61 3.66 3.65 3.68 3.69 3.69 3.66 3.73 3.74 3.78 3.33 3.33 3.32 3.32 3.35 3.38 3.39 3.39 3.41 3.43 3.49 3.51 3.50 3.54 3.57 3.60 3.63 3.68 3.65 3.64 3.71 3.74 4.13 4.19 4.18 4.23 4.27 4.33 4.34 4.37 4.39 4.39 4.46 3.60 3.56 3.50 3.46 3.40 3.36 3.32 3.42 3.51 3.63 3.69 3.20 3.25 3.24 3.28 3.24 3.22 3.18 3.25 3.34 3.33 3.36 3.70 3.75 3.71 3.70 3.70 3.82 3.83 3.86 3.88 3.84 3.93 3.11 3.15 3.18 3.23 3.26 3.29 3.26 3.26 3.23 3.24 3.26 3.79 3.83 3.84 3.89 3.75 3.72 3.77 3.78 3.75 3.86 3.93 3.42 3.41 3.43 3.44 3.44 3.44 3.48 3.46 3.46 3.46 3.51 3.58 3.60 3.59 3.60 3.58 3.60 3.64 3.68 3.73 3.80 3.81 4.19 4.27 4.28 4.31 4.35 4.40 4.41 4.37 4.34 4.34 4.36 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED G ESTA TIO N ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) , ROUNDED TO THREE S IG N IF IC A N T D IG IT S AND REPORTED IN KILOGRAMS ( K G ) . ALL CALCULATIONS EXCEPT BODY W EIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) VALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 418-012:PAGE B-40 00072 US 418-012: PAGE B-41 000730 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 16 (PAGE 9): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 RABBIT # DOSAGE GROUP V 3 . 7 5 MG/KG/DAY 8531 P 8532 P 8533 P 8534 P 8535 P 8536 P 8537 P 8538 P 8539 P 8540 P 8541 P 8542 P 8543 P 8544 P 8545 P 8546 P 8547 P 8548 P 8549 P 8550 P 8551 P 8552 NP 3.36 3.42 3.55 3.28 3.42 3.32 3.43 3.55 3.47 3.52 3.64 3.40 3.47 3.54 3.54 3.47 3.66 3.33 3.52 3.56 3.48 3.48 3.63 3.71 3.56 3.53 3.48 3.38 3.57 3.72 3.61 3.55 3.46 3.33 3.51 3.77 3.66 3.48 3.49 3.31 3.63 3.74 3.63 3.60 3.52 3.29 3.69 3.77 3.68 3.58 3.55 3.30 3.80 3.74 3.74 3.52 3.58 3.35 3.82 3.72 3.83 3.46 3.56 3.19 3.78 3.74 3.25 2.86 3.07 3.58 3.16 3.37 2.96 3.36 3.47 3.25 3.36 2.92 3.43 3.52 3.31 3.27 2.84 3.36 3.53 3.34 3.31 2.79 3.33 3.65 3.35 3.31 2.72 3.29 3.64 3.38 3.42 2.74 3.30 3.67 3.42 3.40 2.78 3.29 3.76 3.44 3.32 2.74 3.23 3.84 3.52 3.33 2.68 3.17 3.84 3.53 3.22 2.66 3.12 3.73 3.52 3.58 3.68 3.00 3.02 3.21 3.69 3.81 3.12 3.25 3.36 3.72 3.82 3.18 3.30 3.38 3.74 3.86 3.20 3.35 3.38 3.71 3.88 3.21 3.43 3.41 3.70 3.86 3.27 3.40 3.46 3.74 3.79 3.28 3.42 3.51 3.71 3.73 3.23 3.41 3.54 3.74 3.67 3.14 3.47 3.56 3.77 3.62 3.08 3.50 3.58 3.76 3.61 3.01 3.54 3.61 3.53 3.50 3.60 3.61 3.63 3.65 3.62 3.58 3.54 3.46 3.42 3.59 3.59 3.59 3.65 3.73 3.80 3.88 3.81 3.85 3.89 3.84 3.20 3.12 3.49 3.26 3.25 3.40 3.32 3.31 3.46 3.30 3.38 3.49 3.34 3.45 3.51 3.40 3.51 3.60 3.39 3.52 3.69 3.40 3.54 3.66 3.43 3.54 3.70 3.41 3.53 3.77 3.37 3.57 3.60 3.90 3.98 3.99 4.06 3.94 3.96 3.96 3.93 3.90 3.96 3.90 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED G ESTA TIO N ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) , ROUNDED TO THREE S IG N IFIC A N T D IG IT S AND REPORTED IN KILOGRAMS (KG) ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED WITH THE UNROUNDED GRAM (G) V A LU E. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 17 3.70 3.43 3.57 3.22 3.79 3.68 3.25 2.58 3.06 3.60 3.53 3.77 3.52 2.94 3.54 3.62 3.34 3.81 3.32 3.56 3.72 3.93 18 3.78 3.34 3.51 3.14 3.80 3.66 3.24 2.56 3.04 3.55 3.54 3.77 3.50 2.89 3.56 3.60 3.31 3.79 3.32 3.60 3.75 3.96 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 16 (PAGE 10): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 19 20 21 22 23 24 25 26 27 28 29 RABBIT # DOSAGE GROUP V 3 . 7 5 MG/KG/DAY 8531 P 8532 P 8533 P 8534 p 8535 P 8536 P 8537 p 8538 P 8539 P 8540 P 8541 p 8542 P 8543 P 8544 p 8545 P 8546 P 8547 P 8548 P 8549 P 8550 p 8551 P 8552 NP 3.78 3.84 3.87 3.90 3.97 3.97 3.98 4.08 4.03 4.10 4.13 3.30 3.24 3.20 3.36 3.41 3.49 3.49 3.56 3.51' 3.60 3.65 3.48 3.46 3.42 3.45 3.48 3.51 3.56 3.59 3.56 3.57 3.63 3 . 0 3 3 . 0 5 2 . 9 3 ABORTED ON DAY 2 2 OF GESTATION 3.82 3.80 3.75 3.66 3.61 3.55 3.49 3.43 3.49 3.53 3.63 3.68 3.73 3.82 3.83 3.83 3.92 3.90 3.95 3.92 3.95 4.02 3 . 1 0 3 . 1 0 3 . 1 2 3 . 0 5 3 . 0 7 3 . 0 2 ABORTED ON DAY 2 5 OF GESTATION 2 . 5 5 2 . 5 1 2 . 4 9 2 . 5 3 2 . 5 3 2 . 3 2 ABORTED ON DAY 2 4 OF GESTATION 3 . 0 2 2 . 9 4 2 . 9 6 2 . 8 5 2 . 7 9 ABORTED ON DAY 2 4 OF GESTA TION 3 . 5 2 3 . 4 0 3 . 3 6 3 . 3 2 3 . 2 8 3 . 2 1 ABORTED ON DAY 25 OF GESTATION 3.57 3.61 3.65 3.66 3.71 3.73 3.73 3.70 3.62 3.64 3.73 3 . 7 0 3 . 6 6 3 . 6 6 3 . 5 8 3 . 5 9 3 . 5 4 3 . 5 8 3 . 5 2 3 . 5 7 ABORTED ON DAY 2 8 OF G ESTA TIO N 3.45 3.44 3.40 3.36 3.30 3.25 3.19 3.20 3.16 3.11 3.08 2 . 8 4 2 . 8 8 2 . 8 5 2 . 8 6 2 . 8 0 2 . 7 4 ABORTED ON DAY 2 5 OF GESTATION 3.61 3.64 3.66 3.60 3.59 3.66 3.69 3.66 3.69 3.66 3.70 3.63 3.65 3.73 3.67 3.67 3.69 3.70 3.70 3.68 3.73 3.76 3 . 2 5 3 . 2 4 3 . 1 9 ABORTED ON DAY 22 OF GESTATION 3 . 7 6 3 . 6 7 3 . 7 0 3 . 6 2 3 . 5 8 3 . 5 8 ABORTED ON DAY 25 OF GESTATION 3.30 3.29 3.33 3.36 3.39 3.46 3.52 3.50 3.56 3.54 3.59 3.60 3.62 3.64 3.62 3.68 3.68 3.76 3.76 3.77 3.79 3.73 3.76 3.83 3.85 3.82 3.74 3.74 3.80 3.81 3.82 3.87 3.96 3.89 3.88 3.88 3.81 3.92 3.89 3.93 3.89 3.92 3.88 3.93 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED G ESTA TIO N ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) , ROUNDED TO THREE S IG N IF IC A N T D IG IT S AND REPORTED IN KILOGRAMS ( K G ) . ALL CALCULATIONS EXCEPT BODY WEIGHT AVERAGES ARE PERFORMED W ITH THE UNROUNDED GRAM (G) V ALUE. BODY WEIGHT AVERAGES ARE CALCULATED WITH THE ROUNDED KILOGRAM (KG) VALUE. 418-012: PAGE B-42 000731 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 16 (PAGE 11): MATERNAL BODY WEIGHTS - INDIVIDUAL 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 8553 P 8554 P 8555 P 3.95 3.96 4.05 4.06 4.09 4.11 3.87 4.07 4.09 4.01 4.18 3.36 3.44 3.45 3.52 3.61 3.67 3.60 3.56 3 . 5T 3.68 3.67 3.09 3.05 3.06 3.12 3.13 3.17 3.13 3.09 3.12 3.18 3.29 DAY 1 9 2 0 21 8553 p 8554 P 8555 P 4.23 4.25 4.34 3.74 3.75 3.84 3.33 3.39 3.39 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED G ESTA TIO N ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) , ROUNDED TO THREE SIG N IF IC A N T D IG IT S AND REPORTED IN KILOGRAMS ( K G ) . 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 4.20 3.71 3.26 18 4.21 3.74 3.28 418-012: PAGE B-44 000733 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 16 (PAGE 12) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 RABBIT # SATELLITE DOSAGE GROUP I I 0 .1 MG/KG/DAY 8556 P 8557 P 8558 P 8559 P 8560 P 3.80 3.92 3.88 3.88 3.88 3.86 3.80 3.88 3.98 4.00 3.95 3.39 3.41 3.45 3.51 3.46 3.47 3.44 3.46 3.44 3.46 3.51 3.56 3.51 3.58 3.61 3.70 3.76 3.66 3.58 3.57 3.67 3.69 3.61 3.50 3.60 3.60 3.64 3.63 3.61 3.68 3.72 3.71 3.75 3.12 3.22 3.31 3.26 3.28 3.36 3.26 3.34 3.43 3.47 3.52 DAY 19 20 21 8556 P 8557 P 8558 P 8559 P 8560 P 3.95 3.98 4.03 3.63 3.66 3.72 3.82 3.83 3.92 3.86 3.86 3.88 3.50 3.50 3.52 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED G ESTA TIO N ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE S IG N IF IC A N T D IG IT S 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 3.89 3.57 3.71 3.82 3.53 18 3.91 3.58 3.74 3.81 3.56 418-012: PAGE B-45 000734 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 16 (PAGE 13) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 7 8 9 10 i i 12 13 14 IS 16 RABBIT # SATELLITE DOSAGE GROUP I I I 1 .0 MG/KG/DAY 8561 P 8562 P 8563 P 3.98 3.54 3.87 3.55 3.95 3.58 3.96 3.64 3.97 3.63 4.04 3.65 3.92 3.65 3.96 3.70 3.98 3.73 3.98 3.80 4.01 3.81 2.98 3.16 3.19 3.15 3.20 3.26 3.23 3.24 3.27 3.30 3.32 DAY 19 20 21 8561 P 8562 P 8563 P 4.12 4.08 4.06 3.84 3.84 3.90 3.37 3.36 3.35 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED G ESTA TIO N ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) , ROUNDED TO THREE SIG N IF IC A N T D IG IT S AND REPORTED IN KILOGRAMS ( K G ) . 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 4.03 3.83 3.32 18 4.04 3.81 3.34 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 16 (PAGE 1 4 ) : MATERNAL BODY WEIGHTS - 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 8564 P 8565 P 8566 P 3.86 3.88 3.91 3.95 3.98 4.03 3.95 3.95 4.02 4.07 4.04 3.34 3.36 3.42 3.51 3.49 3.55 3.38 3.37 3.34 3.28 3.21 3.08 3.09 3.19 3.24 3.30 3.39 3.30 3.32 3.26 3.23 3.24 DAY 19 20 21 8564 P 8565 P 8566 P 4.10 4.07 4.18 3.49 3.57 3.60 3.27 3.35 3.39 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) , ROUNDED TO THREE S IG N IF IC A N T D IG IT S AND REPORTED IN KILOGRAMS ( K G ) . 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 4.04 3.33 3.24 18 4.04 3.44 3.21 418-012: PAGE B-46 oo Co tn PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 16 (PAGE 15): MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 RABBIT # SATELLITE DOSAGE GROUP V 3 . 7 5 MG/KG/DAY 8567 P 8568 P 8569 NP 8570 P 8571 P 3.91 3.86 3.91 3.94 3.91 3.90 3.97 3.90 3.95 3.96 4.03 3.37 3.31 3.34 3.36 3.31 3.30 3.23 3.22 3.28' 3.31 3.32 3.60 3.59 3.58 3.59 3.51 3.53 3.37 3.31 3.26 3.20 3.17 3.75 3.58 3.59 3.65 3.72 3.78 3.75 3.71 3.62 3.53 3.45 2.75 2.85 2.84 2.89 2.88 2.87 2.90 2.91 2.88 2.85 2.84 DAY 1 9 20 21 8567 P 8568 P 8569 NP 8570 P 8571 p 3.85 3.78 3.68 3.34 3.34 3.39 3.06 3.02 3.00 3.52 3.60 3.65 2.84 2.88 2.90 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED G ESTA TIO N ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) , ROUNDED TO THREE S IG N IF IC A N T D IG IT S AND REPORTED IN KILOGRAMS ( K G ) . 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 3.98 3.31 3.13 3.40 2.87 18 3.94 3.31 3.10 3.49 2.84 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 17 (PAGE 1) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA 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 RABBIT # DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8443 NP 8444 P 8445 NP 8446 P 8447 P 8448 P 8449 P 8450 P 8451 P 8452 P 8453 P 8454 P 8455 P 8456 P 8457 P 8458 P 8459 P 8460 P 8461 P 8462 P 8463 P 8464 P 185. 180 . 184 . 180 . 181. 185. 183 . 183 . 146 . 96. 89. 53 . 87 . 41 . 185. 180. 185 . 183 . 185. 180 . 185 . 151. 94 . 92 . 124 . 171 . 185 . 185 . 183 . 180 . 180. 183 . 183 . 177 . 180. 116. I l l . 185. 157. 165 . 165. 184 . 80 . 12 . 81. 169. 151. 184 . 150 . 180 . 184 . 166 . 168 . 166 . 161. 125 . 181. 182 . 182. 180 . 185 . 185 . 183 . 16. 26. 27. 107. 90 . 65 . 86 . 183 . 180 . 180 . 185. 182. 181. 185. 184. 180 . 15. 180 . 185. 160 . 107. 185. 180 . 180 . 169. 180 . 185 . 180. 4. 5 . 107. 159. 118. 90 . 169. 185. 184 . 165. 133 . 97. 74 . 93 . 183. 94 . 98. 115 . 110 . 139. 183 . 180. 184 . 180. 182 . 185 . 185. 184 . 180. 183. 183 . 184 . 185 . 183 . 181. 171. 165 . 150 . 131. 81. 119. 123 . 184 . 185 . 167. 130 . 110. 114 . 152 . 180 . 184 . 164 . 184 . 160 . 145 . 121. 90. 134 . 164 . 185 . 148 . 181. 185 . PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) . 1 4-1 5 180 . Ill. 180 . 184 . 166 . 171. 127. 182 . 181. 143 . 182 . 181. 180 . 185. 183 . 151. 184 . 183 . 146 . 166. 165 . 165 . 15-1 6 167. 97'. 182. 157. 185. 182 . 127. 184 . 182 . 185. 182. 180. 184. 183 . 182 . 154 . 181. 182 . 148 . 182. 183 . 165. 1 6-1 7 183. 185. 185. 182 . 182 . 181. 152. 182. 185. 181. 185. 185. 181. 185. 167. 181. 180. 185. 153 . 172 . 183 . 150 . 17 - 18 18 - 19 19 - 20 180. 183 . 180 182 . 181. 184 182 . 183. 185 181. 182 . 185 180. 184 . 180 183 . 185 . 183 180 . 185. 185 185 . 184 . 180 185. 185. 180 185. 185. 180 184 . 185. 185 185. 185 . 180 181. 180. 181 185. 180 . 182 173 . 180 . 185 184 . 124 . 111 180. 180. 184 184. 185. 185 154 . 101. 104 181. 184. 180 180. 185. 185 158 . 184 . 159 418-012:PAGE B-48 000737 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 17 (PAGE 2): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 2 0 - 2 1 2 1 - 2 2 2 2 - 2 3 2 3 -- 2 4 24 - 2 5 2 5 - 2 6 2 6 - 2 7 RABBIT # DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8443 NP 8444 P 8445 NP 8446 P 8447 P 8448 P 8449 P 8450 P 8451 P 8452 P 8453 P 8454 P 8455 P 8456 P 8457 P 8458 P 8459 P 8460 P 8461 P 8462 P 8463 P 8464 P 182 . 180. 180 . 181. 180. 180 . 180 . 163 . 180 . 122. 106 . 173 . 100 . 101. 184 . 185. 185 . 182 . 180. 182 . 180 . 182. 180 . 185. 182 . 180. 63 . 19. 180. 185 . 184 . 182 . 182 . 185 . 167. 183 . 185 . 185. 181. 185. 182 . 152. 180 . 185. 180 . 185. 185 . 185 . 138. 175. 172. 174 . 147 . 172 . 158 . 180. 185 . 185. 185 . 177 . 182 . 125 . 99. 185. 185. 185 . 182 . 183 . 185. 180 . 185. 185. 184 . 180 . 182 . 181. 180 . 182. 180 . 182 . 166 . 159 . 132 . 154 . 171. 168 . 182. 161 . 180. 130 . 155 . 177. 181. 166. 180 . 135. 142 . 84 . 185. 182. 153 . 182 . 145. 154 . 83 . 116. 87. 55 . 69. 51. 66 . 15 . 184. 181. 184 . 180 . 183. 183 . 180 . 181. 180 . 180 . 180 . 182 . 182 . 184 . 141. 128 . 148. 117 . 98 . 45 . 77 . 143 . 53 . 121. 102 . 128 . 90 . 86. 185. 172. 155. 112 . 151. 113 . 102. 185. 140 . 157. 125 . 2 . 105 . a PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) . a. S pilled feed precluded the calcu latio n of th is value. 2 7 -- 2 8 180 . 102 . 181. 37. 185 . 180 . 120 . 153 . 35. 120. 138 . 104 . 100 . 99. 91. 2. 96 . 184 . 95 . 115. 91. 109. 28 - 29 184 . 122'. 180. 94 . 181. 107. 66. 137. 130 . 135. 134. 83 . 96. 73. 68 . 1. 184 . 181. 89. 86 . 90. 85 . 418-012: PAGE B-49 000738 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 17 (PAGE 3) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL 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 1 9 - 20 RABBIT # DOSAGE GROUP I I 0 .1 MG/KG/DAY 8465 P 8466 NP 8467 NP 8468 P 8469 P 8470 P 8471 P 8472 P 8473 P 8474 P 8475 P 8476 P 8477 NP 8478 P 8479 P 8480 P 8481 P b 8482 P 8483 P 8484 P 8485 P 8486 P 185 . 184 . 183 . 184 . 182 164 . 180 . 184 . 165 . 143 185 . 185 . 183 . 184 . 180 183 . 185. 180. 180. 183 181. 181. 185 . 180. 181 180 . 139. 79. 55. 97 184 . 180 . 183 . 129. 3 184. 183 . 183 . 181. 148 62. 165 . 182 . 153 . 180 184 . 180. 180 . 147. 149 184 . 181. 180. 159. 185 180 . 181. 184. 133 . 79 185. 184. 156. 162. 184 180. 125. 95. 17. 14 185. 180. 117. 127. 118 181. 184 . 184. 183 . 180 131. 6 . 72. 109. 94 184. 150. 123 . 158. 130 184 . 180. 182 . 184 . 183 168. 183 . 181. 183 . 184 182 . 184 . 182 . 185. 138 181. 185 . 185. 151. 85 180 . 185. 184 . 183 . 181. 184 . 180 . 180. 129. 70 . 118. 121'. 181. 183 . 185 . 185. 135. 185 . 181. 185. 184 . 183 . 185 . 181. 181. 183 . 185. 185. 183 . 185. 183. 181. 181. 183 . 184 . 185. 185. 185 . 183 . 184. 51. 95. 116 . 182 . 183 . 182 . 180 . 183 . 76. 83 . 102 . 181. 164 . 181. 181. a 173 . 183 . 166 . 135 . 185 . 99. 184 . 71 . 180 . 137. 185. 138. 181. 160. 185. 180 . 123 . 108 . 170 . 174 . 183 . 175. 181. 184 . 185 . 92 . 185 . 115 . 180 . 183 . 185. 185 . 182 . 180 . 185 . 184 . 183. 182 . 180. 181. 185. 181. 180 . 130 . 108 . 159. 180. 180. 81. 102 . 182 . 184 . 80 . 184 . 185. 67. 180 . 144 . 89. 184 . 116. 128 . 183 . 181. 155. 184 . 185. 181. 183 . 185. 185 . 185. 166. 182 . 184 . 185 . 185 . 181. 168. 184 . 183 . 123 . 180 . 182. 73 . 185. 180 . 184 . 184. 183 . 181. 184 . 181. 180 . 181. 184. 180. 181. 59 . 183 . 185 . 68 . 185. 181. 110 . 180. 180 . 115 . 182 . 180 . 115 . 182 . 180. 166 . C 185 . 182. 185. 185. 168 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) . a. Wet feed p re c lu d e d th e c a lc u la tio n o f th is v alu e . b. Doe 8481 had a l i t t e r w hich c o n s is te d o f 10 dead f e tu s e s ; v a lu e s e x c lu d e d from g ro u p a v e rag e s and s t a t i s t i c a l a n a ly se s . c. S pilled feed precluded the calcu latio n of th is value. 418-012: PAGE B-50 000739 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 17 (PAGE 4) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA 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 I 0 .1 MG/KG/DAY 8465 P 8466 NP 8467 NP 8468 P 8469 P 8470 P 8471 P 8472 P 8473 P 8474 P 8475 P 8476 P 8477 NP 8478 P 8479 P 8480 P 8481 P a 8482 P 8483 P 8484 P 8485 P 8486 P 183 . 181. 183 . 185. 181 180 . 185. 180. 182 . 183 . 184. 170 . 180 . 185 167. 182 . 144 . 126 . 180 . 184 . 184 . 183 . 182 180 . 180 . 180 . 180. 180. 180 . 182 . 126 . 163 120 . 140. 86 . 81. 181. 180 . 185 . 85. 183 180 . 182 . 180 . 183 . 132 . 93 . 172 . 50 . 81 123 . 98 . 134 . 90 . 185 . 185. 180 . 103 . 70 99. 97. 161. 110. 181. 185. 181. 183 . 180 181. 181. 181. 155. 185 . 159. 157. 158 . 134 . 119. 112. 104 . 81. 153 . 152. 157. 109. 121 103 . 119. 80. 82 . 182 . 185. 184 . 181 . 180 183 . 185. 184 . 160. 185 . 183 . 180 . 158 . 159 147. 182 . 160. 154 . 183 . 180 . 180 . 182 . 183 185 . 183 . 184 . 172 . 185. 184. 131. 164 . 147 75 . 19. 96. 98. 180. 184 . 180. 181. 133 181. 113 . 100 . 67. 180. 185. 183. 180 . 185 168. 172 . 167. 140 . 185. 180 . 182 . 185. 180 153 . 154 . 132 . 0. 185. 183 . 184 . 156 . 183 181. 163 . 166. 133 . 182 . 181. 181 . 180 . 181 180 . 157. 143 . 131. 185 . 160 . 162 . 118. 98. 40. 50 . 64. 48. b 181. 180 . 182 . 180 161. 180. 140 . 181. 184 . 185 . 182 . 154 . 150. 96. b 70. 69. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) . a. Doe 8481 had a l i t t e r w hich c o n s is te d o f 10 dead fe tu s e s ; v a lu e s e x c lu d e d from g ro u p a v e rag e s and s t a t i s t i c a l a n a ly s e s . b. S pilled feed precluded the calcu latio n of th is value. oo *0 C 418-012: PAGE B-i cn PROTOCOL 418*012 : TABLE 17 (PAGE 5 ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA 6295.10) PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 1 0 1 0 - 1 1 1 1 - 1 2 1 2 - 1 3 RABBIT # DOSAGE GROUP I I I 1 .0 MG/KG/DAY 8487 P 8488 P 8489 P 8490 P 8491 P 8492 P 8493 P 8494 P 8495 P 8496 P 8497 P 8498 P 8499 P 8500 P 8501 P 8502 NP 8503 P 8504 P 8505 NP 8506 P 8507 P 8508 NP 143 . 144 . 162 . 185 . 184 . 185 . 185. 150 . 133 . 163 . 170 . 152 . 182 . 182 . 181. 180. 181. 185 . 149- 69. 145. 167. 185. 185 . 182 . 183 . 180. 170 . 182 . 176 . 156 . 90 . 84. 84 . 109. 86 . 180 . 156 . 182. 182 . 181. 185 . 185. 180. 171. 184 . 185. 153 . 185. 185. 182 . 180 . 118 . 183 . 184. 115. 139. 146. 156 . 152 . 132. 138 . 138. 158. 140 . 92 . 185. 184 . 142. 173 . 173 . 158 . 180. 181. 181. 183 . 183 . 183 . 180. 126 . 123 . 145. 155. 143 . 180. 184 . a 183 . 114 . 156. 180 . 132. 60 . 131. 145. 123 . 180. 184. 183 . 116 . 118. 158 . 180. 185 . 184 . 163 . 125 . 115. 184 . 163 . 163. 185. 181. 184 . 181. 132 . 156 . 158 . 126. 184 . 183 . 170 . 154 . 166. 168 . 181. 180 . 182 . 182. 185. 185 . 183 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. S pilled feed precluded the calcu latio n of th is v alu e . 1 3 -1 4 184 . 110 . 185. 181. 184 . 67. 182 . 185. 185 . 153 . 31. 148 . 180 . 183 . 183 . 113 . 180 . 180 . 181. 174. 170 . 180 . 14-1 5 182 . 150 . 180 . 163 . 183 . 83 . 180 . 182 . 183 . 182 . 29. 183 . 185. 184 . 170. 135 . 181. 156. 184 . 182 . 157. 183 . 1 5 -1 6 184 . 144 . 185. 183 . 185. 87. 139. 184 . 184 . 184. 105. 184 . 184 . 183 . 182. 165. 183. 98. 180. 185. 180 . 182. 1 6-1 7 144 . 183 . 182. 181. 184 . 116. 142 . 184 . 125. 185. 124. 184 . 185. 183 . 184 . 160 . 181. 70. 180. 180 . 184 . 185. 17 - 18 18 - 19 19 - 20 185. 183 . 180. 185. 183 . 185. 185. 185. 183 . 180 . 185. 185. 184 . 180 . 180. 135 . 169. 162. 153 . 110. 118 . 180. 180. 185. 115. 148. 164 . 185 . 181. 185. 26 . 97. 183 . 183 . 185. 183 . 182. 185. 184 . 182 . 137. 102 . 173 . 184 . 172 . 149. 165. 150 . 180. 180. 185. 47. 126. 107. 182 . 185. 180 . 182. 185. 183. 181. 184 . 184 . 183 . 185. 184 . 418-012: PAGE B-52 000741 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 17 (PAGE 6) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 RABBIT # DOSAGE GROUP I I I 1 .0 MG/KG/DAY 8487 P 8488 P 8489 P 8490 P 8491 P 8492 P 8493 P 8494 P 8495 P 8496 P 8497 P 8498 P 8499 P 8500 P 8501 P 8502 NP 8503 P 8504 P 8505 NP 8506 P 8507 P 8508 NP 185. 182 . 182 . 185. 183 184 . 184 . 180 . 185 . 185 185. 182 . 180 . 182 . 185 184 . 183 . 185. 180 . 180 185 . 185 . 182 . 180. 160 170. 178. 173 . 182 . 133 135. 147 . 136 . 182 . 114 185. 185. 155. 94 . 139 162 . 181. 162 . 109. 83 167. 154 . 136 . 106 . 149 185 . 181. 184 . 180 . 184 164 . 162 . 165 . 109. 183 185. 185. 180 . 183 . 184 178. 185. 166. 120 . 151 107. 74 . 75. 130. 129 154 . 184 . 130. 180. 80 184 . 181. 184 . 167. 153 151. 147. 142 . 183 . 84 181. 184 . 184 . 182 . 185 180. 180. 2 . 180. 184. 180. 166. 181. 125. 142 182 . 181. 181. 159. 182. 128 . 181. 183 . 183 . 180 . 157. 138 . 117. 56 . 127. 153 . 88. 180. 183 . 182 . 114 . 165. 98. 165. 140. 82 . 52 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) . 26 - 27 110. 181. 185. 114 . 120. 138. 132. 161. 90. 152. 175. 101. 184 . 121. 161. 112. 103 . 8. 174 . 136. 81. 95. 27 - 28 77. 181. 168. 144 . 127. 184 . 154. 116. 66. 124. 119. 73 . 180. 133 . 169. 134. 119. 7. 175. 132. 103 . 154 . 28 - 29 99. 181. 173. 85. 94 . 120. 103 . 101. 62 . 127. 107. 50. 157. 55. 125. 46 . 94 . 52 . 146. 120. 110. 155. 418-012:PAGE B-53 000742 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 17 (PAGE 7): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 RABBIT # DOSAGE GROUP IV 2 .5 MG/KG/DAY 8509 P 8510 P 8511 NP 8512 P 8513 NP 8514 P 8515 P 8516 P 8517 P 8518 P 8519 P 8520 P 8521 P 8522 P 8523 NP 8524 NP 8525 P 8526 NP 8527 P 8528 P 8529 P 8530 P 146. 130 . 72 . 102 . 85 182 . 185 . 183 . 180 . 184 185. 182. 181. 181. 181 182 . 181. 181. 180 . 169 183 . 185 . 159. 163 . 147 184 . 134 . 80. 76. 108 182 . 125. 182 . 180. 182 180. 158. 108. 79. 101 112. 180 . 184 . 165. 161 179. 184 . 185 . 182 . 185 121. 185. 185 . 162 . 125 181. 173 . 125. 147. 121 180. 153 . 136. 133 . 88 180. 185. 184 . 185. 185 185. 183 . 164. 149. 185 184 . 167. 155 . 127 . 140 185. 133 . 124 . 154 . 164 162 . 147. 133 . 106. 155 180. 184 . 147. 150. 88 159. 145. 156. 106. 84 185. 135. 152 . 151. 136 183 . 184. 181. 185. 184 140. 183 . 173 . 178. 168. 184 . 183 . 49. 130. 127. 138. 149. 100. 182. 185. Ill . 151. 143 . 80. 62. 184 . 183 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) . 13 - 14 125. 182. 112. 184 . 136. 185 . 185 . 110. 52 . 133 . 110 . 133 . 137. 183 . 184 . 175. 181. 159. 57 . 113 . 169. 184 . 14 - 15 50. 130 . 100 . 185 . 112 . 133 . 185. 138. 6. 129. 162 . 176 . 182 . 185 . 183 . 166 . 184 . 136. 81. 146 . 160. 180 . 15 - 16 108. 106 . 119. 180 . 108 . 122 . 185. 180. 18. 184 . 180 . 153 . 166 . 185 . 109. 159. 183 . 143 . 20 . 143 . 160 . 183 . 16 - 17 130 . 153 . 142 . 180 . 161. 182 . 182 . 169. 1. 171. 144 . 148 . 124 . 180 . 39. 153 . 180 . 152 . 89. 132. 143 . 180 . 17 - 18 180 . 167. 147. 180 . 115. 180 . 182 . 140 . 3. 92. 145 . 127. 99 . 180 . 8. 118 . 180 . 148 . 155. 135. 143 . 182. 18 - 19 133 . 144 . 153 . 182 . 94. 182 . 183 . 98 . 0. 172 . 144 . 130 . Ill . 180. 1. 102 . 183 . 163 . 180 . 150. 109. 185. 19 - 2i 158. 170. 145. 184. 97. 153 . 183 . 113 . 5. 163 . 181. 142. 131. 184 . 58 . 117. 183 . 166. 171. 94. 127. 181. 418-012: PAGE B-54 000743 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 17 (PAGE 8): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 2 7 - 28 RABBIT # DOSAGE GROUP IV 2 .5 MG/KG/DAY 8509 P 8510 P 8511 NP 8512 P 8513 NP 8514 p 8515 P 8516 P 8517 p 8518 P 8519 P 8520 p 8521 p 8522 P 8523 NP 8524 NP 8525 P 8526 NP 8527 p 8528 P 8529 p 8530 P 184 . 119. 87. 59. 114 94. 117. 93 . 150. 154 . 138 . 152 . 180 166. 157. 133 . 143 . 153 . 146. 135 . 150 144 . 159. 147. 183 . 185 . 185 . 176 . 146 92. 76 . 98 . 139. 128 . 122 . 135 . 144 122. 154 . 143 . 132 . 92 . 153 . 109. 164 105. 147 . 121. 183 . 185 . 185 . 180 . 110 154 . 106. 90 . 122 . 125. 154 . 167 . 130 109. 97. 180. 0 . 3 8 . 54 . 7 5 . ABORTED ON DAY 2 5 OF GESTATION 132. 118 . 119. 52 . 2 0. 0. 7 . 148. 137. 134 . 90 . 94 78 . 126 . 104 . 91. 133 . 144 . 125. 140 116. 134 . 107. 120 . 137. 147. 126 . 134 108. 136 . 118. 185. 181. 150 . 180 . 154 180. 160 . 166 . 4 . 0 . 2. 0. 0 93 . 108. 163 . 128. 98. 67. 28. 78 176 . 158. 145. 185. a 185 . 181. 108 138. 102 . 106 . 160. 185. 166 . 183 . 133 133. 116. 158. 182 . 149. 30 . 89. 128 168. 84 . 180 . 140 . 101. 105 . 73 . 62 74 . 66. 79. 124 . 92 . 87. 84 . 144 122. 150 . 159. 185. 180 . 183 . 182. 181 116 . 103 . 62 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) . a. S pilled feed precluded the calcu latio n of th is value. 28 - 29 86. 118'. 132 . 90. 116. 117. 10 . 123 . 26 . 108 . 106 . 120. 183 . 172. 110. 88. 141. 170 . 80. 126. 94. 418-012: PAGE B-55 000744 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 17 (PAGE 9) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 RABBIT # DOSAGE GROUP V 3 .7 5 MG/KG/DAY 8531 P 8532 P 8533 P 8534 P 8535 P 8536 P 8537 P 8538 P 8539 P 8540 P 8541 P 8542 P 8543 P 8544 P 8545 P 8546 P 8547 P 8548 P 8549 P 8550 P 8551 P 8552 NP 181. 185 . 184 . 181. 181. 152 . 184 . 146 . 117. 93 . 64 . 183 . 183 . 139. 102 . I l l . 118 . 142 . 147. 145. 86 . 66 . 19. 56. 167. 93 . 65 . 105 . 185 . 185. 44 . 184 . 183 . 184 . 178 . 144 . 134 . 73 . 99. 102 . 165 . 73 . 8. 44 . 18 . 2 . 46 . 23 . 184 . 103 . 65. 23 . 83 . 5. 184 . 184 . 185. 183 . 180 . 185 . 180. 183. 180 . 180 . 171 . 174 . 184 . 182 . 149. 147. 113 . 100. 185. 163 . 159. 118. 86. 22 . 185. 180 . 184. 182 . 143 . 84 . 180 . 180. 179. 165 . 159. 129. 0 . 182. 182 . 183 . 182 . 180. 181. 181. 151. 90. 28 . 22 . 180 . 183. 183 . 185 . 183 . 184 . 185. 185. 185. 185. 126 . 157. 183 . 185 . 182 . 185. 160. 171. 183 . 183 . 180 . 184 . 185. 183 . 161. 161. 125 . 119. 106. 144 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) . 13 - 14 135 . 131. 113 . 29. 185 . 81. 3. 5. 3. 184 . 165. 107. 6. 10 . 175. 183 . 4. 150 . 145 . 183 . 185 . 122 . 14 - 15 185. 21. 90 . 3. 150 . 66 . 0. 0 0 .. 169. 182 . 1 5 81.. 2. 183 . 182 . i. 147. 113 . 184 . 182 . 127. 15 - 16 184 . 5'. 64 . 11 . 181. 80 . 12. 2. 3. 78. 181. 76. 9. 2. 185. 183 . 7. 140. 60. 184 . 185. 143 . 16 - 17 184 . 10. 94 . 2. 180. 8 10.. 0. 3. 3. 184. 121. 4. 24. 184 . 182. 3. 121. 6. 173 . 166. 104 . 17 - 18 185. 0. 96. 0. 152. 67. 4. 10 . 13 . 0. 185. 84. 0. 12. 183 . 150. 5. 104 . 17. 152. 183 . 130. 18 - 19 182. 10. 61. 6. 150. 127. 7. 16 . 2. 0. 180 . 3 021... 182 . 185. 3. 40. 15. 148. 182. 94 . 19 - : 185 3 58 6 115 129 2 5 0 0 180 8 14 27 133 185 0 7 70 160 180 110 418-012: PAGE B-56 eo vi PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 17 (PAGE 10): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 20 - 21 2 1 - 2 2 22 - 23 2 3 - 2 4 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 RABBIT # DOSAGE GROUP V 3 .7 5 MG/KG/DAY 8531 P 8532 P 8533 P 8534 P 8535 P 8536 P 8537 P 8538 P 8539 P 8540 P 8541 P 8542 P 8543 P 8544 P 8545 P 8546 P 8547 P 8548 P 8549 P 8550 P 8551 P 8552 NP 180. 180. 185. 184 . 185 . 182 . 180 . 127. 141. 0 . 89. 124 . 137. 183 . 180 . 182 . 185 . 182'. 17 . 46 . 81. 78 . 114 . 92 . 108. 70 . 103 . 5 . ABORTED ON DAY 2 2 OF GESTATION 40 . 4 . 1. 2. 2 . 1. 41 . 171. 82 . 166 . 167. 180 . 185. 164 . 182. 124 . 183 . 121. 0 . 0 . 0 . 0 . ABORTED ON DAY 2 5 OF GESTATION 9. 10. 7 . ABORTED ON DAY 24 OF GESTATION 0 . 0 . 0 . ABORTED ON DAY 24 OF GESTATION 4 . 1 . 0 . 6 . ABORTED ON DAY 2 5 OF GESTATION 185. 180. 183 . 147. 138 . 70 . 23 . 56. 107 . 1 . 2 . 7 . 3 . 13 . 8 . 1 0 . ABORTED ON DAY 2 8 OF GESTATION 2 . 2 . 0 . 1 . 1. 0 . 0 . 0 . 0. 1 . 4 . 4 . 0 . ABORTED ON DAY 2 5 OF GESTATION 118. 182 . 181. 180 . 157. 183 . 119. 11. 71. 159. 124 . 145. 5 . 132 . 84 . 105. 106. 112 . 0 . ABORTED ON DAY 22 OF GESTATION 180. 12 . 2 . 1 2 2 . ABORTED ON DAY 2 5 OF GESTATION 92 . 95. 99. 181. 180 . 144 . 166 . 128 . 131. 175. I l l . 184 . I l l . 181. 131. 136. 127. 65 . 127. 91. 41. 56 . 139. 116 . 149. 169. 154 . 99. 78. 141 . 107. 143 . 95 . 107. 104 . 110. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) . 418-012: PAGE B-57 000746 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 17 (PAGE 11) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 1 0 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 RABBIT # SATELLITE DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8553 P 8554 P 8555 P 184. 185 . 169. 184 . 7 . 180. 185 . 185 . 185. 184 . 180 . 185. 185. 183 . 184 . 184 . 103 . 142 . 114 . 97. 87. 113 . 85. 126. DAYS 20 - 21 8553 P 8554 P 8555 P 180 . 182. 120. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) . 15 - 16 180. 180 . 107. 16 - 17 180 . 180. 150 . 17 - 18 184 . 184 . 171. 18 - 19 185. 185 . 139. 19 - 20 184. 180. 158. 418-012: PAGE B-58 000747 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 17 (PAGE 12) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 1 0 10 - 11 11 - 12 12 - 13 13 - 14 RABBIT # SATELLITE DOSAGE GROUP I I 0 .1 MG/KG/DAY 8556 P 8557 P 8558 P 8559 P 8560 P 147. 142 . 133 . 130 . 128. 165. 143. 181. 172 . 104 . 180 . 94 . 150. 92. 185 . 183 . 184 . 182 . 151. 132 . 30. 182 . 180 . 183 . 185 . 83 . 182 . 184 . 185 . 153 . 115. 126. 90. 182 . 184 . DAYS 20 - 21 8556 P 8557 P 8558 P 8559 P 8560 P 182 . 183 . 159. 184 . 108 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) . 14 - 15 165. 110. 118. 183. 184 . 15 - 16 85. 146. 159. 185. 185. 16 - 17 68. 154 . 180 . 185. 180 . 17 - 18 157. 180. 183 . 181. 166. 18 - 19 166. 183 . 179. 185. 101. 19 - : 184 181 180 183 122 418-012:PAGE B-59 000748 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 17 (PAGE 13): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 1 0 1 0 - 1 1 11 - 12 12 - 13 13 - 14 RABBIT # SATELLITE DOSAGE GROUP I I I 1 .0 MG/KG/DAY 8561 P 8562 P 8563 P 184 . 180 . 185. 138. 74 . 155. 184. 181. 180 . 180 . 184 . 134 . 185. 185. 134 . 124 . 151. 147. 125 . 166. 141. DAYS 2 0 - 21 8561 P 8562 P 8563 P 180. 173 . 95. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 14 - 15 180. 183 . 139. 15 - 16 180. 180. 150. 16 - 17 184 . 185. 147. 17 - 18 184 . 180 . 140 . 18 - 19 185. 185. 100 . 19 - 20 184 . 182 . 109. PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 17 (PAGE 1 4 ) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 RABBIT # SATELLITE DOSAGE GROUP IV 2 .5 MG/KG/DAY 8564 P 8565 P 8566 P 164 . 180 . 177 . 141. 116 . 158. 125. 183 . 163 . 185. 151. 38. 30. 2. 185 . 184 . 183 . 180 . 107. 126. 49. DAYS 20 - 21 8564 P 8565 P 8566 P 166 . 123 . 151. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . 14 - 15 139. 1. 32 . 15 - 16 127. l'. 63 . 16 - 17 132 . 154 . 57. 17 - 18 180 . 185. 86 . 18 - 19 163 . 185. 139. 19 - 20 185. 185 . 183 . 418-012: PAGE C/! 00 0> PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 17 (PAGE 1 5) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 1 0 10 - 11 11 - 12 12 - 13 13 - 14 RABBIT # SATELLITE DOSAGE GROUP V 3 .7 5 MG/KG/DAY 8567 P 8568 P 8569 NP 8570 P 8571 P 182 . 183 . 114 . 116 . 153 . 65 . 182 . 140 . 139. 79. 63 . 55 . 64 . 73 . 185 . 132. 67. 182. 0. 4. 2. 185. 184 . 184 . 182. 148. 180. 83 . 119. 118. 115 . 184 . 72 . 79. 19. DAYS 20 - 21 8567 P 8568 P 8569 NP 8570 P 8571 p 0. 132 . 0. 174 . 84 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) . 14 - 15 143 . 83 . 0. 4. 25. 15 - 16 129. 83 . 5. 7. 48 . 16 - 17 34. 81. 12 . 13 . 66. 17 - 18 109 . 113 . 8. 6. 107. 18 - 19 4. 119. 0. 54 . 97. 19 - 20 3. 139. 2. 164 . 105 . 418-012: PAGE B-62 00075 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 18 (PAGE 1) : CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION SITE S 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 8443 NOT PREGNANT 8444 5 2 2 5 7 0 0 0 0 0 0 0 0 0 2 5 7 2 6 8 8 44 5 NOT PREGNANT 8446 3 4 2 5 7 0 0 0 0 0 0 0 0 0 2 5 7 6 7 13 8447 5 7 5 7 12 0 0 0 0 0 0 0 0 0 5 7 12 7 8 15 8448 6 4 6 4 10 0 0 0 0 0 0 1 0 1 7 4 11 7 5 12 8449 7 2 4 5 9 0 0 0 0 0 0 0 0 0 4 5 9 6 6 12 8450 6 4 6 4 10 0 0 0 0 1 1 0 0 0 6 5 11 7 6 13 8451 5 2 5 2 7 0 0 0 0 0 0 0 0 0 5 2 7 7 2 9 8452 2 4 5 1 6 0 0 0 0 1 1 0 0 0 5 2 7 6 3 9 8453 5 4 5 4 9 0 0 0 0 0 0 0 0 0 5 4 9 6 7 13 8454 3 7 6 4 10 0 0 0 0 0 0 0 0 0 6 4 10 7 5 12 8455 5 6 5 6 11 0 0 0 0 0 0 0 0 0 5 6 11 6 7 13 8456 4 2 3 3 6 0 0 0 0 0 0 0 0 0 3 3 6 3 4 7 8457 4 4 5 3 8 0 0 0 0 0 0 0 0 0 5 3 8 5 3 8 8458 6 8 7 7 14 0 0 0 0 0 0 0 0 0 7 7 14 7 7 14 8459 2 5 6 1 7 0 0 0 0 0 0 0 0 0 6 1 7 6 1 7 8460 4 3 4 3 7 0 0 0 0 0 0 0 0 0 4 3 7 4 4 8 8461 3 3 2 4 6 0 0 0 0 0 0 0 0 0 2 4 6 6 4 10 8462 3 6 5 4 9 0 0 0 0 0 0 0 0 0 5 4 9 6 5 11 8463 6 4 9 1 10 0 0 0 1 0 1 0 0 0 10 1 11 10 3 13 8464 3 7 7 3 10 0 0 0 0 0 0 0 0 0 7 3 10 7 3 10 M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 418-012: PAGE B-63 00075 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 18 (PAGE 2) : CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION SITE S 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 I 0. 1 MG/KG/DAY 8465 1 5 3 3 6 0 0 0 1 0 1 0 0 0 4 3 7 4 3 7 8 46 6 NOT PREGNANT 8 46 7 NOT PREGNANT 8468 3 7 4 6 10 0 0 0 0 0 0 0 0 0 4 6 10 8 7 15 8469 2 5 6 1 7 0 0 0 0 0 0 0 0 0 6 1 7 7 2 9 8470 6 1 4 3 7 0 0 0 0 0 0 0 0 0 4 3 7 4 5 9 8471 3 6 3 6 9 0 0 0 0 0 0 0 0 0 3 6 9 5 8 13 8472 3 6 6 3 9 0 0 0 0 0 0 0 0 0 6 3 9 6 4 10 8473 4 4 5 3 8 0 0 0 1 0 1 0 0 0 6 3 9 6 5 11 8474 4 5 4 5 9 0 0 0 0 0 0 0 0 0 4 5 9 5 5 10 8475 2 5 3 4 7 0 0 0 0 0 0 0 0 0 3 4 7 4 4 8 8476 6 4 6 4 10 0 0 0 0 0 0 0 0 0 6 4 10 6 6 12 8 47 7 NOT PREGNANT 8478 6 4 6 4 10 0 0 0 0 0 0 0 0 0 6 4 10 7 5 12 8479 6 9 6 9 15 0 0 0 0 0 0 0 0 0 6 9 15 8 9 17 8480 6 3 6 3 9 0 0 0 0 0 0 0 0 0 6 3 9 6 3 9 8481a 0 0 0 0 0 3 7 10 0 0 0 0 0 0 3 7 10 3 8 11 8482 4 5 3 6 9 0 0 0 0 0 0 0 0 0 3 6 9 3 7 10 8483 6 2 5 3 8 0 0 0 0 0 0 0 0 0 5 3 8 7 4 11 8484 6 3 6 3 9 0 0 0 0 0 0 0 0 0 6 3 9 6 3 9 01 CO 8485 3 6 6 3 9 0 0 0 0 0 0 0 0 0 6 3 9 7 4 11 8486 3 8 5 6 11 0 0 0 0 0 0 0 0 0 5 6 11 7 6 13 M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. a. Doe 8481 had a l i t t e r w hich c o n s is te d o f 10 dead fe tu s e s ; v a lu e s exclu ded from group a v e rag e s and s t a t i s t i c a l a n a ly se s . 418-012: PAGE B-64 0007 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 18 (PAGE 3): CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION S IT E S 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 I I 1. 0 MG/KG/DAY 8487 4 2 3 3 6 0 0 0 0 0 0 0 0 0 3 3 6 3 4 7 8488 3 4 2 5 7 0 0 0 1 0 1 0 0 0 3 5 8 5 6 11 8489 2 4 2 4 6 0 0 0 1 0 1 0 0 0 3 4 7 3 5 8 8490 1 4 0 5 5 0 0 0 0 0 0 0 0 0 0 5 5 2 5 7 8491 5 4 3 6 9 0 0 0 0 0 0 0 1 1 3 7 10 5 8 13 8492 2 7 6 3 9 0 0 0 0 0 0 0 0 0 6 3 9 6 3 9 8493 2 3 1 4 5 0 0 0 0 0 0 0 3 3 1 7 8 2 10 12 8494 2 4 2 4 6 0 0 0 0 0 0 0 0 0 2 4 6 5 6 11 8495 7 3 7 3 10 0 0 0 0 0 0 0 0 0 7 3 10 9 4 13 8496 1 8 7 2 9 0 0 0 0 0 0 0 0 0 7 2 9 8 5 13 8497 4 3 3 4 7 0 0 0 0 0 0 0 0 0 3 4 7 3 5 8 8498 3 6 1 8 9 0 0 0 0 0 0 0 0 0 1 8 9 1 8 9 8499 6 2 3 5 8 0 0 0 0 0 0 0 0 0 3 5 8 3 5 8 8500 5 5 2 8 10 0 0 0 0 0 0 0 1 1 2 9 11 3 9 12 8501 8 3 6 5 11 0 0 0 0 0 0 0 0 0 6 5 11 8 6 14 8502 NOT PREGNANT 8503 5 5 8 2 10 0 0 0 0 0 0 0 0 0 8 2 10 9 4 13 8504 4 6 3 7 10 0 0 0 0 0 0 0 0 0 3 7 10 5 7 12 8505 NOT PREGNANT 8506 4 5 7 2 9 0 0 0 0 0 0 0 0 0 7 2 9 8 3 11 8507 3 3 0 6 6 0 0 0 0 0 0 0 0 0 0 6 6 3 6 9 8508 NOT PREGNANT M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 418-012: PAGE B-65 00075 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 18 (PAGE 4) : CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION S IT E S 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 8509 2 5 3 4 7 0 0 0 1 0 1 0 0 0 4 4 8 4 7 11 8510 4 4 5 3 8 0 0 0 0 0 0 0 0 0 5 3 8 7 5 12 8511 NOT PREGNANT 8512 3 4 5 2 7 0 0 0 0 0 0 0 0 0 5 2 7 7 4 i l 8513 NOT PREGNANT 8514 3 4 3 4 7 0 0 0 0 0 0 0 0 0 3 4 7 6 7 13 8515 4 5 3 6 9 0 0 0 0 0 0 0 0 0 3 6 9 4 6 10 8516 4 3 2 5 7 0 0 0 0 0 0 0 0 0 2 5 7 3 6 9 8 5 1 7 ABORTED ON DAY 2 5 OF GESTATION 8518 7 2 4 5 9 0 0 0 0 0 0 1 0 1 5 5 10 7 5 12 8519 6 2 3 5 8 0 0 0 0 0 0 0 0 0 3 5 8 3 5 8 8520 3 2 2 3 5 0 0 0 0 0 0 0 0 0 2 3 5 2 4 6 8521 6 4 6 4 10 0 0 0 0 0 0 0 0 0 6 4 10 7 5 12 8522 3 6 5 4 9 0 0 0 0 0 0 0 1 1 5 5 10 6 7 13 8523 NOT PREGNANT 8524 NOT PREGNANT o 8525 5 6 5 6 11 0 0 0 0 0 0 0 0 0 5 6 11 6 7 13 8526 NOT PREGNANT 8527 7 4 6 5 11 0 0 0 0 0 0 0 0 0 6 5 11 6 5 11 8528 3 4 5 2 7 0 0 0 0 0 0 0 0 0 5 2 7 6 3 9 8529 2 3 1 4 5 0 0 0 1 0 1 0 0 0 2 4 6 3 4 7 incn 8 5 3 0 4 6 7 3 10 0 0 0 0 0 0 0 0 0 7 3 10 7 3 10 M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 418-012: PAGE B-66 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 18 (PAGE 5) : CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION S IT E S 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 3 . 75 MG/KG/DAY 8531 6 3 4 5 9 0 0 0 0 0 0 0 0 0 4 5 9 4 7 i l 8532 4 4 5 3 8 0 0 0 0 0 0 0 0 0 5 3 8 6 6 12 8533 2 4 3 3 6 0 0 0 0 0 0 0 0 0 3 3 6 7 5 12 8 5 3 4 ABORTED ON DAY 22 OF GESTATION 8535 8 3 8 3 11 0 0 0 0 0 0 0 0 0 8 3 i l 8 3 il 8536 3 5 2 6 8 0 0 0 1 0 1 0 0 0 3 6 9 3 8 11 8 5 3 7 ABORTED ON DAY 2 5 OF GESTATION 8 5 3 8 ABORTED ON DAY 24 OF GESTATION 8 5 3 9 ABORTED ON DAY 24 OF GESTATION 8 5 4 0 ABORTED ON DAY 25 OF GESTATION 8541 2 5 5 2 7 0 0 0 0 0 0 0 0 0 5 2 7 5 3 8 8 5 4 2 ABORTED ON DAY 2 8 OF GESTATION 8543 2 7 6 3 9 0 0 0 0 0 0 0 1 1 6 4 10 7 5 12 8 5 4 4 ABORTED ON DAY 25 OF GESTATION 8545 5 8 6 7 13 0 0 0 0 0 0 0 0 0 6 7 13 6 7 13 8546 0 7 2 5 7 0 0 0 0 0 0 0 0 0 2 5 7 3 5 8 8 5 4 7 ABORTED ON DAY 22 OF GESTATION 8 5 4 8 ABORTED ON DAY 2 5 OF GESTATION 8549 6 4 5 5 10 0 0 0 0 0 0 0 0 0 5 5 10 7 5 12 8550 7 3 5 5 10 0 0 0 0 0 0 0 0 0 5 5 10 7 6 13 8551 5 5 5 5 10 0 0 0 0 0 0 0 0 0 5 5 10 5 5 10 8552 NOT PREGNANT M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 418-012: PAGE B-67 000756 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 18 (PAGE 6) : CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA VIABLE FETUSES DEAD FETUSES EARLY ]RESORPTIONS LATE R ESO RPT IO N S IMPLANTATION S I T E S CORPORA LUTEA RABBIT # RIGHT LEFT HORN TOTAL SATELLITE DOSAGE GROUP I RIGHT LEFT RIGHT LEFT HORN TOTAL HORN TOTAL 0 (VEHICLE) MG/KG/DAY RIGHT LEFT HORN TOTAL RIGHT LEFT HORN TOTAL RIGHT LEFT OVARY TOTAL 8553 8554 8555 4 5 3 9 13 5 10 58 0 0 0 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 5 3 9 13 5 10 58 4 5 3 9 13 5 10 58 SATELLITE DOSAGE GROUP I I 0 .1 MG/KG/DAY 8556 8557 8558 8559 8560 44800000000044844 8 3 5 7 4 47 5 10 4 11 7 il 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 0 0 0 0 0 0 0 1 0 0 0 4 5 7 4 48 5 10 4 11 7 11 4 5 7 4 48 5 10 4 11 7 11 SATELLITE DOSAGE GROUP I I I 1 .0 MG/KG/DAY 8561 8562 8563 0 5 1 2 4 6 2 9 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 5 1 2 4 6 2 9 7 0 5 2 3 4 6 3 9 8 SATELLITE DOSAGE GROUP IV 2 .5 MG/KG/DAY 8564 8565 5 7 5 10 3 10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5 7 5 10 3 10 5 7 5 10 3 10 8566 4 4 8 0 0 0 0 0 0 0 0 0 4 4 8 4 5 9 SATELLITE DOSAGE GROUP V 3 .751 MG/KG/DAY 8567 3 7 10 0 0 0 0 0 0 0 0 0 3 7 10 3 7 10 8568 5 8 5 6 9 NOT PREGNANT 2 7 0 0 0 0 0 0 0 0 0 5 2 7 5 3 8 8570 4 5 9 0 0 0 0 0 0 0 0 0 4 5 9 6 6 12 8571 0 2 2 0 0 0 1 0 1 0 0 0 1 2 3 2 3 5 PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. 418-012:PAGE B-68 000757 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 19 (PAGE 1 ) : L IT T ER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA NUMBER OF LIV E FETUSES AVERAGE FETAL BODY WEIGHT (G) --------C O N C E P T U S E S ---------------DEAD OR RESORBED RABBIT # MALE FEMALE TOTAL MALE FEMALE TOTAL a N N% DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8443 NOT PREGNANT 8444 5 2 7 51..30 49..86 50..89 8445 NOT PREGNANT 8446 3 4 7 51..60 46..62 48,.75 8447 5 7 12 44..66 42.,94 43..66 8 4 4 8 6 4 10 4 7 . .2 4 4 4 ..6 0 4 6 . .1 8 8449 7 2 9 44..62 47..62 45..29 8450 6 4 10 44,.86 42 .48 43 .91 8451 5 2 7 47..34 49..38 47..92 8452 2 4 6 47,.98 50..26 49,.50 8453 5 4 9 50..65 45..67 48,.44 8454 3 7 10 44..11 39,.29 40 .74 8455 5 6 11 46..24 42.,17 44..02 8456 4 2 6 46.. 98 51..80 48..59 8457 4 4 8 44 .81 41..70 43 .26 8458 6 8 14 37,,79 36..06 36,.80 o 8459 2 5 7 39..94 43..44 42..44 c 8460 4 3 7 44..86 44..63 44 .76 o 8461 3 3 6 44,.44 47..33 45 .88 > 8462 3 6 9 38,.30 38..28 38 .29 or oc 8463 6 4 10 40..69 38..04 39 .63 8464 3 7 10 31..60 34 .98 33 .97 a . TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF L IV E FET U SE S. 7 7 12 11 9 11 7 7 9 10 11 6 8 14 7 7 6 9 11 10 0 0.. 0 0 0 .0 0 0..0 1 9.,1 0 0..0 1 9.. 1 0 0,.0 1 14..3 0 0.. 0 0 0,.0 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 9,.1 0 0..0 418-012: PAGE B-69 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 19 (PAGE 2) : LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) -------- C O N C E P T U S E S --------------DEAD OR RESORBED RABBIT # MALE FEMALE TOTAL MALE FEMALE TOTAL a N N% DOSAGE GROUP :I I o.:1 MG/KG/DAY 8465 1 5 6 45 .60 47.. 09 46 . 84 7 1 14 . 3 8466 NOT PREGNANT 8 46 7 NOT PREGNANT 8468 3 7 10 43 .49 39 .60 40 . 77 10 0 0 . 0 8469 2 5 7 43 . 00 47.. 51 46 .22 7 0 0 .0 8470 6 1 7 41 .04 36 . 76 40 .43 7 0 0.0 8471 3 6 9 41 .56 41 .22 41..33 9 0 0 .0 8472 3 6 9 44 . 55 40 . 00 41..52 9 0 0 . 0 8473 4 4 8 38 .61 39 . 84 39..23 9 1 11..1 8474 4 5 9 44 . 18 43 .07 43 .57 9 0 0 .0 8475 2 5 7 41 .22 39 .68 40 .12 7 0 0 .0 8476 6 4 10 41 . 29 36 .39 39,.33 10 0 0 . 0 8 47 7 NOT PREGNANT 8478 6 4 10 38 .49 38 .54 38..51 10 0 0 .0 8479 6 9 15 37 .45 34 .32 35 .57 15 0 0 .0 8 4 8 0 6 3 9 43 . 58 4 4 . 1 6 4 3 ,. 78 9 0 0 ,.0 8481b 0 0 0 -- -- 10 10 100 . 0 01 8482 8483 4 6 5 2 9 37 . 77 36 . 95 37..31 8 47 .47 48 . 04 4 7 ., 61 9 8 0 0 .0 0 0 ,. 0 8484 6 3 9 41 . 16 43 . 89 42..07 9 0 0 . 0 8485 8486 3 6 9 42 . 66 4 5 . 7 1 4 4 ,.7 0 9 0 0 ..0 3 8 11 39 .65 41 .71 41..14 11 0 0 . 0 a . TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF L IV E F E T U S E S . b. Doe 8481 had a l i t t e r w hich c o n s is te d o f 10 dead f e tu s e s ; v a lu e s exclu ded from group a v e rag e s and s t a t i s t i c a l a n a ly se s . 418-012:PAGE B-70 0007 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 19 (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 h i 1 .0 MG/KG/DAY 8487 4 2 6 45.08 47.92 46.03 8488 3 4 7 44.95 48.43 46.94 8489 2 4 6 47.74 45.64 46.34 8490 1 4 5 52.43 49.38 49.99 8491 5 4 9 43.39 38.25 41.11 8492 2 7 9 39.84 39.32 39.44 8493 2 3 5 45.12 40.46 42.33 8494 2 4 6 40.86 41.00 40.95 8495 7 3 10 3 9.8 2 3 7 .3 6 3 9 .0 9 8496 i 8 9 50.85 43.20 44.05 8497 4 3 7 44.44 46.43 45.30 8498 3 6 9 32.90 35.34 34.52 8499 6 2 8 38.95 39.98 39.21 8500 5 5 10 40.43 37.51 3 8.9 7 8501 8 3 11 40.83 35.95 39.50 8502 NOT PREGNANT 8503 5 5 10 40.58 37.54 39.06 8504 4 6 10 34.81 37.76 36.58 8505 NOT PREGNANT 8506 4 5 9 49.77 45.23 47.25 8507 3 3 6 29.49 50.22 39.85 8508 NOT PREGNANT a . TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF L IV E F E T U S E S . -- CONCEPTUSES ------------DEAD OR RESORBED N N% 6 0 0.0 8 1 12.5 7 1 14.3 5 0 0.0 10 1 1 0.0 9 0 0.0 8 3 37.5 6 0 0.0 10 0 0 .0 9 0 0.0 7 0 0.0 9 0 0.0 8 0 0.0 11 1 9 .1 11 0 0 .0 10 0 0 .0 10 0 0 .0 9 0 0.0 6 0 0.0 418-012:PAGE B- 0007G0 ~n| PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 19 (PAGE 4) : 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 IV 2 . E1 MG/KG/DAY 8509 2 5 7 42 . 72 44 .49 43 . 98 8510 4 4 8 46 . 61 34 .32 40 .46 8511 NOT PREGNANT 8512 3 4 7 46 . 69 46 . 17 46..39 8513 NOT PREGNANT 8514 3 4 7 44 .41 40 .65 42..26 8515 4 5 9 36 . 02 35 .39 35..67 8 5 1 6 4 3 7 4 4 . 57 4 1 ,. 71 4 3 . 3 4 8 5 1 7 ABORTED ON DAY 2 5 OF GESTATION 8518 7 2 9 33 . 81 29 . 02 32,. 74 8519 6 2 8 37. 80 36 .28 37..42 8520 3 2 5 38. 96 44 . 59 41 .21 8521 6 4 10 41 . 46 36 .27 39 .39 8522 3 6 9 43 . 88 44 . 50 44 .29 8523 NOT PREGNANT 8524 NOT PREGNANT 8525 5 6 11 35 . 57 31..32 33 .25 8526 NOT PREGNANT 8527 7 4 11 32 . 91 33 . 76 33 .22 8528 3 4 7 45 . 15 43 . 71 44 .32 8529 2 3 5 38 . 80 41 .40 40 .36 8530 4 6 10 39. 56 40 . 17 39 . 93 a . TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF L IV E F E T U S E S . --------C O N C E P T U S E S --------------DEAD OR RESORBED N N% 8 1 12..5 8 0 0.0 7 0 0.0 7 0 0.0 9 0 0..0 7 0 0 ,.0 10 1 10 ,.0 8 0 0..0 5 0 0 .0 10 0 0.. 0 10 1 10..0 11 0 0 .0 11 0 0 .0 7 0 0 .0 6 1 16 .7 10 0 0 .0 418-012:PAGE B-72 000761 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 19 (PAGE 5): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA NUMBER OF LIV E FETUSES AVERAGE FETAL BODY WEIGHT (G) RABBIT # MALE FEMALE TOTAL MALE FEMALE TOTAL a DOSAGE GROUP V 3 .7 5 MG/KG/DAY 8531 6 3 9 40.47 39.78 40.24 8532 4 4 8 34.20 34.17 34.18 8533 2 4 6 40.65 37.75 38.72 8 5 3 4 ABORTED ON DAY 22 OF GESTATION 8535 8 3 11 32.41 22.67 29.75 8536 3 5 8 36.22 36.17 36.19 8 5 3 7 ABORTED ON DAY 25 OF GESTATION 8 5 3 8 ABORTED ON DAY 24 OF GESTATION 8 5 3 9 ABORTED ON DAY 24 OF GESTATION 8 5 4 0 ABORTED ON DAY 25 OF GESTATION 8541 2 5 7 43.72 39.86 40.96 8 5 4 2 ABORTED ON DAY 28 OF GESTATION 8543 2 7 9 17.69 13.84 14.70 8 5 4 4 ABORTED ON DAY 25 OF GESTATION 8545 8546 5 0 8 7 137 2 7---.-5--8- 25.53 38.59 26.32 38.59 8 5 4 7 ABORTED ON DAY 22 OF GESTATION 8 5 4 8 ABORTED ON DAY 25 OF GESTATION 8549 6 4 10 28.54 26.52 27.73 8550 7 3 10 36.26 34.96 35.87 8551 5 5 10 37.36 37.93 37.64 8552 NOT PREGNANT a . TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF L IV E F E T U S E S . -------- CONCEPTUSES DEAD OR RESORBED N N% 9 0 0.0 8 0 0.0 6 0 0.0 i l 0 0.0 9 1 11.1 7 0 0.0 10 1 10.0 13 0 0 .0 7 0 0.0 10 0 0.0 10 0 0.0 10 0 0.0 418-012: PAGE B-73 OC0762 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 19 (PAGE 6): LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - INDIVIDUAL DATA NUMBER OF LIVE FETUSES AVERAGE FETAL BODY WEIGHT (G) RABBIT # TOTAL TOTAL a SATELLITE DOSAGE GROUP i 0 (VEHICLE) MG/KG/DAY 8553 13 8554 10 8555 8 4.96 4.59 5.14 SATELLITE DOSAGE GROUP i i 0 .1 MG/KG/DAY 8556 8 8557 7 8558 10 8559 11 8560 11 5.17 4.69 4.56 5.21 4.96 SATELLITE DOSAGE GROUP I I I 1 .0 MG/KG/DAY 8561 2 8562 9 8563 7 5.37 5.12 5.06 SATELLITE DOSAGE GROUP IV 2 .5 MG/KG/DAY 8564 10 8565 10 8566 8 4.89 5.49 4.14 SATELLITE DOSAGE GROUP V 3 .7 5 MG/KG/DAY 8567 10 8568 7 8569 NOT PREGNANT 8570 9 8571 2 4.30 4.61 5.18 5.78 a . TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF L IV E F E T U S E S . -- CONCEPTUSES -----------DEAD OR RESORBED N N% 13 0 0 .0 10 0 0 .0 8 0 0.0 8 0 0.0 8 1 12.5 10 0 0 .0 i i 0 0.0 11 0 0 .0 2 0 0.0 9 0 0.0 7 0 0.0 10 0 0 .0 10 0 0 .0 8 0 0.0 10 0 0.0 7 0 0.0 9 0 0.0 3 1 33.3 418-012: PAGE B-74 000763 418-012:PAGE B-75 000764 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 20 (PAGE 1) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RABBIT # CLs 8443 NOT PREGNANT 8 4 4 4 2 / 6 MA FA /' MA MA FA MA MA 56.21 51.03 53.74 53.50 48.70 49.27 43.80 8445 NOT PREGNANT 8 4 4 6 6 / 7 MA MA j' MA FA FA FA FA 52.73 45.56 56.50 52.59 46.91 43.50 43.48 8 4 4 7 7 / 8 FA FA MA FA MA / MA MA FA FA FA FA MA 52.34 43.91 43.11 44.81 44.16 44.38 43.14 46.06 44.06 32.77 36.63 48.49 8 4 4 8 7 / 5 MA FA MA MA L MA FA / FA MA FA MA 44.73 43.94 50.24 48.10 45.20 42.35 48.09 50.37 44.00 44.83 8 4 4 9 6 / 6 FA FA MA MA ,/ MA MA MA MA MA 46.84 48.40 42.94 48.11 49.00 46.13 42.21 39.98 44.01 8 4 5 0 7 / 6 MA MA FA FA MA FA / MA E FA MA MA 50.79 47.41 45.63 41.80 37.55 40.11 50.49 42.39 37.99 44.95 8 4 5 1 7 / 2 MA MA MA FA MA / FA MA 47.90 49.72 44.85 45.48 49.43 53.27 44.79 8 4 5 2 6 / 3 FA FA FA MA MA / E FA 45.63 55.44 52.04 48.77 47.20 47.92 8 4 5 3 6 / 7 MA FA MA MA FA / FA MA MA FA 62.37 51.25 52.51 50.58 36.80 48.85 39.38 48.41 45.78 8 4 5 4 7 / 5 FA FA FA FA FA FA / FA MA MA MA 41.88 38.46 37.67 41.55 36.23 39.41 39.85 42.97 45.40 43.97 8 4 5 5 6 / 7 MA FA MA FA FA / MA FA MA FA FA MA 46.20 43.72 42.71 44.40 46.73 48.40 45.18 45.99 36.63 36.36 47.92 M = MALE F = FEMALE A = A LIVE D = DEAD E = EARLY RESORPTION L = LATE RESORPTION " / " DENOTES PO S IT IO N OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . 19 418-012: PAGE B-76 000765 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 20 (PAGE 2) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RABBIT # CLs 8456 3/ 4 8457 5/ 3 8458 7/ 7 8459 6/ 1 8460 4/ 4 8461 6/ 4 8462 6/ 5 8463 10/ 3 8464 7/ 3 FA MA MA /' FA MA MA 50.69 48.39 46.64 52.91 47.19 45.70 MA MA FA FA MA / FA MA FA 49.24 40.91 45.36 41.77 39.57 43.53 49.51 36.15 MA FA FA FA MA FA MA / FA FA MA MA FA FA MA 48.33 34.86 37.64 41.01 30.01 32.55 38.35 41.70 37.67 40.03 35.05 33.42 29.59 34.98 FA FA MA MA FA FA / FA 50.26 46.54 43.89 35.98 37.66 40.16 42.57 FA MA FA MA ,/ MA FA MA 47.79 45.01 47.77 40.17 49.24 38.33 45.04 MA FA ,/ FA FA MA MA 43.96 43.13 48.41 50.44 42.14 47.23 MA FA FA MA FA / FA FA FA MA 40.36 38.51 38.20 41.28 40.99 39.45 38.36 34.18 33.26 E FA MA FA MA MA FA FA MA MA / MA 41.92 43.20 44.40 38.14 34.30 37.73 28.09 34.76 42.28 51.47 MA FA FA FA FA MA FA / FA MA FA 34.27 30.24 35.00 32.69 30.71 26.55 36.96 40.65 33.98 38.63 M = MALE F = FEMALE A = A LIV E D = DEAD E = EARLY RESORPTION L = LATE RESORPTION " / " DENOTES P O S IT IO N OF CERVIX CLS = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . 19 418-012: PAGE B-77 00076 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 20 (PAGE 3) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 DOSAGE GROUP I I 0 .1 MG/KG/DAY RABBIT # CLS 8 4 6 5 4 / 3 MA FA FA 45.60 43.81 48.51 8466 NOT PREGNANT E / FA FA FA 48.37 48.03 46.75 8467 NOT PREGNANT 8 4 6 8 8 / 7 MA MA MA FA / FA FA FA FA FA FA 47.27 40.38 42.81 36.38 44.10 44.88 39.45 35.81 37.69 38.89 8 4 6 9 7 / 2 FA FA FA FA MA FA / MA 53.28 51.18 45.06 44.83 39.47 43.21 46.53 8 4 7 0 4 / 5 MA FA MA MA / MA MA MA 42.48 36.76 36.81 42.03 46.43 41.31 37.18 8 4 7 1 5 / 8 MA MA FA / FA FA MA FA FA FA 33.93 45.03 40.91 38.12 40.87 45.72 42.20 41.34 43.88 8 4 7 2 6 / 4 FA FA MA FA FA FA / MA FA MA 44.77 42.76 40.73 41.27 32.00 33.58 52.07 45.61 40.86 8 4 7 3 6 / 5 MA FA E MA MA FA / FA FA MA 49.18 38.09 34.07 25.96 29.61 47.33 44.35 45.23 8 4 7 4 5 / 5 MA MA MA FA / FA FA FA MA FA 43.52 44.47 43.89 38.06 47.20 45.16 43.96 44.86 40.99 8 4 7 5 4 / 4 FA MA FA / MA FA FA FA 33.93 42.02 41.30 40.42 38.71 43.59 40.89 8 4 7 6 6 / 6 FA MA FA FA FA MA / MA MA MA MA 44.27 44.37 38.82 30.39 32.09 37.95 47.12 42.34 35.65 40.30 8477 NOT PREGNANT M = MALE F = FEMALE A = ALIVE D = DEAD E = EARLY RESORPTION L = LATE RESORPTION " / " DENOTES PO SITIO N OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS ( G ) . 19 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 20 (PAGE 4) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 DOSAGE GROUP I I 0 .1 MG/KG/DAY RABBIT # CLs 8478 7/ 5 8479 8/ 9 8480 6/ 3 8481a 3/ 8 8482 3/ 7 8483 7/ 4 8484 6/ 3 8485 7/ 4 8486 7/ 6 MA FA MA MA MA FA / MA FA MA FA 46.49 39.16 38.92 33.12 35.57 41.39 44.32 35.54 32.50 38.05 FA FA FA FA FA MA / MA MA MA MA FA MA FA FA FA 22.79 35.71 35.64 38.48 43.11 35.88 34.26 42.60 41.00 43.87 45.69 27.08 25.39 32.10 29.98 MA FA FA MA MA MA / FA MA MA 46.60 41.98 40.91 46.54 39.30 42.05 49.60 45.06 41.95 FD FD FD / FD MD FD FD FD FD FD 45.86 46.91 45.99 51.11 47.50 45.01 38.98 41.14 38.31 41.88 MA FA FA / MA MA FA MA FA FA 43.89 45.85 37.85 39.97 35.69 31.76 31.53 30.39 38.88 MA FA FA MA MA / MA MA MA 55.20 51.95 44.14 38.19 45.14 45.41 47.60 53.27 FA MA MA MA FA MA / MA FA MA 48.76 48.13 42.50 46.08 39.88 25.38 42.43 43.02 42.47 FA MA FA FA MA FA / FA FA MA 49.61 48.36 43.09 44.08 38.45 43.78 52.45 41.27 41.17 FA MA FA FA FA / FA FA MA FA MA FA 45.21 44.96 44.27 37.15 39.12 44.51 45.63 40.85 36.11 33.13 41.65 M = MALE F = FEMALE A = ALIVE D = DEAD E = EARLY RESORPTION L = LATE RESORPTION " / " DENOTES P O S IT IO N OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . a. Doe 8481 had a l i t t e r w hich c o n s is te d o f 10 dead f e tu s e s ; v a lu e s e x clu d ed from g ro u p a v e rag e s and s t a t i s t i c a l a n a ly se s. 19 418-012: PAGE B-78 000767 418-012:PAGE B-79 000768 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 20 (PAGE 5): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 DOSAGE GROUP I I I 1 .0 MG/KG/DAY RABBIT # 8487 8488 8489 8490 8491 8492 8493 8494 8495 8496 8497 8498 8499 CLS 3 / 4 FA MA MA / FA MA MA 46.05 48.00 43.38 49.80 45.05 43.88 5 / 6 E FA FA / FA FA MA MA MA 46.18 49.04 50.97 47.52 43.30 42.11 49.43 3 / 5 MA FA E / FA MA FA FA 47.90 46.58 44.56 47.57 43.24 48.17 2 / 5 / MA FA FA FA FA 52.43 50.12 43.68 48.93 54.79 5 / 8 MA FA MA / FA MA L MA MA FA FA 46.90 38.03 43.41 45.04 48.94 1.26 41.01 36.71 35.45 34.47 6 / 3 MA FA FA MA FA FA ,/ FA FA FA 42.28 38.88 39.50 37.41 33.81 36.29 44.06 40.60 42.09 2 / 1 0 FA / MA L L L MA FA FA 45.19 45.57 5.95 0.79 0.98 44.67 37.65 38.55 5 / 6 MA MA ,/ FA FA FA FA 41.15 40.58 43.50 40.57 38.44 41.47 9 / 4 MA MA FA MA FA MA MA / MA FA MA 43.56 42.88 35.41 31.44 32.83 28.21 45.91 45.94 43.85 40.84 8 / 5 FA FA FA FA FA FA FA / FA MA 53.70 48.23 45.40 35.33 41.06 34.07 35.52 52.26 50.85 3 / 5 MA FA FA / FA MA MA MA 47.84 47.91 44.18 47.21 47.13 39.11 43.69 1 / 8 MA ,/ FA FA FA MA FA FA MA FA 38.14 38.40 36.49 35.23 32.16 30.78 32.92 28.40 38.21 3 / 5 MA MA MA / FA FA MA MA MA 42.91 40.01 39.98 41.98 37.98 34.30 37.94 38.55 M = MALE F = FEMALE A = ALIVE D = DEAD E = EARLY RESORPTION L = LATE RESORPTION CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS ( G ) . 14 15 16 17 18 DENOTES POSITION OF CERVIX 19 418-012: PAGE B-80 000769 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 20 (PAGE 6): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 DOSAGE GROUP I I I 1 .0 MG/KG/DAY RABBIT # CLs 8 5 0 0 3 / 9 FA MA / FA MA FA MA L FA FA MA MA 43.88 42.23 35.01 43.85 35.53 36.84 1.33 38.59 34.52 42.42 36.79 8 5 0 1 8 / 6 MA MA MA MA MA MA / MA FA FA MA FA 43.17 36.70 41.88 42.12 40.72 40.73 48.19 39.68 33.34 33.14 34.84 8502 NOT PREGNANT 8 5 0 3 9 / 4 MA MA MA MA FA FA MA FA / FA FA 49.13 46.49 39.69 39.73 37.16 28.48 27.87 30.10 47.22 44.76 8 5 0 4 5 / 7 FA FA FA / MA FA MA MA FA MA FA 43.92 40.39 34.65 39.94 38.17 32.76 35.21 36.00 31.32 33.46 8505 NOT PREGNANT 8 5 0 6 8 / 3 FA FA MA FA FA FA MA / MA MA 48.96 49.18 52.74 49.93 43.75 34.33 47.69 50.65 48.01 8 5 0 7 3 / 6 / MA FA FA FA MA MA 51.22 52.40 48.86 49.39 47.99 40.47 8508 NOT PREGNANT M = MALE F = FEMALE A A LIV E D = DEAD E = EARLY RESORPTION L = LATE RESORPTION " / " DENOTES P O S IT IO N OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS ( G ) . 19 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 20 (PAGE 7) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 DOSAGE GROUP IV 2 .5 MG/KG/DAY RABBIT # CLs 8 5 0 9 4 / 7 MA E FA FA / FA FA FA MA 48.53 41.94 46.99 44.40 40.30 48.82 36.91 8 5 1 0 7 / 5 MA MA FA FA FA / MA FA MA 52.02 46.80 33.61 35.29 30.02 51.25 38.34 36.38 8511 NOT PREGNANT 8 5 1 2 7 / 4 MA FA MA FA MA / FA FA 52.12 47.92 42.50 43.65 45.46 49.14 43.96 8513 NOT PREGNANT 8 5 1 4 6 / 7 FA FA FA / MA MA FA MA 44.25 42.18 37.29 44.61 45.67 38.88 42.96 8 5 1 5 4 / 6 FA FA MA / FA MA FA MA FA MA 39.20 36.77 37.54 34.18 37.55 34.51 33.67 32.27 35.34 8 5 1 6 3 / 6 MA FA / MA MA FA MA FA 45.09 41.03 48.93 42.06 42.55 42.20 41.54 8 5 1 7 ABORTED ON DAY 2 5 OF GESTATION 8 5 1 8 7 / 5 MA MA MA MA L / MA FA MA MA FA 35.13 37.26 33.35 31.55 0.58 37.57 34.95 30.47 31.32 23.08 8 5 1 9 3 / 5 MA MA FA / MA FA MA MA MA 40.52 35.27 34.34 37.48 38.23 37.67 36.38 39.47 8 5 2 0 2 / 4 FA MA / MA MA FA 44.00 43.14 35.80 37.94 45.18 8 5 2 1 7 / 5 MA MA MA MA FA FA / FA MA FA MA 45.57 45.12 37.02 37.95 35.74 36.05 38.45 39.43 34.83 43.70 M = MALE F = FEMALE A = ALIVE D = DEAD E = EARLY RESORPTION L = LATE RESORPTION " / " DENOTES PO S ITIO N OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . 19 418-012:PAGE B-l 000770 00 418-012: PAGE B-82 000771 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PROS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 20 (PAGE 8) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 5 6 7 8 9 10 i i 12 13 DOSAGE GROUP IV 2 .5 MG/KG/DAY RABBIT # CLs 8 5 2 2 6 / 7 FA FA FA MA MA / MA FA FA FL FA 46.76 45.76 45.05 44.61 38.81 48.21 43.39 43.87 24.30 42.16 8523 NOT PREGNANT 8524 NOT PREGNANT 8 5 2 5 6 / 7 MA FA MA FA FA / FA MA MA MA FA FA 40.08 38.03 34.97 27.49 29.49 36.56 38.99 34.21 29.61 26.10 30.27 8526 NOT PREGNANT 8 5 2 7 6 / 5 MA MA MA MA MA MA / FA FA FA MA FA 41.16 41.97 38.11 30.51 21.05 18.80 35.72 30.23 34.01 38.80 35.06 8 5 2 8 6 / 3 FA MA FA FA MA / FA MA 47.70 45.44 41.92 43.95 42.15 41.26 47.86 8529 3/ 4 E MA / FA FA MA FA 42.11 42.69 43.75 35.48 37.75 8 5 3 0 7 / 3 FA MA MA FA FA MA FA / FA FA MA 41.58 41.84 34.18 38.16 38.01 38.42 40.79 43.07 39.43 43.79 M = MALE F = FEMALE A = ALIVE D = DEAD E = EARLY RESORPTION L = LATE RESORPTION C Ls = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . 14 15 16 17 18 DENOTES POSITION OF CERVIX 19 418-012: PAGE B-83 00077 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 20 (PAGE 9) : FETAL SEX, V ITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 DOSAGE GROUP V 3 .7 5 MG/KG/DAY RABBIT # CLs 8 5 3 1 4 / 7 FA FA FA MA / MA MA MA MA MA 40.31 40.21 38.81 31.50 49.16 42.77 39.52 38.03 41.82 8 5 3 2 6 / 6 MA FA FA FA MA / FA MA MA 38.54 34.70 33.13 29.40 30.58 39.44 33.18 34.49 8 5 3 3 7 / 5 FA MA FA / MA FA FA 41.03 39.95 37.99 41.35 36.50 35.49 8 5 3 4 ABORTED ON DAY 22 OF GESTATION 8 5 3 5 8 / 3 MA MA MA FA MA FA MA MA / FA MA MA 38.06 35.58 37.84 14.27 23.13 21.76 24.00 27.76 31.98 34.42 38.48 8 5 3 6 3 / 8 MA MA E / FA FA FA FA MA FA 39.65 44.51 46.24 41.41 33.54 25.63 24.51 34.03 8 5 3 7 ABORTED ON DAY 2 5 OF GESTATION 8 5 3 8 ABORTED ON DAY 2 4 OF GESTATION 8 5 3 9 ABORTED ON DAY 24 OF GESTATION 8 5 4 0 ABORTED ON DAY 25 OF GESTATION 8 5 4 1 5 / 3 MA FA MA FA FA / FA FA 47.60 42.99 39.85 31.84 38.05 44.51 41.90 8 5 4 2 ABORTED ON DAY 28 OF GESTATION 8 5 4 3 7 / 5 FA MA MA FA FA FA / L FA FA FA 18.98 21.05 14.33 9.61 12.62 11.15 5.01 13.45 17.13 13.97 M = MALE F = FEMALE A = ALIVE D = DEAD E = EARLY RESORPTION L = LATE RESORPTION " / " DENOTES PO SITIO N OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS ( G ) . 19 418-012:PAGE B-84 000773 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 20 (PAGE 10) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 DOSAGE GROUP V 3 .7 5 MG/KG/DAY RABBIT # CLs 8544 ABORTED ON DAY 2 5 OF GESTATION 8 5 4 5 6 / 7 FA FA MA FA FA FA / FA FA MA MA MA FA MA 33.44 23.74 31.73 30.19 15.63 14.05 34.34 29.81 34.38 26.13 20.57 23.06 25.11 8546 3 / 5 FA FA / FA FA FA FA FA 39.89 43.53 39.73 37.76 40.56 34.02 34.62 8 5 4 7 ABORTED ON DAY 2 2 OF GESTATION 8 5 4 8 ABORTED ON DAY 2 5 OF GESTATION 8 5 4 9 7 / 5 FA FA MA MA MA / MA FA MA MA FA 32.68 19.63 27.15 26.92 31.62 32.57 25.28 30.14 22.82 28.47 8550 7/ 6 FA MA FA MA MA / MA MA FA MA MA 37.27 36.52 39.52 34.53 34.56 41.67 39.86 28.09 32.32 34.34 8 5 5 1 5 / 5 FA MA MA MA FA / FA FA MA MA FA 41.03 37.47 42.30 33.52 36.51 45.27 36.10 37.49 36.02 30.74 8552 NOT PREGNANT M = MALE F = FEMALE A = ALIVE D = DEAD E = EARLY RESORPTION L = LATE RESORPTION " / " DENOTES PO SITIO N OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS ( G ) . 19 418-012:PAGE B-85 000774 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 20 (PAGE 11): FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 SATELLITE DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RABBIT # 8553 8554 8555 CLs 4/ 9 5/ 5 3/ 5 A A A A/ A A A A A A A A A 4.78 4.78 4.99 5.18 5.59 4.45 5.56 4.67 4.97 5.12 4.87 4.57 4.89 A A A A A/ A A A A A 4.80 3.99 5.19 4.34 4.69 4.63 4.56 4.41 4.25 5.05 A A A/ A A A A A 5.37 5.03 5.58 5.27 5.61 4.18 5.09 5.01 SATELLITE DOSAGE GROUP I I 0 .1 MG/KG/DAY RABBIT # CLs 8556 4/ 4 8557 4/ 4 8558 5/ 5 8559 7/ 4 8560 4/ 7 A A A A/ A A A A 5.44 5.41 5.49 4.02 4.99 5.31 5.62 5.10 A A A L/ A A A A 4.05 4.89 5.05 4.81 4.70 4.87 4.45 A A A A A/ A A A A A 3.74 4.78 5.08 4.67 4.46 4.09 4.77 4.53 4.93 4.57 A A A A A A A/ A A A A 5.32 5.54 4.57 5.05 5.54 5.41 4.99 5.33 5.32 5.11 5.10 A A A A/ A A A A A A A 4.37 5.19 5.20 4.59 5.43 4.70 4.63 5.77 4.99 4.55 5.20 SATELLITE DOSAGE GROUP I I I 1 .0 MG/KG/DAY RABBIT # CLs 8561 0/ 3 / A A 5.38 5.36 8562 5/ 4 A A A A A / A A A A 5.24 4.76 5.55 5.27 5.34 4.77 5.48 5.00 4.67 8563 2/ 6 A / A A A A A A 5.24 5.06 4.40 5.13 5.17 4.82 5.64 A = ALIVE D = DEAD E = EARLY RESORPTION L = LATE RESORPTION " / " DENOTES POSITIO N OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS ( G ) . 19 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: 6295.10) TABLE 20 (PAGE 12) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 SATELLITE DOSAGE GROUP IV 2 .5 MG/KG/DAY RABBIT # 8564 8565 8566 CLs 5/ 5 7/ 3 4/ 5 A A A A A/ A A A A A 4.71 5.07 4.76 4.89 5.06 4.72 4.96 4.84 4.81 5.05 A A A A A A A/ A A A 6.03 5.78 5.32 5.82 5.76 5.34 4.77 6.15 5.14 4.78 A A A A/ A A A A 4.33 4.06 3.71 3.82 4.42 4.35 4.37 4.10 SATELLITE DOSAGE GROUP V 3 . 75 MG/KG/DAY RABBIT # CLs 8567 3/ 7 8568 5/ 3 8569 A A A/ A A A A A * A A 4.82 4.53 4.08 4.65 4.49 4.44 4.18 4.28 3.62 3.95 A A A A A/ A A 4.64 4.69 4.61 4.46 4.41 4.63 4.82 NOT PREGNANT 8570 6/ 6 8571 2/ 3 A A A A/ A A A A A 5.60 5.44 5.43 4.85 5.51 5.34 4.79 4.85 4.86 E/ A A 5.93 5.62 A = ALIVE D = DEAD E = EARLY RESORPTION L = LATE RESORPTION " / " DENOTES PO SITIO N OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS ( G ) . soi 19 418-012:PAGE B-86 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 1) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) 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 8443 NOT PREGNANT 8444 K 14.3) 0/ 7 0/ 7 8445 NOT PREGNANT 8446 0( 0.0) 0/ 7 8447 5( 41.7) 0/12 0/ 7 0/12 o o N /N = NUMBER OF SPECIMENS WITH ALTERAT IONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION 1 / 7 FETUS 4 HYOID: ALA, ANGULATED, b ilateral 0/ 7 5 /1 2 FETUS 4 HYOID: ALA, ANGULATED, b ilateral FETUS 7 HYOID: ALA, ANGULATED, le ft FETUS 8 CAUDAL VERTEBRAE: MISALIGNED, 1 7 th FETUS 10 THORACIC VERTEBRAE: CENTRUM, UNILATERAL OSSIFICATION, l e f t 5 th FETUS 11 HYOID: ALA, ANGULATED, b ilateral 418-012:PAGE B-87 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 2) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP I RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8448 1( 10.0) 0 (VEHICLE) MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N DESCRIPTION 1 /10 FETUS 1 FORELIMB: POLLEX ABSENT, b i l a t e r a l FETUS 5 LATE RESORPTION, a u to ly sis precluded fu rth er evaluation N/N 0/10 DESCRIPTION 8449 3( 33.3) 0/ 9 1 / 9 FETUS 6 EYES : CIRCUMCORNEAL HEMORRHAGE, l e f t e y e o o \i N /N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED a SKELETAL EXAMINATION N/N DESCRIPTION 1 /1 0 FETUS 1 FORELIMB: 4 METACARPALS PRESENT, b i l a t e r a l , 1st m etacarpal absent; 4 DIGITS PRESENT, b ilateral, 1st d ig it a b s e n t ; FOREPHALANGES, 1 s t MEDIAL AND D ISTAL PHALANGES ABSENT, b ilateral 3 / 9 FETUS 2 HYOID: ALA, ANGULATED, b ilateral FETUS 6 SKULL: NASAL - FRONTAL, IRREGULAR SUTURE, b ilateral HYOID: ALA, ANGULATED, b ilateral FETUS 7 HYOID: ALA ANGULATED, b ilateral 418-012:PAGE B-88 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 3) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP I RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8450 3 ( 30.0) 0 (VEHICLE) MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N DESCRIPTION 0/10 N/N DESCRIPTION 1/10 FETUS 7 LUNGS : INTERMEDIATE LOBE ABSENT 8451 K 14.3) 0/ 7 0/ 7 8452 1( 16.7) 0/ 6 0/ 6 oo *0 d 8453 0( 0.0) 0/ 9 8454 1( 10.0) 0/10 0/ 9 0/10 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION 2 /1 0 FETUS 2 SKULL: NASAL, CONTAINED AN INTRANASAL, r i g h t , 2 . 0 mm x 3 . 0 mm, l e f t , 2 . 5 mm x 4 . 0 mm FETUS 3 SKULL: NASALS, CONTAINED AN INTERNASAL, 1 . ) 0 . 5 mm x 2 . 5 mm 2 . ) 0 . 5 mm x 2 . 0 mm 1 / 7 FETUS 1 SKULL: NASAL, CONTAINED AN INTRANASAL, l e f t , 3 . 0 mm x 5 . 0 mm 1 / 6 FETUS 1 HYOID: ALA, ANGULATED, le ft THORACIC VERTEBRAE: HEMIVERTEBRA, l e f t 3 rd , arch and centrum RIBS: SPLIT, l e f t 2nd, m edial - d ista l STERNAL CENTRA: ASYMMETRIC, 1 s t - 3 r d 0/ 9 1 /1 0 FETUS 3 SKULL: NASALS, FUSED, p a r t i a l l y , 4 . 0 mm 418-012: PAGE B-89 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 4 ) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP I RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8455 0( 0.0) 8456 1( 16.7) 0 (VEHICLE) MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSU E EXAMINATION N/N DESCRIPTION 0/11 0/ 6 N/N DESCRIPTION 0/11 0/ 6 8457 0( 0.0) 0/ 8 8458 1( 7.1) 0/14 0/ 8 0/14 8459 2( 28.6) 0/ 7 0/ 7 8460 2( 28.6) 0/ 7 0/ 7 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION 0/11 1 / 6 FETUS 4 RIBS: THICKENED, l e f t 8th and 9th, m edially 0/ 8 1 /1 4 FETUS 4 STERNAL CENTRA: FUSED, 3 rd and 4 th 2 / 7 FETUS 4 STERNAL CENTRA: FUSED, 3 rd and 4 th FETUS 6 SKULL: NASAL, CONTAINED AN INTRANASAL, r i g h t , 1 . 0 mm x 2 . 0 mm, l e f t , 1 . 5 mm x 2 . 0 mm 2 / 7 FETUS 5 CERVICAL VERTEBRAE: CERVICAL RIB PRESENT AT 7TH CERVICAL VERTEBRA, b ilateral FETUS 6 SKULL : FRONTALS, CONTAINED AN INTERFRONTAL, 0 . 4 mm x 2 . 0 mm 418-012:PAGE B-90 000779 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 5) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP I RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N(%) 8461 0( 0.0) 8462 0( 0.0) 8463 1( 10.0) 0 (VEHICLE) MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N DESCRIPTION 0/ 6 0/ 9 0/10 N/N DESCRIPTION 0/ 6 0/ 9 0/10 8464 2( 20.0) 0/10 1/10 FETUS 1 LUNGS : INTERMEDIATE LOBE ABSENT N /N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION 0/ 6 0/ 9 1/10 FETUS 8 HYOID: ALA, ANGULATED, le ft 1/10 FETUS 7 HYOID: ALA, ANGULATED, rig h t 418-012: PAGE B-! 000780 CD PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 6) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP I I RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8465 2( 33.3) 0 .1 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N DESCRIPTION 0/ 6 N/N DESCRIPTION 0/ 6 8466 NOT PREGNANT 8467 NOT PREGNANT 8468 0( 0.0) 0/10 8469 2( 28.6) 0/ 7 0/10 0/ 7 8470 2( 28.6) 0/ 7 0/ 7 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION 2 / 6 FETUS 6 SKULL: NASALS, MIDLINE SUTURE DISPLACED, rig h t FETUS 7 HYOID: ALA, ANGULATED, b ilateral 0/10 2 / 7 FETUS 5 SKULL: NASALS, CONTAINED AN INTERNASAL, 1 . 5 mm x 2 . 5 mm FETUS 6 SKULL : NASALS, CONTAINED AN INTERNASAL, 0 . 5 mm x 1 . 0 mm HYOID: ALA, ANGULATED, rig h t 2 / 7 FETUS 1 SKULL: NASALS, MIDLINE SUTURE DISPLACED, rig h t FETUS 3 SKULL: NASALS, MIDLINE SUTURE DISPLACED, le ft 418-012: PAGE B-92 000781 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 7 ) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP I I RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8471 M 11.1) 0 .1 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N DESCRIPTION 0/ 9 N/N DESCRIPTION 0/ 9 8472 0( 0.0) 0/ 9 8473 2( 25.0) 1 / 8 FETUS 6 FORELIMBS FLEXED DOWNWARD, f o r e p a w s b ilateral 8474 M 11.1) 0/ 9 0/ 9 0/ 8 0/ 9 8475 4( 57.1) 0/ 7 1 / 7 FETUS 2 LUNGS : INTERMEDIATE LOBE ABSENT N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION 1 / 9 FETUS 1 SKULL: PREMAXILLAE, NOT OSSIFIED, b i l a t e r a l 0/ 9 1 / 8 FETUS 4 STERNAL CENTRA: FUSED, 3 rd and 4 th 1 / 9 FETUS 7 SKULL: NASAL - FRONTAL, IRREGULAR SUTURE, b ilateral 3 / 7 FETUS 5 SKULL: NASAL - FRONTAL, IRREGULAR SUTURE, b ilateral FETUS 6 SKULL : NASALS, CONTAINED AN INTERNASAL, 0 . 5 mm x 1 . 5 mm HYOID: ALA, ANGULATED, le ft FETUS 7 HYOID: ALA, ANGULATED, b ilateral 418-012: PAGE B-93 000782 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 8) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP I I 0 .1 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 8476 3( 30.0) 0/10 1 /10 FETUS 8 LUNGS: INTERMEDIATE LOBE ABSENT 3 /1 0 FETUS 1 THORACIC VERTEBRAE: CENTRUM, B IF ID , 1 2 t h ; CENTRA, FUSED, 1 1 th t o le f t 12th FETUS 7 RIBS: FUSED, l e f t 5 th and 6th, m edial d istal FETUS 8 STERNAL CENTRA: FUSED, 3 rd and 4 th 8477 NOT PREGNANT 8478 0( 0.0) 0/10 0/10 0/10 8479 3( 20.0! 0/15 2/15 FETUS 4 LUNGS: INTERMEDIATE LOBE ABSENT FETUS 12 LUNGS: INTERMEDIATE LOBE ABSENT 1 /1 5 FETUS 10 SKULL: NASALS, MIDLINE SUTURE DISPLACED, le ft 8480 0( 0.0) 0/ 9 0/ 9 0/ 9 8481a 4( 40.0) 1 /1 0 FETUS 1 (DEAD) FORELIMBS : FLEXED DOWNWARD 0/10 3 /1 0 FETUS 5 (DEAD) HYOID: ALA, ANGULATED b ilateral N /N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED a. L itte r 8481 c o n siste d o f te n dead fe tu s e s ; a l l em bryonic sacs c o n tain ed a dark red su b stan ce. V alues were excluded from group averages and s ta tis tic a l analy ses. 418-012-PAGE B-94 000783 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 9) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP I I 0 .1 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 8481a (C o n t.) FETUS 7 (DEAD) CAUDAL VERTEBRAE: 10 PRESENT FETUS 9 (DEAD) CAUDAL VERTEBRAE : 6 PRESENT 8482 0( 0.0) 0/ 9 0/ 9 0/ 9 8483 4( 50.0) 0/ 8 3 / 8 FETUS 3 LUNGS: INTERMEDIATE LOBE ABSENT FETUS 4 LUNGS : INTERMEDIATE LOBE ABSENT FETUS 7 LUNGS : INTERMEDIATE LOBE ABSENT 2 / 8 FETUS 1 CERVICAL VERTEBRAE: CENTRUM, UNILATERAL OSSIFICATION, l e f t 2nd FETUS 4 STERNAL CENTRA: FUSED, 3 rd and 4 th 8484 0( 0.0) 0/ 9 0/ 9 0/ 9 8485 1( 11.1) 0/ 9 0 / 9 1 / 9 FETUS 2 THORACIC VERTEBRAE: ARCH, SMALL, l e f t 1 1 th ; CENTRA, FUSED, l e f t 11th and 12th R IBS: PROXIMATE, l e f t 10th and 11th, bases 8486 0( 0.0) 0/11 0/11 0/11 N /N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED a. L itte r 8481 c o n siste d o f te n dead fe tu s e s ; a l l em bryonic sacs co n tain ed a dark red su b stan ce. V alues were excluded from group averages and s ta tis tic a l analy ses. 418-012:PAGE B-95 000784 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PROS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 1 0 ) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP I I I RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8 4 8 7 0 i( 0 . 0 ) 8488 0 ( 0.0) 8 4 8 9 11( 1 6 . 7 ) 8 4 9 0 0 ( 0 . 0 ) 8491 1 ( 11.1) 8492 0 ( 0.0) 8 4 9 3 11( 2 0 . 0 ) 1 .0 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N DESCRIPTION 0/ 6 0/ 7 0/ 6 0/ 5 0 / 9 FETUS 6 LATE RESORPTION, a u to ly sis precluded fu rth er evaluation 0/ 9 0 / 5 FETUS 3 LATE RESORPTION, au to ly sis precluded fu rth er evaluation FETUS 4 LATE RESORPTION, au to ly sis precluded fu rth er evaluation FETUS 5 LATE RESORPTION, au to ly sis precluded fu rth er evaluation N/N 0/ 6 0/ 7 1/ 6 0/ 5 0/ 9 DESCRIPTION FETUS 6 LUNGS: INTERMEDIATE LOBE ABSENT 0/ 9 0/ 5 N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION 0/ 6 0/ 7 0/ 6 0/ 5 1 / 9 FETUS 4 SKULL: NASAL, CONTAINED AN INTRANASAL, l e f t , 1 . 0 mm x 2 . 0 mm 0/ 9 1 / 5 FETUS 7 RIBS: THICKENED, l e f t 6th - 8th, m edially 418-012: PAGE B-96 000785 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 1 1 ) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP I I I RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N {%) 84 94 2( 3 3.3 ) 1 .0 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N DESCRIPTION 0/ 6 N/N DESCRIPTION 0/ 6 8495 1( 10.0) 0/10 8496 3( 33.3) 0/ 9 0/10 0/ 9 8497 0( 0.0) 0/ 7 0/ 7 8498 0( 0.0) 0/ 9 0/ 9 8499 0( 0.0) 0/ 8 0/ 8 N /N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIM ENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION 2 / 6 FETUS 3 HYOID: ALA, ANGULATED, b ilateral FETUS 6 HYOID: ALA, ANGULATED, b ilateral 1 /10 FETUS 3 SKULL: NASALS, MIDLINE SUTURE DISPLACED, rig h t 3 / 9 FETUS 4 HYOID: ALA, ANGULATED, rig h t FETUS 7 HYOID: ALA, ANGULATED, rig h t FETUS 9 HYOID: ALA, ANGULATED, b ilateral 0/ 7 0/ 9 0/ 8 418-012:PAGE B-97 0007S6 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 12) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP I I I RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N (%) 8500 2 ( 20.0) 1 .0 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N DESCRIPTION 0 /10 FETUS 7 LATE RESORPTION, au to ly sis precluded fu rth er evaluation N/N DESCRIPTION 0/10 8501 0( 0.0) 0/11 8502 NOT PREGNANT 8503 2 ( 20.0) 0/10 0/11 0/10 8504 0 ( 0.0) 0/10 8505 NOT PREGNANT 8506 0 ( 0.0) 0/ 9 8507 1( 16.7) 0/ 6 0/10 0/ 9 0/ 6 8508 NOT PREGNANT N/N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION 2 /10 FETUS 3 RIBS: SPLIT, r ig h t 8 th, proxim al - d is ta l, le ft 7th, proxim al d ista l FETUS 8 LUMBAR VERTEBRAE: HEMIVERTEBRA, l e f t 1 s t , arch and centrum ; CENTRUM, B IF ID , 2 n d 0/11 2 /1 0 FETUS 1 HYOID: ALA, ANGULATED, b ilateral FETUS 9 HYOID: ALA, ANGULATED, rig h t 0/10 0/ 9 1 / 6 FETUS 3 SKULL: NASAL, CONTAINED AN INTRANASAL, l e f t , 1 . 0 mm x 2 . 0 mm 418-012: PAGE B-98 000787 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 1 3 ) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) 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 8509 0 ( 0.0) 0/ 7 0/ 7 0/ 7 8510 0 ( 0.0) 0/ 8 0/ 8 0/ 8 8511 NOT PREGNANT 8512 0 ( 0.0) 0/ 7 0/ 7 0/ 7 8513 NOT PREGNANT 8514 0( 0.0) 0/ 7 0/ 7 0/ 7 8515 0 ( 0.0) 0/ 9 0/ 9 0/ 9 8516 1( 14.3) 0/ 7 0/ 7 1 / 7 FETUS 1 SKULL : NASALS, CONTAINED AN INTERNASAL, 2 . 0 mm x 3 . 0 mm 8 5 1 7 ABORTED ON DAY 2 5 OF GESTA TIO N a Qo 8518 0 ( 0.0) 0 / 9 FETUS 5 LATE RESORPTION, au to ly sis precluded furth er evaluation 03 00 8519 1( 12.5) 0/ 8 0/ 9 0/ 8 0/ 9 1 / 8 FETUS 2 CERVICAL VERTEBRAE: CERVICAL RIB PRESENT AT 7TH CERVICAL VERTEBRA, b ilateral N /N = NUMBER OF SPECIM ENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED a. Doe 8517 a b o rte d e ig h t la te r e s o r p tio n s on day 25 o f g e s ta tio n ; a u to ly s is p re c lu d e d f u r th e r e v a lu a tio n . 418-012:PAGE B-99 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 14) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP IV RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N {%) 8520 0 ( 0.0) 8521 0 ( 0.0) 8522 2 ( 22.2) 2 .5 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N DESCRIPTION 0/ 5 0/10 0 / 9 FETUS 9 LATE RESORPTION, a u to ly sis precluded furth er evaluation N/N DESCRIPTION 0/ 5 0/10 0/ 9 8 5 2 3 NOT PREGNANT 8524 NOT PREGNANT 8525 1( 9.1) 0/11 0/11 o 8526 oo U 8527 8528 GO 8 5 2 9 NOT PREGNANT 0 ( 0.0) 0/11 0( 0.0) 0/ 7 0 ( 0.0) 0/ 5 0/11 0/ 7 0/ 5 8530 0 ( 0.0) 0/10 0/10 N /N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIM ENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION 0/ 5 0/10 2 / 9 FETUS 4 HYOID: ALA, ANGULATED, b ilateral FETUS 5 HYOID: ALA, ANGULATED, b ilateral 1/11 FETUS 9 HYOID: ALA, ANGULATED rig h t 0/11 0/ 7 0/ 5 0/10 418-012: PAGE B-100 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 1 5 ) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP V 3 .7 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 8531 2( 22.2) 0/ 9 0/ 9 2 / 9 FETUS 3 SKULL : FRONTALS, CONTAINED AN INTERFRONTAL, 2 . 0 mm x 3 . 0 mm FETUS 8 SKULL : FRONTALS, CONTAINED AN INTERFRONTAL, 2 . 5 mm x 4 . 0 mm 8532 1( 12.5) 0/ 8 1 / 8 FETUS 5 LUNGS : INTERMEDIATE LOBE ABSENT 0/ 8 8533 0( 0.0) 0/ 6 0/ 6 0/ 6 8 5 3 4 ABORTED ON DAY 2 2 OF GESTA TIO N a 8535 1( 9.1) 0/11 0/11 1 /1 1 FETUS 6 LUMBAR VERTEBRAE: CENTRUM, B IF ID , 1 s t 8536 3( 37.5) 0/ 8 0/ 8 3 / 8 FETUS 5 SKULL: NASAL, CONTAINED AN INTRANASAL, l e f t , 2 . 0 mm x 3 . 0 mm FETUS 6 HYOID: ALA, ANGULATED, b ilateral N /N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED a. Doe 8534 a b o rte d one dead f e tu s and had sev en liv e f e tu s e s ijj u te ro on day 22 o f g e s ta tio n . A ll fe tu s e s ap p eared norm al a t g ross ex tern al and so ft tiss u e exam ination. F etuses 1, 2, 3, 4, 5, 6, 7. and 8 had p e lv is, pubis not o s sifie d (b ila te ra l! at sk ele tal exam ination. 418-012:PAGE B-101 000790 PROTOCOL 4 1 8 - 0 1 2 : ORAL (STOMACH TUBE) DEVELOPMENTAL T O X IC IT Y STUDY OF PFO S IN R A B B IT S (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 1 6 ) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP V 3 .7 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 8536 (C o n t.) FETUS 7 HYOID: ALA, ANGULATED, b ilateral 8 5 3 7 ABORTED ON DAY 2 5 OF GESTATION a 8 5 3 8 ABORTED ON DAY 24 OF GESTATION b 8 5 3 9 ABORTED ON DAY 2 4 OF G ESTATION c 8 5 4 0 ABORTED ON DAY 2 5 OF GESTATIO N d 8541 1( 14.3) 0/ 7 0/ 7 1 / 7 FETUS 1 HYOID: ALA, ANGULATED, b ilateral 8 5 4 2 ABORTED ON DAY 28 OF GESTATION e 8543 7( 77.8) 1 / 9 FETUS 3 FORELIMBS FLEXED DOWNWARD, b i l a t e r a l forepaw s 0 /9 7 / 9 FETUS 1 SKULL: PARIETAL, CONTAINED A HOLE, r i g h t , 2 . 5 nun x 3 . 5 mm - l a r g e , l e f t , 2 . 0 mm x 4 . 0 mm - l a r g e N /N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED a. Doe 8537 a b o rte d fiv e la te re s o r p tio n s on day 25 o f g e s ta tio n ; a u to ly s is p re c lu d e d f u r th e r e v a lu a tio n . b. Doe 8538 a b o rte d e ig h t la te r e s o rp tio n s on day 24 o f g e s ta tio n ; a u to ly s is p re c lu d e d f u r th e r e v a lu a tio n . One a d d itio n a l fe tu s was presum ed c a n n ib a liz e d . c. Doe 8539 a b o rte d seven liv e fe tu s e s on day 24 o f g e s ta tio n . A ll f e tu s e s ap p eared norm al a t g ro ss e x te rn a l and s o ft tis s u e exam ination. F etuses 1, 2, 3, 4, 5, 6 and 7 had p elv is, pubis not o s sifie d (b ila te ra l) and fetu ses 2 and 3 hadste rn a l cen tra (firs t) not o ssifie d a t s k e le ta l exam ination. d. Doe 8540 a b o rte d fo u r dead f e tu s e s and had th re e liv e f e tu s e s , one dead fe tu s and s ix la te r e s o r p tio n s in u te r o on day 25 of g esta tio n . A utolysis precluded fu rth e r ev alu atio n of the la te reso rp tio n s. A ll rem aining fetu ses appeared norm al at g ro ss e x te r n a l and s o f t t i s s u e e x a m in a tio n . F e tu se s 1, 2, 3, 5, 7, 8, 9 and 10 had p e lv is , p u b is n o t o s s if ie d ( b ila te r a l) and fetu s 2 had sk u ll, n asals incom pletely o ssifie d and m axillae, sh ort at sk e le ta l exam ination. e. Doe 8542 a b o rte d s ix dead f e tu s e s on day 28 o f g e s ta tio n . A ll f e tu s e s w ere p a r t i a l l y c a n n ib a liz e d . A ll pups ap p eared normal a t so ft tiss u e exam ination. 418-012:PAGE B-102 000791 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 1 7 ) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP V RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N ( %) 8543 (C o n t.) 3 .7 5 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N DESCRIPTION FETUS 7 LATE RESORPTION, a u to ly sis precluded fu rth er evaluation N/N DESCRIPTION N /N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION FETUS 3 SKULL: PARIETAL, CONTAINED A HOLE, r i g h t , 6 . 0 mm x 8 . 0 mm - l a r g e , l e f t , 6 . 0 mm x 8 . 5 mm - l a r g e FETUS 4 SKULL: PARIETAL, CONTAINED A HOLE, r i g h t , 2 . 0 mm x 4 1 . 0 mm - l a r g e , l e f t , 2 . 5 mm x 5 . 0 mm - l a r g e PELVIS: PUBIS, NOT OSSIFIED, b i l a t e r a l FETUS 5 SKULL: PARIETAL, CONTAINED A HOLE, r i g h t , 2 . 5 mm x 3 . 5 mm - l a r g e , l e f t , 4 . 0 mm x 4 . 5 mm - l a r g e FETUS 6 SKULL: PARIETAL, CONTAINED A HOLE, r i g h t , 3 . 0 mm x 5 . 0 mm - l a r g e , l e f t , 4 . 0 mm x 5 . 5 mm - l a r g e PELV IS: PU B IS, NOT OSSIFIED, b i l a t e r a l 418-012: PAGE B-103 000792 PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 1 8 ) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP V 3 .7 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 8543 (C o n t.) FETUS 8 SKULL: PARIETAL, CONTAINED A HOLE, r i g h t , 1 . 0 mm x 1 . 5 mm - s m a l l , l e f t , 2 . 0 mm x 2 . 5 mm - l a r g e FETUS 10 SKULL: PARIETAL, CONTAINED A HOLE, r i g h t , 5 . 0 mm x 8 . 0 mm - l a r g e , l e f t , 5 . 0 mm x 8 . 5 mm - l a r g e 8 5 4 4 ABORTED ON DAY 2 5 OF GESTATIO N a 8545 2( 15.4) 0/13 0/13 2 /1 3 FETUS 5 PELVIS: PUBIS, NOT OSSIFIED, b i l a t e r a l FETUS 6 PELV IS: PU B IS, NOT OSSIFIED, b i l a t e r a l 8546 0( 0.0) 0/ 7 0/ 7 0/ 7 8 5 4 7 ABORTED ON DAY 22 OF GESTATION b 8 5 4 8 ABORTED ON DAY 2 5 OF GESTATIO N c N /N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED a. Doe 8544 a b o rte d n in e dead fe tu s e s on day 25 o f g e s ta tio n . A ll f e tu s e s ap p eared norm al a t g ro ss e x te rn a l and s o ft tis s u e s exam inations. F etuses 1, 2, 3, 4, 5, 6, 7, 8 and 9 had p e lv is, pubis not o ssifie d (b ila te ra l) and fetu s 3 had s te rn a l cen tra (firs t) not o ssifie d a t sk e le ta l exam ination. b. Doe 8547 a b o rte d e ig h t la te re s o r p tio n s on day 22 of g e s ta tio n ; a u to ly s is p re c lu d e d f u rth e r e v a lu a tio n . c. Doe 8548 a b o rte d one dead fe tu s and had seven liv e fe tu s e s , one d ead fe tu s and two la te re s o r p tio n in u te ro on day 25 o f g e s ta tio n . The la te re so rp tio n s appeared norm al a t g ro ss e x te rn a l exam ination; a u to ly s is p reclu d ed fu rth e r e v a lu a tio n . A ll f e tu s e s a p p e are d norm al a t g ro s s e x te r n a l and s o f t t i s s u e e x a m in a tio n s. F e tu se s 1, 2, 3, 4, 5, 6, 7, 8 and 11 had p e lv is, pubis not o ssifie d (b ila te ra l) a t sk e le ta l exam ination. 418-012: PAGE B-104 000793 PROTOCOL 418-012 : ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: TABLE 21 (PAGE 1 9 ) : FETAL ALTERATIONS - INDIVIDUAL DATA 6295.10) DOSAGE GROUP V RABBIT NUMBER SPECIMENS WITH ANY ALTERATIONS N<%) 8549 0( 0.0) 8550 2( 20.0) 3 .7 5 MG/KG/DAY GROSS EXTERNAL EXAMINATION SOFT TISSUE EXAMINATION N/N DESCRIPTION 0/10 0/10 N/N DESCRIPTION 0/10 0/10 8551 0( 0.0) 0/10 0/10 8552 NOT PREGNANT N /N = NUMBER OF SPECIMENS WITH ALTERATIONS/NUMBER OF SPECIMENS EXAMINED SKELETAL EXAMINATION N/N DESCRIPTION 0/10 2 /10 FETUS 9 HYOID: ALA, ANGULATED, le ft FETUS 10 HYOID: ALA, ANGULATED, rig h t 0/10 418-012: PAGE B-105 000794 APPENDIX C PROTOCOL AND AMENDMENT 000795 418-012: 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 418-012 SPONSOR'S STUDY NUMBER: 6295.10 STUDY TITLE: PURPOSE: TESTING FACILITY. STUDY DIRECTOR: SPONSOR: STUDY MONITOR: ALTERNATE STUDY MONITOR: Oral (Stomach Tube) Developmental Toxicity Study of PFOS in Rabbits The purpose of this study is to detect adverse effects of PFOS 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 000796 418-012:PAGE C-2 Protocol 418-012 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. 000797 418-012: PAGE C-3 Protocol 418-012 Page 3 TEST ARTICLE AND VEHICLE: Identification: Test Article: Name: Physical Description: Lot/Batch Number: Specific Gravity: Purity: Expiration Date: PFOS. Light-colored powder. 217. - 0.6. 98.9%. May 2000. Information on the identity, composition, strength and purity of the test article is on file with the Sponsor. Vehicle: 0.5% 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 (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. 000798 418-012: PAGE C-4 Protocol 418-012 Page 4 FORMULATION: Frequency of Preparation: Formulations (suspensions) will be prepared daily at the Testing Facility. Detailed preparation procedures are attached to this protocol (ATTACHMENT 3). Adjustment for Purity: 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: Homogeneity and stability of prepared formulations is on file with the Sponsor. However, records will be maintained to document how the test article formulations were prepared. Concentration of Test Article Formulations: Concentration of the prepared formulations will be verified during the course of this study. Duplicate samples (2 mL each) will be taken from the first and last preparation on the day prepared. One sample of each set will be shipped for analysis; the remaining samples will be retained at the Testing Facility as backup samples. Backup samples will be stored under the previously cited conditions and discarded at the Testing Facility upon request of the Sponsor. 000799 418-012: PAGE C-5 Protocol 418-012 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: 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: 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 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, and the weight range will be included in the final report. OOOSOQ 418-012: PAGE C-6 Protocol 418-012 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 of presumed gestation body weights. ANIMAL HUSBANDRY: All cage sizes are in compliance with the Guide for the Care and Use of Laboratory Animalsw. 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. ooosoi 418-012: PAGE C-7 Protocol 418-012 Page 7 Water: 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. 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 418-012P). 000802 418-012:PAGE C-8 Protocol 418-012 Page 8 Dosage Levels. Concentrations. Volumes and Injection Rates: Dosage Group Number of Rabbits Dosage (mg/kg/day) Concentration (mg/mL) Dosage Volume (mUkq) Arqus Batch Number I 22+3* 0 (Vehicle) 0 5 B-418-012-A(Dav.Month.Year) II 22+5* 0.1 0.02 5 B-418-012-B(Day. Month.Year) III 22+3* 1.0 0.2 5 B-418-012-C(Day.Month.Year) IV 22+3* 2.5 0.5 5 B-418-012-D(Day.Month.Year) V 22+5* 3.75 0.75 5 B-418-012-E(Dav.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: 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 one hour postdosage. Postdosage Period: Once daily. Clinical observations may be recorded more frequently than cited above, if deemed appropriate by the Study Director and/or Study Monitor. Body Weights: Predosage Period: Day 0 of presumed gestation and on the day of arrival at the Testing Facility. Dosage Period: Daily. Postdosage Period: Daily. Feed Consumption Values: Predosage Period: Recorded daily after arrival at the Testing Facility (values not tabulated). Dosage Period: Recorded daily. 000803 418-012: PAGE C-9 Protocol 418-012 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 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 and Identification: The body weight of each fetus will be recorded. Only body weights of live fetuses will be used to determine litter fetal body weight averages. Fetuses will be tagged with identification noting study number, litter number 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. 000804 418-012: PAGE C-10 Protocol 418-012 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 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. 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 will 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 000805 418-012: PAGE C-11 Protocol 418-012 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). 000S06 418-012:PAGE C-12 Protocol 418-012 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 Test8 I. Parametric II. Nonoarametricb A. Bartlett's Test0" I 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 psO.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. 000807 418-012: PAGE C-13 Protocol 418-012 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 (if required). 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. 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 000808 418-012: PAGE C-14 Protocol 418-012 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 of visceral alterations in mammalian fetuses. Teratology 9(3):A37-38. 000S09 418-012: PAGE C-15 Protocol 418-012 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. 000810 PROTOCOL APPROVAL: FOR THE TESTING FACILITY /L C ia I* George E^Dearlove, Ph.D., DABT Associate Director of Research 418-012: PAGE C-16 Protocol 418-012 Page 16 Date Date _____ _____________________________________________________ Dena C. Lebo, V.M.D. Member, Institutional Animal Care and Use Committee FOR THE SPONSOR Marvin T. Case, D.V.M., Ph.D. Study Monitor ______Il L L l Date L. /<? 4 jaa 9j^ Date O O O S ll 418-012:PAGE C-17 ATTACHMENT 1 SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE 000812 ATTACHMENT 1 418-012:PAGE C-18 Protocol 418-012 Page 1 of 2 STUDY SCHEMATIC RABBIT DEVELOPMENTAL TOXICITY STUDY8 Sta rt of Dosage Rabbits Day 7 of Presijmed Gest ation CaesareanSectioning6 EntJ of Dos age Day 20 of Presijmed Gest ation Day 29 of Presumed Gestation = Dosage Period a= For additional details see "Tests, Analyses and Measurements" section of the protocol. b = Fetal evaluations (external, soft tissue and skeletal). 000813 ATTACHMENT 1 418-012: PAGE C-19 Protocol 418-012 Page 2 of 2 SCHEDULE8 21 AUG 98 23 AUG 98 - 09 SEP 98 06 SEP 98-10 SEP 98 14 SEP 98-18 SEP 98 17 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 000814 418-012:PAGE C-20 ATTACHMENT 2 MATERIAL SAFETY DATA SHEET 000S1 material safety DATA SHEET 418-012:PAGE C-21 3M 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 inforaation for the purpose of properly utilizing 3M products is allowed provided that: 1) the inforaation is copied in full with no changes unless prior agreeaent is obtained froa 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-95 FLUORAD Brand Fluorocheaical Surfactant ID NUMBER/U.P.C.: 98-0207-0103-7 00-51135-09054-1 98-0207-0104-5 98-0211-0888-5 00-51135-09362-7 98-0211-3916-1 Z F - 0002-1044-1 ISSUED: January 29, 1998 SUPERSEDES: Noveaber 05, 1997 DOCUMENT: 10-3796-9 00-51135-09055-8 00-51135-02311-2 1. INGREDIENT C.A.S. NO. PERCENT POTASSIUM PERFLUOROALKYL SULFONATE.... POTASSIUM PERFLUOROALKYL SULFONATE.... POTASSIUM PERFLUOROALKYL SULFONATE.... POTASSIUM PERFLUOROALKYL SULFONATE.... POTASSIUM PERFLUOROALKYL SULFONATE.... 2795-39-3 3871-99-6 29420-49-3 60270-55-5 3872-25-1 82 3 3 2 1 - 86 -8 -7 -6 -3 2. PHYSICAL DATA BOILING POINT:..... VAPOR PRESSURE:.... VAPOR DENSITY:..... EVAPORATION RATE:... SOLUBILITY IN WATER: SPECIFIC GRAVITY:... PERCENT VOLATILE:... pH: ................. VISCOSITY:......... MELTING POINT:..... N/A N/A N/A N/A slight ca. 0.6 Water=1 (Bulk) 0% 7 -8 (0.1% Aqueous) N/D N/D APPEARANCE AND ODOR: Light colored, free flowing powder. Abbreviations: N/D - Not Deterained N/A - Not Applicable CA - Approximately 000816 MSDS: FC-95 FLUORAD Brand Fluorocheaical Surfactant January 29, 1998 418-012: PAGE C-22 PAGE 2 3. FIRE AND EXPLOSION HAZARD DATA FLASH POINT:................... FLAMMABLE LIMITS - LEL:.. FLAMMABLE LIMITS - UEL:.. AUTOIGNITION TEMPERATURE:..... None N/A N/A N/A EXTINGUISHING MEDIA: Mater, Carbon dioxide, Dry chemical, Foam SPECIAL FIRE FIGHTING PROCEDURES: Near 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 Sulfur, Hydrogen Fluoride, Toxic Vapors, Gases or Particulates. 5. ENVIRONMENTAL INFORMATION SPILL RESPONSE: Observe precautions from other sections. Vacuum, use wet sweeping compound or water to avoid dusting. CAUTION! A vacuum cleaner could be an ignition source. Clean up residue with water. Place in an approved metal container. Seal the container. RECOMMENDED DISPOSAL: Do not release to waterways or sewer. Do not use in products or processes that could result in aquatic concentrations greater than 1/10 of the lowest EC50 or LCSO concentration. Incinerate in an industrial or commercial facility in the presence of a combustible material. Combustion products will include HF. Disposal alternative: Dispose of waste product in a facility permitted to Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 000517 USDS: FC-95 FLUORAD Brand Fluorocheaical Surfactant January 29, 1998 418-012:PAGE C-23 PAGE 3 5. ENVIRONMENTAL INFORMATION (continued) accept chemical waste. ENVIRONMENTAL DATA: 9 6 -Hr. Aquatic Fish LC50, Fathead Minnow(Pinephales promelas)=38 mg/1, Bluegill Sunfish(Lepomis macrochirus)68 mg/1, Rainbow Trout(Salmo gairdneri)=11 mg/1; 48-Hr. EC50, Daphnia Magna = 50 mg/1; COD=.004 g/g; BOD20 - Nil. REGULATORY INFORMATION: Volatile Organic Compounds: N/A. VOC Less H20 & Exempt Solvents: N/A. Since regulations vary, consult applicable regulations or authorities before disposal. U.S. EPA Hazardous Waste Number = None (Not U.S. EPA Hazardous). This product complies with the chemical registration requirements of TSCA, EINECS, CDSL, AICS, MITI 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 for at least 15 minutes. Get immediate medical attention. SKIN CONTACT: Immediately flush skin with large amounts of water. Remove contaminated clothing. If irritation persists, call a physician. Nash contaminated clothing before reuse. INHALATION: If signs/symptoms occur, remove person to fresh air. If signs/symptoms continue, call a physician. IF SWALLOWED: Drink two glasses of water. Call a physician. 7. PRECAUTIONARY INFORMATION EYE PROTECTION: Avoid eye contact. Wear vented goggles. Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 000818 USDS: FC-95 FLUORAD Brand Fluorocheaical Surfactant January 29, 199B 418-012: PAGE C-24 PAGE 4 7. PRECAUTIONARY INFORMATION (continued) SKIN PROTECTION: Avoid skin contact. Near appropriate gloves when handling this Material. A pair of gloves nade from the following aaterial(s) are recommended: butyl rubber. Use one or more of the following personal protection items as necessary to prevent skin contact: head covering, coveralls. Protective garments (other than gloves) should be made of either of the following materials: polyethylene/polyvinylidene chloride (Saranex). RECOMMENDED VENTILATION: Use with appropriate local exhaust ventilation. Use in a wellventilated area. 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 dust. Select one of the following NIOSH approved respirators based on airborne concentration of contaminants and in accordance with OSHA regulations: half-mask dust and mist respirator, half-mask supplied air respirator, full-face dust and mist respirator, full-face supplied air respirator. PREVENTION OF ACCIDENTAL INGESTION: Do not eat, drink or smoke when using this product. Mash exposed areas thoroughly with soap and water. Mash hands after handling and before eating. RECOMMENDED STORAGE: Keep container dry. 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: 2 FLAMMABILITY: 0 REACTIVITY: 0 PERSONAL PROTECTION: X (See precautions, section 7.) EXPOSURE LIMITS INGREDIENT VALUE UNIT TYPE AUTH SKIN POTASSIUM PERFLUOROALKYL SULFONATE... 0.1 MG/ M3 POTASSIUM PERFLUOROALKYL SULFONATE... 0.1 MG/ M3 POTASSIUM PERFLUOROALKYL SULFONATE... 0.1 MG/M3 POTASSIUM PERFLUOROALKYL SULFONATE... 0.1 MG/M3 TMA 3M TMA 3M TMA 3M TMA 3M Y Y Y Y Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 000819 418-012: PAGE C-25 MSDS: FC-95 FLUORAD Brand Fluorochomical Surfactant January 29, 1998 EXPOSURE LIMITS (continued) PAGE 5 INGREDIENT VALUE UNIT TYPE AUTH SKIN* POTASSIUM PERFLUOROALKYL SULFONATE... 0.1 MG/M3 THA 3M 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: Mild Eye Irritation: signs/symptoms can include redness, swelling, pain, and tearing. SKIN CONTACT: Mild Skin Irritation (after prolonged or repeated contact): signs/symptoms can include redness, swelling, and itching. May be absorbed through the skin and persist in the body for an extended time. INHALATION: May be harmful if inhaled. May be absorbed by inhalation and persist in the body for an extended time. Single overexposure, above recommended guidelines, may cause: Irritation (upper respiratory): signs/symptoms can include soreness of the nose and throat, coughing and sneezing. IF SWALLOWED: Ingestion is not a likely route of exposure to this product. Illness may result from a single swallowing of a moderate quantity of this material. May be harmful if swallowed. MUTAGENICITY: Mutagenicity assays indicate the product is not mutagenic. Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 000820 MSDS: FC-95 FLU0RA0 Brand Fluorocheaical Surfactant January 29, 1998 418-012:PAGE C-26 PAGE 6 8. HEALTH HAZARD DATA (continued) REPRODUCTIVE/DEVELOPMENTAL TOXINS: Not teratogenic in the rat at oral doses below aaternally toxic levels. 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. 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. 000821 418-012:PAGE C-27 ATTACHMENT 3 TEST ARTICLE PREPARATION PROCEDURE 000822 418-012: PAGE C-28 ATTACHMENTS Protocol 418-012 Version: 4 1 8 -0 1 2 (09 AUG 98i Page 1 of 3 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE Test Article: PFOS Vehicle: 0.5% Tween 80 in R.O. Deionized Water A. Purpose: The purpose of this procedure is to provide a method for the preparation of dosage suspensions of PFOS and the vehicle for oral administration to rabbits on Argus Study 418-012. 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 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. 000823 418-012.PAGE C-29 ATTACHMENT 3 Protocol 418-012 Version: 418-012 (09 AUG 98) Page 2 of 3 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE NOTE: Test article will be prepared as a serial dilution from the high dosage to the low dosage. Once the final volumes are achieved, stir bars are to be added to the containers; mixing should occur during sampling and/or administration. C. Preparation of Vehicle 1. Add the required amount of R.O. deionized water to an appropriately labeled container. Heat the water to 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 0.75 mg/mL, Group V suspension, add the required amount of test article (See TEST ARTICLE CALCULATIONS) into an appropriately sized, labeled container. QS ad to the required amount with 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 while the suspension cools. (Be sure there is a visible vortex, this will achieve the desired emulsion. This may be prepared the day before use.) 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. 000824 418-012: PAGE C-30 ATTACHMENT 3 Protocol 418-012 Version: 418-012 (09 AUG 981 Page 3 of 3 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE 6. To prepare the 0 mg/mL, Group I suspension, add required amount of vehicle to an appropriately sized, labeled container (See TEST ARTICLE CALCULATIONS) and mix. Written by: . CdL_ Date: / t ' ^ 6 - 9 Clarification: Initials/Date : s (See attached clarification form.) c Ax 000825 OPrimedica 418-012:PAGE C-31 Arg9u0s5TReSelhTseeepeaehlrehoHcfynahoxeDrL::sra((hi22bva11eom,5r5a,)B)tP44uoA44ril3i3de--1si88n9,75g0I1n84A0c74. PROTOCOL 418-012 ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS SPONSOR'S STUDY NUMBER: 6295.10 Amendment 1 - 1 1 December 1998 1. Sponsor (page 1 of the protocol): The Sponsor is 3M Corporate Toxicology, rather than 3M Toxicology Services. Reason for Change: This change was made at the request of the Sponsor. 2. Species/Strain and Reason for Selection (page 5 of the protocol): The test article is biologically active, rather than pharmacologically active in this strain. Reason for Change: This change was made at the request of the Sponsor. 3. Route and Reason for Choice (page 7 of the protocol): The oral (gavage) route is a possible route of human exposure, rather than the one proposed for clinical use. 000826 418-012:PAGE C-32 Reason for Change: This change was made at the request of the Sponsor. Amendment 1 Protocol 418-012 Page 2 'a l U -D Z-fi in M. Hoberman, Ph.D., DABT Date G. York, Director of Research Associate Director and Study Director DABT search Date U 'b ic - `i i Dena a IqIoo, V.M.D.i/ Date Chairpfson, Institutional Animal Care and Use Committee . _____/ Marvin T. Case, D.V.M., Ph.D. Study Monitor p' Date 000827 APPENDIX D PILOT REPORT 000828 418-012:PAGE D-1 FINAL PILOT REPORT Study Title Oral (Stomach Tube) Dosage-Range Developmental Toxicity Study of PFOS in Rabbits SPONSOR'S STUDY NUMBER: T-6295.10 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: 418-012P 000829 418-012: PAGE D-2 418-012P:PAGE 2 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS SPONSOR'S STUDY NUMBER: T-6295.10 TABLE OF CONTENTS SUBJECT ABSTRACT I. Purpose II. Methods III. Results IV. Conclusion Figure 1. Maternal Body Weights Table 1. Clinical Observations - Summary Table 2. Necropsy Observations - Summary Table 3. Uterine Contents for the Individual Rabbits that were Found Dead or Aborted Table 4. Maternal Body Weights - Summary Table 5. Maternal Body Weight Changes - Summary Table 6. Maternal Absolute Feed Consumption Values (g/day) Summary Table 7. Maternal Relative Feed Consumption Values (g/kg/day) - Summary PAGE 4 6 6 7 12 13 14 16 20 22 26 28 30 000830 418-012: PAGE D-3 SUBJECT 418-012P:PAGE 3 PAGE Table 8. Caesarean-Sectioning Observations - Summary 32 Table 9. 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 42 Table 13. Maternal Body Weights - Individual Data 45 Table 14. Maternal Feed Consumption Values - Individual Data 52 Table 15. Caesarean-Sectioning Observations - Individual Data 59 Table 16. Litter Observations (Caesarean-Delivered Fetuses) Individual Data 61 Table 17. Fetal Sex, Vital Status and Body Weight Individual Data 63 ATTACHMENT 1 - PROTOCOL 66 000831 418-012:PAGE D-4 418-012P:PAGE 4 TITLE: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS ARGUS RESEARCH LABORATORIES, INC. PROTOCOL NUMBER: 418-012P SPONSOR'S STUDY NUMBER: T-6295.10 ABSTRACT Thirty-five presumed pregnant New Zealand White [Hra:(NZW)SPF] rabbits were randomly assigned to seven dosage groups, five per group. Suspensions of PFOS were administered orally once daily on days 7 through 20 of presumed gestation (DGs 7 to 20) at dosages of 0 (Vehicle), 0.1, 1, 2.5, 5,10 and 20 mg/kg/day. The vehicle was 0.5% Tween80 in reverse osmosis membrane processed deionized water. The dosage volume was 10 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 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. Two does in the 5 mg/kg/day dosage group and four in the 10 mg/kg/day dosage group aborted and were sacrificed. Additionally, four does in the 20 mg/kg/day dosage group were found dead and one doe in the same dosage group aborted and was sacrificed. Dosage-dependant increases in adverse clinical observations (scant or no feces, ungroomed coat and excess salivation) occurred in the 2.5, 5, 10 and 20 mg/kg/day dosage groups. Rabbits in the 10 and 20 mg/kg/day dosage groups had body weight losses and severely reduced absolute and relative feed consumption values for all recorded 000832 418-012:PAGE D-5 418-012P:PAGE 5 intervals after initiation of dosage; there were no surviving pregnant rabbits in these groups after DGs 26 and 19, respectively. The 2.5 and 5 mg/kg/day dosage groups had decreased body weight gains or body weight losses for the entire dosage and gestation periods. Absolute and relative feed consumption values for the entire dosage period were reduced in the 2.5 and 5 mg/kg/day dosage groups. Feed consumption values were reduced in the 2.5 and 5 mg/kg/day dosage groups for the entire gestation period after the initiation of dosing. Fetal body weights were severely reduced and the number of early and late resorptions and the percentage of conceptuses per litter were increased in the 5 mg/kg/day dosage group, however, only two of the four pregnant does in this dosage group survived to Caesarean-sectioning. Fetal body weights were reduced in the 2.5 mg/kg/day dosage group as compared to the concurrent controls but were at the lower end of the range observed historically at the Testing Facility. All other Caesarean-sectioning or litter parameters were unaffected by administration of the test article at dosages as high as 5 mg/kg/day. One fetus in the 2.5 mg/kg/day dosage group had a cleft snout and absent incisors. Two fetuses in the 0.1 mg/kg/day dosage group had fetal gross malformations. One fetus had a short snout, displaced and small nares and the other fetus had abdominal distention. Based on these data, dosages of 0 (Vehicle), 0.1, 1.0, 2.5 and 3.75 mg/kg/day PFOS were recommended for the developmental toxicity study in rabbits (Argus Protocol 418-012). 000833 418-012:PAGE D-6 I. Purpose: 418-012P: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 PFOS administered orally via stomach tube to New Zealand White [Hra:(NZW)SPF] presumed pregnant female rabbits. II. Methods9: The test article, PFOS (Lot 217), an off white powder, was received on 20 May 1998, and was stored at room temperature. The vehicle, 0.5% Tween80 (lot M03H05), a clear viscous fluid was received on 1 July 1998, and was stored at room temperature. The vehicle diluent, reverse osmosis membrane processed deionized water (R.O. Deionized Water) was available from a continuous source at the Testing Facility and was 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 PFOS were administered orally (stomach tube) once daily on days 7 through 20 of presumed gestation (DGs 7 to 20) at dosages of 0 (Vehicle), 0.1, 1, 2.5, 5, 10 and 20 mg/kg/day. The dosage volume was 10 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 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 attached protocol and amendments. Deviations from the Protocol and Standard Operating Procedures of the Testing Facility are available in the raw data. 000834 418-012: PAGE D-7 III. Results: 418-012P:PAGE 7 A. Mortality. Clinical and Necropsy Observations (Summaries - Tables 1 and 2: Individual Data - Tables 3.11 and 121 A.1. Mortality. Abortions and Uterine Contents of Aborted Rabbits Two does (8257 and 8259) in the 5 mg/kg/day dosage group and four does (8261, 8262, 8364 and 8265) in the 10 mg/kg/day dosage group aborted and were sacrificed. Additionally, four does (8266, 8267, 8268 and 8270) in the 20 mg/kg/day dosage group were found dead and one doe (8269) in the same dosage group aborted and was sacrificed. The death of doe 8266 was due to an intubation accident. These does are described below. All other does survived to scheduled sacrifice. 5 mq/kq/dav dosage Doe 8257 in the 5 mg/kg/day dosage group aborted and was sacrificed on DG 23 after 14 daily dosages. The only adverse clinical observation was scant feces (DGs 13 to 22). No gross lesions were revealed by necropsy and five late resorptions were aborted and one late resorption was in utero. This doe lost body weight and feed consumption values were reduced throughout the dosage period. Doe 8259 in the 5 mg/kg/day dosage group aborted and was sacrificed on DG 22 after 14 daily dosages. The only adverse clinical observation was scant feces (DGs 14 and 16 to 21). No gross lesions were revealed by necropsy. This doe aborted seven dead fetuses and two late resorptions; no conceptuses remained in utero. This doe lost body weight and feed consumption values were reduced after DG 11. 10 mq/kq/dav dosage Doe 8261 in the 10 mg/kg/day dosage group aborted and was sacrificed on DG 26 after 14 daily dosages. Adverse clinical observations included scant feces (DGs 12, 16 to 20, 23 and 24), no feces (DG 13 to 15, 21, 22, 25 and 26) and an ungroomed coat (DGs 24 to 26). All lobes of the liver were mottled red and tan and the mucosal surface of the stomach had numerous black areas at necropsy. This doe aborted seven dead fetuses and two dead fetuses were in utero. The fetuses that were in utero had edematous heads and necks; all other fetuses appeared normal for their developmental ages. This doe generally lost weight and had reduced feed consumption values after DG 9. 000835 418-012:PAGE D-8 418-012P:PAGE 8 Doe 8262 in the 10 mg/kg/day dosage group aborted and was sacrificed on DG 22 after 14 daily dosages. Adverse clinical observations included a mass on the nose (DGs 7 to 21), scant feces (DGs 11 to 12, 14 to 21) and no feces (DG 13). At necropsy, the cut surface of the small mass on the nose revealed a smooth pink material. Nine late resorptions were aborted and no conceptuses remained in utero. This doe lost body weight and feed consumption values were reduced after DG 9. Doe 8264 in the 10 mg/kg/day dosage group aborted and was sacrificed on DG 23 after 14 daily dosages. Adverse clinical observations included scant feces (DGs 12, 14, 15, 19 and 20), no feces (DGs 13, 16 to 18, 21 and 22) and a red substance in the cage pan (DG 22). All tissues appeared normal at necropsy. Nine late resorptions were aborted and no conceptuses remained in utero. This doe lost body weight after DG 8 and feed consumption values were reduced after DG 9. Doe 8265 in the 10 mg/kg/day dosage group aborted and was sacrificed on DG 25 after 14 daily dosages. Adverse clinical observations included scant feces (DGs 9 to 20, 23 and 24), no feces (DGs 21 and 22) and a red substance in the cage pan (DG 25). All tissue s appeared normal at necropsy. This doe aborted one dead fetus and five live fetuses and one early resorption were in utero. All fetuses appeared normal for their developmental ages. Body weight losses occurred after DG 8 and feed consumption values were reduced throughout the dosage period. 20 mq/kq/dav dosage Doe 8266 in the 20 mg/kg/day dosage group was found dead on DG 17 after 11 daily dosages. Adverse clinical observations prior to death included scant feces (DGs 12 to 15), a red substance in cage pan, no feces, ungroomed coat, a red perivaginal substance (DGs 16 and 17) and excess salivation (DG 17). Necropsy revealed a white frothy material in the esophagus and inflated lungs. Necropsy also revealed tears in the left diaphragmatic lobe and in the left lateral lobe of the lungs (approximately 2.0 cm in length) and two eroded areas in the fundic mucosa of the stomach (1.5 x 0.5 cm and 1.5 x 0.5 cm). Ten early resorptions were in utero. All fetuses appeared normal for their developmental ages. Body weight loss occurred after DG 8 and its feed consumption values were reduced throughout the dosage period. The death of this doe was considered an intubation accident because of the tear in the left lung lobe; however, this doe had adverse clinical and necropsy observations that indicated the doe was moribund. 000836 418-012:PAGE D-9 418-012P:PAGE 9 Doe 8267 in the 20 mg/kg/day dosage group was found dead on DG 20 after 13 daily dosages. Adverse clinical observations included scant feces (DGs 9,10 and 16 to 19), no feces (DGs 11 to 15) and excess salivation (DG 19). No gross lesions were observed by necropsy and thirteen dead fetuses were in tero. All fetuses appeared normal for their developmental ages. Body weight losses occurred after DG 8 and feed consumption values were reduced throughout the dosage period. Doe 8268 in the 20 mg/kg/day dosage group was found dead on DG 17 after 10 daily dosages. Adverse clinical observations included scant feces (DGs 9 to 15), soft or liquid feces (DGs 12 and 13), a tan perivaginal substance (DG 16) and no feces (DG 16). Necropsy revealed approximately 18 mL of cloudy green fluid in the abdominal cavity, a friable stomach and a ruptured gall bladder. Nine dead fetuses and one early resorption were in tero. All fetuses appeared normal for their developmental ages. Body weight losses occurred after DG 9 and feed consumption values were reduced throughout the dosage period. Doe 8269 in the 20 mg/kg/day dosage group aborted and was sacrificed on DG 19 after 13 daily dosages. Adverse clinical observations included scant feces (DGs 11 to 19), excess salivation (DGs 18 and 19) and a red substance in the cage pan (DG 19). Other than an observation of ungroomed coat and confirmation of persistent adverse clinical observations, no gross lesions were observed by necropsy. This doe aborted three dead fetuses and five live fetuses were in utero\ all fetuses appeared normal for their developmental ages. Body weight losses occurred and feed consumption values were reduced after DG 8. Doe 8270 in the 20 mg/kg/day dosage group was found dead on DG 16 after nine daily dosages. The only adverse clinical observation prior to death was scant feces (DGs 9 to 15). Necropsy revealed the non-glandular mucosal surface of the stomach to be red and diffuse. Five fetuses and one early resorption were in tero. All fetuses appeared normal for their developmental ages. Body weight losses occurred after DG 7 and feed consumption values were reduced throughout the dosage period. A.2. Clinical Observations Dosage-dependant increases in adverse clinical observations occurred in the 2.5, 5, 10 and 20 mg/kg/day dosage groups. One rabbit in the 2.5 dosage group and all rabbits in the 5, 10 and 20 mg/kg/day dosage groups had scant feces (first observed on DGs 14, 13, 9 and 9, respectively). One, five and three rabbits in the 5, 10 and 20 mg/kg/day dosage groups had no feces (first observed on OOO837 418-012:PAGE D-10 418-012P:PAGE 10 DG 18,12 and 11, respectively). Three rabbits in the 20 mg/kg/day dosage group had excess salivation (first observed on DG 17). Two rabbits that aborted or were found dead in each of the 10 and 20 mg/kg/day dosage groups had a red substance in the cage pan (first observed on DGs 22 and 16, respectively). Two rabbits in the 20 mg/kg/day dosage group had a red or tan perivaginal substance (first observed on DG 16). One rabbit in each of the 2.5, 5, 10 and 20 mg/kg/day dosage groups had an ungroomed coat (first observed on DG 18, 23, 24, 24 and 16, respectively). All other clinical observations were considered unrelated to the test article because: 1) the incidences were not dosage-dependent; or 2) the observations occurred in only one rat. These clinical observations included localized alopecia (underside, head, back and/or limbs) for 2, 1, 1, 0, 2, 0 and 0 does in the seven respective dosage groups, a mass on the nose of one 10 mg/kg/day dosage group doe that aborted, one rabbit in each of the 0.1 and 20 mg/kg/day dosage groups that had soft or liquid feces (first observed on DG 12) and scant feces in one 0.1 mg/kg/day dosage group rabbit on one day of the study. A. 3. Necropsy Observations There were no necropsy observations for the rabbits that survived until scheduled sacrifice. All necropsy observations in rabbits that died or aborted were described previously. B. Maternal Body Weights and Body Weight Changes (Figure 1: Summaries - Tables 4 and 5: Individual Data - Table 13) Rabbits in the 10 and 20 mg/kg/day dosage groups had body weight losses for all recorded intervals after initiation of dosage; there were no surviving pregnant rabbits in these groups after DGs 26 and 19, respectively. The 2.5 and 5 mg/kg/day dosage groups had decreased body weight gains or body weight losses for the entire dosage period (calculated as DGs 7 to 21). During the postdosage period (DGs 21 to 29), body weight gains were increased in the 2.5 and 5 mg/kg/day dosage groups, a rebound phenomenon that commonly occurs in these types of studies. Body weight gains for the entire gestation period (DGs 0 to 29) and the entire gestation period after the initiation of dosing (DGs 7 to 29) were reduced in the 2.5 and 5 mg/kg/day dosage groups. Body weights and body weight gains were unaffected by the 1 mg/kg/day dosage of the test article. 000838 418-012: PAGE D-11 418-012P:PAGE 11 C. Absolute (a/davl and Relative (a/ka/dav) Feed Consumption Values (Summaries - Tables 6 and 7: Individual Data - Table 141 Rabbits in the 10 and 20 mg/kg/day dosage groups had severely reduced absolute and relative feed consumption values for all recorded intervals after initiation of dosage; there were no surviving pregnant rabbits in these groups after DGs 26 and 19, respectively. Absolute and relative feed consumption values for the entire dosage period (calculated as DGs 7 to 21) were reduced in the 2.5 and 5 mg/kg/day dosage groups. During the postdosage period (DGs 21 to 29), feed consumption values were generally comparable among the five surviving groups, although the 5 mg/kg/day dosage group had slightly increased feed consumption values during this period, a rebound phenomenon that commonly occurs in these types of studies. Feed consumption values were reduced in the 2.5 and 5 mg/kg/day dosage groups for the entire gestation period after the initiation of dosing (DGs 7 to 29). Absolute and relative feed consumption values were unaffected by the 1 mg/kg/day dosage of the test article. D. Caesarean-Sectioning and Litter Observations (Summaries - Tables 8 and 9: Individual Data - Tables 15 through 17) Caesarean-sectioning observations were based on 5, 4, 4, 5 and 2 pregnant rabbits with one or more live fetuses in the 0, 0.1, 1, 2.5 and 5 mg/kg/day dosage groups, respectively. There were no pregnant rabbits that survived to DG 29 Caesarean-sectioning in the 10 and 20 mg/kg/day dosage groups. Fetal body weights were severely reduced and the number of early and late resorptions and the percent resorbed conceptuses per litter were increased (along with the concomitant decrease in litter size) in the 5 mg/kg/day dosage group. Only two of the four pregnant does in this dosage group survived to Caesareansectioning. Fetal body weights were also reduced in the 2.5 mg/kg/day dosage group as compared to the concurrent controls but were at the lower end of the range observed historically at the Testing Facility. All other Caesarean-sectioning or litter parameters were unaffected by administration of the test article at dosages as high as 5 mg/kg/day. The litter averages for corpora ltea, implantations and percent live male fetuses were comparable among the five surviving dosage groups. No does had a litter consisting of only resorbed conceptuses, there were no dead fetuses and all placentae appeared normal. 000839 418-Q12.PAGE D-12 E. Fetal Gross Observations (Summary - Table 10) 418-012P:PAGE 12 Totals of 42, 37, 34, 42 and 11 fetuses were examined externally for gross alterations in the five respective dosages groups with live litters. Three fetuses had gross external alterations. One fetus (8251-10) in the 2.5 mg/kg/day dosage group had a cleft snout and absent incisors. Two fetuses (8243-8 and 8244-7) in the 0.1 mg/kg/day dosage group had fetal gross malformations; fetus 8243-8 had a short snout, displaced and small nares and fetus 8244-7 had abdominal distention. IV. Recommendation: Based on these data, dosages of 0 (Vehicle), 0.1, 1.0, 2.5 and 3.75 mg/kg/day PFOS were recommended for the developmental toxicity study in rabbits (Argus Protocol 418-012). The 0.1 mg/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 minimal maternal toxicity and little or no developmental toxicity. Alan M. Hoberman, Ph.D., DABT Director of Research Date and Study Director 000840 000841 MATERNAL BODY WEIGHTS Figure 1 4.20 4.00 3.80 360 0* 3.40 0 3.20 3.00 2.80 260 I 7 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 2 27 28 29 DAY OF GESTATION 0 (VEHICLE) MG/KG/DAY - i- - 0.1 MG/KG/DAY A 1 MG/KG/DAY 2.5 MG/KG/DAY 5-3 5 MG/KG/DAY Z 10 MG/KG/DAY 20 MG/KG/DAY o9 M 5 mo w o0I0 ho TJ > o m 01 CO 418-012P:PAGE 14 000842 PROTOCOL 418-012P; ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 1 (PAGE 1 ) : CLINICAL OBSERVATIONS SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY) a I II 0 (VEHICLE) 0 .1 I I I IV 1 2.5 MAXIMUM POSSIBLE INCIDENCE 115/ 5 115/ 5 115/ 5 115/ 5 MORTALITY FOUND DEAD ABORTED AND SACRIFICED 0000 0 00 0 0 00 0 SCANT FECES 0/ 0 1/ 1 0/ 0 8/ 1 NO FECES 0/ 0 0/ 0 0/ 0 0/ 0 EXCESS SALIVATION 0/ 0 0/ 0 0/ 0 0/ 0 RED SUBSTANCE IN CAGE PAN 0/ 0 0/ 0 0/ 0 0/ 0 RED OR TAN PERIVAGINAL SUBSTANCE 0/ 0 0/ 0 0/ 0 0/ 0 SOFT OR LIQUID FECES 0/ 0 2/ 1 0/ 0 0/ 0 UNGROOMED COAT 0/ 0 0/ 0 0/ 0 12/ 1 NOSE: MASS 0/ 0 0/ 0 0/ 0 0/ 0 LOCALIZED ALOPECIA: TOTAL UNDERSIDE HEAD BACK LIMBS 15/ 2/ 0/ 2 1 0 0/ 0 13/ 1 3/ 1 0/ 0 0/ 0 3/ 1 0/ 0 2/ 1 0/ 2/ 0 1 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 occu rred on days 7 through 20 o f presum ed g e s ta tio n . --CDx 000843 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 1 (PAGE 2) : CLINICAL OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a V VI VII 5 10 20 MAXIMUM POSSIBLE INCIDENCE 102/ 5 95/ 5 59/ 5 MORTALITY FOUND DEAD ABORTED AND SACRIFICED 2 0 2f.9 4 0 4h -k 5 4b-e 1i SCANT FECES 50/ 5 49/ 5 33/ 5 NO FECES 2/ 1 23/ 5 8/ 3b-d EXCESS SALIVATION 0/ 0 0/ 0 4/ 3b,c,1 RED SUBSTANCE IN CAGE PAN 0/ 0 2/ 2j ,k 3/ 2b, 1 RED OR TAN PERIVAGINAL SUBSTANCE 0/ 0 0/ 0 3/ 2b, d SOFT OR LIQUID FECES 0/ 0 0/ 0 2/ Id UNGROOMED COAT 2/ 1 3/ lh 2/ lb NOSE: MASS 0/ 0 15/ li 0/ 0 LOCALIZED ALOPECIA: TOTAL UNDERSIDE HEAD BACK LIMBS 16/ 2 16/ 2 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 0/ 0 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 8266 was ound dead c. Doe 8267 was found dead d. Doe 826B was found dead e . Doe 8270 was found dead f . Doe 8257 aborted on day gh . Doe 8259 aborted on day Doe 8261 aborted on day i . Doe 8262 aborted on day j Doe 8264 aborted on day k. Doe 8265 aborted on day 1. Doe 8269 aborted on day o010 Oho TJ K> TJ > 0 m mO D1 Ot 1 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-629S.10) TABLE 2 (PAGE 1 ) : NECROPSY OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) II 0.1 I I I IV 1 2.5 RABBITS EXAMINED b N5 5 5 5 MORTALITY FOUND DEAD ABORTED N0 N0 N0 0 0 0 0 0 0 0 0 0 APPEARED NORMAL N5 5 5 5 ESOPHAGUS: WHITE FROTHY MATERIAL N 0 0 0 0 LUNGS: APPEARED INFLATED AND LEFT DIAPHRAGMATIC LOBE, TEAR N 0 0 0 0 ABDOMINAL CAVITY: CLOUDY GREEN FLUID N0 0 0 0 GALLBLADDER : RUPTURED N0 0 0 0 a. Dosage o ccu rred on days 7 through 20 o f presum ed g e s ta tio n . b. R efer to th e in d iv id u a l c lin ic a l o b s e rv a tio n s ta b le (Table 11) fo r e x te rn a l o b se rv a tio n s confirm ed a t necropsy. 418-012P:PAGE 17 000845 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-G295.10) TABLE 2 (PAGE 2 ) : NECROPSY OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I II I I I IV 0 (VEHICLE) 0.1 1 2.5 RABBITS EXAMINED b N STOMACH: FUNDIC MUCOSA, TWO ERODED AREAS N 5 0 5 0 5 0 5 0 NON-GLANDULAR MUCOSA, RED AND DIFFUSE N 0 0 0 0 FRIABLE N0 0 0 0 MUCOSAL SURFACE, NUMEROUS BLACK AREAS N 0 0 0 0 LIVER: LEFT LATERAL LOBE, TEAR N 0 0 0 0 MOTTLED RED AND TAN N0 0 0 0 EXTERNAL OBSERVATIONS: UNGROOMED COAT N0 0 0 0 NOSE, MASS, CUT SURFACE REVEALED SMOOTH PINK MATERIAL N 0 0 0 0 a. Dosage occurred on days 7 through 20 o f presum ed g e s ta tio n , b. R efer to th e in d iv id u a l c lin ic a l o b s e rv a tio n s ta b le (Table 11) fo r e x te rn a l o b se rv a tio n s confirm ed a t necro psy . o0i0 000846 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 2 (PAGE 3): NECROPSY OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a RABBITS EXAMINED b V 5 N5 VI VII 10 20 5s MORTALITY FOUND DEAD ABORTED N2 N0 N 2g, h 4 0 4i-l 5 4c- f lm APPEARED NORMAL N 5g, h 3k,1 2d,m ESOPHAGUS : WHITE FROTHY MATERIAL N 0 0 lc LUNGS : APPEARED INFLATED AND LEFT DIAPHRAGMATIC LOBE, TEAR N 0 0 lc ABDOMINAL CAVITY: CLOUDY GREEN FLUID N0 0 le GALLBLADDER: RUPTURED N0 0 le 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. Doe 8266 was found dead o n d a y 17 of gestation. d. Doe 8267 was found dead on d a y 20 of gestation. e. Doe 8268 was found dead on day 17 of gestation. f. Doe 8270 was found dead on d a y 16 of gestation. 9 Doe 8257 aborted on day 23 of gestation h. Doe 8259 aborted on day 22 of gestation i . Doe 8261 aborted on day 26 of gestation j Doe 8262 aborted on day 22 of gestation k. Doe 8264 aborted on day 23 of gestation 1. Doe 8265 aborted on day 25 of gestation m . Doe 8269 aborted on day 19 of gestation tx 00 6 O? NJ T> N )p > 0m m5o D1 00 00 000847 PROTOCOL 418 012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-629S.I0) TABLE 2 (PAGE 4) : NECROPSY OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a V VI VII 5 10 20 RABBITS EXAMINED b N5 5 5 MORTALITY FOUND DEAD ABORTED N2 N0 N 2g,h 4 0 4i -1 5 4c- f lili STOMACH : FUNDIC MUCOSA, TWO ERODED AREAS N 0 0 le NON-GLANDULAR MUCOSA, RED AND DIFFUSE N 0 0 If FRIABLE N0 0 le MUCOSAL SURFACE, NUMEROUS BLACK AREAS N 0 l i 0 LIVER : LEFT LATERAL LOBE. TEAR N 0 0 le MOTTLED RED AND TAN N0 li 0 EXTERNAL OBSERVATIONS: UNGROOMED COAT N0 0 lm NOSE, MASS. CUT SURFACE REVEALED SMOOTH PINK MATERIAL N 0 Ij 0 a. Dosage occu rred on days 7 through 20 o f presum ed g e s ta tio n . b. R efer to th e in d iv id u a l c l in i c a l o b se rv a tio n s ta b le (T able 11) fo r e x te rn a l o b se rv a tio n s confirm ed a t necropsy. c. Doe 8266 was found dead on day 17 o f g e s ta tio n . d. Doe 8267 was found dead on day 20 of g e s ta tio n . e. Doe 8268 was found dead on day 17 of g e s ta tio n . f . Doe 8270 was found d ea d on d ay 16 o f g e s t a t i o n . g. Doe 8257 ab o rted on day 23 o f g e s ta tio n . h. Doe 8259 a b o rted on day 22 o f g e s ta tio n . i . Doe 8261 ab o rted on day 26 o f g e s ta tio n . j . Doe 8262 ab o rted on day 22 o f g e s ta tio n . k. Doe 8264 a b o rted on day 23 o f g e s ta tio n . l. Doe 8265 a b o rted on day 25 o f g e s ta tio n . m. Doe 8269 a b o r t e d on d a y 19 o f g e s t a t i o n . oai> M--UVoi fj " > CD >oJ m m 01 CD PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 3 (PAGE 1 ) : UTERINE CONTENTS AND LITTER DATA FOR RABBITS THAT WERE FOUND DEAD OR ABORTED DOSAGE GROUP RABBIT DOSAGE (MG/KG/DAY) a NUMBER DAY OF DEATH CORPORA LUTEA R LT IMPLANTATIONS R LT EMBRYOS/FETUSES b RLAT RESORPTIONS C RLAT I 0 (VEHICLE) - - -- - -- - --- - -- - - II 0.1 III 1 IV 2.5 V 65 8257 A BORTED ON DAY 23 24 6 24 6 000 0 0 1 5d OF GESTATION (SLR) 8259 ABORTED ON DAY 22 OF GESTATION 4 7 11 36 9 0 0 7e 7 0 0 2d 2 (2LR) VI 7 010 8261 ABORTED ON DAY 26 4 7 11 2 9 2 f 0 7e 9 00 0 OF GESTATION 8262 ABORTED ON DAY 22 s 5 10 45 9 000 0 0 0 9d 9 OF GESTATION (9LR) 8264 ABORTED ON DAY 23 45 9 45 9 000 0 0 0 9d 4 OF GESTATION (9LR) 8265 ABORTED ON DAY 25 43 7 43 7 2 3 le 6 10 0 1 fe. OF GESTATION R = RIGHT L = LEFT T = TOTAL A = ABORTED a. Dosage occurred on days 7 through 20 of g e sta tio n . b. Conceptuses appeared normal for developm ental ages. 0oI0 o9 K) TJ c. Early resorptions, unless noted otherw ise. d. A utolysis precluded further evaluation. fToJ > 0 e. Dead fetu ses. f. Fetus 8261-1 and 8261-2 had edema on th e d o rsal head and v e n tra l neck. TJ m mO NOD1> 8 000848 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 3 (PAGE 2) : UTERINE CONTENTS AND LITTER DATA FOR RABBITS THAT WERE FOUND DEAD OR ABORTED DOSAGE GROUP RABBIT DOSAGE (MG/KG/DAY)a NUMBER DAY OF DEATH CORPORA LUTEA RL T IMPLANTATIONS Rh T EMBRYOS/FETUSES b RLA T VII 20 8 2 6 6 FOUND DEAD ON DAY 5 5 10 55 17 OF GESTATION 8 2 6 7 FOUND DEAD ON DAY 20 OF GESTATION 9 6 15 76 8 2 6 8 FOUND DEAD ON DAY 17 OF GESTATION 6 4 10 64 8 2 6 9 ABORTED ON DAY 19 OF GESTATION 7 3 10 53 8 2 7 0 FOUND DEAD ON DAY 16 OF GESTATION 52 7 51 R = RIGHT L = LEFT T = TOTAL A = ABORTED a. Dosage o ccu rred on days 7 through 20 o f g e s ta tio n . b. Conceptuses appeared normal for developm ental ages. c. Early resorptions, unless noted otherw ise. d. Unable to determ ine v ia b ility of conceptuses because of death of doe. e. Dead fetu ses. 10 13 10 8 6 000 0 7 6 0 13d 630 9d 3 2 3e a 410 5d RESORPTIONS C RLA T 5 5 0 10 000 0 010 1 000 0 100 1 418-012P:PAGE 22 ooosso PROTOCOL 4X8-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 4 (PAGE 1) : MATERNAL BODY WEIGHTS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) RABBITS TESTED N 5 PREGNANT N5 MATERNAL BODY WEIGHT (KG) DAY 0 MEAN+S. D . 3.45 + 0.22 DAY 7 MEAN+S. D. 3.49 + 0.18 DAY 8 MEAN+S. D. 3.53 + 0.17 DAY 9 MEAN+S.D . 3.54 + 0.17 DAY 10 MEAN+S.D. 3.57 + 0.19 DAY 11 MEAN+S.D . 3.58 + 0.19 DAY 12 MEAN+S.D . 3.61 + 0.20 DAY 13 MEAN+S.D. 3.67 + 0.20 DAY 14 MEAN+S.D . 3.71 + 0.23 DAY 15 MEAN+S.D- 3.70 + 0.20 DAY i e MEAN+S.D. 3.73 + 0.20 DAY 17 MEAN+S. D . 3.75 + 0.22 DAY 18 MEAN+S.D. 3 -77 + 0.22 DAY 19 MEAN+S. D . 3.80 + 0.22 DAY 20 MEAN+S.D. 3.81 + 0.21 DAY 21 MEAN+S.D. 3.81 + 0.20 DAY = DAY OF GESTATION a. Dosage occu rred on days 7 through 20 o f g e s ta tio n . II 0.1 5 4 3.32 + 0.30 3.36 + 0.17 3-42 + 0.21 3.44 + 0.22 3.43 + 0.21 3.42 + 0.24 3.44 + 0.22 3.50 + 0.24 3.53 + 0.25 3 . 56 + 0 .2 9 3.60 + 0.31 3.62 + 0.28 3.62 + 0.28 3.66 + 0.28 3.69 + 0.28 3.71 + 0.25 III 1 5 4 3.34 + 0.18 3.49 + 0.23 3.53 + 0.24 3.54 + 0.22 3.57 + 0.22 3.60 + 0.19 3.62 + 0.25 3.66 + 0.27 3.71 + 0.28 3.74 + 0.28 3.76 + 0.28 3.78 + 0.30 3.81 + 0.28 3.83 + 0.30 3.84 + 0.28 3.83 + 0.31 IV 2 .5 5 5 3.49 + 0.39 3.62 + 0.37 3.64 + 0.39 3.65 + 0.38 3.67 + 0.38 3.70 + 0.37 3.72 + 0.38 3.75 + 0.43 3.74 + 0.43 3.77 + 0.42 3.74 + 0.45 3.73 + 0.45 3.75 + 0.42 3.72 + 0.46 3.72 0.48 3.73 + 0.45 _-f_ek. 00 000851 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 4 (PAGE 2) : MATERNAL BODY WEIGHTS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) RABBITS TESTED N 5 PREGNANT N5 MATERNAL BODY WEIGHT (KG) DAY 22 MEAN+S. D. 3.84 + 0.21 DAY 23 MEAN+S.D . 3.86 + 0.19 DAY 24 MEAN+S. D . 3.87 + 0.20 DAY 25 MEAN+S. D . 3-89 + 0.21 DAY 26 MEAN+S.D . 3.87 + 0.23 DAY 27 MEAN+S. D . 3.91 + 0.23 DAY 28 MEAN+S.D . 3.93 + 0.24 DAY 29 MEAN+S.D. 3.96 + 0.22 DAY = DAY OF GESTATION a. Dosage o ccu rred on days 7 through 20 o f g e s ta tio n . II 0.1 5 4 3.72 + 0.26 3.74 + 0.26 3.76 + 0.23 3.77 + 0.20 3.76 + 0.20 3.76 + 0.18 3.74 + 0.14 3.75 + 0.16 III 1 5 4 3.87 + 0.29 3.92 + 0.27 3.95 + 0.27 4.01 + 0.28 3.97 + 0.30 4.00 + 0.29 4.03 + 0.30 4.06 + 0.32 IV 2.5 5 5 3.74 + 0.47 3.78 + 0.44 3.81 + 0.41 3.84 + 0.42 3.83 + 0.42 3.88 + 0.41 3.90 + 0.45 3.93 + 0.42 -fc. 00 _k ? fT>GoToJJ mttoo o K> >T l om D CCOO 418-012:PAGE D-24 000852 PROTOCOL 4 1 B - 0 1 2 P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T - 6 2 9 5 . 1 0 ) TABLE 4 (PAGE 3 ) : MATERNAL BODY WEIGHTS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a V 5 RABBITS TESTED N 5 PREGNANT N4 MATERNAL BODY WEIGHT' (KG) DAY 0 MEAN+S. D. 3.36 + 0.40 DAY 7 MEAN+S. D . 3.44 + 0.33 DAY 8 MEAN+S.D . 3.45 + 0.35 DAY 9 MEAN+S.D . 3.49 + 0.36 DAY 10 MEAN+S.D. 3.47 + 0.39 DAY 11 MEAN+S. D . 3.49 + 0.37 DAY 12 MEAN+S. D . 3.44 + 0.37 DAY 13 MEAN+S. D. 3.44 + 0.39 DAY 14 MEAN+S. D . 3.35 + 0.38 DAY 15 MEAN+S.D. 3.28 + 0.37 DAY 16 MEAN+S.D. 3.25 + 0.36 DAY 17 MEAN+S.D. 3.20 + 0.35 DAY 18 MEAN+S.D. 3.20 + 0.35 DAY 19 MEAN+S.D. 3 . 16 + 0.3 4 DAY 20 MEAN+S-D . 3.12 + 0.35 DAY 21 MEAN+S.D. 3.10 + 0.38 DAY = DAY OF GESTATION t ) = NUMBER OF VALUES AVERAGED a. Dosage o ccurred on days 7 through 20 of g e s ta tio n . b. Excludes values for rab b its th at died or aborted. VI 10 5 4 3.28 + 0.41 3.45 + 0.39 3.48 + 0.38 3.47 + 0.42 3.38 + 0.42 3.28 + 0.39 3.19 + 0.40 3.16 + 0.43 3.10 + 0.42 3.06 + 0.42 3.04 + 0.39 3.00 + 0-38 2.96 + 0.44 2.92 + 0.42 2.90 + 0.44 2.87 + 0.43 VII 20 5 5 3.40 + 0.18 3.54 0.22 3.53 + 0.27 3.44 + 0.25 3.34 + 0.24 3.27 + 0.24 3.20 + 0.24 3.15 + 0.24 3.10 + 0.25 3.04 + 0.26 3.06 + 0.16 [ 4]b 3.03 + 0.15 i 3 1b 2.99 + 0.18 t 21b 2.79 + 0.00 t lib b ______ ________ A 9o IuS> TJ <*? {" ^ 000853 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 4 (PAGE 4) : MATERNAL BODY WEIGHTS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a V 5 RABBITS TESTED N 5 PREGNANT N4 INCLUDED IN ANALYSES N 3b MATERNAL BODY WEIGHT (KG) DAY 22 MEAN+S.D . 3.17 + 0.48 DAY 23 DAY 24 DAY 25 DAY 26 DAY 27 DAY 28 DAY 29 MEAN+S.D . MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. MEAN+S.D. 3.40 + 0.66 [ 2]b 3.47 + 0.66 [ 21b 3.52 + 0.60 [ 2Jb 3.50 + 0.59 { 2] b 3.58 + 0.56 [ 21 b 3.56 + 0.64 I 21b 3.58 + 0.66 ( 2]b 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 aborted. VI 10 5 4 3b 2.85 + 0.52 2.78 + 0.71 ( 21b 2.74 + 0.70 [ 21b 3.20 + 0.00 [ lib 3.03 + 0.00 I lib b VII 20 5 5 0b U 0Oi0 <O?> NO TJ MT J > O m O mhino o NO in 000854 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 5 (PAGE 1 ) : MATERNAL BODY WEIGHT CHANGES - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) RABBITS TESTED N 5 PREGNANT N5 MATERNAL BODY WEIGHT CHANGE (KG) DAYS 0 - 7 MEAN+S.D . +0.04 + 0.09 DAYS 7 - 10 MEAN+S.D . +0.09 + 0.04 DAYS 10 - 13 MEAN+S.D . +0.10 + 0.04 DAYS 13 - 16 DAYS 16 - 19 DAYS 1 9 - 21 DAYS 21 - 25 MEAN+S.D . MEAN+S.D . MEAN+S.D . MEAN+S.D . +0.05 + 0.01 +0.07 + 0.02 +0.01 + 0.04 +0.09 + 0.06 DAYS 25 - 29 MEAN+S.D . +0.06 + 0.04 DAYS 7 - 21 MEAN+S.D . +0.32 _+ 0.04 DAYS 21 - 29 MEAN+S.D . +0.15 + 0.08 DAYS 7 - 29 MEAN+S.D . +0.47 + 0.11 DAYS 0 - 29 MEAN+S.D. +0.51 + 0.18 DAYS = DAYS OF GESTATION a. D osage o cc u rre d on days 7 th ro u g h 20 o f g e s ta tio n . II 0 .1 5 4 +0.04 + 0.14 +0.07 + 0.05 +0.06 + 0.05 +0-10 + 0.08 +0.07 + 0.04 +0.04 + 0.03 +0.07 + 0.08 -0.02 + 0.12 +0.34 + 0.10 +0.04 + 0 .16 +0.38 + 0.07 +0.43 + 0.21 III 1 5 4 +0.14 + 0.10 +0.08 + 0.02 +0.10 + 0.05 +0.09 + 0.06 +0.08 + 0.05 +0.00 + 0.05 +0.18 + 0.05 +0.06 + 0.09 +0.34 + 0.09 +0.23 + 0.09 +0.57 + 0.12 +0.72 + 0.20 IV 2 .5 5 5 +0.13 + 0.08 +0.05 + 0.02 +0.08 + 0.10 -0.01 + 0.11 -0.02 + 0.11 +0.01 + 0.05 +0.11 + 0.06 +0.09 + 0.06 +0.11 + 0.28 +0.20 + 0.06 +0.31 + 0-25 +0.44 + 0.31 00 *_>+ 6 o9 N) "D M> TJ O TJ m > o Di m N> NOJ CD 000855 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 5 (PAGE 2) : MATERNAL BODY WEIGHT CHANGES SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a V 5 RABBITS TESTED N 5 PREGNANT N4 MATERNAL BODY WEIGHT CHANGE (KG) DAYS 0 - 7 MEAN+S. D . +0.08 + 0.08 DAYS 7 - 10 MEAN+S.D . +0.02 + 0.10 DAYS 10 - 13 MEAN+S. D . -0.03 + 0.04 DAYS 13 - 16 MEAN+S.D. -0.19 + 0.04 DAYS 16 - 19 MEAN+S.D. -0.08 + 0.07 DAYS 19 - 21 MEAN+S. D . -0.06 + 0.06 DAYS 21 - 25 DAYS 2 5 - 29 DAYS 7 - 21 MEAN+S.D. MEAN+S.D. MEAN+S. D . +0.29 + 0.01 +0 . 0i5 2)b + 0.06 i 2]b -0.34 + 0.09 DAYS 21 - 29 DAYS 7 - 29 DAYS 0 - 29 MEAN+S. D. MEAN+S.D. MEAN+S. D . +0.35 + 0.04 +0 . 0i6 2]b + 0.11 +0 .1 0 2] b + 0.01 I 21 b DAYS = DAYS OF GESTATION ( ] = NUMBER OF VALUES AVERAGED a. Dosage occu rred on days 7 through 20 of g e s ta tio n . b. Excludes values for rab b its th at died or aborted. VI 10 5 4 +0.17 + 0.11 -0.08 + 0.05 -0.22 + 0.02 -0.12 + 0.06 -0.12 + 0.03 -0.05 + 0.02 -0.16 + 0.00 t 1)b b -0.58 + 0.06 b VII 20 5 5 +0.15 + 0. -0.2 0 + 0. -0 .2 0 + 0. -0.18 + 0. [ 4]b -0.21 + 0. I lib b -tx 0oI0 rO?or p M TJ > o m OD rmo r-voi -4 000856 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 6 (PAGE 1) : MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a I 0 (VEHICLE) RABBITS TESTED N 5 PREGNANT N5 MATERNAL FEED CONSUMPTION (G/DAY) DAYS 7 - 10 MEAN+S.D. 181.0 + 3.2 DAYS 10 - 13 MEAN+S.D . 172. S + 22.9 DAYS 13 - 16 MEAN+S.D. 167.6 + 32.4 DAYS 16 - 19 MEAN+S- D . 176.4 + 12.0 DAYS 19 - 21 MEAN+S. D . 172.3 + 17.5 DAYS 21 - 25 MEAN+S. D . 153.6 + 40.4 DAYS 25 - 29 MEAN+S. D . 138.9 + 37.1 DAYS 7 - 21 MEAN+S.D. 174.1 + 17.5 DAYS 21 - 29 MEAN+S.D . 146.2 + 37.4 DAYS 7 - 29 MEAN+S.D. 164.0 + 22.0 DAYS = DAYS OF GESTATION a. Dosage occu rred on days 7 through 20 o f g e s ta tio n . b. Excludes a value th a t was a sso c ia te d w ith s p illa g e . II 0.1 5 4 163.2 + 21.9 144.2 + 41.8 152.1 + 51.5 1 7 8 .l8 31b + 8.4 182.5 + 1.8 158.0 + 37.2 89.0 56.2 163.0 + 23.6 121.7 + 45.1 148.4 + 10.6 III 1 5 4 161.8 + 1.3 169.5 + 21.3 173.9 + 14.0 175.3 + 11.8 181.0 + 4.1 169.6 + 10.8 144.2 + 35.8 176.0 + 10.8 156.9 + 23.0 169.0 + 13.9 IV 2.5 5 5 181.4 + 1.6 162.8 + 33.4 135.3 + 72.7 122.0 + 80.3 114.4 + 83.9 125.0 + 56.2 143.2 + 27.7 1 4 5 - 2 + 4 9 . 4 134.1 + 35.8 141.2 + 42.9 4A 0L0 A IO Q9 v K; p) > D m a m tooo oM00 000857 PROTOCOL 418 012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 6 (PAGE 2 ) : MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY) a V 5 RABBITS TESTED N 5 PREGNANT N4 MATERNAL FEED CONSUMPTION (G/DAY) DAYS 7 - 10 MEAN+S. D. 168.4 + 25.3 DAYS 10 - 13 MEAN+S. D . 88.4 37.4 DAYS 13 - 16 MEAN+S.D. 3.7 + 5.7 DAYS 16 - 19 MEAN+S.D. 11.2 + 11.3 DAYS 19 - 21 MEAN+S. D . 17.8 + 27.9 DAYS 21 - 25 DAYS 25 - 29 DAYS 7 - 21 MEAN+S.D. MEAN+S. D . MEAN+S. D . 135.2 + 50.1 [ 2) b 182.6 + 1.6 [ 2]b 60.8 + 17.6 DAYS 21 - 29 DAYS 7 - 29 MEAN+S-D . MEAN+S.D. 158.9 + 25.9 [ 2] b 103-2 + 21.7 t 2]b DAYS = DAYS OF GESTATION [ 1 = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of g e s ta tio n . b. Excludes values for rab b its th at died or aborted. VI 10 5 4 111.8 + 42.6 3.3 + 3.6 0.7 + 0.5 1.2 + 0.9 0.4 + 0.8 1.8 + 0.0 I b1 ) b 25.1 + 9.3 b VII 20 5 5 4 6 . 2 + 24 0.7 + 0. 1.2 + 0 ( 4)b 0 . 7 + 0. t 1] b b -tx 00 3 00 ro Hi tToJ O>T l m ro > Om o r<oo to 000S58 PROTOCOL 418 012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 7 (PAGE 1) : MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY) a I 0 (VEHICLE) RABBITS TESTED N 5 PREGNANT N5 MATERNAL PEED CONSUMPTION (G/KG/DAY) DAYS 7 - 10 MEAN+S. D. 51.3 + 2.0 DAYS 10 - 13 DAYS 13 _ 16 MEAN+S. D. MEAN+S.D. 47.7 + 4.8 45.0 + 7.2 DAYS 16 19 MEAN+S.D . 4 6 . 9 + 1 . 7 DAYS 19 - 21 MEAN+S. D. 45.3 + 3.2 DAYS 21 - 25 MEAN+S. D . 3 9 . 8 + 9 . 8 DAYS 25 - 29 MEAN+S. D. 35.4 4 9.1 DAYS 7 - 21 MEAN+S. D. 4 7 . 4 + 3 . 2 DAYS 21 - 29 MEAN+S.D . 37.6 + 9.1 DAYS 7 29 MEAN+S.D. 4 3 . 7 + 4 . 9 DAYS = DAYS OF GESTATION ( ) = NUMBER OF VALUES AVERAGED a. Dosage occurred on days 7 through 20 of g e s ta tio n . b. Excludes a value th a t was a sso c ia te d w ith sp illa g e . II 0.1 5 4 47.8 + 6.0 41.6 + 11.0 42.8 + 12.0 i 49.4 3) b + 1.8 49.6 + 3.2 42.7 + 11.4 24.0 + 15.6 46.0 + 5.0 32.9 + 13.1 41.3 + 3.8 III 1 5 4 51.6 + 3.2 4 6 . 8 + 3 . 2 46.8 + 0.7 46.2 + 0.5 47.4 + 2.8 4 3 . 4 + 3 . 4 35.7 + 7.2 47.8 0.5 3 9 . 6 +- 4 . 4 44.6 + 1.7 IV 2.S 5 5 50.2 + 5.2 43.9 + 8.3 3 5 . 8 + 1 9 . 8 32.4 + 22.1 30.4 + 22.8 3 3 3 + 14-4 3 6 . 8 4- 4 . 9 39.2 + 13.8 35-1 + 8.6 3 7 . 6 --+ 1 1 . 5 o--0I0X 9o to TJ Fu o > O ij m >G m DCO oco o GSSOOO PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 7 (PAGE 2 ) : MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - SUMMARY DOSAGE GROUP DOSAGE (MG/ KG/ DAY) a V 5 RABBITS TESTED N 5 PREGNANT N4 MATERNAL FEED CONSUMPTION (G/KG/DAY) DAYS 7 - 10 MEAN+S.D. 48.9 + 8.3 DAYS 10 - 13 MEAN+S. D. 25.0 + 7.5 DAYS 13 - 16 MEAN+S.D . 1.0 + 1.5 DAYS 16 - 19 MEAN+S.D . 3.5 + 3.6 DAYS 19 - 21 MEAN+S.D . 5.0 + 7.5 DAYS 21 - 25 DAYS 25 - 29 DAYS 7 - 21 MEAN+S. D. MEAN+S.D . MEAN+S.D . 39.3 + 7.5 5 2 .[2 2] b + 8.6 1 8 .I1 2] b + 3.6 DAYS 21 - 29 DAYS 7 - 29 MEAN+S.D . MEAN+S. D. 46.0 + 0.8 [ 2] b 29.8 + 1.1 [ 2] b DAYS - DAYS OF GESTATION [ ) = NUMBER OF VALUES AVERAGED a. Dosage occu rred on days 7 through 20 of g e s ta tio n b. Excludes values for rab b its th at died or aborted. VI 10 5 4 31.7 + 9.9 1.0 + 1. 1 0.2 + 0.2 0 .4 f 0 .4 0.1 + 0.2 0.5 + 0.0 [ lib b 7.8 + 2.2 b VII 20 5 5 13.1 + 6.0 0.2 t 0 1 0.4 + 0.0 4]b 0.2 + 0.0 [ lib b 0I0 o o9 " V toO > o T> J Omto m o to 000860 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) 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 N ( %) 5 ( 1 0 0 . 0 ) N ( %) 0 ( 0 . 0 ) N ( %) 0 ( 0 . 0 ) RABBITS PREGNANT AND CAESAREAN-SECTIONED ON DAY 29 OF GESTATION N 5 CORPORA LUTEA MEAN+S. D . 10.2 t 1.6 IMPLANTATIONS MEAN+S. D. 8.8 + 1.6 LITTER SIZES MEAN+S. D . 8.4 + 1.1 LIVE FETUSES N MEAN+S. D . 42 8.4 + 1.1 DEAD FETUSES N 0 RESORPTIONS MEAN+S. D . 0.4 + 0.5 EARLY RESORPTIONS N MEAN+S.D. 0 0 .0 + 0.0 LATE RESORPTIONS N MEAN+S. D . 2 0 .4 + 0.5 DOES WITH ANY RESORPTIONS N <%) 2 ( 40.0) DOES WITH ALL CONCEPTUSES RESORBED N 0 DOES WITH VIABLE FETUSES N <%) 5(100.0) PLACENTAE APPEARED NORMAL N<%) 5(100.0) a . D osage o c c u rre d on days 7 th ro u g h 20 of g e s ta tio n . II 0.1 5 4 ( 80.0) 0( 0.0) 0( 0.0) 4 1 1 .8 + 2.9 9.5 + 1.7 9.2 + 1.5 37 9 .2 + 1.5 0 0 .2 + 0.5 0 0 .0 + 0.0 1 0 .2 + 0.5 1 ( 25.0) 0 4(100.0) 4 (100.0) III 1 5 4( 80.0) 0< 0 .0 ) 0( 0.0) 4 1 0 .0 + 0.8 8.5 + 1.3 8.5 + 1.3 34 8.5 + 1.3 0 0 .0 + 0.0 0 0 .0 + 0.0 0 0 .0 + 0.0 0( 0.0) 0 4 (100.0) 4(100.0) IV 2.5 5 5(100.0) 0( 0.0) 0( 0.0) 5 11.0 + 1.4 8 .8 + 2.0 8.4 + 1.5 42 8.4 + 1.5 0 0.4 + 0.5 1 0.2 + 0.4 1 0 .2 + 0.4 2 ( 40.0) 0 5 (100.0) 5(100.0) -N 9* > 0o10 NJ O N"DJ > O m om wKJ D cNoO 418-012P:PAGE 33 000861 PROTOCOL 41B-012P: ORAL (STOMACH TUBE) DOSAGE RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 8 (PAGE 2) : CAESAREAN SECTIONING OBSERVATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a V 5 RABBITS TESTED N 5 PREGNANT FOUND DEAD ABORTED N (%) 4 ( 8 0 . 0 ) N (%) 0< 0 . 0 ) N ( %) 2 ( 5 0 . 0 ) RABBITS PREGNANT AND CAESAREAN- SECTIONED ON DAY 2 9 OF GESTATION N 2 CORPORA LUTEA MEAN+S. D . 10.5 + 0.7 IMPLANTATIONS MEAN+S.D. 9.5 + 0.7 LITTER SIZES MEAN+S. D . 5.5 + 2.1 LIVE FETUSES N MEAN+S. D . 11 5.5 + 2.1 DEAD FETUSES N 0 RESORPTIONS MEAN+S. D . 4 .0 + 1.4 EARLY RESORPTIONS N MEAN+S. D . 5 2.5 + 3.5 LATE RESORPTIONS N MEAN+S.D. 3 1.5 + 2.1 DOES WITH ANY RESORPTIONS N (%) 2(100.0) DOES WITH ALL CONCEPTUSES RESORBED N 0 DOES WITH VIABLE FETUSES n u ) 2(100.0) PLACENTAE APPEARED NORMAL N (%) 2(100.0) a. Dosage o cc u rre d on days 7 th ro u gh 20 o f g e s ta tio n . VI 10 5 4 ( 80.0) 0( 0.0) 4(100.0) 0 VII 20 5 5(100.0) 4( 80.0) 1< 2 0 .0 ) 0 00 000862 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE -RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-629S.10) TABLE 9 (PAGE 1 ) : LITTER OBSERVATIONS (CAESAREAN - DELIVERED FETUSES) - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY) a I 0 (VEHICLE) LITTER S WITH ONE OR MORE LIVE FETUSES N 5 IMPLANTATIONS MEAN+S. D . 8.8 + 1.6 LIVE FETUSES N MEAN+S.D. 42 8.4 + 1.1 LIV E MALE FETUSES N 23 % LIV E MALE FETUSES/LITTER MEAN+S . D . 53.9 + 9.4 LIV E FETAL BODY WEIGHTS (GRAMS)/LITTER MEAN+S. D . 43.77 + 5.95 MALE FETUSES MEAN+S.D . 44.06 + 5.55 FEMALE FETUSES MEAN+S. D . 43.37 + 7.09 % RESORBED CONCEPTUSES/LITTER MEAN+S.D. 3.8 + 5.2 a. Dosage occurred on days 7 th ro u gh 20 of g e s ta tio n . II 0.1 4 9.5 i 37 9.2 + 14 1.7 1.5 37.2 + 5.7 40.76 + 7.53 41.31 + 7.46 40.40 + 7.66 2.3 + 4.6 III 1 4 8.5 + 34 8.5 + 13 1.3 1.3 38.0 + 8.9 44.05 + 2.70 45.67 + 2.75 42.82 + 3.12 0.0 + 0.0 IV 2.5 5 8.8 + 42 8.4 + 20 2.0 1.5 48.5 17.8 38.18 + 5.65 39.44 + 5.84 30.04 + 7.04 3.6 + 5.0 0D10 to O nb r- oo TJ > (m7) Sm w4Di*. 000863 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T 6295.10) TABLE 9 (PAGE 2 ) : LITTER OBSERVATIONS (CAESAREAN-DELIVERED FETUSES) - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a V 5 LITTERS WITH ONE OR MORE LIVE FETUSES N 2 IMPLANTATIONS MEAN+S.D. 9.5 + 0.7 LIVE FETUSES N MEAN+S.D . 11 5.5 + 2.1 LIVE MALE FETUSES N 5 % LIVE MALE PETUSES/LITTER MEAN+S. D . 46.4 + 5.1 LIVE FETAL BODY WEIGHTS (GRAMS)/LITTER MEAN+S. D. 26.05 + 5.40 MALE FETUSES MEAN+S. D . 28.52 + 11.60 FEMALE FETUSES MEAN+S. D. 23.35 + 0.47 % RESORBED CONCEPTUSES/LITTER MEAN+S.D. 4 2 .8 + IB . 1 a. Dosage o ccu rred on days 7 through 20 o f g e s ta tio n . VII 20 0 ---tV. 00 Ao 9o NTJ) Ni T3 > O m mO> Cc On D mc o 418-012: PAGE D-36 000864 PROTOCOL 418 -012P : ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 10 (PAGE 1 ) : FETAL GROSS EXTERNAL ALTERATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a LITTERS EVALUATED FETUSES EVALUATED LIVE SNOUT: CLEFT LITTER INCIDENCE FETAL INCIDENCE N N N N (% ) N (%) I 0 (VEHICLE) 5 42 42 0< 0.0) 0 ( 0.0) INCISORS: ABSENT LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) 0( 0.0) 0 ( 0.0) SNOUT: SHORT LITTER INCIDENCE FETAL INCIDENCE N(*) N (%) 0( 0.0) 0( 0.0) NARES: DISPLACED LITTER INCIDENCE FETAL INCIDENCE N <* ) N (%) 0< 0.0) 0 ( 0.0) NARES: SMALL LITTER INCIDENCE FETAL INCIDENCE N (%) N (% ) 0 ( 0.0) 0( 0.0) BODY: ABDOMINAL DISTENTION LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) 0( 0.0) 0 ( 0.0) a . D osage o c c u rre d on days 7 th ro u g h 20 o f g e s ta tio n . b. Fetus 8251-10 had o th er gross ex tern al a lte ra tio n s c. F etus 8243 8 had o th er g ro ss e x te rn a l a lte r a tio n s . II 0.1 4 37 37 0( 0.0) 0( 0.0) 0( 0.0) 0( 0.0) 1< 25.0) 1 ( 2.7) c 1( 25.0) 1( 2.7) c 1 ( 25.0) 1< 2.7 )c 1( 25.0) 1 ( 2.7) m 1 4 34 34 0 ( 0.0) 0( 0.0) 0( 0.0) 0< 0.0) 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 5 42 42 1< 20.0) 1( 2.4 )b 1 ( 20.0) 1 ( 2.4 )b 0< 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 0 ( 0.0) 0( 0.0) 0( 0.0) 0 ( 0.0) 0I0 o fuo T>CJ mQ S98000 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 10 (PAGE 2 ) : FETAL GROSS EXTERNAL ALTERATIONS - SUMMARY DOSAGE GROUP DOSAGE (MG/KG/DAY)a V 5 LITTERS EVALUATED FETUSES EVALUATED LIVE N2 N 11 N 11 SNOUT: CLEFT LITTER INCIDENCE FETAL INCIDENCE N ( %) N(%) 0 ( 0.0) 0 ( 0.0) INCISORS: ABSENT LITTER INCIDENCE FETAL INCIDENCE N ( %) N() 0 ( 0.0) 0 ( 0.0) SNOUT: SHORT LITTER INCIDENCE FETAL INCIDENCE N ( %) N (%) 0 ( 0.0) 0 ( 0.0) NARES: DISPLACED LITTER INCIDENCE FETAL INCIDENCE N (%) N (%) 0 ( 0.0) 0 ( 0.0) NARES: SMALL LITTER INCIDENCE FETAL INCIDENCE N ( %) N (%) 0 ( 0.0) 0 ( 0.0) BODY : ABDOMINAL DISTENTION LITTER INCIDENCE N (%) FETAL INCIDENCE N (%) 0 ( 0.0) 0 ( 0.0) a. Dosage o ccu rred on days 7 through 20 o f g e s ta tio n . VI 10 0 0 0 VII 20 0 0 0 00 ->O0 mt"oJ 418-012: PAGE D-37 998000 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T 6295.10) TABLE 11 (PAGE 1 ) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA RABBIT ft DESCRIPTION DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8 2 3 6 DG ( 1 7 - 2 9) 8 237 DG( 2 8- 29) 8238 8239 8240 LOCALIZED ALOPECIA: LOCALIZED ALOPECIA: NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LIMBS a UNDERSIDE a DOSAGE GROUP XI 0 .1 MG/KG/DAY 8241 DG( 28 ) DG ( 2 8 - 29) 8242 8243 8 2 4 4 DG ( 2 7 - 2 9 ) 8245 SCANT FECES SOFT OR LIQUID FECES NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: BACK a NO ADVERSE FINDINGS DOSAGE GROUP I I I 1 MG/KG/DAY 8246 8 2 4 7 DG ( 2 8 - 2 9) 8248 8249 8250 NO ADVERSE FINDINGS LOCALIZED ALOPECIA: NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS HEAD a DOSAGE GROUP IV 2 .5 MG/KG/DAY 8251 8252 7650 825 4 DG ( 14 ) DG ( 1 6 - 22) DG ( 1 8 - 29) 8255 NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS SCANT FECES SCANT FECES UNGROOMED COAT NO ADVERSE FINDINGS DG = DAY OF PRESUMED GESTATION a. O bservation confirm ed at necropsy. fe. o0I0 9o ro > V 0m O5 m oo CD1O oo PROTOCOL 418 -012P: ORAL (STOMACH TUBE) DOSAGE -RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 11 (PAGE 2) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP V S MG/KG/DAY RABBIT If DESCRIPTION 8 2 5 6 DG ( 14 ) DG ( 1G- 2 1) DG ( 1 9 - 2 9) 8 2 5 7 DG ( 1 3 - 2 2) DG ( 23 ) 8 2 5 8 DG ( 1 3 - 2 7) DG ( 2 5 - 2 9) DG ( 29 ) 8 25 9 DG( 14 ) DG ( 1 6 - 2 1) DG( 22 ) 8260 DG( 1 3 - 17) DG( 1 8 - 19) DG( 2 0 - 24) DG ( 2 3 - 2 4) SCANT FECES SCANT FECES LOCALIZED ALOPECIA: UNDERSIDE a SCANT FECES ABORTED AND SACRIFICED SCANT FECES LOCALIZED ALOPECIA: UNDERSIDE SCANT FECES SCANT FECES SCANT FECES ABORTED AND SACRIFICED SCANT FECES NO FECES SCANT FECES UNGROOMED COAT DG = DAY OF PRESUMED GESTATION a. O bservation confirm ed at necropsy. PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 11 (PAGE 3) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP VI 10 MG/KG/DAY RABBIT DESCRIPTION 8261 DG( 12 ) SCANT FECES DG( 13- 15) NO FECES DG( 16- 20) SCANT FECES DG ( 2 1 - 2 2) NO FECES DG( 2 3- 24) SCANT FECES DG ( 2 4 - 2 6) UNGROOMED COAT DG ( 2 5 - 26) NO FECES DG ( 26 ) ABORTED AND SACRIFICED 826 2 DG ( 7 - 2 1) NOSE: MASS ( 0 . 3 CM IN DIAMETER)a DG ( 1 1 - 12) SCANT FECES DG ( 13 ) NO FECES DG ( 1 4 - 2 1 ) SCANT FECES DG ( 22 ) ABORTED AND SACRIFICED 8 2 6 3 DG ( 11 ) SCANT FECES DG ( 1 2 - 1 3) NO FECES DG ( 1 4 - 2 0 ) SCANT FECES DG ( 2 1 - 2 3) NO FECES DG ( 2 4 - 2 7) SCANT FECES DG ( 2 8 - 2 9) NO FECES 8 2 6 4 DG ( 12 ) SCANT FECES o DG ( 13 ) DG ( 1 4 - 15) NO FECES SCANT FECES o o 00 DG ( 1 6 - 18) DG ( 1 9 - 2 0) DG ( 2 1 - 2 2) DG ( 22 ) NO FECES SCANT FECES NO FECES RED SUBSTANCE IN CAGE PAN o DG ( 23 ) ABORTED AND SACRIFICED 09 8 2 6 5 DG ( 9- 2 0) DG ( 2 1 - 2 2) SCANT FECES NO FECES DG ( 2 3 - 24) SCANT FECES DG ( 25 ) RED SUBSTANCE IN CAGE PAN DG ( 25 ) ABORTED AND SACRIFICED DG = DAY OF PRESUMED GESTATION a. O bservation confirm ed at necropsy. 418-012P:PAGE 40 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 11 (PAGE 4) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP V II 20 MG/KG/DAY RABBIT # DESCRIPTION 8 2 6 6 DG ( 1 2 - 15) DG ( 1 6 - 17) DG ( 1 6 - 17) DG ( 1 6 - 17) DG ( 1 6 - 17) DG ( 17 ) DG< 17 ) 8 2 6 7 DG ( 9 - 10) DG ( 1 1 - 15) DG ( 1 6 - 1 9) DG ( 1 9 ) DG ( 2 0 ) 8 2 6 8 DG ( 9 - 1 5) DG ( 1 2 - 1 3) DG ( 16 ) DG ( 16 ) DG ( 1 7 ) 8 2 6 9 DG ( 1 1 - 19) DG ( 1 8 - 1 9) DG ( 19 ) DG ( 19 ) 0 2 7 0 DG ( 9 - 15) DG ( 16 ) SCANT FECES RED SUBSTANCE IN CAGE PAN RED PERIVAGINAL SUBSTANCE a UNGROOMED COAT NO FECES EXCESS SALIVATION FOUND DEAD SCANT FECES NO FECES SCANT FECES EXCESS SALIVATION FOUND DEAD SCANT FECES SOFT OR LIQUID FECES TAN PERIVAGINAL SUBSTANCE a NO FECES FOUND DEAD SCANT FECES EXCESS SALIVATION RED SUBSTANCE IN CAGE PAN ABORTED AND SACRIFICED SCANT FECES FOUND DEAD DG = DAY OF PRESUMED GESTATION oo a . O b s e r v a t i o n c o n f i r m e d a t n e c r o p s y . 00 C0 4 18 -0 1 2 P :P A G E 00 418-012: PAGE D-42 000870 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 12 (PAGE 1) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA DOSAGE GROUP DOSAGE (MG/KG/DAY) I 0 (VEHICLE) II 0.1 RABBIT NUMBER 8236 8237 8238 8239 8240 8241 8242 8243 8244 8245 DAY OF PREGNANCY DOSAGES NECROPSY STATUS ADMINISTERED OBSERVATIONS a DG 29 P 14 ALL TISSUES APPEARED NORMAL. DG 29 P 14 ALL TISSUES APPEARED NORMAL. DG 29 DG 29 P P 14 14 ALL TISSUES APPEARED NORMAL. ALL TISSUES APPEARED NORMAL. DG 29 P 14 ALL TISSUES APPEARED NORMAL. DG 29 P 14 ALL T ISSUE S APPEARED NORMAL. DG 29 NP 14 ALL T ISSUE S APPEARED NORMAL. DG 29 P 14 ALL TISSUES APPEARED NORMAL. DG 2 9 P 14 ALL TISSUES APPEARED NORMAL. DG 29 P 14 ALL T ISSUE S APPEARED NORMAL. hi 1 8246 DG 29 NP 14 ALL TISSUES APPEARED NORMAL. 8247 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. 8248 DG 2 9 P 14 ALL TISSUES APPEARED NORMAL. 8249 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8250 DG 2 9 P 14 ALL TISSUES APPEARED NORMAL. IV 2.5 8251 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8252 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 7650 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8254 DG 29 P 14 ALL TISSUES APPEARED NORMAL. 8255 DG 29 P 14 ALL TISSUES APPEARED NORMAL. P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. R efer to the in d iv id u a l c l in i c a l o b se rv a tio n s ta b le (T able 11) fo r e x te rn a l o b se rv a tio n s confirm ed a t n ecro psy . 00 to 5 ma M 000871 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T 6295.10) 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 V 5 8256 DG 2 9 P 14 ALL TISSUES APPEARED NORMAL. 8257 DG 23 P 14 ABORTED ON DAY 23 OF GESTATION. ALL TISSU ES APPEARED NORMAL. 8258 DG 2 9 NP 14 ALL TISSUES APPEARED NORMAL. 8259 DG 22 P 14 ABORTED ON DAY 2 2 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8260 DG 2 9 P 14 ALL TISSU ES APPEARED NORMAL. VI 10 8261 DG 26 P 14 ABORTED ON DAY 26 OF GESTATION. LIV ER: MOTTLED RED AND TAN. STOMACH: MUCOSAL SURFACE, NUMEROUS BLACK AREAS (PIN POINT TO 0 . 2 CM IN DIAMETER). ALL OTHER TISSU ES APPEARED NORMAL. 8262 DG 22 P 14 ABORTED ON DAY 22 OF GESTATION. EXTERNAL OBSERVATIONS: NOSE, MASS ( 1 . 0 CN1 X 1 . 0 CM X 0 . 3 CM), CUT SURFACE REVEALED SMOOTH PINK MATERIAL.b ALL OTHER TISSU ES APPEARED NORMAL. 8263 DG 29 NP 14 ALL TISSUES APPEARED NORMAL. 8264 DG 23 P 14 ABORTED ON DAY 23 OF GESTATION. ALL TISSUES APPEARED NORMAL. 8265 DG 25 P 14 ABORTED ON DAY 25 OF GESTATION. ALL TISSUES APPEARED NORMAL. P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. R efer to the in d iv id u a l c lin ic a l o b se rv a tio n s ta b le (Table 11) for e x tern al o b serv atio n s confirm ed at necropsy. b. Confirms a c lin ic a l observation. o0i0 (JO f o O T) > "0 CD >m"oD to m O Lc o PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) 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 VII 20 8266 DG 17 P 11 FOUND DEAD ON DAY 17 OF GESTATION ( 1 1 MINUTES AFTER DOSAGE). ESOPHAGUS: WHITE FROTHY MATERIAL. LUNGS: APPEARED INFLATED AND LEFT DIAPHRAGMATIC LOBE, TEAR ( 2 . 0 CM IN LENGTH). LIV ER: LEFT LATERAL LOBE, TEAR ( 2 . 0 CM IN LENGTH). STOMACH: FUNDIC MUCOSA, TWO ERODED AREAS ( 1 . 5 CM X 0 . 5 CM AND 1 . 5 CM X 0 . 5 C M ). ALL OTHER T ISSU E S APPEARED NORMAL. 8267 DG 20 P 13 FOUND DEAD ON DAY 20 OF GESTATION (DEATH OCCURRED OVERNIGHT). ALL TISSUES APPEARED NORMAL. 8268 DG 17 P 10 FOUND DEAD ON DAY 17 OF GESTATION (22 HOURS AND 27 MINUTES AFTER DOSAGE). ABDOMINAL CAVITY: CLOUDY GREEN FLUID (APPROXIMATELY 18 M L). STOMACH: FRIABLE. GALLBLADDER: RUPTURED. ALL OTHER T ISSU E S APPEARED NORMAL. 8269 DG 19 P 13 ABORTED ON DAY 19 OF GESTATION. EXTERNAL OBSERVATIONS: UNGROOMED COAT. ALL OTHER T ISSU E S APPEARED NORMAL. oo 8270 DG 16 P 9 FOUND DEAD ON DAY 16 OF GESTATION (DEATH OCCURRED OVERNIGHT). o00 STOMACH: NON-GLANDULAR MUCOSA, RED AND DIFFUSE. ALL OTHER TISSU ES APPEARED NORMAL. >1 P = PREGNANT NP = NOT PREGNANT DG = DAY OF PRESUMED GESTATION a. R efer to th e in d iv id u a l c l in i c a l o b se rv a tio n s ta b le (T able 11) fo r e x te rn a l o b se rv a tio n s confirm ed a t necropsy. o9 tUo m>O COID to "D > Om D -t*. PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 13 (PAGE 1) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 17 18 RABBIT # DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8236 P 8237 P 8238 P 8239 8240 Pp 3.76 3.38 3.44 3.52 3.14 3.64 3.47 3.49 3.64 3.20 3.71 3.50 3.47 3.67 3.28 3.74 3.54 3.48 3.66 3.30 3.75 3.57 3.50 3.76 3.29 3.74 3.59 3.53 3.76 3.30 3.74 3.62 3.51 3.84 3.32 3.80 3.68 3.61 3.91 3.37 3.86 3.70 3.63 3.99 3.38 3.82 3.72 3.62 3.94 3.41 3.86 3.72 3.66 3.96 3.43 3.87 3.75 3.71 4.01 3.43 3.91 3.76 3.73 4.01 3.42 DAY 19 20 21 22 23 24 2 5 26 2 7 28 29 8236 P 8237 P 8238 P 8239 8240 Pp 3.93 3.82 3.94 3.81 3.98 3.84 4.01 3.85 3.97 3.91 3.95 3.96 3.98 3.98 3.96 4.00 4.00 4.01 4.01 4.03 4.04 4.05 3.74 3.78 3.75 3.80 3.82 3.78 3.83 3.77 3.74 3.83 3.84 4.03 4.03 3.97 4.02 4.04 4.08 4.12 4.12 4.18 4.21 4.23 3.46 3.48 3.50 3.50 3.54 3.56 3.56 3.52 3.61 3.58 3.64 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGN IFICAN T D IG IT S 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. 000873 A o0I0 o9 ro " tToJ 5O > Gm) D m-A O i (Ji PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-629S.10) TABLE 13 (PAGE 2) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 17 18 RABBIT ft DOSAGE GROUP I I 0 .1 MG/KG/DAY 8241 P 8242 NP 6243 P 6244 P 8245 P 3.68 3.53 3.62 3.62 3.66 3.70 3.71 3 -75 3.77 3.85 3.89 3.88 3.89 3.36 3.42 3.20 2.98 3.49 3.49 3.27 3.17 3.60 3.58 3.30 3.18 3.56 3.63 3.32 3.19 3.57 3.54 3.35 3.18 3.64 3.51 3.34 3.13 3.62 3.49 3.39 3.19 3.68 3.58 3.47 3.18 3.70 3.64 3.53 3.19 3.71 3.70 3.53 3.17 3.81 3.74 3-58 3.17 3.78 3.73 3.62 3.23 3.77 3.77 3.59 3.24 DAY 19 20 21 22 23 24 25 26 27 28 29 8241 P 8242 NP 8243 P 8244 P 8245 P 3.95 3.96 3.99 4.01 4.00 4.00 3.94 3.88 3.82 3.78 3.82 3.82 3.78 3.88 3.84 3.88 3.79 3.88 3.78 3.91 3.86 3.92 3.85 3.91 3.88 3.90 3.90 3.96 3.92 4.03 3.90 4.02 3.94 3.63 3.30 3.63 3.33 3.66 3.40 3.68 3.39 3.72 3.40 3.75 3.45 3.79 3.48 3.77 3.47 3.78 3.50 3.70 3.56 3.65 3.59 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIG N IFIC A N T D IG ITS 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. 000874 0oI0 9O w V > O m O5 o m o> Ok) 418-012P.PAGE 47 000875 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 13 (PAGE 3 ) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 17 18 RABBIT # DOSAGE GROUP I I I 1 MG/KG/DAY 8246 NP 8247 P 8248 P 8249 P 8250 P 3.57 3.63 3.76 3.76 3.79 3.80 3.84 3.86 3.87 3.86 3.94 3.94 3.97 3.29 3.46 3.52 3.11 3.57 3.63 3.61 3.15 3.63 3.64 3.69 3.17 3.62 3.63 3.69 3.22 3.65 3.68 3-71 3.25 3.63 3.68 3.75 3.32 3.74 3.67 3.81 3.26 3.76 3.76 3.87 3.27 3.79 3.87 3.68 3.30 3.80 3.94 3.90 3.34 3.82 3.94 3.92 3.34 3.88 3.94 3.96 3.34 3.92 3.93 3.99 3.39 DAY 19 20 21 22 23 24 25 26 27 28 29 8246 NP 8247 p 8248 P 8249 p 8250 P 4 .0 2 4 .0 5 4 .0 3 4 .0 6 4 .0 5 4 .0 9 4 . 11 4 .1 1 4 .1 6 4 .1 9 4 .2 1 3.93 3.94 3.90 3.93 3.96 3.98 4.03 4.01 4.06 4.12 4.16 3.97 3.99 4.04 4.06 4.10 4.14 4.23 4.21 4.24 4.29 4.35 4.04 4.00 4.02 4.05 4.09 4.12 4.17 4.11 4.12 4.12 4.13 3.38 3.41 3.37 3.44 3.53 3.55 3.60 3.54 3.58 3.59 3.60 P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS ( G ) , ROUNDED TO THREE SIG N IFIC A N T D IG IT S AND REPORTED IN KILOGRAMS (K G ). 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. --- bx. 00 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 13 (PAGE 4) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 17 18 RABBIT # DOSAGE GROUP XV 2 .5 MG/KG/DAY 8251 P 8252 P 7650 P 8254 P 8255 P 3.62 3.31 3.80 3.55 3.80 3.56 3.81 3.56 3.86 3.60 3.88 3.64 3.94 3.67 4 -01 3.73 4.05 3.64 4.08 3.75 4.11 3.72 4.09 3.76 4.11 3.79 4.05 3.47 3.00 4.12 3.52 3.12 4 . 18 3.56 3.12 4.18 3.55 3.14 4.16 3.59 3.14 4.20 3.58 3.20 4.23 3.54 3.23 4.31 3.50 3.20 4.29 3.46 3.25 4.30 3.39 3.34 4.27 3.33 3.28 4.25 3.26 3.29 4.20 3.36 3.29 DAY 19 20 21 22 23 24 25 26 27 28 29 8251 P 8252 P 7650 P 8254 P 8255 P 4.13 4.19 4.20 4.24 4.27 4.29 4.32 4.31 4.34 4.40 4.41 3.84 3.03 3.82 3.89 3.88 3.93 3.94 3.92 3.94 3.93 3.94 4.16 4.14 4.11 4.08 4.09 4.07 4.14 4.15 4.21 4.26 4.28 3.17 3.13 3.19 3.16 3.30 3.37 3.40 3.40 3.46 3.47 3.48 3.29 3.29 3.33 3.35 3.35 3.40 3.41 3.39 3.47 3.42 3.54 P = PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY - DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIG N IFIC A N T D IG IT S 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 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 13 (PAGE 5) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 17 18 RABBIT ft DOSAGE GROUP V 5 MG/KG/DAY 8256 P 8257 P 8258 NP 8259 P 8260 p 3.93 3.90 3.94 4.01 4.04 4.02 3.97 4.01 3.91 3.82 3.27 3.44 3.40 3.40 3.34 3.33 3.30 3-25 3.23 3.14 3.40 3.44 3.50 3.48 3.46 3.43 3.42 3.35 3.30 3.24 3.22 3.29 3.33 3.35 3.34 3.42 3.37 3.35 3.21 3.17 3.02 3.14 3.12 3.19 3.15 3.18 3.12 3.14 3.05 2.97 3.77 3.71 3.71 3.12 3.15 3.10 3.20 3.16 3.13 3.15 3.06 3.06 2.95 2.90 2.92 DAY 19 20 21 22 23 24 25 26 27 28 2 9 8256 P 8257 P 8258 NP 8259 P 8260 P 3.66 3.64 3.66 3.72 3.87 3.94 3.95 3.92 3.98 4.01 3 . 0 8 3 . 0 3 2 . 9 9 2 . 9 4 ABORTED ON DAY 23 OF GESTATION 3.12 2.98 2.93 2.88 2.83 2.80 2.76 2.69 2.69 2.67 2 . 9 8 2 . 9 8 2 . 9 5 ABORTED ON DAY 22 OF GESTATION 2.93 2.84 2.80 2.85 2.93 3.00 3.10 3.08 3.18 3.10 4.04 2.62 3.11 P * PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) , ROUNDED TO THREE SIGN IFICAN T D IG IT S 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. 418-012:PAGE D-49 000877 00 o w mO co PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 13 (PAGE 6) : MATERNAL BODY WEIGHTS INDIVIDUAL DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 17 RABBIT (t DOSAGE GROUP VI 10 MG/KG/DAY 8261 P 8262 P 8263 NP 8264 P 8265 P 3.77 3.33 3.94 3.35 3.92 3.40 3.95 3.41 3.87 3.28 3.73 3.18 3.64 3.10 3.68 3.04 3.60 2.98 3.54 2.97 3.48 2.97 3.44 2.96 3.42 3.26 3.45 3.52 3.51 3.60 3.52 3.57 3.41 3.50 3.29 3.42 3.24 3.33 3.17 3.27 3.15 3.22 3.08 3.17 3.00 3.15 2.92 3.10 2.77 3.00 3.02 2.94 2.86 2.81 2.69 2.64 2.59 2.54 2.54 2.51 DAY 19 20 21 22 23 24 25 26 27 28 29 8261 P 8262 P 8263 NP 8264 P 8265 P 3 . 3 9 3 . 3 9 3 . 3 6 3 . 3 4 3 . 2 8 3 . 2 4 3 . 2 0 3 . 0 3 ABORTED ON DAY 26 OF GESTATION 2 . 8 2 2 . 8 0 2 . 7 4 ABORTEDi ON DAY 22 OF GESTATION 2.91 2.88 2.83 2.77 2.73 2.68 2.64 2.56 2.57 2.56 2.53 3 . 0 6 3 . 0 4 3 . 0 3 2 . 9 0 ABORTED ON DAY 23 OF GESTATION 2 . 4 0 2 . 3 5 2 . 3 4 2 . 3 0 2 . 2 7 2 . 2 5 ABORTED ON DAY 25 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 SIGN IFICAN T D IG IT S 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 3.46 2.90 2.90 3.08 2.41 418-012: PAGE D-50 000878 9o KTJJ mT>o ) oc n PROTOCOL 418 -012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 13 (PAGE 7 ) : MATERNAL BODY WEIGHTS - INDIVIDUAL DATA PREGNANCY STATUS DAY 0 7 8 9 10 11 12 13 14 15 16 17 18 RABBIT n DOSAGE GROUP V II 20 MG/KG/DAY 8266 P 8267 P 8268 P 8269 P 8270 P 3.59 3.37 3.70 3.37 3.74 3.37 3.61 3.28 3.51 3.21 3.42 3.18 3.34 3.15 3.29 3.14 3.24 3.13 3.16 3.09 3 . 10 3.00 2.98 2.92 a 2.86 3 .4 3 3 .6 4 3 .4 8 3.3 6 3 .2 7 3 . 19 3 .1 2 3 .0 6 3 .0 0 2 .9 4 2 .8 8 b 3.49 3.10 3.75 3.26 3.87 3.21 3.77 3.16 3.67 3.06 3.59 2.98 3.51 2.88 3.45 2.80 3.39 2.72 3.34 2.65 3.26 c 3.20 3.12 DAY 19 20 21 22 23 24 25 26 27 28 29 8266 P 8267 P 8268 P 8269 P 8270 P FOUND DEAD ON DAY 17 OF GESTATION 2 . 7 9 FOUND DEAD ON DAY 20 OF GESTATION FOUND DEAD ON DAY 17 OF GESTATION ABORTED ON DAY 19 OF GESTATION FOUND DEAD ON DAY 16 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 SIGN IFICAN T D IG ITS 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 8266 was found dead on day 17 of g e s ta tio n b. c. Doe Doe 8268 8270 was was found found dead dead on on day day 17 16 of of g e sta tio n g e sta tio n 000879 -t*. t* 0o10 ro o9* " MU T>0 J m m 01 CD 01 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T 6295.10) TABLE 14 (PAGE 1) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 RABBIT # DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8236 P 8237 p 8238 p 8239 p 8240 p 181. 183 . 183 . 185. 180. 180. 185. 181 . 183 . 181. 184 . 185. 181. 185 . 184. 182. 182. 182 . 181 . 181. 178. 166. 182 . 159. 127. 183. 184 . 183 . 181. 185 . 180 . 182. 184 . 109. 102 . DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 8236 p 8237 p 8238 p 8239 p 8240 p 184 . 151 . 106. 75. 82 . 92. 96 . 184 . 185. 185. 184 . 182. 170 . 119. 180. 182 . 180. 185. 184 . 182. 180. 183. 133. 182. 120. 180 . 182 . 184 . i n . 114 . 118. 182. 97. 170 . 116. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS ( G ) . 14 - 15 185. 182. 183 . 183 . 122 . 27 - 28 108 . 124 . 184 . 151 . 71. 15 - 16 181 . 180. 182. 180. 105. 28 - 29 121 . 125. 185. 180 . 125. 16 17 182. 181. 181. 180. 180 . 17 - 18 182. 184 . 182 . 184 . 135 . 18 - 19 183. 181. 180. 181 . 150. 19 - 20 157. 185. 182. 183 . 152. 0S8000 fc. 00 A CD fo T3 M> UO TCJ m > o 01 m cn cn ho M PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 14 (PAGE 2 ) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 RABBIT # DOSAGE GROUP I I 0.. 1 MG/KG/DAY 8241 P 8242 NP 8243 P 8244 p 8245 P 181. 184. 182. 182 . 183 . 167 . 185. 181. 184 . 165. 182 . 98. 181. 126 . 184 . 102 . 181. 123 . 180. 182. 183 . 181 . 182. 184 . 138. 143 . 141 . 93 . 118. 89. DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 8241 P 8242 NP 8243 P 8244 P 8245 P 185. 160. 127. 78. 45 . 15 . 181. 180. 180. 182 . 185. 181. 105. 181. 182. 181. 184 . 152. 180. a 180. 182. 163 . 104 . 182. 153. 173. 183 . 182. 145. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G) . a. S pilled feed precluded the calcu latio n of th is value. 13 - 14 182 . 181. 125. 180. 124 . 26 - 27 4. 185. 124 . 123 . 140 . 14 - 15 181. 180. 185. 184. 93. 27 - 28 8. 185. 83 . 58. 135. 15 - 16 182 . 181 . a 182 . 61. 28 - 29 41. 185. 132 . 8. 152. 16 - 17 183 . 184 . 184. 181. 136. 17 - 18 184 . 162 . 183 . 182. 182. 18 - 19 184 . 180 . 185. 180. 181. 19 - 20 183 . 183. 182. 185. 178. 000881 -fc. N 0oI0 -i Vo M TJ w 0 mtwT>OnJ > o m D o0 0n PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 14 (PAGE 3): 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 # DOSAGE GROUP III 1 MG/KG/DAY 8246 NP 8247 P 8248 P 8249 P 8250 p 181 . 181 . 182. 185. 180. 182 . 182 . 181. 181. 180. 183. 181 . 182. 185. 182. 181. 182. 181. 184. 182. 183 . 181. 181. 180. 107. 185. 168. 182 . 182. 124 . 185. 182. 185. 185. 131. 181 . 181 . 183. 183 . 183 . 180. 180 . 169. 180. 145. 180180. 180. 181. 145- 182. 181180. 184. 176. 184. 180. 184 . 181. 152. 185. 180. 184. 185. 168 . DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 B246 NP 8247 P 8248 P 8249 P 8250 p 185. 183. 184 . 182. 182. 182 . 182. 182. 182. 181. 183 . 183 . 176. 167. 175. 182 . 183 . 175. 146. 153. 184. 181. 167. 143. 138. 183 . 173 . 166 . 150. 114. 184 . 181. 181. 115. 113 . 183 . 174 . 152 . 115. 93 . 181 . 183. 181 . 126. 90 . P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G). 000882 A A . 0o10 o9 K J fo > y0 m Gm DU1l a PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 14 (PAGE 4): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS RABBIT n 7- 8 8- 9 DOSAGE GROUP IV 9 - 10 10 - 11 11 - 12 12 - 13 2 .5 MG/KG/DAY 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 8251 P 8252 P 7650 P 8254 P 8255 P 183. 184. 185. 180 . 182. 180. 181. 182. 181. 179. 180. 183 . 182. 176. 183. 182 . 183 . 184 . 153 . 166. 184 . 182. 183 . 122. 164 . 184. 160 . 184 . 43 . 148. 183 . 126 . 167. 17 . 162 . 185. 184 . 181 . 1. 180 . 182. 180. 110. 2. 169. 180. 183 . 102 . 0. 166 . 182. 181. 76. 2. 165. 184 . 183 . 58. 0. 168. 181. 183. 47. 0. 172 . DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 8251 P 8252 P 7650 P 8254 P 8255 P 168. 183. 37. 11. 162. 180. 152. 30. 38. 158. 182. 152. 30. 100. 134. 182. 148 . 10. 130. 156. 181. 161 . 94 . 117 . 166 . 181. 148. 123 . 84 . 153. 163 . 148. 161 . 102 . 142 . 160. 141. 155. 93. 115. 183. 181. 169. 113. 149. P = PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G) . 418-012: PAGE D-55 000883 0oI0 N Jp omttnn PROTOCOL 41B-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 14 (PAGE 5): MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 7 - 8 0 - 9 9 - 10 10 - 11 11 - 12 12 - 13 13 - 14 14 - 15 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 RABBIT * DOSAGE GROUP V 5 MG/KG/DAY 8256 P 8257 P 8258 NP 8259 P 8260 P 185. 183. 182. 168. 137. 123 . 36 . 0. 1. 0. 45. 13. 40. 117 . 144. 131. 115. 66. 9. 1 . 0. 3 . 1. 3. 0 . 3. 182. 182. 169. 134. 84 . 13 . 1. 0 . 0. 0 . 2. 0. 1. 184 . 180. 182. 173. 56. 21. 0. 0. 0. 2 . 2. 1 . 0. 182. 166. 185. 142. 44. 7 . 0 . 0. 4. 5 . 6. 57. 11 . DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 26 - 27 27 - 28 28 - 29 8256 P 8257 P 8258 NP 8259 P 8260 P 79. 133. 181. 184 . 185. 184 . 185. 181. 185. 7. 7. 14 . ABORTED ON DAY 23 OF GESTATION 2. 3. 1. 0. 0. 1. 4 . 1. 1. 2. ABORTED ON DAY 22 OF GESTATION 0. 55. 62. 113 . 169. 180. 181. 182. 183. P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS (G). 418-012: PAGE D-56 oo NT J) >) o m PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-629S.10) TABLE 14 (PAGE 6 ) : 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 RABBIT tf DOSAGE GROUP VI 10 MG/KG/DAY 8261 P 8262 P 8263 NP 181 . 171. 180. 145. 180. 164 . 86. 28. 28. 2. 1. 2. 0. 0. 1. 3. 2. 2. 0. 0. 0. 0. 2. 0. 0. 0. 0. 8264 P 8265 P 179. 128. 121. 30. 93. 0. 0. 24 . 3. 0. 2. 2. 0. 0. 4. l. 0. 1. DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 2 6 - 2 7 27 - 28 28 - 29 8261 P 8262 P 8263 NP 8264 p 8265 P 1 . 5 . 0 . 1 . 1 . ABORTED ON DAY 26 OF GESTATION 0. 0. 0. 0. ABORTED ON DAY 22 OF GESTATION 2. 1 . 0. 2. 4 . 3. 0. 0. 2 . 1 . ABORTED ON DAY 23 OF 'GESTATION 1 . 0 . 3 . 1 . ABORTED ON DAY 25 OF GESTATION P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS > DAYS OF PRESUMED GESTATION ALL HEIGHTS HERE RECORDED IN GRAMS ( G ) . 16 - 17 1. 0. 1. 4. 2. 17 - 18 0. 0. 0. 0. 5. 18 - 19 1. 1. 1. 0. 0. 19 - 20 2. 0. 0. 0. 0. 000885 00 <b o jO r"oO > o T>J O m O m tn C-JJl PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 14 (PAGE 7) : MATERNAL FEED CONSUMPTION VALUES - INDIVIDUAL DATA PREGNANCY STATUS DAYS 7 - 8 8 - 9 9 - 10 10 - 11 11 - 12 12 - 13 RABBIT n DOSAGE GROUP V II 20 MG/KG/DAY 8266 P 8267 P 8268 P 8269 p 0270 P 143. 12 . 124 . 71. 5. 4. 0. 3. 0. 1. 0. 2. 2. 0. 0. 0. 1. 0. 181. 69 . 52. 27. 2. 0. 2. 1. 0. 0. 1. 0. DAYS 20 - 21 21 - 22 22 - 23 23 - 24 24 - 25 25 - 26 8266 P 8267 P 8268 P 8269 p 8270 P FOUND DEAD ON DAY 17 OF GESTATION FOUND DEAD ON DAY 20 OF GESTATION FOUND DEAD ON DAY 17 OF GESTATION ABORTED ON DAY 19 OF GESTATION FOUND DEAD ON DAY 16 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 8266 was found d ead on day 17 o f g e s ta tio n b . Doe 8267 was found d ead on day 20 o f g e s ta tio n c . Doe 8268 was fou n d d ead on day 17 o f g e s ta tio n d. Doe 8269 a b o rte d on day 19 o f g e s ta tio n . e . Doe 8270 was fou n d d ead on day 16 o f g e s t a t io n 13 - 14 0. 0. 1Q. 026 - 27 14 - 1 5 2. 2. 2. 2. 2. 27 - 2 8 15 - 16 16 - 17 17 - 18 18 - 19 19 - 20 2. 0. a 1. 0. 1. 1. b 1. c 1. 3 . 2. d e 28 - 29 000886 0oI0 O? N) v R- 0j > O m >o Qm cono co no 418-012: PAGE D-59 0008S7 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T 6295.10) TABLE 15 (PAGE 1 ) : CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION S IT E S CORPORA LUTEA SEX RABBIT # M F RIGHT LEFT HORN TOTAL RIGHT LEFT HORN TOTAL RIGHT LEFT HORN TOTAL RIGHT LEFT HORN TOTAL RIGHT LEFT HORN TOTAL RIGHT LEFT OVARY TOTAL DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY 8236 6 B237 3 8238 6 8239 4 8240 4 4 4 3 4 4 3 4 4 5 5 7 10 37 59 36 38 0 0 0 0 0 0 0 0 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 0 0 1 0 0 0 0 1 0 1 0 0 3 4 5 5 5 8 il 37 5 10 38 38 4 4 5 7 6 8 12 48 6 11 4 11 39 DOSAGE GROUP I I 0 .1 MG/KG/DAY 8241 4 6 6 4 10 0 0 0 0 0 0 0 0 0 6 4 10 7 5 12 6 2 4 2 HOT1 PREGNANT 8243 4 6 6244 4 6 8245 2 5 6 5 5 4 10 5 10 27 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 6 5 5 4 10 6 11 27 8 6 5 4 12 9 15 38 DOSAGE GROUP I I I 1 MG/KG/DAY 6 2 4 6 NOT1 PREGNANT 8247 2 8248 4 8249 3 8250 4 6 6 4 5 2 5 3 5 68 5 10 47 49 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 5 3 5 68 5 10 47 49 3 5 5 5 7 10 6 11 5 10 49 DOSAGE GROUP IV 2 .5 MG/KG/DAY 6251 4 8252 4 7650 5 8254 5 8255 2 6 6 2 3 5 7 2 4 4 6 3 10 6 10 37 48 17 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 8 2 4 4 6 3 11 9 11 37 48 17 9 4 5 6 7 3 12 9 13 5 10 4 10 3 10 M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. -tk 00 M13 5O m (UDl 000888 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T 6295.10) TABLE 15 (PAGE 2) : CAESAREAN-SECTIONING OBSERVATIONS - INDIVIDUAL DATA VIABLE FETUSES DEAD FETUSES EARLY RESORPTIONS LATE RESORPTIONS IMPLANTATION S IT E S CORPORA LUTEA SEX RIGHT 1LEFT 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 5 MG/KG/DAY 8256 2 2 2 2 4 0 8 2 5 7 ABORTED ON DAY 23 OF GESTATION 0 0 0 5 5 0 0 0 2 7 9 2 8 10 8 2 5 8 NOT PREGNANT 8259 8260 ABORTED 34 ON >DAY 22 5 OF GESTATION 70 0 0 0 0 0 2 1 3 4 6 10 4 7 11 DOSAGE GROUP VI 10 MG/KG/DAY 8 2 6 1 ABORTED ON DAY 26 OF GESTATION 8 2 6 2 ABORTED ON DAY 22 OF GESTATION 8 2 6 3 NOT PREGNANT 8 2 6 4 ABORTED ON DAY 23 OF GESTATION 8 2 6 5 ABORTED ON DAY 25 OF GESTATION DOSAGE GROUP V II 20 MG/KG/DAY 8 2 6 6 FOUND DEAD ON DAY 17 OF GESTATION 8 2 6 7 FOUND DEAD ON 1DAY 20 OF GESTATION 8 2 6 8 FOUND DEAD ON DAY 17 OF GESTATION 8 2 6 9 ABORTED ON DAY 19 OF GESTATION 8 2 7 0 FOUND DEAD ON DAY 16 OF GESTATION M = MALE F = FEMALE PLACENTAE APPEARED NORMAL UNLESS NOTED OTHERWISE. A oo 6 to o9 - &N--"0Jfc. m >O m Oo) o o> 418-012: PAGE D-61 000889 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 16 (PAGE 1 ) : 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 I 0 (VEHICLE) MG/KG/DAY 8236 6 4 10 41.51 44.35 42.64 B237 3 4 7 4 9.4 2 48.62 49.08 8238 8239 8240 6 4 4 3 4 4 9 35.68 8 47.94 8 45.74 3 2 .0 3 4 9 .6 8 4 1 .9 9 3 4 .4 6 4 8 .8 0 4 3 .8 7 DOSAGE GROUP I I 0 .1 MG/KG/DAY 6241 4 6 10 31.86 32.38 32.17 824 2 NOT PREGNANT 8243 4 6 10 4 0.2 4 3 6.6 2 38.06 8244 4 6 10 43.30 4 2.58 42.86 8245 2 5 7 49.83 5 0 .0 2 4 9 .9 7 DOSAGE GROUP I I I 1 MG/KG/DAY 8 2 4 6 NOT PREGNANT 8247 2 6 8 43.46 44.07 43.92 8248 4 6 10 4 5 .8 7 4 0.8 3 42.84 8249 3 4 7 49.48 4 6 .6 0 4 7 .8 4 8250 4 5 9 43.88 3 9 .7 7 4 1 .5 9 DOSAGE GROUP IV 2 .5 MG/KG/DAY 8251 4 6 10 3 7.6 3 33.19 34.97 8252 4 6 10 3 6.2 6 33.94 34.86 7650 5 2 7 43.25 4 8 .3 2 4 4 .7 0 8254 5 3 8 32.69 32.30 32.54 8255 2 5 7 47.36 4 2 .4 4 4 3 .8 5 a . TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIV E FETUSES. CONCEPTUSES RESORBED N N% 11 1 9 .1 7 0 0.0 10 1 10.0 8 0 0.0 8 0 0.0 10 0 0 .0 10 0 0 .0 11 1 9 .1 7 0 0.0 8 0 0.0 10 0 0 .0 7 0 0.0 9 0 0.0 11 1 9 .1 11 1 9 .1 7 0 0.0 8 0 0.0 7 0 0.0 A O tToJ 5 Q mo> 418-012P:PAGE 62 000890 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T 6295.10) TABLE 16 (PAGE 2 ) : LITTER OBSERVATIONS (CAESAREAN - DELIVERED FETUSES) - INDIVIDUAL DATA NUMBER OF LIV E FETUSES AVERAGE FETAL BODY WEIGHT (G) RABBIT # MALE FEMALE TOTAL MALE FEMALE TOTAL a DOSAGE GROUP V 5 MG/KG/DAY 8256 8257 2 2 4 36.72 ABORTED ON DAY 23 OF GESTATION 2 3 .0 2 2 9 .8 7 8258 NOT PREGNANT 8 25 9 ABORTED ON DAY 22 OF GESTATION 8260 3 4 7 20.31 2 3 .6 8 2 2 .2 3 DOSAGE GROUP VI 10 MG/KG/DAY 8261 ABORTED ON DAY 26 OF GESTATION 8262 ABORTED ON DAY 22 OF GESTATION 8263 NOT PREGNANT 8264 ABORTED ON DAY 23 OF GESTATION 8265 ABORTED ON DAY 25 OF GESTATION DOSAGE GROUP V II 20 MG/KG/DAY 8266 FOUND DEAD ON DAY 17 OF GESTATION 826 7 FOUND DEAD ON DAY 20 OF GESTATION 8268 FOUND DEAD ON DAY 17 OF GESTATION 8 26 9 ABORTED ON DAY 19 OF GESTATION 827 0 FOUND DEAD ON DAY 16 OF GESTATION TOTAL = SUM OF FETAL WEIGHTS/NUMBER OF LIV E FETUSES. ------- CONCEPTUSES ------RESORBED N N% 9 5 55.6 10 3 30.0 /0--I0* 000891 PROTOCOL 41B-012P: ORAL (STOMACH TUBE) DOSAGE -RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T 6295.10) TABLE 17 (PAGE 1) : FETAL SEX, V ITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 S 6 7 8 9 10 11 12 13 14 15 16 17 18 19 DOSAGE GROUP I 0 (VEHICLE) MG/KG/DAY RABBIT # 8236 8237 8238 8239 8240 CLs 4 / 8 MA MA FA / FA MA MA MA MA FA FA 49.46 45.09 46.98 50.29 40.84 41.52 34.50 37.65 40.06 40.06 4 / 4 FA FA MA FA / MA FA MA 51.77 48.72 51.46 50.21 4 7.56 44.56 49.25 5/ 6 FA MA MA MA 28.71 39.23 34.06 29.22 FL / MA FA MA MA FA 3.4 3 37.90 34.83 36.81 36.85 32.56 7/ 4 FA FA MA MA MA / FA MA FA 51.85 48.42 44.55 46.27 53.37 48.22 47.55 50.21 6/ 3 MA FA MA FA FA / MA MA FA 48.74 46.03 42.81 39.01 41.58 44.95 46.48 41.33 L 1 .9 5 DOSAGE iGROUP I I 0 . 1 MG/KG/DAY 8241 7/ 5 FA FA FA MA MA FA / FA FA MA MA 35.65 35.91 34.09 28.52 29.38 27.65 29.03 31.97 34.81 34.72 8242 NOT PREGNANT 8243a 8 / 4 8244b 6 / 9 8245 5 / 3 FA FA FA FA MA MA / MA FA FA MA 36.00 44.04 41.86 31.80 35.20 36.12 44.09 27.20 38.79 45.53 MA FA FA FA FA / MA FA MA MA FL FA 47.16 48.85 44.45 39.22 32.31 39.16 52.80 51.48 35.38 7.3 2 37.84 FA FA FA FA FA / MA MA 52.45 48.54 52.22 46.73 50.17 52.15 47.51 MC L=s M= ACLOERPORFA = FEMALE A LUTEA/OVARY = ALIVE FETAL E= BODY EARLY RESORPTION L = LATE RESORPTION WEIGHTS WERE RECORDED IN GRAMS (G) . a. F etus 8243-8 had a sh o rt sn ou t, and sm all and d isp la c e d n a re s. b . F etu s 8244-7 had abdom inal d is te n tio n . " /" DENOTES POSITION OF CERVIX ooo NO 9o> "tJ io > y G) m Om5 CD o w> to 000892 PROTOCOL 418 -012P: ORAL (STOMACH TUBE) DOSAGE-RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T 6295.10) TABLE 17 (PAGE 2) : FETAL SEX, VITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 DOSAGE GROUP I I I 1 MG/KG/DAY RABBIT ft CLs 8246 NOT PREGNANT 8247 3/ 7 MA 4 8 .5 7 FA / FA 46.46 45.73 FA 4 2 .9 0 FA 4 5 .1 2 FA 4 6 .6 3 FA 3 7 .6 0 MA 3 8 .3 4 8248 5/ 6 MA FA FA MA FA / MA FA FA FA MA 51.27 39.44 44.56 37.77 37.44 54.03 44.11 42.15 37.26 40.42 8249 5/ 5 MA FA FA / MA MA FA FA 52.58 47.34 42.63 50.08 45.79 49.87 46.58 8250 5/ 4 MA MA FA MA FA / MA FA FA FA 46.56 43.22 42.44 40.21 33.62 45.52 38.82 43.04 40.91 DOSAGE: GROUP IV 2 .5 MG/KG/DAY 8251a 9/ 3 8252 4 / 9 7650 5/ 5 8254 6/ 4 8255 7/ 3 MA 4 7 .0 6 FA L FA 1.11 31.11 FA / MA FA 3 1 .1 9 FA MA 3 1 .4 9 MA FA 2 8 .1 9 FA FA 2 9 .3 4 MA MA / FA 4 0.4 9 40.44 FA E MA 3 1 .4 8 MA FA 3 8 .8 7 FA 40.31 37.60 39.80 30.92 36.40 30.75 36.62 32.98 32.20 31.05 MA 5 5 .6 1 FA 5 0 .5 4 MA 4 5 .6 8 MA / fa 49.64 46.11 MA 3 4 .1 4 MA 3 1 .1 8 FA MA MA FA / MA FA MA MA 38.36 37.08 32.34 32.57 38.10 25.98 28.90 27.03 FA MA FA FA FA FA / MA 47.02 46.53 41.50 40.14 38.39 45.17 48.19 M = MALE F _ FEMALE A = ALIVE E = EARLY RESORPTION L = LATE RESORPTION CLs CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) . a. F etus 8251-10 had a c le f t snout and no in c is o rs . " /" DENOTES POSITION OF CERVIX _ _fLc. 0 0 A- o9 N n > u>o O m o m 2 000893 PROTOCOL 418-012P: ORAL (STOMACH TUBE) DOSAGE~RANGE DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS (SPONSOR'S STUDY NUMBER: T-6295.10) TABLE 17 (PAGE 3) : FETAL SEX, V ITAL STATUS AND BODY WEIGHT - INDIVIDUAL DATA FETUS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 DOSAGE GROUP V 5 MG/KG/DAY RABBIT # CLs 8 2 5 6 2 / 8 MA MA / FA E E E E E FA 40.97 32.48 31.20 1 4 .8 4 8 2 5 7 ABORTED ON DAY 23 OF GESTATION 825 8 NOT PREGNANT 8 2 5 9 ABORTED ON DAY 22 OF GESTATION 8 2 6 0 4 / 7 FA L FA L / MA MA FA MA L 26.90 4.03 28.15 4 .33 19.67 20.02 21.85 21.23 3 .13 17.82 DOSAGE GROUP VI 10 MG/KG/DAY 8 2 6 1 ABORTED ON DAY 26 OF GESTATION 8 2 6 2 ABORTED ON DAY 22 OF GESTATION 8 2 6 3 NOT PREGNANT 8 2 6 4 ABORTED ON DAY 23 OF GESTATION 8 2 6 5 ABORTED ON DAY 25 OF GESTATION DOSAGE GROUP V II 20 MG/KG/DAY RABBIT # CLS 8266 FOUND DEAD ON DAY 17 OF GESTATION 8 2 6 7 FOUND DEAD ON DAY 20 OF GESTATION 8 2 6 8 FOUND DEAD ON DAY 17 OF GESTATION 8 2 6 9 ABORTED ON DAY 19 OF GESTATION 8 2 7 0 FOUND DEAD ON DAY 16 OF GESTATION M = MALE F = FEMALE A = ALIVE E = EARLY RESORPTION L = LATE RESORPTION " / " DENOTES PO SITIO N OF CERVIX CLs = CORPORA LUTEA/OVARY FETAL BODY WEIGHTS WERE RECORDED IN GRAMS (G) U 9o Go_IIO_Ok Tl K> > o m om ac n D cn> 418-012: PAGE D-66 418-012P:PAGE 66 ATTACHMENT 1 PROTOCOL 000894 418-012:PAGE D-67 418-012P:PAGE 67 Argus Research Laboratories, Inc. 905 Sheehy Drive, Building A HoTrs: (h2a15m) 4, 4P3e-8n7n10syFl:v(a21n5ia) 44139-8054847 PROTOCOL 418-012P SPONSOR'S STUDY NUMBER: T-6295.10 STUDY TITLE: PURPOSE: TESTING FACILITY: STUDY DIRECTOR: SPONSOR: STUDY MONITOR: ALTERNATE STUDY MONITOR: Oral (Stomach Tube) Dosage-Range Developmental Toxicity Study of PFOS 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 PFOS 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 000895 418-012: PAGE D-68 418-012P:PAGE 68 Protocol 418-012P 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. SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE: See ATTACHMENT 1 to the protocol. 000896 418-012:PAGE D-69 418-012P:PAGE 69 Protocol 418-012P Page 3 TEST ARTICLE AND VEHICLE: Identification: Test Article: Name: Physical Description: Lot/Batch Number: Specific Gravity: Purity: Expiration Date: PFOS. Light-colored powder. 217. - 0.6 . 98.9%. May 2000. Information on the identity, composition, strength and purity of the test article is on file with the Sponsor. Vehicle: 0.5% Tween 80 in Reversed 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 dosage 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. 000897 418-012:PAGE D-70 418-012P:PAGE 70 Protocol418-012P 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. 000S98 418-012: PAGE D-71 4 18-012P :P A G E 71 Protocol 418-012P 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 Facility0'3'; 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 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. 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{A). 000899 418-012:PAGE D-72 418-012P:PAGE 72 Protocol418-012P 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. Water: 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. 000900 418-012: PAGE D-73 418-012P:PAGE 73 Protocol418-012P 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 1 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 will be selected by the Sponsor on the basis of previous studies conducted with the test article. 000901 418-012: PAGE D-74 418-012P:PAGE 74 Protocol 418-012P Page 8 Dosage Levels. Concentrations and Volumes: Dosage Group I II III IV V VI VII Number of Animals 5 5 5 5 5 5 5 Dosage (mg/kg/day) 0 (Vehicle) 0.1 1 2.5 5 10 20 Concentration Volume (mg/mL) (mL/kg) Argus Batch Number 0 10 B-418-012P-A(Day.Month.Year) 0.01 10 B-418-012P-B(Day.Month.Year) 0.1 0.25 0.5 10 B-418-012P-C(Day.Month.Year) 10 B-418-012P-D(Day.Month.Year) 10 B-418-012P-E(Day.Month.Year) 1 10 B-418-012P-F(Day.Month.Year) 2 10 B-418-012P-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 one hour postdosage. Postdosage Period: Once daily. Clinical observations may be recorded more frequently than cited above, if deemed appropriate by the Study Director and/or Study Monitor. Body Weights: Predosage Period: Day 0 of presumed gestation and on the day of arrival at the Testing Facility. Dosage Period: Daily. Postdosage Period: Daily. 000902: 418-012: PAGE D-75 418-012P:PAGE 75 Protocol 418-012P 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-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 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. 000903 418-012: PAGE D-76 418-012P:PAGE 76 Protocol 418-012P 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'51. 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'51. 000904 418-012:PAGE D-77 418-012P:PAGE 77 Protocol 418-012P 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. 000905 418-012:PAGE D-78 418-012P:PAGE 78 Protocol 418-012P 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. 000906 418-012: PAGE D-79 418-012P:PAGE 79 Protocol 418-012P 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 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. Salewski, E. (1964). Farbemethode zum makroskopischen Nachweis von Implantationsstellen am Uterus der Ratte. Arch. Pathol. Exp. Pharmakol. 247:367. 000907 PROTOCOL APPROVAL: FOR THE TESTING FACILITY Dearlove, Ph.D., DABT Director of Research >nd G. York, PhV .l DABT Sciate Director of Research Study Director Dena C. Lebo, V.M.D. Member, Institutional Animal Care and Use Committee FOR THE SPONSOR Marvin T. Case, D.V.M., Ph.D. Study Monitor 418-012: PAGE D-80 418-012P:PAGE 80 Protocol 418-012P Page 14 Date n - Z i S t j - y^ Date '1 M Date /77 Date 000908 418-012:PAGE D-81 418 -0 12 P :P A G E 81 ATTACHMENT 1 SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE 000909 ATTACHMENT 1 418-012: PAGE D-82 418-012P:PAGE 82 Protocol 418-012P Page 1 of2 STUDY SCHEMATIC DOSAGE-RANGE DEVELOPMENTAL TOXICITY 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 Dosage Period. a. For additional details see "Tests, Analyses and Measurements" section of the protocol. b. Fetal evaluations (all fetuses - external examinations). 000910 ATTACHMENT 1 418-012:PAGE D-83 418-012P:PAGE 83 Protocol 418-012P Page 2 of2 SCHEDULE* 26 JUN 98 02 JUL98- 15 JUL 98 24 JUL 98 31 JUL 98 08 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. 000911 418-012: PAGE D-84 418-012P:PAGE 84 ATTACHMENT 2 MATERIAL SAFETY DATA SHEET 000912 418-012: PAGE D-85 MATERIAL SAFETY DATA SHEET 3M 3M Center St. Paul, Minnesota 55144-1000 1-800-364-3577 or (612) 737-6501 (24 hours) 418-012P:PAGE 85 PPOS Copyright, 1998, Minnesota Mining and Manufacturing Coapany. 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-95 FLUORAD Brand Fluorochemical Surfactant ID NUMBER/U .P .C .: 98-0207-0103-7 00-51135-09054-1 98-0207-0104-5 98-0211-0888-5 00-51135-09362-7 98-0211-3916-1 ZF-0002-1044-1 ISSUED: January 29, 1998 SUPERSEDES: November 05, 1997 DOCUMENT: 10-3796-9 00-51135-09055-8 00-51135-02311-2 1. INGREDIENT C.A.S. NO. PERCENT POTASSIUM PEHFLUOROALKYL SULFONATE.... POTASSIUM PEHFLUOROALKYL SULFONATE.... POTASSIUM PERFLUOROALKYL SULFONATE.... POTASSIUM PERFLUOROALKYL SULFONATE____ POTASSIUM PERFLUOROALKYL SULFONATE____ 2795-39-3 3871-99-6 29420-49-3 60270-55-5 3872-25-1 82 3 3 2 1 - 86 -8 -7 -6 -3 2. PHYSICAL DATA BOILING POINT:.... VAPOR PRESSURE:___ VAPOR DENSITY:.... EVAPORATION RATE:.. SOLUBILITY IN WATER SPECIFIC GRAVITY:.. PERCENT VOLATILE:.. PH:.............. VISCOSITY:........ MELTING POINT:.... N/A N/A N/A N/A slight ca. 0.6 Water*1 (Bulk) 0\ 7 -8 (0.1% Aqueous) N/D N/D APPEARANCE AND ODOR: Light colored, free flowing powder. Abbreviations: N/O - Not Determined N/A - Not Applicable CA - Approximately 000913 418-012: PAGE D-86 MSOS: FC-95 FLUORAD Brand Fluorochemical Surfactant January 29, 1998 418-012P:PAGE 86 PAGE 2 3. FIRE AND EXPLOSION HAZARD DATA FLASH POINT:................. None FLAMMABLE LIMITS -LEL:....... N/A FLAMMABLE LIMITS - UEL:...... N/A AUTOIGNITION TEMPERATURE:..... N/A EXTINGUISHING MEDIA: Hater, Carbon dioxide, Dry chemical, Foaa SPECIAL FIRE FIGHTING PROCEDURES: Hear full protective clothing, including helmet, self-contained, positive pressure or pressure demand breathing apparatus, bunker coat and pants, bands around aras, 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 Sulfur, Hydrogen Fluoride, Toxic Vapors, Gases or Particulates. 5. ENVIRONMENTAL INFORMATION SPILL RESPONSE: Observe precautions from other sections. Vacuum, use wet sweeping compound or water to avoid dusting. CAUTION! A vacuum cleaner could be an ignition source. Clean up residue with water. Place in an approved metal container. Seal the container. RECOMMENDED DISPOSAL: Do not release to waterways or sewer. Do not use in products or processes that could result in aquatic concentrations greater than 1/10 of the lowest EC50 or LC50 concentration. Incinerate in an industrial or commercial facility in the presence of a combustible material. Combustion products will include HF. Disposal alternative: Dispose of waste product in a facility permitted to Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 000914 418-012:PAGE D-87 HSDS: FC-95 FLUORAD Brand Fluorochemical Surfactant January 29, 1998 418-012P:PAGE 87 PAGE 3 5. ENVIRONMENTAL INFORMATION (continuad) accept cheaical waste. ENVIRONMENTAL OATA: 96-Hr. Aquatic Fish LC50, Fathead Minnow(Piaephales promelas)*38 ag/1, Bluegill Sunfish(Lepoais aacrochirus)68 ag/1, Rainbow Trout(Salmo gairdneri)*11 ag/1; 48-Hr. EC50, Daphnia Magna 50 ag/1; COD*.004 g/g; B0020 * Nil. REGULATORY INFORMATION: Volatile Organic Coapounds: N/A. VOC Less H20 & Except Solvents: N/A. Since regulations vary, consult applicable regulations or authorities before disposal. U.S. EPA Hazardous Waste Nuaber * None (Not U.S. EPA Hazardous). This product coaplies with the cheaical registration requirements of TSCA, EINECS, CDSL, AICS, MITI 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 for at least 15 minutes. Get immediate medical attention. SKIN CONTACT: Immediately flush skin with large amounts of water. Remove contaminated clothing. If irritation persists, call a physician. Wash contaminated clothing before reuse. INHALATION: If signs/symptoms occur, remove person to fresh air. If signs/symptoms continue, call a physician. IF SWALLOWED: Drink two glasses of water. Call a physician. 7. PRECAUTIONARY INFORMATION EYE PROTECTION: Avoid eye contact. Wear vented goggles. Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 000915 418-012: PAGE D-88 NSOS: FC-95 FLU0RA0 Brand Fluorochaaieml Surfactant January 29, 1998 418-012P:PAGE 88 FAQE 4 7. PRECAUTIONARY INFORMATION (continued) SKIN PROTECTION: Avoid skin contact. Wear appropriate gloves when handling this aterial. A pair of gloves aade froa the following Material(s) are recoMMended: butyl rubber. Use one or More of the following personal protection itens as necessary to prevent skin contact: head covering, coveralls. Protective garnents (other than gloves) should be aade of either of the following Materials: polyethylene/polyvinylidene chloride (Saranex). RECOMMENDED VENTILATION: Use with appropriate local exhaust ventilation. Use in a we11ventilated area. Provide sufficient ventilation to Maintain emissions below reconnended exposure limits. If exhaust ventilation is not adequate, use appropriate respiratory protection. RESPIRATORY PROTECTION: Avoid breathing of dust. Select one of the following NIOSH approved respirators based on airborne concentration of contaminants and in accordance with OSHA regulations: half-mask dust and mist respirator, half-mask supplied air respirator, full-face dust and mist 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. Wash hands after handling and before eating. RECOMMENDED STORAGE: Keep container dry. 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: 2 FLAMMABILITY: 0 REACTIVITY: 0 PERSONAL PROTECTION: X (See precautions, section 7.) EXPOSURE LIMITS INGREDIENT VALUE UNIT TYPE AUTH SKIN* POTASSIUM PERFLUOROALKYL SULFONATE... 0.1 MG/M3 POTASSIUM PERFLUOROALKYL SULFONATE... 0.1 MG/M3 POTASSIUM PERFLUOROALKYL SULFONATE... 0.1 MG/M3 POTASSIUM PERFLUOROALKYL SULFONATE... 0.1 MG/M3 TWA 3M TWA 3M TWA 3M TWA 3M Y Y Y Y Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 009946 418-012: PAGE D-89 418-012P:PAGE 89 NSD8: FC-9S FLUORAD Brand Fluorochaaical Surfactant January 29, 1998 PAGE 5 EXPOSURE LIMITS (continued) INGREDIENT VALUE UNIT TYPE AUTH SKIN* POTASSIUM PERFLUOROALKYL SULFONATE... 0.1 MG/M3 TMA 3M Y * SKIN NOTATION: Listed substances indicated with 'Y' under SKIN refer to the potential contribution to the overall exposure by the cutaneous route including aucous aeabrane and eye, either by airborne or, aore particularly, by direct contact with the substance. Vehicles can alter skin absorption. SOURCE OF EXPOSURE LIMIT DATA: - 3M: 3M Recoaaended Exposure Guidelines 8. HEALTH HAZARD DATA EYE CONTACT: Mild Eye Irritation: signs/syaptoas can include redness, swelling, pain, and tearing. SKIN CONTACT: Mild Skin Irritation (after prolonged or repeated contact): signs/symptoms can include redness, swelling, and itching. May be absorbed through the skin and persist in the body for an extended time. INHALATION: May be harmful if inhaled. May be absorbed by inhalation and persist in the body for an extended time. Single overexposure, above recommended guidelines, may cause: Irritation (upper respiratory): signs/symptoms can include soreness of the nose and throat, coughing and sneezing. IF SMALLOHED: Ingestion is not a likely route of exposure to this product. Illness may result from a single swallowing of a moderate quantity of this material. May be harmful if swallowed. MUTAGENICITY: Mutagenicity assays indicate the product is not mutagenic. Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately 091'? 418-012:PAGE D-90 HSDS: PC-85 FLUORAD Brand Fluorochemical 8urfactant January 2 9 , 1998 418-012P:PAGE 90 PAGE 6 8. HEALTH HAZARD DATA (continued) REPRODUCTIVE/DEVELOPMENTAL TOXINS: Not teratogenic in the rat at oral doaes below aaternally toxic levels. 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. SECTION CHANGE DATES HEADING SECTION CHANGED SINCE Noveaber 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 fora 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. 000918 418-012: PAGE D-91 418-012P:PAGE 91 ATTACHMENT 3 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE 000919 418-012:PAGE D-92 418-012P:PAGE 92 ATTACHMENT 3 Protocol 418-012P Version: 418-012P (12 JUN 98) Page 1 of3 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE Test Article: PFOS Vehicle: 0.5% 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 PFOS and the vehicle for oral administration to rabbits on Argus Study 418-012P. 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 10 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. 000920 418-012: PAGE D-93 418-012P:PAGE 93 ATTACHMENT 3 Protocol 418-012P Version: 418-012P M2 JUN 981 Page 2 of3 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE NOTE: Test article will be prepared as a serial dilution from the high dosage to the low dosage. Once the final volumes are achieved, stir bars are to be added to the containers; mixing should occur during sampling and/or administration. C. Preparation of Vehicle 1. Add the required amount of R.O. deionized water to an appropriately labeled container. Heat the water to 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 2-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 while the solution cools. (Be sure there is a visible vortex, this will achieve the desired emulsion. This may be prepared the day before use.) 3. To prepare the 1-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 .25-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. 000921 418-012:PAGE D-94 418-012P:PAGE 94 ATTACHMENT 3 Protocol 418-012P Version: 418-012P (12 JUN 981 Page 3 of3 TEST ARTICLE AND VEHICLE PREPARATION PROCEDURE 6. To prepare the 0.1-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 0.01-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 b Date: Clarification No __ Yes (See attached clarification form.) Initials/Date: 000922 APPENDIX E HISTORICAL CONTROL DATA 000923 418-012: PAGE E-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) 000924 418-012:PAGE E-2 SUMMARY OF REPRODUCTIVE INDICES NZW RABBIT RANGE/STUDY MEAN or % 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) 000925 418-012: PAGE E-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 000926 418-012:PAGE E-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^.0) 0.11 0-1 (0-4.3) 0.11 0-1 (0-5.0) 3.26 0-5 (0-25.0) 000927 418-012: PAGE E-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 Upper jaw in two 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) 000928 418-012: PAGE E-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 (0-20.0) 10 0.14 04 (0-2.3) L: LITTER INCIDENCE F: FETAL INCIDENCE 000929 418-012: PAGE E-7 SUMMARY OF FETAL SOFT TISSUE ALTERATIONS NZW 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 00093& 418-012: PAGE E-8 SUMMARY OF FETAL SOFT TISSUE ALTERATIONS NZW RABBITS ALTERATION KIDNEY(S) Absent Displaced caudally SPLEEN Pale GONADS Right testis displaced caudally RANGE/STUDY N% N % L 1 0.15 0-1 (0-5.6) F 1 0.02 0-1 (0-0.6) L 1 0.15 0-1 (0-4.3) F 1 0.02 0-1 (0-0.5) L 1 0.15 0-1 (0-7.1) F 1 0.02 0-1 (0-0.9) L 1 0.15 0-1 (0-5.9) F 1 0.02 0-1 (0-0.6) L: LITTER INCIDENCE F: FETAL INCIDENCE 000931 S U M M A R Y OF FETAL SKELETAL ALTERATIONS N Z W RABBITS 418-012:PAGE E-9 PERIOD JANUARY 1996 -JANUARY 1998 # STUDIES # LITTERS EXAMINED 37 668 # 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 Anterior Fontanelle :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 :Interfrontals present :Fused :Two segments :Suture large :Small 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 Parietal(s) :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) 3 1 1 1 L:LITTER INCIDENCE F: FETAL INCIDENCE 000932 418-012: PAGE E-10 SUM M A R Y 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 2.27 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/or misaligned 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 Irregularly shaped 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 L: LITTER INCIDENCE F: FETAL INCIDENCE 000933 418-012: PAGE E-11 S U M M A R Y 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/or Centra, fused :Centrum, unilateral ossification :Centra, one ormore asymmetric :Centrum, bifid :Centra, not ossified :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 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 L: LITTER INCIDENCE F: FETAL INCIDENCE 000934 418-012: PAGE E-12 SUMMARY OF FETAL SKELETAL ALTERATIONS N Z W RABBITS # 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 (0-4.3) F 1 0.02 0-1 (0-0.5) L 1 0.15 0-1 (0-4.3) F 2 0.04 0-2 (0-1.0) L 3 0.45 0-1 (0-5.6) F 3 0.05 0-1 (0-0.6) L 1 0.15 0-1 (0-4.3) F 1 0.02 0-1 (0-0.5) L 1 0.15 0-1 (0-5.0) F 1 0.02 0-1 (0-0.6) 24 8 1 1 3 1 1 VERTEBRAE/RIB Interrelated Vertebral /Rib malformations L F 3 0.45 3 0.05 0-3 (0-15.8) 0-3 (0-1.6) 1 RIBS Cervical Rib present Two ormore, fused Bases proximate One or more, 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 0-1 (0-5.6) 0-1 (0-0.6) 0-2 (0-10.5) 0-2 (0-1.2) 0-2 (0-9.1) 0-2 (0-1.1) 0-1 (0-5.6) 0-1 (0-0.6) 0-3 (0-16.7) 0-3 (0-2.2) 0-1 (0-5.6) 0-1 (0-0.6) 2 5 9 8 19 2 L: LITTER INCIDENCE F: FETAL INCIDENCE 000935 418-012:PAGE E-13 S U M M A R Y 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) Broad 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 notossified 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 000936 418-012:PAGE E-14 S U M M A R Y 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:LITTER INCIDENCE F: FETAL INCIDENCE 000937 A PPEN D IX F STATEMENT OF THE STUDY DIRECTOR 000938 418-012:PAGE F-1 Arg9u0s5TReSelhTseeepeaelhrehocHfynahoxeDrL::srah((ib22va1oe1m,r55a,)B)t4P4ou4A4ril3i3de-1-si88n9, 750Ign184Ac074. PROTOCOL 418-012: ORAL (STOMACH TUBE) DEVELOPMENTAL TOXICITY STUDY OF PFOS IN RABBITS SPONSOR'S STUDY NUMBER: 6295.10 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 Administration (FDA) Good Laboratory Practice Regulations; Final Rule3, the Japanese Ministry of Health and Welfare (MHW) Good Laboratory Practice Standard for Safety Studies on Drugs'3and the European Economic Community (EEC) 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 practicec occurred that affected the quality or integrity of the study. and Study Director 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 Ordinance Number 21, March 26, 1997. c. 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. 000939 APPENDIX G QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT 000940 O P r im e d ic a 418-012:PAGE G-1 Argus Research Laboratories, Inc. 905 S heehy Drive, Building A Horsham, PA 19044 Telephone: (215) 443 -8 71 0 Telefax: (215) 443-8587 QUALITY ASSURANCE UNIT FINAL REPORT STATEMENT Study Director: Raymond G. York, Ph.D., DABT Executive Director of Research: Mildred S. Christian, Ph D., Fellow, ATS Protocol 418-012: Oral (Stomach Tube) Developmental Toxicity Study of PFOS in Rabbits Sponsor's Study Number: 6295.10 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 five 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 [except for Appendix F, the Pilot Report, which was conducted in the spirit of Good Laboratory Practice (GLP)] 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 04 DEC 98 and 17 DEC 98, for revisions requested by the Sponsor 23 DEC 98, and for finalization on 11 JAN 99. 000941 418-012:PAGE G-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. and Compliance Heather L. Rabuttino, M.S. Date Quality Assurance Supervisor and Principal Auditor 000942 TABLE 1 CRITICAL PHASES INSPECTED 418-012:PAGE G-3 Test Article Administration - Gavaae Date of inspection: 25 AUG 98 Date results reported to the Study Director and Management: 12 SEP 98 Test Article Preparation Date of inspection: 04 SEP 98 Date results reported to the Study Director and Management: 12 SEP 98 Blood Collection Date of inspection: 10 SEP 98 Date results reported to the Study Director and Management: 10 SEP 98 Caesarean-Sectioning Dates of inspection: 10 SEP 98, 18 SEP 98 Dates results reported to the Study Director and Management: 10 SEP 98, 24 SEP 98 000943 TABLE 2 418-012:PAGE G-4 RAW DATA AUDIT(S) The following study information and raw data were audited on 12 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 13 OCT 98. The following study information and raw data were audited on 13 OCT 98: Protocol. Protocol amendments. 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. Necropsy. Organ weights. Tissue packing lists. General comments. Study maintenance records. Tempscribes. Feed and water analyses. Edit requests. Dosage volumes. Deviations. Data review page. Blood collection. 000944 The results of this audit were reported to the Study Director and Management on 14 OCT 98.