Document ym96DEGdwaQ0pKd0MNMNnkJMV
FINAL REPORT
PROTOCOL 418-028 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
SPONSOR'S STUDY NUMBER: T-7706.1
FINAL REPORT DATE: 31 JULY 2003
PROTOCOL 418-028 -
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
SPONSOR'S STUDY NUMBER: T-7706.1
TABLE OF CONTENTS SUBJECT 1. SUMMARY AND CONCLUSION 1.1. Methods 1.2. Results 1.3. Conclusion 2. DESCRIPTION OF TEST PROCEDURES 2.1. Conduct of Study 2.2. Test Substance Information 2.3. Vehicle Information 2.4. Test Substance Preparation and Storage Conditions 2.5. Test System 2.6. Husbandry 2.7. Methods 3. RESULTS - Male Rats 3.1. Mortality, Clinical and Necropsy Observations 3.2. Terminal Body Weights and Organ Weights and Ratios (%) of Organ
Weight to Terminal Body Weight and Brain Weight
PAGE 1-1 1-1 1-3 1-6 2-1 2-1 2-4 2-4 2-5 2-6 2-7
2-10 3-1 3-1
3-2
11
SUBJECT
PAGE
3.3. Hematology and Clinical Chemistry
3-2
3.4. Body Weights and Body Weight Changes
3-3
3.5. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values 3.6. Mating and Fertility
3-3 3-3
3.7. Functional Observational Battery
3-3
3.8. Motor Activity
3-4
3.9. Sperm
3-4
4. RESULTS - Female Rats
4-1
4.1. Mortality, Clinical and Necropsy Observations
4-1
4.2. Terminal Body Weights, Organ Weights and Ratios (%) of Organ Weight to
Terminal Body Weight and Brain Weight and Primordial Follicle Counts
4-2
4.3. Hematology and Clinical Chemistry
4-2
4.4. Body Weights and Body Weight Changes
4-3
4.5 Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values
4-3
4.6. Estrous Cycling, Mating and Fertility
4-4
4.7. Functional Observational Battery
4-4
4.8. Motor Activity
4-4
4.9. Natural Delivery and Litter Observations
4-5
4.10. Pup Clinical and Necropsy Observations
4-5
4.11. Pup Liver Weight and Ratio of Liver Weight to Terminal Body Weight
4-5
REFERENCES
4-6
APPENDIX A - REPORT FIGURES
Figure 1. Fo Generation Male Rats
A-l
in
SUBJECT Figure 2. Fo Generation Female Rats
PAGE A-2
Figure 3. Motor Activity - Number of Movements - Fo Generation Male Rats A-3
Figure 4. Motor Activity - Time Spent in Movement - Fo Generation Male Rats A-4
Figure 5. Motor Activity - Number of Movements - Fo Generation Female Rats A-5
Figure 6.
Motor Activity - Time Spent in Movement - Fo Generation Female Rats
A-6
APPENDIX B - REPORT TABLES - Fo GENERATION MALE RATS
Table B l. Table B2.
Clinical Observations - Summary - Fo Generation Male Rats Necropsy Observations - Summary - Fo Generation Male Rats
B-l B-2
Table B3.
Terminal Body Weights and Organ Weights - Summary Fo Generation Male Rats
B-3
Table B4.
Ratios (%) of Organ Weight to Terminal Body Weight - Summary -
Fo Generation Male Rats
B-5
Table B5.
Ratios (%) of Organ Weight to Brain Weight - Summary Fo Generation Male Rats
B-7
Table B6. Hematology - Summary - Fo Generation Male Rats
B-9
Table B7. Clinical Chemistry - Summary - Fo Generation Male Rats
B-12
Table B8. Body Weights - Summary - Fo Generation Male Rats
B-15
Table B9. Body Weight Changes - Summary - Fo Generation Male Rats
B-16
Table BIO. Absolute Feed Consumption Values (g/day) - Summary Fo Generation Male Rats
B-17
Table B 11. Relative Feed Consumption Values (g/kg/day) - Summary Fo Generation Male Rats
B -l8
Table B12. Mating and Fertility - Summary - Fo Generation Male Rats
B-19
Table B13. Functional Observational Battery Observations - Summary Fo Generation Male Rats
B-20
IV
SUBJECT
PAGE
Table B14. Motor Activity - Summary - Fo Generation Male Rats
B-26
Table B15. Sperm Motility, Count and Density - Summary Fo Generation Male Rats
B-28
Table B 16. Sperm Morphology - Summary - Fo Generation Male Rats
B-29
Table B17. Clinical Observations - Individual Data - Fo Generation Male Rats B-30
Table B18. Necropsy Observations - Individual Data - Fo Generation Male Rats B-33
Table B19.
Terminal Body Weights and Organ Weights and Ratios (%) of Organ
Weight to Terminal Body Weight - Individual Data -
Fo Generation Male Rats
B-38
Table B20. Organ Weights and Ratios (%) Of Organ Weight to Brain Weight -
Individual Data - Fo Generation Male Rats
B-48
Table B21. Body Weights - Individual Data - Fo Generation Male Rats
B-58
Table B22. Feed Consumption Values - Individual Data - Fo Generation Male Rats
B-68
Table B23. Mating and Fertility - Individual Data - Fo Generation Male Rats B-71
Table B24. Functional Observational Battery Observations - Individual Data -
Fo Generation Male Rats
B-74
Table B25. Motor Activity - Individual Data - Fo Generation Male Rats
B-79
Table B26. Sperm Motility, Count and Density - Individual Data Fo Generation Male Rats
B-89
Table B27. Sperm Morphology - Individual Data - Fo Generation Male Rats
B-92
APPENDIX C - REPORT TABLES - Fo GENERATION FEMALE RATS
T a b le d . Clinical Observations - Summary - Fo Generation Female Rats
C-l
Table C2. Necropsy Observations - Summary - Fo Generation Female Rats
C-4
Table C3.
Terminal Body Weights and Organ Weights and Primordial Follicle
Count - Summary - Fo Generation Female Rats
C-5
v
SUBJECT
PAGE
Table C4.
Ratios (%) of Organ Weight to Terminal Body Weight - Summary -
Fo Generation Female Rats
C-7
Table C5.
Ratios (%) of Organ Weight to Brain Weight - Summary Fo Generation Female Rats
C-8
Table C6. Hematology - Summary - Fo Generation Female Rats
C-9
Table Cl. Clinical Chemistry - Summary - Fo Generation Female Rats
C-12
Table C8.
Body Weights - Precohabitation - Summary - Fo Generation Female Rats
C-15
Table C9.
Body Weight Changes - Precohabitation - Summary - Fo Generation
Female Rats
C-16
Table CIO. Maternal Body Weights - Gestation - Summary - Fo Generation Female Rats
C-17
Table C l 1. Maternal Body Weight Changes - Gestation - Summary Fo Generation Female Rats
C-19
Table C l2. Maternal Body Weights - Lactation - Summary Fo Generation Female Rats
C-20
Table C13. Maternal Body Weight Changes - Lactation - Summary Fo Generation Female Rats
C-22
Table C14. Absolute Feed Consumption Values (g/day) - Precohabitation Summary - Fo Generation Female Rats
C-23
Table C15. Relative Feed Consumption Values (g/kg/day) - Precohabitation -
Summary - Fo Generation Female Rats
C-24
Table C l6. Maternal Absolute Feed Consumption Values (g/day) - Gestation -
Summary - Fo Generation Female Rats
C-25
Table C17. Maternal Relative Feed Consumption Values (g/kg/day) - Gestation -
Summary - Fo Generation Female Rats
C-26
Table C18. Maternal Absolute Feed Consumption Values (g/day) - Lactation -
Summary - Fo Generation Female Rats
C-27
vi
SUBJECT
PAGE
Table C l9. Maternal Relative Feed Consumption Values (g/kg/day) - Lactation -
Summary - Fo Generation Female Rats
C-28
Table C20. Mating and Fertility, Estrous Cycling and Days in Cohabitation Summary - Fo Generation Female Rats
C-29
Table C21. Functional Observational Battery - Summary Fo Generation Female Rats
C-31
Table C22. Motor Activity - Summary - Fo Generation Female Rats
C-37
Table C23. Natural Delivery Observations - Summary - Fo Generation Female Rats
C-39
Table C24. Litter Observations (Naturally Delivered Pups) - Summary FI Generation Litters
C-40
Table C25. Clinical Observations from Birth to Day 22 Postpartum Summary - FI Generation Pups
C-43
Table C26. Necropsy Observations - Summary - FI Generation Pups
C-44
Table C27. Pup Liver Weights - Summary - FI Generation Pups
C-45
Table C28. Clinical Observations - Individual Data Fo Generation Female Rats
C-46
Table C29. Necropsy Observations - Individual Data Fo Generation Female Rats
C-51
Table C30.
Terminal Body Weights and Organ Weights and Ratios (%) of Organ
Weight to Terminal Body Weight - Individual Data -
Fo Generation Female Rats
C-55
Table C31. Organ Weights and Ratios (%) Of Organ Weight to Brain Weight -
Individual Data - Fo Generation Female Rats
. C-60
Table C32. Primordial Follicle Count - Individual Data - Fo Generation Female Rats
C-65
Table C33. Body Weights - Precohabitation - Individual Data Fo Generation Female Rats
C-67
Vll
SUBJECT
PAGE
Table C34. Maternal Body Weights - Presumed Gestation - Individual Data Fo Generation Female Rats
C-70
Table C35. Maternal Body Weights - Lactation - Individual Data Fo Generation Female Rats
C-75
Table C36. Feed Consumption Values - Precohabitation - Individual Data Fo Generation Female Rats
C-80
Table C37. Maternal Feed Consumption Values - Presumed Gestation Individual Data - Fo Generation Female Rats
C-83
Table C38. Maternal Feed Consumption Values - Lactation - Individual Data -
Fo Generation Female Rats
C-86
Table C39. Mating and Fertility, Estrous Cycling and Days in Cohabitation Individual Data - Fo Generations Female Rats
C-89
Table C40. Functional Observational Battery - Individual Data Fo Generation Female Rats
C-92
Table C41. Motor Activity - Individual Data - Fo Generation Female Rats
C-97
Table C42. Natural Delivery, Implantation Sites, and Pup Viability and Sex Individual Data - Fo Generation Female Rats/Fl Generation Litters C-107
Table C43. Pup Body Weight Litter Averages from Birth to Day 22 Postpartum
Individual Data - FI Generation Litters
C-110
Table C44. Pup Body Weights from Birth to Day 22 Postpartum Individual Data - FI Generation Pups
C-113
Table C45. Pup Vital Status and Sex from Birth to Day 22 Postpartum Individual Data - FI Generation Pups
C-125
Table C46. Clinical Observations from Birth to Day 22 Postpartum Individual Data - FI Generation Pups
C-128
Table C47. Necropsy Observations - Individual Data - FI Generation Pups C-130
Table C48. Pup Liver Weights - Individual Date - FI Generation Pups
C-136
APPENDIX D - PROTOCOL AND AMENDMENTS
D -l to D-52
SUBJECT
PAGE
APPENDIX E - DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY
E -l to E-3
APPENDIX F - CERTIFICATE OF ANALYSIS
F-l to F-3
APPENDIX G - ANALYTICAL AND BIOANALYTICAL REPORT G -l to G-153
APPENDIX H - TEMPERATURE AND RELATIVE HUMIDITY REPORT
H-l
APPENDIX I - POSITIVE CONTROL DATA
1-1 to 1-4
APPENDIX J - HISTOPATHOLOGY REPORT
J-l toJ-105
APPENIDX K - HEMATOLOGY AND CLINICAL CHEMISTRY REPORTS
K -l to K-150
APPENDIX L - STATEMENT OF THE STUDY DIRECTOR
L-l
APPENIDIX M - QUALITY ASSURANCE STATEMENT
M -l to M-2
IX
418-028:PAGE 1-1
TITLE:
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
ARGUS RESEARCH PROTOCOL NUMBER: 418-028 SPONSOR'S STUDY NUMBER: T-7706.1
1. SUMMARY AND CONCLUSION
1.1. Methods3
Seventy-five Crl:CD(SD)IGS VAF/Plus rats per sex were assigned to five dosage groups (Groups I through V), 15 rats per sex per group. An additional three rats per sex per group were assigned to Groups I through V for toxicokinetic sample collection. The test substance, T-7706 [Perfluorohexane Sulfonate Potassium Salt (PFHS)], or vehicle, aqueous 0.5% carboxymethylcellulose (CMC), was administered via gavage to male rats once daily beginning 14 days before cohabitation and continuing through the day before sacrifice, after completion of the cohabitation period, after a minimum of 42 days of administration, and to female rats once daily beginning 14 days before cohabitation and continuing through the day before sacrifice, day 21 of lactation (DL 21) or day 25 of presumed gestation (DG 25, rats that did not deliver a litter). Dosages were 0 ,0 .3 ,1 , 3 and 10 mg/kg/day. The dosage volume, 10 mL/kg, was adjusted daily on the basis of the individual body weights recorded before intubation. FI generation pups were not directly administered the test substance or vehicle.
Within each dosage group, rats were assigned to cohabitation, one male rat per female rat.
Rats were observed for viability at least twice each day of the study. Observations for clinical signs of effects of the test substance and deaths were made on the first day of dosage at approximately hourly intervals for the first four hours and at the end of the normal working day. Observations for clinical signs of effects of the test substance and deaths were made on subsequent days daily before dosage and approximately 60 10 minutes after dosage administration and on the day of sacrifice. Once before the first dosage and at least once weekly thereafter, detailed clinical observations were conducted for all male and female rats assigned to the main study.
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 D (PROTOCOL AND AMENDMENTS).
418-028:PAGE 1-2
Body weights were recorded daily during the dosage period and at sacrifice. Feed consumption values for male rats assigned to the main study were recorded weekly during the dosage period. Feed consumption values for female rats assigned to the main study were recorded weekly to cohabitation, on DGs 0 ,7 , 10,12,15, 18,20 and 25 (if necessary) and on DLs 1, 5, 8 and 15. During cohabitation, individual values w'ere not recorded or tabulated.
Estrous cycling was evaluated in rats assigned to the main study by examination of vaginal cytology beginning with the day after the first administration and then until spermatozoa were observed in a smear of the vaginal contents and/or a copulatory plug was observed in situ during the cohabitation period. Estrous cycling was evaluated in rats assigned to the toxicokinetic study during the cohabitation period until spermatozoa were observed in a smear of the vaginal contents and/or a copulatory plug was observed in situ.
Female rats were evaluated for adverse clinical signs observed during parturition, duration of gestation, litter sizes and pup viability at birth. Maternal behavior was evaluated on DLs 1,5, 8 ,1 5 and 22.
Shortly before scheduled sacrifice, a functional observational battery (FOB) was conducted and motor activity was evaluated on 10 male and 10 female rats per group.
On days 14 and 42 of study, blood samples were collected from each male rat assigned to the toxicokinetic sample collection portion of the study and on day 14 of study and DG 21, blood samples were collected from each female rat assigned to the toxicokinetic sample collection portion of the study.
Each litter was evaluated for viability at least twice daily. The pups in each litter were counted once daily. Clinical observations were recorded once daily. Pup body weights were recorded on DLs 1, 8,15 and 22.
Male and female rats assigned to the toxicokinetic study were sacrificed on day 42 of study and DG 21, respectively. Liver weights were recorded. The median liver lobe was shipped for analysis. Blood samples were collected from each fetus and pooled by litter and serum was shipped for analysis. The liver from each fetus was collected, pooled per litter and shipped for analysis. The number of implantation sites was recorded.
Male and female rats assigned to the main study were sacrificed after a minimum of 42 days of dosage and on DL 22, respectively. A gross necropsy of the thoracic, abdominal and pelvic viscera was performed. The number of implantation sites were recorded. Gross lesions were examined histologically.
Ten rats per sex per group assigned to functional observational battery and motor activity tests were assigned to histological evaluations. The following organs were individually weighed: liver, kidneys, adrenals, thymus, testes, right epididymis, left epididymis (corpus and caput), seminal vesicles (with and without fluid), prostate, spleen, brain, heart, ovaries and uterus (with cervix). The following tissues or representative samples
418-028 :PAGE 1-3
were retained: brain, small and large intestines, lungs, lymph nodes, peripheral nerve, stomach, kidneys, spleen, thymus, trachea, urinary bladder, spinal cord, liver, adrenals, heart, thyroid/parathyroid, bone marrow, testes, prostate, seminal vesicles, ovaries, uterus, vagina, mammary gland (female rats only) and gross lesions. Histological examination of retained tissues, including reproductive organs, was conducted for the assigned ten rats per sex from the control and high dosage groups. A quantitative evaluation of primordial follicles was conducted for Fo generation female rats.
Sperm evaluations (concentration, motility and morphology) were performed for 10 male rats in each dosage group.
At scheduled sacrifice, blood samples were collected from the 10 male and 10 female rats per group assigned to hematology and clinical chemistry sample collection. The following hematologic parameters were evaluated: erythrocyte count, hematocrit, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, total leukocyte count, differential leukocyte count, platelet count, mean platelet volume and cell morphology. Two blood smear slides were prepared for measurements of differential leukocyte count. Plasma samples evaluated for prothrombin time and activated partial thromboplastin time. Sera samples were evaluated for total protein, triglycerides, albumin, globulin, albumin/globulin ratio, glucose, cholesterol, total bilirubin, urea nitrogen, creatinine, creatinine kinase, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, calcium, phosphorus, sodium, potassium and chloride.
On DL 22, pups were sacrificed and examined for gross lesions. Necropsy included a single cross-section of the head at the level of the frontal-parietal suture and examination of the cross-sectioned brain for apparent hydrocephaly.
Blood samples were collected from five pups per sex per litter from the 10 female rats per group selected for FOB and motor activity assessment, blood sample collection for hematology and clinical chemistry and histological evaluations. Sera was shipped for analysis. The liver from each selected pup was weighed.
1.2. Results
1.2.1. Male Rats
All male rats survived to scheduled sacrifice and all clinical and necropsy observations
were considered unrelated to the test substance.
.
Body weight gains were significantly reduced in the 0.3, 3 and 10 mg/kg/day dosage groups on study days (DSs) 29 to 36. Significantly reduced body weight gain occurred in the 0.3,1, 3 and 10 mg/kg/day dosage groups on study days DS 29 to termination. Body weight gain was also significantly reduced for the 10 mg/kg/day dosage group for the entire dosage period. Absolute and relative feed consumption values for the male rats were unaffected by dosages of the test substance as high as 10 mg/kg/day.
418-028:PAGE 1-4
Terminal body weights of the male rats were slightly reduced in the 10 mg/kg/day dosage group. The absolute weights of the liver, the ratios of the liver weights to terminal body weights and ratios of the liver weights to brain weight were significantly increased in the 3 and 10 mg/kg/day dosage groups. The ratio of the heart weights to brain weight was significantly decreased in the 10 mg/kg/day dosage group.
Hemoglobin concentrations were significantly decreased in the 1, 3 and 10 mg/kg/day dosage groups and average values for red blood cells and hematocrit were significantly decreased in the 3 and 10 mg/kg/day dosage groups. Prothrombin time was significantly increased in the 0.3, 3 and 10 mg/kg/day dosage groups. Average values for cholesterol were significantly decreased in the 0.3,1, 3 and 10 mg/kg/day dosage groups and the average values for triglycerides was significantly decreased in the 10 mg/kg/day dosage group. Albumin, blood urea nitrogen, alkaline phosphatase, calcium and albumin/globulin ratio levels were significantly increased in the 10 mg/kg/day dosage group.
Treatment-related microscopic changes were observed in the liver and thyroid gland of male rats in the 3 and 10 mg/kg/day dosage groups. The treatment-related microscopic changes in the liver consisted of minimal to moderate enlargement of centrilobular hepatocytes and in the thyroid gland as an increased incidence of hypertrophy of follicular cells and hyperplasia. These microscopic changes are consistent with the known effects of compounds that cause microsomal enzyme induction where the hepatocellular hypertrophy results in a compensatory hypertrophy and hyperplasia of the thyroid due to increased plasma turnover of thyroxine and associated stimulation of thyroid-stimulating hormone in rats(1). There were no treatment-related microscopic changes observed in the liver of the FI generation pups from the dams given up to 10 mg/kg/day of the test substance.
All mating and fertility parameters were unaffected by dosages of the test substance as high as 10 mg/kg/day. There were no other statistically significant or biologically important differences among the four dosage groups in the measures of the functional observational battery (FOB) or motor activity on DSs 36 through 39.
Sperm motility was unaffected by dosages of the test substance as high as 10 mg/kg/day. The sperm count and sperm density were comparable among the five dosage groups.
1.2.2. Female Rats
All female rats survived to scheduled sacrifice and all clinical and necropsy observations were considered unrelated to the test substance.
Body weights, body weight gains, and absolute and relative feed consumption values were comparable and did not differ significantly during the precohabitation, gestation or lactation periods at dosages of the test substance up to 10 mg/kg/day.
Terminal body weights, absolute and relative weights of the reproductive organs, brain, liver, left and right kidneys and adrenals, spleen, thymus and heart of the female rats were
418-028: PAGE 1-5
comparable among dosage groups. Average primordial follicle counts for the 10 mg/kg/day dosage group were comparable to the control group.
No treatment-related microscopic changes were observed in any of the female rats administered up to 10 mg/kg/day of the test substance. There were no treatment-related microscopic changes observed in the liver of the FI generation pups from the dams given up to 10 mg/kg/day of the test substance.
Dosages as high as 10 mg/kg/day did not affect any hematology or clinical chemistry values evaluated.
The average numbers of estrous stages per 13 days were comparable among the five dosage groups. All mating and fertility parameters, including the gestation index, viability index and lactation indices were unaffected by dosages of the test substance as high as 10 mg/kg/day.
There were no statistically significant or biologically important differences among the five dosage groups in the measures of the functional observational battery (FOB) or motor activity on DL 17.
All pregnant dams delivered a litter of one or more live pups. Values for the numbers of dams delivering litters, the duration of gestation, averages for implantation sites per delivered litter, the numbers of dams with stillborn pups, the numbers of dams with no livebom pups, dams with all pups dying, were comparable among the five dosage groups. The number of pups surviving per litter, pup sex ratios, litter size and pup body weights per litter were comparable among the five dosage groups.
No clinical or necropsy observations in the FI generation pups were attributable to dosages of the test substance as high as 10 mg/kg/day. F I generation male and female pup terminal body weights, absolute fiver weight and ratio of fiver weight to terminal body weight were comparable across all five dosage groups.
418-028: PAGE 1-6
1.3. Conclusion
On the basis of these data, the maternal no-observable-adverse-effect-level (NOAEL) for T-7706 [Perfluorohexane Sulfonate Potassium Salt] is greater than 10 mg/kg/day (the 10 mg/kg/day dosage caused no deaths, adverse clinical or necropsy/pathology observations, changes in body weight, feed consumption, or hematology or clinical chemistry values throughout precohabitation, gestation or lactation. The paternal NOAEL is less than 0.3 mg/kg/day (the 0.3 and 1 mg/kg/day dosages caused significant differences in body weight gain, hematology and clinical chemistry values and the 3 and 10 mg/kg/day dosages caused significant changes in absolute and relative organ weights and microscopic changes in the liver and thyroid gland).
The reproductive NOAEL is greater than 10 mg/kg/day (the 10 mg/kg/day dosage had no effect on the durations of gestation and parturition or any mating and fertility parameters. There was no effect on the sperm parameters in the male rats).
The NOAEL for viability and growth in the offspring is also greater than 10 mg/kg/day (dosages of 10 mg/kg/day had no effect on perinatal mortality, clinical or necropsy observations or body or liver weights in the FI generation offspring).
Alan M. Hoberman, Ph.D., DABT Director of Research Study Director
Date
Study Director
418-028:PAGE 2-1
2. DESCRIPTION OF TEST PROCEDURES 2.1. Conduct of Study
2.1.1. Sponsor
3M Corporate Toxicology, 3M Center, Building 220-2E-02, St. Paul, Minnesota
55144-1000
.
2.1.2. Testing Facility
Argus Research, 905 Sheehy Drive, Building A, Horsham, Pennsylvania 19044-1297
2.1.3. Study Number
418-028
2.1.4. Sponsor's Study Number
T-7706.1
2.1.5. Purpose of the Study
The purpose of this study was to provide information on the possible health hazards that may result from repeated exposure of Crl:CD(SD)IGS BR VAF/Plus male and female rats to a test substance beginning before cohabitation, through mating and continuing for at least 42 days (male rats) or through parturition until day 21 of lactation (female rats). This repeated dose study incorporated a reproduction/developmental toxicity screening test that can be used to provide initial information on possible effects on male and female reproductive performance (e.g., gonadal function, mating behavior, conception, development of the conceptus and parturition). The study also placed emphasis on neurological effects as a specific endpoint and should identify the neurotoxic potential of a test substance, which may warrant further in-depth investigation.
Because of the selectivity of the endpoints and the short duration of the study, the screening test did not provide evidence for definitive claims of no reproductive/ developmental effects. In particular, it offered only limited means of detecting postnatal manifestations of prenatal exposure or effects that may be induced during postnatal exposure.
2.1.6. Study Design
The requirements of the Organisation for Economic Co-operation and Development (OECD)(2) were used as the basis for study design.
2.1.7. Regulatory Compliance
This study was conducted in compliance with Good Laboratory Practice (GLP) regulations of the OECD(3),U.S. Food and Drug Administration (FDA)(4), the Japanese
418-028: PAGE
Ministry of Health and Welfare (MHW)<5). There were no deviations from the GLP regulations that affected the quality or integrity of the study. Quality Assurance 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.
2.1.8. Ownership of the Study
The Sponsor owns the study. All raw data, analyses, reports and preserved tissues are property of the Sponsor.
2.1.9. Study Monitor
John Butenhoff, Ph.D., CIH, DABT
2.1.10. Study Director
Raymond G. York, Ph.D., DABT (Associate Director of Research) Address as cited previously for Testing Facility.
2.1.11. Technical Performance
John F. Barnett, B.S. (Director of Laboratory Operations) Joseph W. Lech, B.S. (Senior Research Associate) Mary P. Howard, B.S. (Team Leader - General Laboratory) Jaclyn S. Fox, B.S. (Laboratory Technician) Josette M. Provost, B.S. (Necropsy Laboratory Technician/Fixed Tissue Coordinator) Christopher K. Ruppert, B.S. (Formulation Laboratory Technician)
2.1.12. Report Preparation
Raymond G. York, Ph.D., DABT Jo Ann Frazee, M.S. (Study Coordinator) JoAnne M. Conklin, B.S. (Data Management Specialist) Cristina Petrescu (Report Administrator)
2.1.13. Report Review
Valerie A. Sharper, M.S. (Director of Study Management)
2.1.14. Date Protocol Signed
26 March 2002
2.1.15. Dates of Technical Performance
2.1.15.1. Male Rats
Rat Arrival Dosage Period (14 days before cohabitation and
through a 14-day cohabitation period until sacrifice after at least 42 days of dosage) FOB and Motor Activity Evaluation Toxicokinetic Sample Collections DSa 14 DS 42 Scheduled Sacrifice - Toxicokinetic Study Scheduled Sacrifice - Main Study
2.1.15.2. Female Rats
Rat Arrival Dosage Period (14 days before cohabitation
through DLb 21) Cohabitation Period
Male 1 Male 2 Toxicokinetic Sample Collections DS 14 DGC21 DGO DG 25 Sacrifice (Rats that did not deliver a litter) Delivery Periodd (DL. 1) FOB and Motor Activity Evaluation DL 22 Sacrifice Female Rats and Pups
418-028:PAGE 2-3
26 MAR 02
01 APR 0 2 -1 6 MAY 02 06 MAY 02 - 09 MAY 02
14 APR 02 12 MAY 02 12 MAY 02 13 MAY 0 2 -1 7 MAY 02
26 MAR 02 01 APR 02 - 09 JUN 02 14 APR 02 PM - 21 APR 02 AM 21 APR 02 PM - 28 APR 02 AM
14 APR 02 06 MAY 02 -19 MAY 02
15 APR 02 - 28 APR 02 10 MAY 0 2 -2 3 MAY 02 07 MAY 0 2 -2 0 MAY 02 23 MAY 02 - 26 MAY 02 28 MAY 02 - 10 JUN 02
a. DS is an abbreviation used for day of study. b. DL is an abbreviation used for day of lactation/postpartum. c. DG is an abbreviation used for day of (presumed) gestation. d. The day of birth is designated lactation day 0 (postpartum day 0) in the Health
Effects Test Guidelines - Reproduction and Fertility Effects (Office of Prevention, Pesticides and Toxic Substances 870.3800, August, 1998) and in the OECD Guideline for the Testing of Chemicals - Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (Section 4, No. 422, 22 March 1966). This same day is designated day 1 postpartum (day 1 of lactation) in the Standard Operating Procedures of the Testing Facility. Throughout this study, the day of birth was designated as day 1 postpartum (day 1 of lactation) and all subsequent ages of the FI generation rats and days of the lactation period were determined and cited accordingly.
418-028:PAGE 2-4
2.1.16. Records Maintained
The original report, raw data and reserve samples of each lot of bulk test substance and bulk vehicle components are retained in the archives of Argus Research. 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 prepared formulations were discarded at the Testing Facility. All remaining bulk test substance was returned to the Sponsor.
2.2. Test Substance Information
2.2.1. Description
T-7706 [Perfluorohexane Sulfonate Potassium Salt (PFHS)] - a white powder
2.2.2. Date Received and Storage Conditions
The test substance was received on 11 March 2002 and stored at room temperature.
2.2.3. Special Handling Instructions
Standard safety precautions (use of protective clothing, gloves, dust-mist/HEPA-filtered mask, safety goggles or safety glasses and a face-shield) were taken during formulation preparation and dosage. A half-face respirator was worn during formulation preparation.
2.2.4. Analysis of Purity
Information to document or certify the identity, composition, method of synthesis, strength and purity of the test substance was provided by the Sponsor to the Testing Facility. A Certificate of Analysis is available in APPENDIX F.
2.3. Vehicle Information
2.3.1. Description
Aqueous 0.5% carboxymethylcellulose (CMC) (sodium salt; medium viscosity) prepared using carboxymethylcellulose (sodium salt; medium viscosity), an off-white powder, and reverse osmosis membrane processed deionized water (R.O. deionized water).
2.3.2. Lot Number
120K0252
2.3.3. Date Received and Storage Conditions
The carboxymethylcellulose was received from Sigma Chemical Co., St. Louis, Missouri, on 11 September 2001 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.
418-028:PAGE 2-5
2.3.4. Special Handling Instructions
Standard safety precautions (use of protective clothing, gloves, dust-mist/HEPA-fikered mask, safety goggles or safety glasses and a face-shield) were taken when handling the vehicle components and prepared vehicle.
2.3.5. Analysis of Purity
Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the vehicle that would have interfered with the results of this study. The expiration date for the carboxymethylcellulose is September 2005.
2.4. Test Substance Preparation and Storage Conditions
Formulations were prepared weekly at the Testing Facility. Prepared test substance and vehicle formulations were stored refrigerated (2C to 8C).
2.4.1. Sample Information
Sample Type
Date Size Retained
Storage Conditions
Shipped To/ Shipping Conditions
Date Shipped
Bulk Test Substance"
Homogeneity0 (all levels) Concentration11 (all levels) Stability8
Bulk Test Substance Reserve Vehicle Components Reserve
Carboxymethylcellulose R.O. deionized water
lg
2 mL 2 mL 2 mL 1g
lg 5 mL
09 JUN02
29 MAR 02 24 MAY 02e 07 JUN 02f 29 MAR 02 10 JUN 02
10 JUN 02 10 JUN 02
Room temperature
Refrigerated Refrigerated Refrigerated Room temperature Room temperature
Exygenb/ Ambient conditions Sponsor/ Refrigerated Exygen" / Refrigerated Sponsor/ Refrigerated Testing Facility Archives Testing Facility Archives
10 JUN 02
01 APR 02 28 MAY 02 10 JUN 02 01 APR 02 10 JUN 02
10 JUN 02 10 JUN 02
a. A sample of the test article was retained on the last day of treatment and shipped for analysis. b. Exygen Research, State College, Pennsylvania. c. Quadruplicate samples were taken from the top, middle and bottom of each concentration on the first day
of preparation. Two samples from each quadruplicate set were shipped for analysis. The remaining samples were retained at the Testing Facility as backup samples. d. Quadruplicate samples were taken from each concentration on the last day of preparation. Two samples from each quadruplicate set were shipped for analysis. The remaining samples were retained at the
Testing Facility as backup samples. e. Samples for 0.03,0.1 and 1 mg/mL concentrations only. f. Samples for 0 and 0.3 mg/mL concentrations only. g. Two sets of duplicate samples from each concentration were taken on the first day of preparation. One
sample of each duplicate set was shipped on the day of preparation. These samples were analyzed as soon as possible after preparation and ten days after the first analysis. The remaining samples were retained at the Testing Facility as backup samples.
418-028:PAGE 2-6
2.4.2. Analytical Results
Results of the analytical analyses are available in APPENDIX G.
2.5. Test System
2.5.1. Species
Rat
2.5.2. Strain
Crl:CD(SD)IGS VAF/Plus
2.5.3. Supplier (Source)
Charles River Laboratories, Inc. Male Rats - St. Constant, Quebec, CANADA Female Rats - Raleigh, North Carolina
2.5.4. Sex
Male and Female
2.5.5. Rationale for Test System
The Crl:CD(SD)IGS BR VAF/Plus rat was selected as the Test System because: 1) it is one mammalian species accepted for use in toxicity studies and it has been widely used throughout industry; 2) this strain of rat has been demonstrated to be sensitive to reproductive and developmental toxins; and 3) historical data and experience exist at the Testing Facility(6`8).
2.5.6. Test System Data
2.5.6.I. Male Rats
Number of Rats Approximate Date of Birth Approximate Age at Arrival Weight (g) the Day after Arrival Weight (g) at Study Assignment
100 20 JAN 02
66 days 277 - 318
305 -348
2.5.6.2. Female Rats
Number of Rats Approximate Date of Birth Approximate Age at Arrival Weight (g) the Day after Arrival Weight (g) at Study Assignment
100 21 JAN 02
65 days 195 -227 207 -230
418-028:PAGE 2-7
2.5.7. Method of Randomization
Upon arrival, the male and female rats were assigned to individual housing on the basis of computer-generated random units. During an acclimation period of at least five days, male and female rats were selected for study on the basis of physical appearance and body weights recorded during acclimation. The rats were assigned to five dosage groups (Groups I through V), 15 rats per sex per group, using a computer-generated (weightordered) randomization procedure. An additional three rats per sex per group were assigned to Groups I through V for toxicokinetic sample collection. At study initiation, the weight variation of the rats did not exceed 20% of the mean weight of each sex.
Litters were not culled during the lactation period because random selection of pups for culling could have resulted in potential biases in pup viabilities and body weight gains over this period.
Within each dosage group, consecutive order was used to assign the first 10 male and the first 10 female Fo generation rats to a functional observational battery (FOB) and motor activity assessment, blood sample collection for clinical chemistry and hematology and histological evaluations.
On DL 22, a table of random units was used to select five male and five female pups per litter for blood sample and liver collection. These pups were only selected from the 10 dams selected for FOB, motor activity, clinical chemistry and hematology and histological evaluation.
2.5.8. System of Identification
Male and female rats were assigned temporary numbers at receipt and given unique permanent identification numbers when assigned to the study before administration of the first dosage. Rats were permanently identified using a Monel self-piercing ear tag (Gey Band and Tag Co., Inc., No. MSPT 20101). Cage tags were marked with the study number, permanent rat number, sex, test substance identification, generation, dosage group and dosage level.
Pups were not individually identified during lactation; all parameters were evaluated in terms of the litter.
2.6. Husbandry
2.6.1. Research Facility Registration
USDA Registration No. 14-R-0144 under the Animal Welfare Act, 7 U.S.C. 2131 et seq.
2.6.2. Study Room
The study room was maintained under conditions of positive airflow relative to a hallway and independently supplied with a minimum of ten changes per hour of 100% fresh air that had been passed through 99.97% HEPA filters. Room temperature and humidity
418-028:PAGE 2-8
were monitored constantly throughout the study. Room temperature was targeted at 64F to 79F (18C to 26C); relative humidity was targeted at 30% to 70%a.
2.6.3. Housing
Rats were individually housed in stainless steel, wire-bottomed cages except during cohabitation and postpartum periods. During cohabitation, each pair of male and female rats was housed in the male rat's cage. Beginning no later than DG 20, Fo generation female rats were individually housed in nesting boxes until they either naturally delivered litters or were sacrificed (DG 25). Each dam and delivered litter was housed in a common nesting box during the postpartum period. All cage sizes and housing conditions were in compliance with the Guidefo r the Care and Use o f Laboratory Animals(9). Argus Research is an AAALAC-accredited facility.
2.6.4. 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.
2.6.5. Sanitization
Cage pan liners were changed at least three times weekly. Cages were changed approximately every other week. Bedding was changed as often as necessary to keep the rats dry and clean.
2.6.6. Feed
Rats were given ad libitum access to Certified Rodent Diet#5002 (PMI Nutrition International, Inc., St. Louis, Missouri) in individual feeders. Feed was removed the evening prior to the scheduled sacrifice15.
2.6.7. 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 potential contaminants likely to have been present in the feed at concentrations that would have interfered with the results of this study.
a. See APPENDIX H (TEMPERATURE AND RELATIVE HUMIDITY REPORT). b. See APPENDIX E (DEVIATIONS FROM THE PROTOCOL AND THE
STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY), item 1.
418-028:PAGE 2-9
2.6.8. Water
Local water that had been processed by passage through a reverse osmosis membrane (R.O. water) was available to the rats ad libitum from individual water bottles attached to the cages and/or from an automatic watering access system. Chlorine was added to the processed water as a bacteriostat.
2.6.9. 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 potential contaminants likely to have been present in the water that would have interfered with the results of this study.
2.6.10. Bedding Material
Bed-o'cobs bedding (The Andersons Industrial Products Group, Maumee, Ohio) was used as the nesting material.
2.6.11. Bedding Analysis
Analyses for possible contamination are conducted semi-annually. Copies of the restults of the bedding analyses are available in the raw data.
Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the bedding that would have interfered with the results of this study.
418-028-.PAGE 2-10
2.7. Methods
2.7.1. Dosage Administration
Dosage Number Dosage Dosage1 Concentration Volume of Rats
Assigned Numbers
Group (mg/kg/day) (mg/mL) (mlAg) per Sex
Male Rats
Female Rats
I0
0
10 15 + 3b
Main Study:
Main Study:
19109,19115,19116.19119, 19010, 19012,19019, 19021,
19122,19125,19131,19132, 19023,19041,19042,19044,
19134,19135, 19143, 19151, 19050, 19053, 19065,19068,
19157,19161,19167
19072, 19074,19075
Toxicokinetic Study:
Toxicokinetic Study:
19176-19178
19076 - 19078
II 0.3 0.03 10 15 + 3b Main Study:
Main Study:
19102,19106,19108,19110, 19004,19009,19016.19018,
19113,19120,19129,19136, 19026,19036,19037,19043,
19138,19139,19147,19153, 19047, 19048,19052,19055,
19164,19165,19171
19061,19067, 19071
Toxicokinetic Study:
Toxicokinetic Study:
19179-19181
19079- 19081
in 1
0.1
10 15 + 3b
Main Study:
Main Study:
19101,19105,19107, 19112, 19003,19007,19008,19013,
19114,19121,19123,19130, 19014,19015, 19017,19024,
19137,19146,19155,19159, 19029, 19034, 19038,19056,
19172,19173,19174
19057, 19060,19064
Toxicokinetic Study:
Toxicokinetic Study:
19182-19184
19082- 19084
IV 3
0.3 10 15+ 3" Main Study:
Main Study:
19100,19103,19104, 19118, 19002,19005,19035, 19039,
19133,19141,19142,19144, 19040,19045,19046,19051,
19148,19150,19156,19160, 19054,19058,19062,19063,
19162, 19163,19166
19066, 19069,19073
Toxicokinetic Study:
Toxicokinetic Study:
19185-19187
19085 - 19087
v 10
1
10 15+ 3"
Main Study:
Main Study:
19111,19117,19124,19126, 19001,19006,19011,19020,
19127,19128,19140,19145, 19022,19025,19027,19028,
19149,19152,19154,19158, 19030,19031,19032,19033,
19168, 19169,19170
19049,19059,19070
Toxicokinetic Study:
Toxicokinetic Study:
19188-19190
19088 - 19090
a. The test substance was considered 100% pure for the purpose of dosage calculations.
b. Three additional rats per sex were assigned to toxicokinetic sample collection.
2.7.2. Rationale for Dosage Selection
Dosages were selected by the Sponsor based on previous studies conducted with the test substance, taking into account possible differences in sensitivity between pregnant and nonpregnant rats. The highest dosage was expected to cause toxic effects but not mortality or obvious suffering. The descending sequence of the lower dosage levels was selected for the purpose of demonstrating any dosage-related response, with no adverse effects expected at the lowest level.
418-028 :PAGE 2-11
2.7.3. Route and Rationale for Route of Administration
The oral (gavage) route was selected for use because: 1) in comparison with the dietary route, the exact dosage can be accurately administered; and 2) it is one of the possible routes for environmental exposure.
2.7.4. Frequency of Administration
2.7.4.1. Fo Generation Rats
Male rats were administered the test substance or the vehicle once daily beginning 14 days before cohabitation (maximum 14 days) and continuing through the day before sacrifice, after completion of the cohabitation period, after a minimum of 42 days of administration. Female rats were administered the test substance or the vehicle once daily beginning 14 days before cohabitation (maximum 14 days) and continuing through the day before sacrifice, DL 21 or DG 24 (rats that did not deliver a litter). The dosage volume was adjusted daily on the basis of the individual body weights recorded before intubation. The rats were intubated once daily at approximately the same time each day. The first day of dosage was designated as DS 1. Dams in the process of delivering pups were not intubated until completion of parturition, in order to preclude possible disruption of maternal behavior and/or cannibalization of pups. Consequently, some dams were not administered one daily dosage during the delivery period. No dam missed more than one daily dosage.
2.7.4.2. FI Generation Pups
FI generation pups were not directly administered the test substance or vehicle, but may have been possibly exposed to the test substance or vehicle during maternal gestation (in utero exposure) or via maternal milk during the lactation period.
2.7.5. Method of Study Performance
2.7.5.I. Fo Generation Rats
Within each dosage group, consecutive order was used to assign rats to cohabitation, one male rat per female rat. The cohabitation period consisted of a maximum of 14 days. Female rats with spermatozoa observed in a smear of the vaginal contents and/or a copulatory plug in situ were considered to be DG 0 and assigned to individual housing. Female rats not mated with a male rat within the first seven days of cohabitation were assigned an alternate male rat that had mated (same dosage group) and remained in cohabitation for a maximum of seven additional days.
Rats were observed for viability at least twice each day of the study. Rats were examined for clinical observations and general appearance weekly during the acclimation period. Observations for clinical signs of effects of the test substance and deaths were made on the first day of dosage at approximately hourly intervals for the first four hours and at the end of the normal working day. Observations for clinical signs of effects of the test
418-028:PAGE 2-12
substance and deaths were made on subsequent days daily before dosage and approximately 60 10 minutes after dosage administration and on the day of sacrifice3.
Once before the first dosage and at least once weekly thereafter, detailed clinical observations were conducted for all male and female rats assigned to the main studyb. These observations were made outside the cage in a standard arena at the same time each day of conduct. Effort was made to ensure that variations in the test conditions were minimal and that observations were conducted by observers unaware of treatment groups. The rats were observed for (but observations were not limited to) the following signs: changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g., lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypic behavior (e.g., excessive grooming, repetitive circling), difficult or prolonged parturition or bizarre behavior (e.g., self-mutilation, walking backwards) were also recorded.
Body weights were recorded weekly during the acclimation period, daily during the dosage period and at sacrifice. Feed consumption values for male rats assigned to the main study were recorded weekly during the dosage period. Feed consumption values for female rats assigned to the main study were recorded weekly to cohabitation, on DGs 0, 7 ,1 0 ,1 2 ,1 5 ,1 8 ,2 0 and 25 (if necessary) and on DLs 1, 5, 8 and 15c. Because pups begin to consume maternal feed on or about DL 15, feed consumption values were not tabulated after DL 15. During cohabitation, when two rats occupied the same cage with one feed jar, replenishment of the feed jars was documented but individual values were not recorded or tabulated.
Estrous cycling was evaluated in rats assigned to the main study by examination of vaginal cytology beginning with the day after the first administration and then until spermatozoa were observed in a smear of the vaginal contents and/or a copulatory plug was observed in situ during the cohabitation period. Estrous cycling was evaluated in rats assigned to the toxicokinetic study during the cohabitation period until spermatozoa were observed in a smear of the vaginal contents and/or a copulatory plug was observed in situ.
Female rats were evaluated for adverse clinical signs observed during parturition, duration of gestation (DG 0 to the day the first pup was observed), litter sizes (all pups delivered) and pup viability at birth. Maternal behavior was evaluated on DLs 1,5, 8, 15 and 22. Variations from expected maternal behavior were recorded, if and when present, on all other days of the postpartum period.
On one occasion during the course of the study, a functional observational battery (FOB)(10' 13) was conducted on 10 male and 10 female rats per group. For male rats, this assessment was conducted shortly before scheduled sacrifice, but prior to blood sample
a. See APPENDIX E, items 2 and 3. b. See APPENDIX E, item 4. c. See APPENDIX E, item 5.
418-028:PAGE 2-13
collection for hematology and clinical chemistry evaluations. Female rats were tested during the lactation period, shortly before scheduled sacrifice.
The FOB evaluation was conducted by an observer unaware of the group assignment of the rat. The following parameters were assessed:
1. Lacrimation, salivation, palpebral closure, prominence of the eye, pupillary reaction to light, piloerection, respiration, and urination and defecation (autonomic functions).
2. Sensorimotor responses to visual, auditory, tactile and painful stimuli (reactivity and sensitivity).
3. Reactions to handling and behavior in the open field (excitability).
4. Gait pattern in the open field, severity of gait abnormalities, air righting reaction and landing foot splay (gait and sensorimotor coordination).
5. Forelimb and hindlimb grip strength.
6. Abnormal clinical signs including but not limited to convulsions, tremors and other unusual behavior, hypotonia or hypertonia, emaciation, dehydration, unkempt appearance and deposits around the eyes, nose or mouth.
The ability of this battery to detect the effects of positive control substances has been established (Testing Facility Positive Control Data) and is available in APPENDIXI.
Motor activity was evaluated on 10 male and 10 female rats per group once, shortly before scheduled sacrifice, prior to blood sample collection. The movements of each rat were monitored by a passive infrared sensor mounted outside a stainless steel, wirebottomed cage (40.6 x 25.4 x 17.8 cm). Each test session was 1.5 hours in duration with the number of movements and time spent in movement tabulated at each five-minute interval. The apparatus monitored a rack of up to 32 cages and sensors during each session, with each rat tested in the same location on the rack across test sessions. Groups were counterbalanced across testing sessions and cages. Data demonstrating that the test system is capable of detecting increases in activity produced by positive control substances (Testing Facility Positive Control Data) is available in APPENDIX I.
On DSs 14 and 42, blood samples (approximately 1 mL each) were collected from each male rat assigned to the toxicokinetic sample collection portion of the study (three rats per group) and on DS 14 and DG 21, blood samples (approximately 1 mL each) were collected from each female rat assigned to the toxicokinetic sample collection portion of the study (three rats per group). Samples were collected prior to dosage on DS 14. The time of each blood collection was recorded in the raw data. Blood was collected from the orbital sinus on DS 14 of the study and from the vena cava on DS 42 of study (male rats) and DG 21 (female rats). The samples were transferred into EDTA-coated (purple top) tubes and spun in a centrifuge. The resulting serum was transferred into polypropylene
418-028: PAGE 2-14
tubes labeled with the protocol number, Sponsor study number, rat number, sex, group number, dosage level, day of study, collection interval, date of collection, species, generation and storage conditions. All samples were immediately frozen on dry ice and maintained frozen (<-70C) until shipment to Exygen Research, State College, Pennsylvania, for analysis. Results of these analyses are available in APPENDIX G.
2.7.S.2. FI Generation Pups
Day 1 of lactation (postpartum) was defined as the day of birth and was also the first day on which all pups in a litter were individually weighed (pup body weights were recorded after all pups in a litter were delivered and groomed by the dam).
Each litter was evaluated for viability at least twice daily. The pups in each litter were counted once daily. Clinical observations were recorded once daily3. Pups were observed if they were warm and clean, for evidence of a nest and if pups were grouped together and nursing or had milk in stomach. Each pup was examined for general shape of the head, trunk, limbs, tail and presence of anus. Pup body weights were recorded on DLs 1 ,8 ,1 5 and 22 (terminal weight).
2.7.6. Gross Necropsy
2.7.6.I. Fo Generation Rats
Male and female rats assigned to the toxicokinetic study were sacrificed by carbon dioxide asphyxiation on DS 42 and DG 21, respectively. Blood samples were collected from the rats as previously described. After sacrifice, the liver of each rat was excised and the liver weight was recorded. The median liver lobe was frozen and stored (<-20C) until shipment for analysis1*. The fetuses were removed from the uterus and blood samples were collected from each fetus via decapitation. Blood was placed into tubes, pooled per litter, allowed to clot and spun in a centrifuge. The resulting serum was transferred into labeled polypropylene tubes. All samples were immediately frozen on dry ice and maintained frozen (<-70C) until shipment for analysis. The liver from each fetus was collected, pooled per litter and placed into labeled tubes. The samples were frozen and stored (<-20C) until shipment for analysis. The number of implantation sites was recorded. Carcasses were discarded without further evaluation. The livers were shipped to Exygen Research, State College, Pennsylvania, for analysis. Results of the analyses are available in APPENDIX G.
Male and female rats assigned to the main study were sacrificed by carbon dioxide asphyxiation following the last dosage administration, after a minimum of 42 days of dosage and on DL 22, respectively. A gross necropsy of the thoracic, abdominal and pelvic viscera was performed. Gross necropsy included an initial physical examination of external surfaces and all orifices, as well as the cranial, thoracic and abdominal cavities and their contents. Special attention was paid to the organs of the reproductive system. The ovaries and the uterus with cervix of each female rat were weighed, and the
a. See APPENDIX E, items 6 and 7. b. See APPENDIX E, item 8.
418-028:PAGE 2-15
ovaries, uterus, vagina and a mammary gland were retained in neutral buffered 10% formalin. The number of implantation sites were recorded. Uteri of apparently nonpregnant rats were examined after being pressed between glass plates to confirm the absence of implantation sites and were retained in neutral buffered 10% formalin. Gross lesions were retained in neutral buffered 10% formalin and examined histologically. Representative photographs of gross lesions are available in the raw data. Tissue trimming and histopathology were performed under the supervision of or by a Board Certified Veterinary Pathologist.
Ten rats per sex per group assigned to functional observational battery and motor activity tests were assigned to histological evaluations. The following organs were excised, trimmed and individually weighed as soon as possible after excision to avoid drying: liver, kidneys, adrenals, thymus, testes, right epididymis, left epididymis (corpus and caput), seminal vesicles (with and without fluid), prostate, spleen, brain, heart, ovaries and uterus (with cervix). The following tissues or representative samples were retained in neutral buffered 10% formalin: brain (representative regions including cerebrum, cerebellum, pons), small and large intestines (including Peyer's patches), lungs (perfused with neutral buffered 10% formalin), lymph nodes (submandibular and mediastinal), peripheral nerve (sciatic or tibial), stomach, kidneys, spleen, thymus, trachea, urinary bladder, spinal cord (cervical, thoracic and lumbar), liver, adrenals, heart, thyroid/parathyroid, bone marrow (sternum), testes (fixed in Bouin's solution for 48 to 96 hours before being retained in neutral buffered 10% formalin), prostate, seminal vesicles (with coagulating gland), the remaining portion of the left epididymis (corpus and caput), the right epididymis, ovaries, uterus, vagina, mammary gland (female rats only) and gross lesions. Histological examination of retained tissues, including reproductive organs, was conducted for the assigned ten rats per sex from the control and high dosage groups. A quantitative evaluation of primordial follicles was conducted for Fo generation female rats. Examination included enumeration of number of primordial follicles, which were combined with small growing follicles, for comparison of ovaries of rats assigned to treated and control groups. Tissues that were examined histologically were shipped to Research Pathology Services, Inc., New Britain, Pennsylvania, for evaluation. Results of the histological evaluation are available in APPENDIX J.
To assess the potential toxicity of the test substance on the male reproductive system, sperm evaluations were performed for 10 male rats in each dosage group. Sperm concentration and motility were evaluated using computer-assisted sperm analysis (CASA). Motility was evaluated by the Hamilton Thome IVOS by collection of a sample from the left vas deferens. A homogenate was prepared from the left cauda epididymis for evaluation by the Hamilton Thome IVOS to determine sperm concentration (sperm per gram of tissue weight). The remaining portion of the left cauda epididymis was used to manually evaluate sperm morphology. Sperm morphology evaluations included the following: 1) determination of the percentage of normal sperm in a sample of at least 200; and 2) qualitative evaluation of abnormal sperm, including such categories as abnormal head, abnormal tail, and abnormal head and tail.
418-028:PAGE 2-16
At scheduled sacrifice, the 10 male and 10 female rats per group assigned to hematology and clinical chemistry sample collection were exsanguinated from the inferior vena cava following sacrifice. Rats were fasted overnight before sacrifice3. Approximately 5 mL of blood was collected. The tubes containing the samples were labeled with the protocol number, Sponsor study number, rat number, sex, group number, dosage level, day of study, collection interval, date of collection, species, generation and storage conditions.
Approximately 1 mL of blood was collected into EDTA-coated tubes and maintained on wet ice or refrigerated until shipment for analysis of the following hematologic parameters: erythrocyte count (RBC), hematocrit (HCT), hemoglobin (HGB), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), total leukocyte count (WBC), differential leukocyte count, platelet count (PLAT), mean platelet volume (MPV) and cell morphology. Two blood smear slides were prepared at the Testing Facility for each sample for measurements of differential leukocyte count.
Approximately 1.8 mL of blood was added to a tube containing 0.2 mL of sodium citrate (0.129 M). The contents were mixed and maintained on wet ice until the tubes were centrifuged (within 30 minutes of the collection time). The resulting plasma was transferred to 2.0 mL polypropylene tubes and immediately frozen. Plasma samples were maintained on dry ice or in a freezer (<-70C) until shipment for measurement of prothrombin time (PT) and activated partial thromboplastin time (APTT).
Approximately 2 mL of blood was collected into serum separator tubes and centrifuged. The resulting sera samples were immediately frozen on dry ice and maintained frozen (<-70C) until shipment for analysis of the following parameters: total protein (TP), triglycerides (TRI), albumin (A), globulin (G), albumin/globulin Ratio (A/G), glucose (GLU), cholesterol (CHOL), total bilirubin (TBILI), urea nitrogen (BUN), creatinine (CREAT), creatinine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALK), calcium (CA), phosphorus (PHOS), sodium (NA), potassium (K) and chloride (CL).
Samples for hematology and clinical chemistry analyses were shipped to Redfield Laboratories, A Division of CRL-DDS, Redfield, Arkansas. Samples were shipped on dry ice and slides were shipped at ambient conditions. Results of these analyses are available in APPENDIX K.
Female rats that did not deliver a litter were sacrificed on DG 25. Gross necropsy, examination and tissue retention were conducted as described above for rats at scheduled sacrifice. Gross lesions were preserved in neutral buffered 10% formalin for possible future evaluation. Representative photographs of gross lesions are available in the raw data.
a. See APPENDIX E, item 1.
418-028:PAGE 2-17
2.7.6.2. FI Generation Pups
On DL 22, pups were sacrificed by carbon dioxide asphyxiation and examined for gross lesions. Necropsy included a single cross-section of the head at the level of the frontal parietal suture and examination of the cross-sectioned brain for apparent hydrocephaly. Gross lesions were preserved in neutral buffered 10% formalin for possible future evaluation. Representative photographs of gross lesions are available in the raw data.
Blood samples were collected from each selected pup (five per sex per litter from the 10 female rats per group selected for FOB and motor activity assessment, blood sample collection for hematology and clinical chemistry and histological evaluations) from the vena cava. The blood was placed into tubes, pooled per litter, allowed to clot and spun in a centrifuge; the resulting serum was transferred into labeled polypropylene tubes. All samples were immediately frozen on dry ice and maintained frozen (<-70C) until shipment for analysis. The liver from each selected pup was excised and the organ weight recorded3. The median lobe was frozen and stored (<-20C) until shipment for possible analysis. The remaining portion of each liver was retained in neutral buffered 10% formalin for possible histological evaluation. The livers were processed and evaluated histologically as described for the Fo generation rats.
Pups that died before initial examination of the litter for pup viability were evaluated for vital status at birth. The lungs were removed and immersed in water. Pups with lungs that sink were identified as stillborn; pups with lungs that float were identified as livebom, and to have died shortly after birth. Pups found dead were examined for gross lesions and for the cause of death.
2.7.7. Data Collection and Statistical Analyses
Data generated during the course of this study were recorded either by hand or using the A rgu s A u tom ated D a ta C ollection a n d M an agem en t System , the Vivarium T em perature a n d R elative H um idity M on itorin g System , the C ou lbou m Instrum ents P a ssive Infrared M otor A ctivity S ystem , the C ou lbou m Instrum ents A u ditory Startle System , the C ou lboum Instrum ents S p a tia l D e la yed A ltern ation System , and/or the passive avoidance software. All data were tabulated, summarized and/or statistically analyzed using the A rgu s A u to m a ted D a ta C o llectio n a n d M an agem en t System , the Vivarium T em perature a n d R ela tive H u m id ity M o n ito rin g System , M ic ro so ft E xcel [part of Microsoft Office 97 (version SR-2)] and/or The SAS System (version 6.12).
a. See A PPEN D K E, item 9.
418-028:PAGE 2-18
Averages and percentages were calculated. Litter values were used where appropriate. The following schematic represents the statistical analyses of the data:
I. Parametric
A. Bartlett's T e s t c
Type of Test3
II. Nonparametricb
A. Kruskal-W allis Test
(<.75% tie s at a n y c o n c e n tra tio n )
S ig n ific a n t at p<.0.001
Not Significant
S ig n ifica n t at p<.0.05
Not Significant
Nonparam etric
A nalysis of Variance
S ignificant at ps.0.05 Dunnett's T est
Not Significant
D unn's Test
B. Fishe r's Exact T e st on Proportion of Ties
(>75% tie s at an y con ce n tra tio n)
B . A n a ly s is of V a ria n c e with R e p e a te d M e a s u re s
Significant at ps.0.05
Not Significant
(Dosage) Dunnett's T est
(D osage x B lo ck Interaction) One-way A N O V A for each block
Significant at ps0.05
I
Not Significant
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 /?<0.01. b. Proportion data are not included in this category. c. Test for homogeneity of variance.
418-028:PAGE 2-19
Adult data was evaluated with the individual rat as the unit measured. Litter values were used in evaluation of pup data, as appropriate.
Variables with interval or ratio scales of measurement, such as body weights, feed consumption values, latency and errors per trial scores in behavioral tests and percent mortality per litter were analyzed as described under the Parametric heading of the schematic. Bartlett's Test of Homogeneity of Variances(14) was used to estimate the probability that the dosage groups have different variances. A non-significant result (p>0.001) indicated that an assumption of homogeneity of variance was not inappropriate, and the data was compared using the Analysis of Variance0 5). If that test was significant (><0.05), the groups given the test substance were compared with the control group using D unnetf s Test(16). If Bartlett's Test was significant (><0.001), the Analysis of Variance Test was not appropriate, and the data was analyzed as described under the Nonparametric heading of the schematic. When 75% or fewer of the scores in all the groups were tied, the Kruskal-Wallis Test(17) was used to analyze the data, and in the event of a significant result (><0.05), Dunn's Test(18) was used to compare the groups given the test substance with the control group. When more than 75% of the scores in any dosage group were tied, Fisher's Exact Test(19) was used to compare the proportion of ties in the groups.
Data from the motor activity test, with measurements recorded at intervals (Blocks) throughout each test session, were analyzed using an Analysis of Variance with Repeated Measures(20), as described under that heading in the schematic. A significant result (><0.05) in that test could have appeared as effect of Concentration (differences among dosage groups in the totals of all measurements in a session) or as an interaction between Concentration and Block (differences in the patterns of dosage group values across the measurement periods). If the Concentration effect was significant, the totals for the control group and the groups given the test substance were compared using Dunnett's Test(16). If the Concentration x Block interaction was significant, an Analysis of Variance(15) was used to evaluate the data at each measurement period, and a significant result (><0.05) was followed by a comparison of the dosage groups using Dunnett's Test(16).
Variables that had graded or count scores, such as litter size, the number of trials to a criterion in a behavioral test or the day a developmental landmark appeared, were analyzed using the procedures described under the Nonparametric heading of the schematic.
Clinical observation incidence data, as well as the descriptive and quantal data from the FOB, were analyzed as contingency tables using the Variance Test for Homogeneity of the Binomial Distribution(21).
Sperm motility data were expressed as percentages and analyzed, as indicated above, by parametric methods.
418-028:PAGE 3-1
3. RESULTS - Male Rats
3.1. Mortality, Clinical and Necropsy Observations (Summaries - Tables B1 and B2; Individual Data - Tables B17 and B18)
3.1.1. Mortality
All male rats survived to scheduled sacrifice.
3.1.2. Clinical Observations
All clinical observations were considered unrelated to the test substance because: 1) the incidences were not dosage-dependent; and/or 2) the observation occurred in only one or two male rats in any dosage group. These observations included chromorhinorrea, missing/broken or misaligned incisors, chromodacryorrhea, lacrimation, localized alopecia on the head, underside or limbs, dry, brown perioral substance, soft or liquid feces, scab on head and dehydration.
3.1.3. Necropsy Observations
All necropsy observations were considered unrelated to the test substance because the incidences were not dosage-dependent; and/or 2) the observation occurred in only one or two male rats in any dosage group. These observations included discolored/mottled kidneys, slight pelvic dilation of the left kidney, small epididymides, small testes and diverticulum jejunum.
3.1.4. Histopathology (APPENDIX J)
No treatment-related microscopic changes were observed in any of the male rats administered 0.3 or 1 mg/kg/day of the test substance. Treatment-related microscopic changes were observed in the liver and thyroid gland of male rats in the 3 and 10 mg/kg/day dosage groups. The treatment-related microscopic changes in the liver consisted of minimal to moderate enlargement (hypertrophy) of centrilobular hepatocytes. The affected hepatocytes were enlarged with an increased amount of dense eosinophilic granular cytoplasm.
The treatment-related microscopic changes in the thyroid gland consisted of an increased incidence of the male rats in the 3 and 10 mg/kg/day dosage groups with hypertrophy (enlargement) of follicular cells and hyperplasia (increased follicular cells and small follicles). Although the incidence in the 10 mg/kg/day dosage group was minimally increased over the control group values, the hypertrophy and hyperplasia could have been associated with the liver-cell changes.
418-028:PAGE 3-2
3.2. Terminal Body Weights and Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight and Brain Weight (Summaries Tables B3 through B5; Individual Data - Tables B19 and B20)
Terminal body weights of the male rats were slightly reduced (approximately 6%), albeit not significantly, in the 10 mg/kg/day dosage group, as compared with control group values.
The absolute weights of the liver, the ratios of the liver weights to terminal body weights and ratios of the liver weights to brain weight were significantly increased (p<0.05 and/or p<0.01) in the 3 and 10 mg/kg/day dosage groups, as compared with the control group value. The ratio of the heart weights to brain weight was significantly decreased (p<0.05) in the 10 mg/kg/day dosage group, as compared with the control group value.
The absolute and relative (terminal body and brain) weights of the male reproductive organs (left and right epididymes, left cauda epididymes, left and right testes, seminal vesicles with and without fluid and prostate), brain, left and right kidneys and adrenals, spleen, thymus and heart (except relative heart weight as described above) were comparable across dosage groups and did not differ significantly.
3.3. Hematology and Clinical Chemistry (Summaries - Tables B6 and B7; Individual Data - APPENDIX K)
Hemoglobin concentrations (HGB) were significantly decreased (p<0.05 or p<0.01) in the 1, 3 and 10 mg/kg/day dosage groups and average values for red blood cells (RBC) and hematocrit (HCT) were significantly decreased (p<0.05 or p<0.01) in the 3 and 10 mg/kg/day dosage groups, as compared with the control group values. Prothrombin time (PT) was significantly increased (p<0.05 or p<0.01) in the 0.3, 3 and 10 mg/kg/day dosage groups.
Dosages of the test substance as high as 10 mg/kg/day did not affect mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelets (PLAT), mean platelet volume (MPV), volume, white blood counts (WBC), activated partial thromboplastin time (APTT), nucleated red blood cell count (NRBC), lymphocytes, segmented neutrophils, bands, monocytes, eosinophils, basophils and abnormal lymphocytes in male rats. These values were comparable among the four dosage groups and did not differ significantly.
Average values for cholesterol (CHOL) were significantly decreased (p<0.05 or p<0.01) in the 0 .3 ,1 ,3 and 10 mg/kg/day dosage groups and the average values for triglycerides (TRIG) was significantly decreased (p<0.01) in the 10 mg/kg/day dosage group. Albumin (A), blood urea nitrogen (BUN), alkaline phosphatase (ALK), calcium (CA) and albumin/globulin ratio (A/G) levels were significantly increased (p<0.01) in the 10 mg/kg/day dosage group.
Clinical chemistry values for total protein (TP), glucose (GLU), total bilirubin (TBILI), creatinine (CREAT), creatinine kinase (CK), alanine aminotransferase (ALT), aspartate
418-028:PAGE 3-3
aminotransferase (AST), phosphorus (PHOS), sodium (NA), potassium (K), chloride (CL) and globulin (G) in male rats were comparable among the four dosage groups and did not differ significantly.
3.4. Body Weights and Body Weight Changes (Figure 1; Summaries *Tables B8 and B9; Individual Data - Table B21)
Body weight gains were significantly reduced (p<0.05 or p<0.0l) in the 0.3, 3 and 10 mg/kg/day dosage groups on study days (DSs) 29 to 36. As a result of these reductions, significantly reduced (p<0.05 or p<0.01) body weight gain occurred in the 0.3, 1, 3 and 10 mg/kg/day dosage groups on study days DS 29 to termination. Body weight gain was also significantly reduced (p<0.01) for the 10 mg/kg/day dosage group for the entire dosage period (calculated as DS 1 to termination).
3.5. Absolute (g/day) and Relative (g/kg/day) Feed Consumption Values (Summaries - Tables B10 and B ll; Individual Data - Table B22)
Absolute (g/day) and relative (g/kg/day) feed consumption values for the male rats were unaffected by dosages of the test substance as high as 10 mg/kg/day.
3.6. Mating and Fertility (Summary - Table B12; Individual Data - Table B23)
All mating and fertility parameters (numbers of days in cohabitation, rats that mated, fertility index, rats with confirmed mating dates during the first and second week of cohabitation and the number of pregnant rats per number of rats in cohabitation) were unaffected by dosages of the test substance as high as 10 mg/kg/day.
3.7. Functional Observational Battery (Summary - Table B13; Individual Data - Table B24)
Home cage behavior of sleeping and immobile/awake were significantly different (p<0.01) in the 3 mg/kg/day dosage group, compared to the control group. These increases were not considered treatment-related because they were not dosage-dependent.
There were no other statistically significant or biologically important differences among the four dosage groups in the measures of the functional observational battery (FOB). There were no alterations in autonomic functions (lacrimation, salivation, palpebral closure, prominence of the eye, pupillary reaction to light, piloerection, respiration, defecation and urination), sensorimotor functions [responses to visual, auditory, tactile and painful stimuli (reactivity and sensitivity)], excitability (reactions to handling and behavior in the open field), gait and sensorimotor coordination (gait pattern in the open field, severity of gait abnormalities, air righting reaction and landing foot splay) and forelimb and hindlimb grip strength and abnormal clinical observations including but not limited to: convulsions, tremors, unusual behavior, hypotonia or hypertonia, emaciation, dehydration, unkempt appearance and deposits around the eyes, nose or mouth.
418-028:PAGE 3-4
Body weights recorded during the functional operational battery for the treated groups were not significantly different than the control group for the male rats.
3.8. Motor Activity (Figures 3 and 4; Summary - Table B14; Individual Data - Table B25)
There were no statistically significant or biologically important differences among the five dosage groups in the number of movements or time (in seconds) spent in movement measures of motor activity on DSs 36 through 39.
3.9. Sperm (Summary - Tables B15 and B16; Individual Data Tables B26 and B27)
3.9.1. Sperm Motility
Sperm motility was unaffected by dosages of the test substance as high as 10 mg/kg/day. Group mean values were comparable among the five dosage groups and ranged from 85.5% to 93.2% motile sperm.
3.9.2. Sperm Count and Sperm Density
The sperm count and sperm density were comparable among the five dosage groups. No treatment-related differences were observed.
3.9.3. Sperm Morphology
A low incidence of head and/or tail abnormalities was observed for the male rats in all dosage groups. No treatment-related differences were observed.
418-028 PAGE 4-1
4. RESULTS - Female Rats
4.1. Mortality, Clinical and Necropsy Observations (Summaries - Tables C l and C2; Individual Data - Tables C28 and C29)
4.1.1. Mortality
All female rats survived to scheduled sacrifice.
4.1.2. Clinical Observations
All clinical observations were considered unrelated to the test substance because: 1) the incidences were not dosage-dependent; and/or 2) the observation occurred in only one female rat in any dosage group except for localized alopecia which is a common finding in rats that are allowed to deliver. These observations included brown perioral substance, rales, localized alopecia on the limbs, back or head, urine-stained abdominal fur, miosis, abdominal distention, emaciation, cold to touch, swollen nose, scab or ulceration on back or head, dehydration and tip of tail missing.
4.1.3. Necropsy Observations
All necropsy observations were considered unrelated to the test substance because: 1) the incidences were not dosage-dependent; and/or 2) the observation occurred in only one female rat in each of the 1, 3 and 10 mg/kg/day dosage groups. These observations included the cortex of the right kidney adhered to the right lateral liver lobe in a 1 mg/kg/day dosage group female rat (19907), small left ovaries (0.003g) in one 3 mg/kg/day dosage group female rat (19051) that was not pregnant, outer capsule of spleen adhered to the omentum in another 3 mg/kg/day dosage group female rat (19063) and the large and small intestines distented with gas, small spleen and thymus, large adrenals, and approximately 12 black areas (pinpoint to 0.3 cm) on the fundic mucosal surface of the stomach in a 10 mg/kg/day dosage group female rat (19020).
4.1.4. Histopathology (APPENDIX J) No treatment-related microscopic changes were observed in any of the female rats administered up to 10 mg/kg/day of the test substance.
There were no treatment-related microscopic changes observed in the liver of the F I generation pups from the dams given up to 10 mg/kg/day of the test article. There were a few microscopic changes observed in the various organs and tissues which were considered to have occurred spontaneously and not to be treatment-related.
418-028:PAGE 4-2
4.2. Terminal Body Weights, Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight and Brain Weight and Primordial Follicle Counts (Summaries - Tables C3 through C5; Individual Data Tables C30 through C32)
Terminal body weights of the female rats were comparable among dosage groups and did not differ significantly.
The absolute and relative weights (to terminal body and to brain weight) of the female reproductive organs (left and right ovaries and uterus with cervix), brain, liver, left and right kidneys and adrenals, spleen, thymus and heart were comparable across dosage groups and did not differ significantly (except on one occasion). The ratio of the left kidney to the brain weight of the female rats in the 3 mg/kg/day dosage group was significantly increased (p<0.05) over the corresponding control group value. This significant finding was not considered treatment-related because: 1) the incidence was not dosage-dependent; and/or 2) the observation was a single occurrence.
Average primordial follicle counts for the 10 mg/kg/day dosage group were comparable to the control group and did not differ significantly.
4.3. Hematology and Clinical Chemistry (Summaries - Tables C6 and C7; Individual Data - APPENDIX K)
Dosages as high as 10 mg/kg/day did not affect any hematology or clinical chemistry values evaluated. Average values for red blood cells (RBC), white blood cells (WBC), hemoglobin concentration (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelets (PLAT), mean platelet volume (MPV), prothrombin time (PT), activated partial thromboplastin time (APTT), nucleated red blood cell count (NRBC), lymphocytes, segmented neutrophils, bands, monocytes, eosinophils, basophils, abnormal lymphocytes in female rats were comparable among the five dosage groups and did not differ significantly (except on one occasion). The concentration of WBCs (lymphocytes) for of the female rats in the 0.3 mg/kg/day dosage group was significantly increased (p<0.05) over the corresponding control group value. This significant finding was not considered treatment-related because: 1) the incidence was not dosage-dependent; and/or 2) the observation was a single occurrence.
Average values for total protein (TP), albumin (A), glucose (GLU), cholesterol (CHOL), total bilirubin (TBILI), blood urea nitrogen (BUN), creatinine (CREAT), creatinine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALK), calcium (CA), phosphorus (PHOS), triglycerides (TRIG), sodium (NA), potassium (K), chloride (CL), globulin (G) and albumin/globulin ratio (A/G) in female rats were comparable among the five dosage groups and did not differ significantly (except on two occasions). The concentration of G was significantly decreased (p<0.01) and the concentration of A/G was significantly increased (p<0.01) for of the female rats in the 0.3 mg/kg/day dosage group over the corresponding control group values. These significant findings were not considered treatment-related because:
418-028:PAGE 4-3
1) the incidences were not dosage-dependent; and/or 2) the observations were a single occurrence for both parameters.
4.4. Body Weights and Body Weight Changes (Figure 2; Summaries Tables C8 through C13; Individual Data - Tables C33 through C35)
4.4.1. Precohabitation
Body weights and body weight gains were comparable and did not differ significantly during the precohabitation period at dosages of the test substance up to 10 mg/kg/day.
4.4.2. Gestation
Body weights and body weight gains were comparable and did not differ significantly during the gestation period at dosages of the test substance up to 10 mg/kg/day.
4.4.3. Lactation
Body weight gains were not significantly affected by dosages of the test substance up to 10 mg/kg/day during lactation.
Body weights were significantly reduced (p<0.05 or p<0.01) on days of lactation (DLs) 4, 6 through 8,11 and 13 in the 0.3 mg/kg/day dosage group, DLs 7 and 8 in the 3 mg/kg/day dosage group, DLs 4, 6 through 9,1 1 ,1 3 and 14 in the 10 mg/kg/day dosage group. These significant findings were not considered treatment-related because they were not dosage-dependent or they did not persist.
4.5. 4.5.1.
Absolute (g/day) and Relative (g/kg/day)Feed Consumption Values (Summaries - Tables C14through C19; Individual Data Tables C36 through C38)
Precohabitation
Absolute (g/day) and relative (g/kg/day) feed consumption values were not significantly affected by dosages of the test substance up to 10 mg/kg/day during the precohabitation period.
4.5.2. Gestation
Absolute (g/day) and relative (g/kg/day) feed consumption values were not significantly affected by dosages of the test substance up to 10 mg/kg/day during the gestation period.
4.5.3. Lactation
Absolute and relative feed consumption values were not affected by dosages of the test substance up to 10 mg/kg/day during lactation.
418-028:PAGE 4-4
Absolute feed consumption values were significantly reduced (p<0.05 or p<0.0l) on DLs 1 to 5 and 8 to 15 in the 0.3 mg/kg/day dosage group, DLs 1 to 5 and 8 to 15 in the 3 mg/kg/day dosage group and DLs 8 to 15 in the 10 mg/kg/day dosage group. Relative feed consumption values were significantly reduced (p<0.01) on DLs 1 to 5 in the 0.3 mg/kg/day and DLs 5 to 8 in the 3 mg/kg/day dosage group. These significant findings were not considered treatment-related because they were not dosage-dependent and they did not persist.
4.6. Estrous Cycling, Mating and Fertility (Summary - Table C20; Individual Data - Table C39)
The average numbers of estrous stages per 13 days were comparable among the five dosage groups and did not significantly differ. The number of rats with six or more consecutive days of diestras or estras did not differ significantly.
All mating and fertility parameters (numbers of days in cohabitation, rats that mated, fertility index, rats with confirmed mating dates during the first and second week of cohabitation and the number of pregnant rats per number of rats in cohabitation) were unaffected by dosages of the test substance as high as 10 mg/kg/day.
4.7. Functional Observational Battery (Summary - Table C21; Individual Data - Table C40)
There were no statistically significant or biologically important differences among the five dosage groups in the measures of the functional observational battery (FOB). There were no alterations in home cage behavior, autonomic functions (lacrimation, salivation, palpebral closure, prominence of the eye, pupillary reaction to light, piloerection, respiration, defecation and urination), sensorimotor functions [responses to visual, auditory, tactile and painful stimuli (reactivity and sensitivity)], excitability (reactions to handling and behavior in the open field), gait and sensorimotor coordination (gait pattern in the open field, severity of gait abnormalities, air righting reaction and landing foot splay) and forelimb and hindlimb grip strength and abnormal clinical observations including but not limited to: convulsions, tremors, unusual behavior, hypotonia or hypertonia, emaciation, dehydration, unkempt appearance and deposits around the eyes, nose or mouth.
Body weights recorded during the functional operational battery for the treated groups were not significantly different than the control group for the female rats.
4.8. Motor Activity (Figures 5 and 6; Summary - Table C22; Individual Data - Table C41)
There were no statistically significant or biologically important differences among the five dosage groups in the measures of number of movements or time (in seconds) spent in movement motor activity on DL 17.
418-028.-PAGE 4-5
4.9. Natural Delivery and Litter Observations (Summary - Tables C23 and C24; Individual Data - Tables C42 through C45)
Pregnancy occurred in all 15 (100%) rats assigned to the 0 (Vehicle), 0.3 and 10 mg/kg/day dosage groups and 13 (88.7%) of the rats assigned to the 1 and 3 mg/kg/day dosage groups. All pregnant dams delivered a litter of one or more livebom pups. Values for the numbers of dams that delivered litters, the duration of gestation (calculated in days), averages for implantation sites per delivered litter, the numbers of dams with stillborn pups, the numbers of dams with no livebom pups, dams with all pups dying days 1 to 4 and 5 to 22, were comparable among the five dosage groups and did not significantly differ. The number of livebom pups, the number of pups found dead or presumed cannibalized on day 1, and days 2 to 8 ,9 to 15 and 16 to 22 postpartum were comparable among the five dosage groups and did not significantly differ.
The gestation index (number of dams with one or more livebom pups per number of pregnant rats), viability index (number of live pups on DL 8 per number of livebom pups on DL 1) and lactation index (number of live pups on DL 22 per number of livebom pups on DL 8) were compared to the control group value and did not differ significantly.
The number of pups surviving per litter, pup sex ratios, litter size and pup body weights per litter on DLs 1, 8,15 and 22 were comparable among the five dosage groups and did not significantly differ.
4.10.
Pup Clinical and Necropsy Observations (Summary - Tables C25 and C26; Individual Data - Tables C46 and C47)
No clinical or necropsy observations in the F I generation pups were attributable to dosages of the test substance as high as 10 mg/kg/day because: 1) the incidences were not dosage-dependent; and 2) the observation occurred in only one to two litters. These clinical observations included: not nursing, emaciation, dehydration, whole body discolored purple, scab, cold to touch, left eye discolored purple, right eye enlarged, laceration on right hindlimb, bruise on back, not nesting, pale in appearance and comeal opacity of right eye. Necropsy observations of 228, 203, 196, 172 and 211 pups in the five respective dosage groups on postpartum days 5 and 22 were limited to moderate dilation of the renal pelvis of one pup from a 0.3 mg/kg/day dosage group litter.
4.11.
Pup Liver Weight and Ratio of Liver Weight to Terminal Body Weight (Summary - Table C27; Individual Data - Table C48)
FI generation male and female pup terminal body weights, absolute liver weight (by sex) and ratio of liver weight to terminal body weight (by sex) were comparable across all five dosage groups and did not differ significantly.
418-028:PAGE 4-6
REFERENCES
1. Sanders, J.E., Eigenberg, D.A., Bracht, L.J., Wang, W.R., and Zwieten, M.J. (1988): Thyroid and liver trophic changes in rats secondary to liver microsomal enzyme induction caused by an experimental leukotriene antagonist (L-649,923). Toxicology and Pharmacology, 95: 378-387.
2. Organisation for Economic Co-operation and Development (1996). OECD Guideline fo r Testing o f Chemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996.
3. Organisation for Economic Co-operation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final].
4. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58.
5. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standardfo r Safety Studies on Drugs, METW Ordinance Number 21, March 26, 1997.
6. Christian, M.S. and Voytek, P.E. (1982). In Vivo Reproductive and Mutagenicity Tests. Environmental Protection Agency, Washington, D.C. National Technical Information Service, U.S. Department of Commerce, Springfield, VA 22161.
7. 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.
8. Lang, P.L. (1988). Embryo and Fetal Developmental Toxicity (Teratology) Control Data in the Charles River Crl:CDBR Rat. Charles River Laboratories, Inc., Wilmington, MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.)
9. Institute of Laboratory Animal Resources (1996). Guidefo r the Care and Use o f Laboratory Animals. National Academy Press, Washington, D.C.
10. Haggerty, G.C. (1989). Development of Tier I neurobehavioral testing capabilities for incorporation into pivotal rodent safety assessment studies. J. Amer. Col. Toxicol. 8:53-70.
11. Irwin, S. (1968). Comprehensive observational assessment: la. A systemic quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia (Berlin) 13:222-257.
12. Moser, V.C. (1989). Screening approaches to neurotoxicity: Afunctional observational battery. J. Amer. Col. Toxicol. 8:85-94.
418-028:PAGE 4-7
13. O'Donoghue, J.L. (1989). Screening for neurotoxicity using a neurologically based examination and neuropathology. J. Amer. Col. Toxicol. 8:97-116.
14. 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.
15. Snedecor, G.W. and Cochran, W.G. (1967). Analysis of Variance. Statistical Methods, 6th Edition, Iowa State University Press, Ames, pp. 258-275.
16. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1121.
17. Sokal, R.R. and Rohlf, F.J. (1969). Kruskal-Wallis Test. Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389.
18. Dunn, O.J. (1964). Multiple comparisons using rank sums. Technometrics 6(3):241-252.
19. Siegel, S. (1956). Nonparametric Statistics fo r the Behavioral Sciences. Fisher's Exact. McGraw-Hill Co., New York, pp. 96-105.
20. SAS Institute, Inc. (1988). Repeated measures analysis of variance. SAS/STATYU User's Guide, Release 6.03 Edition, Cary, NC, pp. 602-609.
21. 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.
APPENDIX A REPORT FIGURES
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
BODY WEIGHTS
Fo GENERATION MALE RATS Figure 1
320 T 1
0 MG/KG/DAY
0.3 MG/KG/DAY
1 MG/KG/DAY
3 MG/KG/DAY
-X
10 MG/KG/DAY
a. Last value recorded
before cohabitation. b. First value recorded
after cohabitation. c. Terminal body weight.
T i"
8 14a 29b 36 43
c
DAY OF STUDY
418-028:PAGE A-
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
BODY WEIGHTS
Fo GENERATION FEMALE RATS Figure 2
I
--V
0 MG/KG/DAY
0.3 MG/KG/DAY
1 MG/KG/DAY
3 MG/KG/DAY
--K
10 MG/KG/DAY
a. Last value recorded before cohabitation.
[ *p<0.05 |
I **p<0.01 I
418-028 :PAGE A-i
tj
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
MOTOR ACTIVITY - NUMBER OF MOVEMENTS - Fo GENERATION MALE RATS
Figure 3
80 - t-------------------------------------------------------------------------------------------
0 MG/KG/DAY
-- --
0.3 MG/KG/DAY
-- o --
1 MG/KG/DAY -- -3 MG/KG/DAY
-X
10 MG/KG/DAY
10
0 10 20 30 40 50 60 70 80 90 100
TIME (MINUTES)
418-028:PAGE A-3
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
MOTOR ACTIVITY - TIME SPENT IN MOVEMENT - Fo GENERATION MALE RATS
Figure 4
250 -- --------------------------------------------------------------------------------------------------------------
0 MG/KG/DAY
0.3 MG/KG/DAY
1 MG/KG/DAY
3 MG/KG/DAY --10 MG/KG/DAY
0 0 20 40 60 80 100 TIME (MINUTES)
418-028:PAGE A-4
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
MOTOR ACTIVITY - NUMBER OF MOVEMENTS - Fo GENERATION FEMALE RATS
Figure 5
0 MG/KG/DAY
0.3 MG/KG/DAY
1 MG/KG/DAY
3 MG/KG/DAY
--X --
10 MG/KG/DAY
418-028 :PAGE A-5
TIME (MINUTES)
100
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
MOTOR ACTIVITY - TIME SPENT IN MOVEMENT - Fo GENERATION FEMALE RATS
Figure 6
0 MG/KG/DAY 0.3 MG/KG/DAY 1 MG/KG/DAY 3 MG/KG/DAY
X
10 MG/KG/DAY
100
418-028-.PAGE A-6
APPENDIX B REPORT TABLES - Fo GENERATION MALE RATS
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-770G WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B1 (PAGE 1) : CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III IV
0 0.3
13
MAXIMUM POSSIBLE INCIDENCE
680/ 15
680/ 15
680/ 15
680/ 15
MORTALITY
0 0 00
CHROMORHINORRHEA
INCISORS: TOTAL MISSING/BROKEN MISALIGNED
0/ 0
2/ 1 2/ 1 0/ 0
1/ 1
0/ 0 0/ 0 0/ 0
1/ 1
0/ 0 0/ 0 0/ 0
1/ 1
13/ 1 6/ 1
13/ 1
CHROMODACRYORRHEA LACRIMATION
0/ 0 0/ 0
0/ 0 0/ 0
3/ 1 0/ 0
9/ 1 0/ 0
LOCALIZED ALOPECIA:
TOTAL HEAD UNDERSIDE LIMBS
0/ 0 0/ 0 0/ 0 0/ 0
27/ 2 16/ 1
0/ 0 11/ 1
3/ 2 0/ 0 2/ 1 1/ 1
14/ 1 14/ 1
0/ 0 0/ 0
DRY, BROWN PERIORAL SUBSTANCE
0/ 0
1/ 1
0/ 0
0/ 0
SOFT OR LIQUID FECES
0/ 0
1/ I
0/ 0
0/ 0
HEAD: SCAB
8/ 1
0/ 0
0/ 0
0/ 0
DEHYDRATION
7/ 1
0/ 0
0/ 0
0/ 0
STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS. MAXIMUM POSSIBLE INCIDENCE = (DAYS X RATS)/NUMBER OF RATS EXAMINED PER GROUP. N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION.
V 10
680/ 15
0
2/ 2
13/ 1 13/ 1
0/ 0
2/ 1
1/ 1
0/ 0 0/ 0 0/ 0 0/ 0
0/ 0
0/ 0
0/ 0
0/ 0
418-028:PAGE B-
PROTOCOL 418-028 : ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B2 (PAGE 1) : NECROPSY OBSERVATIONS - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III IV
0 0.3
13
RATS EXAMINED a
N 15
15
15 15
MORTALITY
N0 0 0 0
APPEARED NORMAL
N 14
12
15 14
KIDNEYS:
BILATERAL, MOTTLED, MOTTLED TAN
AND RED OR MOTTLED DARK RED N
i
2
00
LEFT, PELVIS, SLIGHT DILATION N
0
1
00
EPIDIDYMIDES:
BILATERAL, SMALL
N0
0
01
LEFT CAUDA, SMALL
N0
0
01
TESTES :
BILATERAL, SMALL
N0
0
01
JEJUNUM:
DIVERTICULUM
N0
0
00
a. Refer to the individual clinical observations table (Table B17) for external observations confirmed at necropsy.
V 10 15
0 14
0 0
0 0
0
1
PROTOCOL 418 028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B3 (PAGE 1): TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I 0
RATS TESTED
N 10
TERMINAL BODY WEIGHT
MEANS.D .
469.7 31.6
EPIDIDYMIS LEFT
MEANS.D.
0.6476 0.0367
CAUDA EPIDIDYMIS LEFT MEANS.D . 0.3308 0.0294
TESTIS LEFT
MEANS.D . 1.6591 0.0879
SEMINAL VESICLES WITH FLUID
MEANS.D . 1.7055 0.2370
SEMINAL VESICLES WITHOUT FLUID
MEANS.D.
0.8440 0.1038
EPIDIDYMIS RIGHT
MEANS.D . 0.6745 0.0424
TESTIS RIGHT
MEAN+S.D.
1.6777 0.0936
PROSTATE
MEANS.D . 1.2902 0.2968
BRAIN
MEANS.D .
2.40 0.11
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
II 0.3
10 448.8 37.8 0.6358 0.0397 0.3182 0.0266 1.7154 0.1239
1.5439 0.2672
0.8118 0.1117 0.6546 0.0409 1.7281 0.1287 1.2000 0.1297
2.44 0.11
III 1
10 455.8 55.2 0.6277 0.0505 0.3232 0.0285 1.6717 0.1646
1.6385 0.2912
0.7965 0.1068 0.6534 0.0555 1.6922 0.1642 1.2267 0.2694
2.38 0.09
IV 3
10 472.3 38.3 0.5916 0.1092 0.2913 0.0650 1.6116 0.3330
V 10 10 440.8 12.6 0.6134 0.0472 0.3041 0.0309 1.7483 0.1549
1.5473 0.3182
1.4424 0.2669
0.7670 0.1477 0.6106 0.1218 1.6175 0.3393 1.2734 0.1659 .
2.38 0.09
0.7772 0.1163 0.6261 0.0409 1.7604 0.1447 1.1918 0.2344
2.40 0.10
418-028:PAGE B-3
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B3 (PAGE 2) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II 0 0 .3
RATS TESTED
N 10
10
TERMINAL BODY WEIGHT LIVER
MEANS.D . MEANS.D.
469.7 31.6 14.63 1.81
448.8 37.8 14.22 1.58
KIDNEY LEFT
MEANS.D.
1.98 0.25
1.86 0.12
KIDNEY RIGHT
MEANS.D.
2.02 0.26
1.90 + 0.15
ADRENAL LEFT
MEANS.D.
0.035 0.007
0.035 0.007
ADRENAL RIGHT
MEANS.D.
0.034 0.006
0.034 0.006
SPLEEN
MEANS.D.
0.79 0.14
0.81 0.07
THYMUS
MEANS.D .
0.41 0.12
0.45 0.09
HEART
MEANS.D.
1.55 0.10
1.52 0.12
ALL WEIGHTS WERE RECORDED IN GRAMS (G) . * Significantly different from the Group I value (p0.05).
** Significantly different from the Group I value (p<0.01).
hi
i 10 455.8 55.2 15.94 3.56 1.96 0.26 2.00 0.24 0.034 0.005 0.030 0.007 0.76 0.12 0.36 0.10 1.54 0.13
IV 3
10 472.3 38.3 17.60 1.64*
2.04 0.17 2.13 0.18 0.032 0.006 0.032 0.007 0.88 0.19 0.42 0.09 1.60 0.13
V 10 10 440.8 12.6 22.83 2.73** 2.01 0.18 2.04 0.14 0.032 0.004 0.029 0.007 0.78 0.10 0.42 0.05 1.44 0.07
418-028:PAGEB4
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B4 (PAGE 1) : RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I 0
RATS TESTED
N 10
TERMINAL BODY WEIGHT EPIDIDYMIS LEFT CAUDA EPIDIDYMIS LEFT TESTIS LEFT SEMINAL VESICLES WITH FLUID SEMINAL VESICLES WITHOUT FLUID EPIDIDYMIS RIGHT TESTIS RIGHT PROSTATE BRAIN
MEANS.D. MEANS.D . MEANS.D . MEANS.D.
MEANS.D.
MEAN+S.D. MEANS.D . MEANS.D. MEANS.D . MEAN+S .D .
469.7 31.6 0.138 0.014 0.068 0.009 0.354 0.024
0.366 0.064
0.181 0.031 0.143 0.016 0.357 0.030 0.276 0.073 0.510 0.030
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
II 0 .3
10
448.8 37.8 0.142 0.015 0.071 0.012 0.385 0.047
III 1
10 455.8 55.2 0.138 0.018 0.071 0.007 0.370 0.041
IV 3
10 472.3 + 38.3 0.126 0.027 0.063 + 0.015 0.342 0.078
V 10 10 440.8 + 12.6 0.138 0.011 0.068 0.008 0.397 + 0.041
0.348 0.073
0.359 0.063
0.329 0.081
0.326 t 0.062
0.183 0.038 0.147 0.018 0.386 0.049 0.267 0.022 0.546 0.053
0.176 0.022
0.163 0.038
0.176 0.026
0.145 0.016
0.127 0.028
0.141 0.012
0.374 0.042
0.344 0.078
0.400 + 0.035
0.271 0.061
0.274 0.052
0.270 0.054
0.528 0.050
0.506 0.041
0.545 0.027
RATIOS (%) = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100.
418-028:PAGE B-5
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B4 (PAGE 2) : RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RATS TESTED
N
I 0
10
II 0 .3
10
TERMINAL BODY WEIGHT LIVER KIDNEY LEFT KIDNEY RIGHT ADRENAL LEFT a ADRENAL RIGHT a SPLEEN THYMUS HEART
MEANS.D. MEANS.D. MEANS.D. MEANS.D . MEANS.D . MEAN+S.D . MEANS.D. MEANS.D. MEANS.D .
469.7 31.6 3.109 0.264 0.419 0.032 0.428 0.036 7.419 1.226 7.202 1.181 0.168 0.025 0.086 0.024 0.331 0.021
448.8 37.8 3.165 0.208 0.415 0.033 0.426 0.044 7.837 1.573 7.587 1.353 0.180 0.024 0.099 0.017 0.339 0.014
ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Value was multiplied by 1000.
** Significantly different from the Group I value (p<0.01).
III IV
V
1 3 10
10 10
10
455.8 55.2
472.3 38.3
440.8 12.6
3.466 0.396
3.728 0.212**
5.190 0.702
0.429 0.030
0.433 0.025
0.456 0.042
0.441 0.030
0.450 0.032
0.463 0.034
7.427 1.196
6.929 1.461
7.280 0.836
6.603 1.636
6.788 1.503
6.6S0 1.514
0.167 0.019
0.183 0.030
0.177 0.023
0.077 0.019
0.089 0.019
0.095 0.013
0.340 0.024
0.337 0.015
0.327 0.012
RATIOS (%) = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100.
418-028:PAGE B-6
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B5 (PAGE 1) : RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I 0
RATS TESTED
N 10
BRAIN WEIGHT
MEANS.D.
2.40 0.11
EPIDIDYMIS LEFT
MEANS.D.
27.10 2.14
CAUDA EPIDIDYMIS LEFT MEANS.D .
13.83 1.28
TESTIS LEFT
MEANS.D.
69.36 4.17
SEMINAL VESICLES WITH FLUID
MEANS.D.
71.40 11.06
SEMINAL VESICLES WITHOUT FLUID
MEANS.D .
35.34 4.98
EPIDIDYMIS RIGHT
MEANtS.D.
28.22 2.23
TESTIS RIGHT
MEANS.D.
70.19 5.17
PROSTATE
MEANS.D .
54.35 14.08
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ii 0.3
10
2.44 0.11 26.11 1.77 13.05 0.96 70.39 4.40
III 1
10 2.38 0.09 26.39 1.99 13.59 1.18 70.28 6.50
IV 3
10
2.38 0.09 24.77 4.51 12.20 2.80 67.41 13.64
V 10
10
2.40 0.10 25.55 2.21 12.66 1.32 72.79 6.71
63.64 12.45
68.84 12.04
64.77 t 12.58
59.83 10.03
33.48 5.71 26.90 2.06 70.94 5.02 49.41 6.63
33.44 4.03
32.14 5.94
32.30 4.57
27.47 2.16
25.57 5.13
26.08 2.00
71.14 6.42
67.66 13.99
73.30 6.34
51.57 11.28
53.52 7.70
49.48 9.23
RATIOS (%) = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028:PAGE B-7
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-770S WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B5 (PAGE 2): RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II 0 0 .3
RATS TESTED
N 10
10
BRAIN WEIGHT LIVER KIDNEY LEFT KIDNEY RIGHT
MEAN+S.D . MEANS.D. MEANS.D . MEANS.D.
2.40 0.11 Gil.89 79.55
82.68 9.11 84.22 9.20
2.44 0.11 584.43 68.39
76.46 5.95 77.94 6.26
ADRENAL LEFT ADRENAL RIGHT SPLEEN
MEAN+S.D. MEANS.D. MEANS.D.
1.46 0.27 1.41 0.25 32.90 5.93
1.44 0.31 1.40 0.26 33.34 3.91
THYMUS HEART
MEANS.D. MEANS.D.
17.22 5.29 64.91 + 3.78
18.37 4.02 62.49 + 5.04
ALL WEIGHTS WERE RECORDED IN GRAMS (G) . * Significantly different from the Group I value (p<0.05).
** Significantly different from the Group I value (p<0.01).
III IV
V
1 3 10
10 10 10
2.38 0.09
2.38 0.09
2.40 0.10
667.08 129.02
739.11 73.28** 948.61 95.12**
82.16 9.05
85.78 7.04
83.64 + 8.05
84.13 7.94
89.26 6.52
85.00 6.56
1.42 0.24
1.36 0.25
1.34 0.18
1.26 0.33
1.34 0.26
1.23 0.29
31.83 4.39
36.64 7.27
32.44 3.96
14.93 4.04
17.75 + 3.63
17.46 2.39
64.67 4.56
66.89 + 4.77
59.97 3.51*
RATIOS (%) = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028-.PAGE B-8
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B6 (PAGE 1) : HEMATOLOGY - SUMMARY - Fo GENERATION MALE RATS (See abbreviations on the last page of this table.)
DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED
i 0 N 10
ii 0.3 10
WBC (THSN/CU MM)
MEAN S.D. 15.3 1.63
14.9 3.03
RBC (MILL/CU MM)
MEAN S.D. 7.51 0.648
7.33 0.396
HGB (GRAMS/DL)
MEAN S.D. 16.5 1.16
15.9 0.42
HCT (%)
MEAN S.D. 43.5 3.48
42.2 1.57
MCV (CU MICRONS)
MEAN S.D. 57.9 1.89
57.7 2.27
MCH (PICO GRAMS)
MEAN S.D. 22.0 0.87
21.8 1.13
MCHC (%)
MEAN S.D. 38.0 0.93
37.7 1.15
PLAT (THSN/CU MM)
MEAN S.D. 1179 130.9
1131 183.7
MPV (CU MICRONS)
MEAN t S.D. 8.1 0.52
7.9
* Significantly different from the Group I value (pSO.05).
** Significantly different from the Group I value (pSO.Ol).
0.54
III 1 10
13.8 2.84 7.32 0.441 15.7 0.59* 42.0 2.22 57.4 1.78 21.5 0.75 37.5 0.79 1115 149.2 8.2 0.72
IV 10 16.2 3.97 6.93 0.305* 15.4 0.67** 40.2 2.29** 57.9 1.15 22.2 0.45 38.4 0.80 1104 91 .4 8.2 0.76
V 10 14.7 3.07 6.99 0.442* 15.6 0.81* 40.7 1.81* 58.3 1.37 22.3 0.56 38.3 0.70 1148 159.9
418-028:PAGE B-9
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B6 (PAGE 2) : HEMATOLOGY - SUMMARY - Fo GENERATION MALE RATS (See abbreviations on the last page of this table.)
DOSAGE GROUP
I
DOSAGE (MG/KG/DAY)
0
RATS TESTED
N 10
II 0.3 10
PT (SECONDS)
MEAN t S.D. 13.4 0.24
14.2 0.27**
APTT (SECONDS)
MEAN S.D. 21.0 3.09
22.1 4.41
NRBC COUNT
MEAN S.D. 0
0.0
0 0.0
Lymphocytes (THSN/CU MM) MEAN S.D. 11.9 1.72
11.0 2.68
Segmented (THSN/CU MM)
MEAN S.D. 2.2 0.73
2.9 1.18
Bands (THSN/CU MM)
MEAN S.D. 0.0 0.00
0.0 0.00
Monocytes (THSN/CU MM)
MEAN S.D. 0.8 0.56
0.7 0.50
Eosinophils (THSN/CU MM) MEAN S.D. 0.3 0.20
0.3 0.21
Basophils (THSN/CU MM)
MEAN S.D. 0.0 0.00
0.0 0.00
Abnormal L (THSN/CU MM) MEAN S.D. 0.1 0.20
0.1 0.14
Other (THSN/CU MM)
MEAN S.D. 0.0 0 . 0 0
0 .0
* Significantly different from the Group I value (pS0.05).
** Significantly different from the Group I value (p<0.01).
0.00
III 1 10
13.6 0.23
20.6 2.38
0 0.0
10.8 2.02
2.0 1.06
0.0 0.03
0.6 0.51
0.3 0.21 0.0 0.00
0.1 0.07
0.0
t 0.00
IV
10
13.8 0.40*
21.2 2.24
0 0.0
12.1 3.57
2.8 0.73
0.0 0.03 0.8 0.67
0.3 0.26 0.0 0.00
0.2 0.22
0.0
0.00
V 10 14.0 0.47** 21.3 1.43 0 0.0 12.4 2.75 1.6 0.78 0.0 0.00 0.5 0.33 0.2 0.15 0.0 0.00 0.1 0.21
0.0
418-028-.PAGE B-10
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B6 (PAGE 3) : HEMATOLOGY - SUMMARY - Fo GENERATION MALE RATS
TABLE
TERMINOLOGY White Blood Cells (Leukocytes)
RBC Red Blood Cells (Erythrocytes)
HGB Hemoglobin
HCT Hematocrit (Packed Cell Volume) MCV Mean Corpuscular Volume
MCH Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
PLAT
Platelet Count
MPV Mean Platelet Volume
PT Prothrombin Time
APTT
Activated Partial Thromboplastin
NRBC
Nucleated Red Blood Cell Count
418-028:PAGE B-ll
Segmented
Segmented Neutrophils
Abnormal L
Abnormal Lymphocytes
Other
Other Cells
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B7 (PAGE 1) : CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION MALE RATS (See abbreviations on the last page of this table.)
DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED
N
i 0 10
ii 0.3 10
TP (G/DL)
MEAN S.D.
6.3 0.36
6.1 0.28
A (G/DL)
MEAN S.D.
4.3 0.22
4.1 0.19
GLU (MG/DL)
MEAN S.D.
145 16.8
141 26.0
CHOL (MG/DL)
MEAN S.D.
57 8.3
41 11.1**
TBILI (MG/DL)
MEAN S.D.
0.2 0.07
0.1 0.05
BUN (MG/DL)
MEAN S.D.
16 1.5
16 0.8
CREAT (MG/DL)
MEAN S.D.
0.3 0.04
0.3 0.05
CK (U/L)
MEAN S.D.
288 172.6
246 111.5
ALT (U/L)
MEAN S.D.
42 6.0
63
* Significantly different from the Group I value (p<0.05).
** Significantly different from the Group I value (p<0.01).
69.9
hi
i 10
6.3 0.33 4.3 0.15 182 58.2 46 11.6* 0.1 0.06 16 + 1.8 0.3 0.06 239 112.9 60 34.4
IV 10 6.2 0.28 4.2 0.17 162 25.2 43 13.1" 0.1 0.05 17 1.6 0.3 0.03 196 53.5 95 124.1
V 10 6.3 0.28 4.5 0.20** 165 33.7 33 7.2** 0.2 0.06 21 2.4** 0.3 0.05 243 117.4 45
418-028-.PAGE B-12
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B7 (PAGE 2) : CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION MALE RATS (See abbreviations on the last page of this table.)
DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED
N
I 0 10
II III 0.3 1 10 10
IV 3 10
V 10 10
AST (U/L) ALK (U/L) CA (MG/DL) PHOS (MG/DL)
MEAN S.D. MEAN S.D. MEAN S.D. MEAN S.D.
96 22.4 105 14.3 10.9 0.48 9.5 1.40
121 92.6 i n 36.9 10.7 0.44 9.4 l.ii
117 40.9 100 12.4 11.1 0.44 9.9 2.09
198 248.7 115 25.1 ii.i 0.34 9.7 1.43
97 15.6 144 37.5** 11.5 0.38** 10.2 1.33
TRI (MG/DL) NA (MMOL/L)
MEAN S.D. MEAN S.D.
52 21.8 146 1.4
47 17.2 146 1.3
36 13.8 147 1.6
36 27.9 147 1.0
17 8.0** 146 2.2
K (MMOL/L)
MEAN S.D.
6.6 2.10
6.1 0.89
6.5 1.27
6.0 0.60
6.9 1.55
CL (MMOL/L) G (G/DL)
MEAN S.D. MEAN S.D.
98 2.7 2.0 0.19
99 1.5 2.0 0.16
100 2.3 2.0 0.24
100 2.7 2.0 0.16
100 1.2 1 .8 0.13
A/G (NONE)
MEAN S.D.
2.1 0.18
2.1
** Significantly different from the Group I value (p<0. 01) .
0.16
2.2 0.26
2.2 0.15
2.5 0.17**
418-028:PAGE B-13
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B7 (PAGE 3) : CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION MALE RATS
KEY TO CLINICAL CHEMISTRY TABLE
A GLU CHOL TBILI BUN CREAT ALT AST ALK CA PHOS TRI NA K CL G A/G
TERMINOLOGY Total Protein Albumin Glucose Cholesterol Total Bilirubin Blood Urea Nitrogen Creatinine Alanine Aminotransferase Aspartate Aminotransferase Alkaline Phosphatase Calcium Phosphorus Triglycerides Sodium Potassium Chloride Globulin Albumin/Globulin Ratio
418-028-.PAGE B-14
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B8 (PAGE 1) : BODY WEIGHTS - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I
0
RATS TESTED
N 15
BODY WEIGHT (G)
DAY 1 DAY 8
MEANS.D . MEANS.D.
342.7 12.6 382.7 22.2
DAY 14a
MEANS.D.
407.3 25.4
DAY 29b
MEANS.D.
456.6 38.9
DAY 36
MEANS.D .
480.2 38.2
DAY 43
MEANS.D.
490.5 37.2
TERMINAL BODY WEIGHT
MEAN+S.D.
472.5 33.9
DAY = DAY OF STUDY a. Last value recorded before cohabitation. b. First value recorded after cohabitation.
Ix
0.3 15
338.9 13.1 376.1 19.5 400.7 23.7 450.3 30.9 466.5 32.6 475.1 38.3
453.7 34.3
15
341.9 14.7 380.5 21.6 404.3 29.8 456.6 + 44.6 476.8 47.7 482.5 53.1
463.1 48.2
15
345.6 11.2 386.6 21.5 412.9 25.4 468.5 32.0 481.1 33.1 490.5 40.2
468.3 37.1
15
343.3 12.4 376.7 11.7 397.3 12.3 437.7 15.4 454.1 16.6 462.1 22.0
441.5 16.5
418-028:PAGE B-15
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B9 (PAGE 1) : BODY WEIGHT CHANGES - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RATS TESTED
BODY WEIGHT CHANGE (G)
N
I 0
15
II 0.3
15
DAYS 1 - 8
MEANS.D .
+3 9.9 12.3
+37.2 11.0
DAYS 8 - 14a
MEANS.D.
+24.7 6.8
+24.6 5.0
DAYS 1 - 14a
MEANS.D .
+64.6 16.5
+61.8 + 14.6
DAYS 29b- 36
MEANS.D .
+23.6 8.6
+16.2 7.8*
DAYS 36 - 43
MEANS.D.
+10.3 10.8
+8.7 11.2
DAYS 29bTERMINATION
MEANS.D.
+15.9 11.7
+3.4 7.9**
DAYS 1 TERMINATION
MEANS.D.
+129.8 25.5
+114.8 27.5
DAY (S) = DAY (S) OF STUDY a. Last value recorded before cohabitation. b. First value recorded after cohabitation.
* Significantly different from the Group I value (p<0.05). ** Significantly different from the Group I value (p<0.01).
III 1
15
+3 8.5 10.0 +23.8 11.1 +62.3 18.3 +20.2 5.6
+5.7 14.4
+6.5 10.1*
+121.2 37.7
IV 3
15
+41.0 + 12.1 +26.3 8.2 +67.3 + 16.3 +12.6 5.4**
+9.4 12.9
-0.2 7.7**
+122.7 30.0
V 10 15
+33.4 5.6 +20.6 4 .8 +54.0 7.0 +16.5 8.4*
+7.9 13.7
+3.8 11.8**
+98.2 13.9**
418-028:PAGE B-16
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE BIO (PAGE 1) : ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RATS TESTED
N
I 0
15
FEED CONSUMPTION (G/DAY)
DAYS 1 - 8a
MEANS.D.
28.4 3.1
DAYS 29b- 36
MEANfS.D.
30.2 2.6 t 14] C
DAYS = DAYS OF STUDY [ ] = NUMBER OF VALUES AVERAGED a. Last value recorded before cohabitation. b. First value recorded after cohabitation. c. Excludes values that were associated with spillage.
II 0.3
15
27.8 28.8
2.0 2.5
III 1
15
29.1 3.3 29.8 2.5
IV 3
15
28.8 29.3
2.6 2.8
V 10
15
26.9 28.2
1.4 2.2
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE Bll (PAGE 1): RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I 0
RATS TESTED
N 15
FEED CONSUMPTION (G/KG/DAY)
DAYS 1 - 8a
MEANS.D.
78.3 7.2
DAYS 29b- 36
MEANS.D.
64.2 3.2 [ 14] C
DAYS = DAYS OF STUDY ( ] = NUMBER OF VALUES AVERAGED a. Last value recorded before cohabitation. b. First value recorded after cohabitation. c. Excludes values that were associated with spillage.
II 0.3
15
77.7 62.8
3.9 4.5
III 1
15
80.1 64.1
6.9 4.2
IV 3
15
78.2 61.7
4.3 3.7
v 10
15
74.7 63.2
3 .3 3 .6
418-028:PAGE B-18
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B12 (PAGE 1) : MATING AND FERTILITY - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III
0 0.3
1
RATS IN COHABITATION
N 15
15
15
DAYS IN COHABITATION a
MEANS.D. 3.2 1.4
1.9 1.2
2.8 1.2
RATS THAT MATED
N(%)
14( 93.3)
15(100.0)
15(100.0)
FERTILITY INDEX b
N/N 14/ 14 (%) (100.0)
15/ 15 (100.0)
13/ 15 ( 86.7)
RATS WITH CONFIRMED
MATING DATES f
N 14 15 15
MATED WITH FIRST FEMALE c DAYS 1-7
N (%)
14(100.0)
15(100.0)
15(100.0)
RATS PREGNANT/RATS IN COHABITATION
N/N 14/ 15 <%> ( 93.3)
15/ 15 (100.0)
13/ 15 ( 86.7)
a. Restricted to rats with a confirmed mating date and rats that did not mate. b. Number of pregnancies/number of rats that mated.
c. Includes only one mating for each male rat.
IV 3
15 3.1 2.0 13( 86.7)
12/ 13 ( 92.3)
13
13(100.0)
12/ 15 ( 80.0)
V 10 15 2.5 1.4 15(100.0) 15/ 15 (100.0)
IS
15(100.0)
15/ 15 (100.0)
418-028-.PAGE B-19
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B13 (PAGE 1) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III IV 0
MALE RATS
N 10
10
10
10
V 10
HOME CAGE BEHAVIOR
1: Sleeping
N2
3
3
8** 2
2: Awake, Immobile N 8
7
7
2** 8
3: Normal movement
N0
0
0
0
0
4: Unusual posture
N0
0
0
0
0
5: Unusual behavior
N
0
0
0
0
0
ALTERATIONS (HOME CAGE) 1: None 2: Stereotyped behavior 3: Bizarre behavior 4: Limb twitches/tremor 5: Whole body tremor/spasm 6: Unusual posture 7: Tonic-clonic seizure
N N N N N N N
9 la 0 0 0 0 0
10 0 0 0 0 0 0
10 0 0 0 0 0 0
10 0 0 0 0 0 0
10 0
o
0 0 0 0
REACTION TO REMOVAL (1) Sits quietly (2) Vocalization (3) Runs or freezes (4) Tail or throat rattles
N N N N MEAN SCORE
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
REACTION TO HANDLING
(1) No resistance
N 10
(2) Vocalization
N0
(3) Tense
N0
(4) Squirming
N0
MEAN SCORE
1.0
n: = Category number for descriptive test item.
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0
10 0 0 0
(n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score and then dividing the sum of the products by the total number of rats
a. Excludes a value for rat 19131, which appeared incorrectly recorded. ** Significantly different from the Group I value (pSO.Ol).
418-028:PAGE B-20
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B13 (PAGE 2) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP
I ii III
DOSAGE (MG/KG/DAY)
0
MALE RATS
N 10
10
10
IV 10
V 10
REARS IN OPEN FIELD
MEANS.D.
3.3 2.5
6.2 3.2
3.9 1.9
4.5 2.1
4.5 3.1
DEFECATION IN OPEN FIELD
1: None
N 10
8
7
9
2 : Feces normal
N0
2
3
1
3: Soft or liquid feces
N
0
0
0
0
9 1 0
URINATION IN OPEN FIELD (1) None (2) Normal urination (3) Excess urination
N N N MEAN SCORE
6 4 0 1.4
1 9 0 1.9
6 4 0 1.4
2 8 0 1.8
3 7 0 1.7
LEVEL OF AROUSAL (1) Stuporous (2) Sluggish (3) Apparently normal (4) Sudden darting (5) Freezing, vocalization
N N N N N MEAN SCORE
0 0 10 0 0 3.0
0 0 10 0 0 3.0
0 0 10 0 0 3.0
0 0 10 0 0 3.0
0 0 10 0 0 3.0
ALTERATIONS (OPEN FIELD)
1: None 2: Stereotyped behavior 3: Bizarre behavior 4: Limb twitches/tremor 5: Whole body tremor/spasm 6: Unusual posture 7: Tonic-clonic seizure
N N N N N N N
10 0 0 0 0 0 0
10 0 0 0 0 0 0
10 0 0 0 0 0
10 0 0 0 0 0
10 0 0 0 0 0
n: Category number for descriptive test item.
(n) Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score and then dividing the sum of the products by the total number of rats
418-028:PAGE B-21
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OP T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B13 (PAGE 3): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS
1 1 1 1 1 1 1 1 1 1
is
1 1
11
1 1 1 1 1 1 1
DOSAGE GROUP
I II III
DOSAGE (MG/KG/DAY)
0
MALE RATS
N 10
10
10
10
V 10
GAIT PATTERN 1: Apparently normal 2: Ataxic 3 : Limbs splay or drag 4 : Spastic, tip-toe 5: Duck-walk 6: Scissors gait
N N N N N N
10 0 0 0 0 0
10 0 0 0 0 0
10 0 0 0 0 0
10 0 0 0 0 0
10 0 0 0 0 0
GAIT ABNORMALITY, SEVERITY (1) Normal gait (2) Slight (3) Moderate (4) Extreme
N N N N MEAN SCORE
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
PALPEBRAL CLOSURE
tu Wide open
(2) Slightly drooping
(3) Half-closed
(4) Completely shut
N N N N MEAN SCORE
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
PROMINENCE OF THE EYE
1: Normal
N 10
2 : Exophthalmos
N0
3: Enophthalmos
N0
n: Category number for descriptive test item.
10 0 0
10 0
10 0
10 0
(n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score and then dividing the sum of the products by the total number of rats
418-028:PAGEB-22
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
1f111t11111
TABLE BI3 (PAGE 4) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS
1111111I111111111 - siI1t11111111111
<
DOSAGE GROUP
I II III
DOSAGE (MG/KG/DAY)
0
MALE RATS
N 10
10
10
10
10
o
LACRIMATION
(1) No excess
N
(2) Excess at eyelid margin
N
(3) Margin persistently damp
N
(4) Extends beyond margin
N
MEANI SCORE
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
SALIVATION
(1) No excess
N
(2) Margin of mouth wet
N
(3) 1/4 to 1/2 submandibular N
(4) Entire submandibular
N
MEAN SCORE
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 o 1.0
PILOERECTION
N0
0
0
0
0
ABNORMAL RESPIRATION
N
0
0
0
0
0
APPEARANCE
(1) Clean and groomed
N
10
10
10
10
(2 ) Unkempt
N0
0
0
0
(3) Urine and/or fecal stain N
0
0
0
0
MEAN SCORE
1.0
1.0
1.0
1.0
10 0 0 1.0
VISUAL REACTION
(1) None
N0
(2) Orienting
N 10
(3) Startle
N0
(4) More energetic reaction
N
0
(5) Attacks
N0
MEAN SCORE
2.0
n: * Category number for descriptive test item,
0 10 0
0 0 2.0
0 10 0 0 0
0 10 0 0 0
0 10 0 0
o
(n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score and then dividing the sum of the products by the total number of rats
418-028:PAGE B-23
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
< 1 1 1 1 1 1 1 1 1 1 1
TABLE B13 (PAGE 5) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS
1 1 I 1
1
1
11
1 1 1
i1 s -
1 1 1 1 1 1 1 1 1 1 1 1 1
1 1 1 t 1 1 1
o
DOSAGE GROUP
I ii III
DOSAGE (MG/KG/DAY)
0
MALE RATS
N 10
10
10
10
10
TACTILE REACTION
(1) None (2) Orienting
N N
(3) Startle
N
(4) More energetic reaction
N
(5) Attacks
N
MEAN SCORE
0 10 0 0 0 2.0
0 10 0 0 0 2.0
0 10 0 0 0 2.0
0 10 0 0 0 2.0
0 10 0 0 0 2.0
AUDITORY REACTION
(1) None
N
(2) Orienting
N
(3) Startle
N
(4) More energetic reaction
N
(5) Intense vocalization
N
MEAN SCORE
0 0 10 0 0 3.0
0 0 10 0 0 3.0
0 0 10 0 0 3.0
0 0 10 0 0 3.0
0 0 10 0 0 3.0
TAIL--PINCH REACTION
(1) None
N0
(2) Orienting
N 10
(3) Startle
N0
(4) More energetic reaction
N
0
(S) Attacks
N0
MEAN SCORE
2.0
n: Category number for descriptive test item.
0 10 0 0 0 2.0
0 10 0 0 0
0 10 0 0 0
0 10 0 0 0
(n) - Score assigned to graded test- items; mean score was calculated by multiplying each score by the number of rats with that score and then dividing the sura of the products by the total number of rats
418-028:PAGE B-24
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B13 (PAGE 6) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION MALE RATS
DOSAGE (MG/KG/DAY)
I II i n n
N 10
10
10
IV 10
V 10
AIR RIGHTING RESPONSE
(1) All feet land on ground
N
(2) Lands on side
N
(3) Lands on back
N
MEAN SCORE
10 0 0 1.0
10 0 0 1.0
10 0 0 1.0
10 0 0 1.0
10 o 0 1.0
PUPIL RESPONSE TO LIGHT
N
10
10
10
10
10
FORELIMB GRIP TEST Maximum (G) Average (G)
MEANS.D. 444.0 49.6 MEANS.D. 410.S 52.7
451.5 57.5 400.6 62.7
456.0 lii.i 409.4 93.7
418.5 125.8 367.5 109.0
406.5 359.2
120.7 104.6
HINDLIMB GRIP TEST Maximum (G) Average (G)
MEANS.D. 386.0 128.8 MEANS.D. 360.9 121.8
456.0 109.4 400.8 101.1
457.0 102.5 419.5 97.8
414.5 58.9 364.5 67.5
467.5 439.4
113 .4 95.8
LANDING FOOT SPLAY Average (CM)
MEANS.D.
7.5 1.0
8.6 2.2
9.0 1.3
8.6 1.9
8.0 2 .1
BODY WEIGHT (G)
N 484.2 34.1
n: Category number for descriptive test item.
465.5 36.8
477.1 58.8
493.2
36.6
(n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score and then dividing the sum of the products by the total number of rats
418-028:PAGE B-25
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B14 (PAGE 1) : MOTOR ACTIVITY - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II 0 0.3
NUMBER OF MALE RATS
N
10
10
NUMBER OF MOVEMENTS
BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK TOTAL
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
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 MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D MEAN S.D
64.8 66.9 69.1 72.3 60.1 48.3 39.4 37.9 27.6 25.0 24.2 37.8 42.1 37.6 23.3 23.6 23.6 22.8 746.4
6.6 9.4 6.8 10.5 12.0 25.4 21.0 34.6 25.2 30.2 27.1 28.0 31.9 30.7 26.0 31.2 26.8 24.7 217.7
64.3 63.6 59.8 61.2 54.7 52.0 50.0 46.7 49.2 53.1 35.1 35.1 43.0 43.8 35.5 37.6 39.2 34.4 859.1
6.7 11.5 16.2
20.0 23.1 26.8 25.8 24.8 22.8 20.5 28.3 25.7 34.6 29.4 22.3 28.5 30.2 23.6 251.7
TOTAL SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
III IV 13
10 10
63.5 64.6 65.1 68.2 65.6 64.2 59.8 54.0 49.7 47.0 51.2 45.5 44.0 36.5 39.8 31.2 29.1 35.9 914.9
8.6 9.0 8.3 12.1 5.4 12.8 14.7 19.9 23.4 28.9 25.5 25.9 35.4 26.3 36.2 31.0 25.9 30.2 212.7
62.1 73.5 71.6 65-4 63.1 59.9 60.6 57.0 55.3 50.0 51.7 49.1 50.4 59.2 51.3 50.9 53.5 42.4 1027.0
10.0 4.4 11.7 11.9 16.5 14.9 8.2 19.4 20.4 23.1 26.7 26.0 25.6 19.0 21.1 22.7 24.3 27.0 176.0
V 10
10
64.0 69.6 67.5 56.0 56.9 57.4 56.8 49.7 52.2 49.6 41.5 47.6 43.0 43.8 43.0 42.5 37.3 34.2 912.6
8.0 7.2 7.8 11.7 15.6 t 9.9 11.5 22.2 16.9 15.6 21.2 13.0 22.3 29.6 25.4 29-4 29.6 23.1 139.0
418-028:PAGEB-26
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B14 (PAGE 2) : MOTOR ACTIVITY - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II 0 0.3
NUMBER OF MALE RATS
N
10
10
TIME (SECONDS) SPENT IN MOVEMENT
BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK TOTAL
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
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 MEAN + S.D MEAN + S.D MEAN S.D MEAN S .D MEAN S.D MEAN S.D MEAN S.D
201.1 187.4 155.5 141 .4 100.7
91.2 70.2 61.3 44.0 48.9 40.2 58.1 66.9 65.6 39.1 31.9 32.0 30.5 1466.0
24.1 22.6 t 26.2 i 33.3 28.5 54.3 44.2 60.8 46.2 68.7 i 59.5 46.2 56.7 58.7 i 49.7 45.1 i 38.5 39.6 453.9
201.8 17.8 174.4 + 32.9
140.3 + 63.3 138.3 53.0 131.1 71.4
89.7 52.6 90.2 55.5 83.7 55.9 80.9 + 40.5 86.6 40.3 71.4 63.0 67.1 60.9 86.9 82.2 75.7 + 55.9 53.1 + 46.5 55.5 47.5 62.5 56.4 47.4 46.1 1736.6 607.9
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
III 1
10
214.8 + 13.0 195.8 33.8 172.5 35.6 142.4 24.7 150.3 20.6 118 .4 41.2 110.2 46.9 109.9 52.7
93.6 59.3 77.4 55.3 86.0 49.1 91.7 62.1 52.1 44.8 54.1 + 47.4 68.0 65.3 60.3 73.9 46.9 53.5 56.3 + 54.7 1900.7 469.7
IV 3
10
204.6 180.2 140.6 140.9 119.2 109.7 118.6 116.1 103.6
83.1 97.7 81.1 80.2 107.8 74.2 87.2 91.4 66.9 2003.1
23.7 20.9 + 27.5 34.1 29.0 48.8 t 45.9 + 50.9 56.4 47.0 61.8 49.1 41.2 40.9 1 35.4 43.5 + 49.7 + 43.5 + 453.4
V 10
10
194.8 27.2 170.1 32.5 148.7 39.4 130.9 + 50.6 113.8 45.7 102.7 40.8 107.9 38.8
72.0 + 35.9 93.6 47.3 76.8 + 44.1 67.2 40.0 72.9 33.7 70.5 48.9 73.3 59.7 64.2 + 36 .9 77.1 + 60.2 51.0 44.8 54 .1 t 41.8 1 7 4 1 . 6 463.4
418-028:PAGE B-27
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B15 (PAGE 1) : SPERM MOTILITY, COUNT AND DENSITY - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III IV 0 n3
V
N 10
10
10 10 10
NUMBER MOTILE
MEANS.D.
289.1 51.3
307.4 77.3
312.0 80.2
307.3 + 149.6
325.4 81.5
MOTILE PERCENT
MEANS.D.
92.1 3.1
93.3 2.8
92.5 + 3.4
85.5 22.3
91 .1 7.4
STATIC COUNT (NONMOTILE)
MEANS.D.
25.2 11.3
23.5 14.4
23.1 7.8
32.7 15.3
32.4 23.4
TOTAL COUNT a
MEANS.D . 314.3 57.7
330.9 89.7
335.1 75.6
340.0 152.4
357.8 81.2
SPERM COUNT b
MEANS.D.
170.1 48.8
158.2 55.2
161.0 41.6
124.6 50.2
174 .5 37.9
SPERM DENSITY C MEANS.D. 1494.26 440.40 1430.20 458.01 1441.89 + 344.28 1214.68 407.71 1664.03
370.30
a. Sum of number motile and static count. Groups of five fields were evaluated until a sperm count of at least 200 was achieved""or"
20 fields were evaluated.
b. Sperm count used in the calculation of sperm density. Ten fields were evaluated.
c. The sperm density was calculated by dividing the sperm countby the volume in the image area (34.3 x 10~6 mL), multiplying by 2
(dilution factor) and multiplying by 10 to obtain the spermconcentration. The calculated sperm concentration value (rounded
to 1 decimal place) was multiplied by 50 (volume) and divided by the weight of the left cauda epididymis (see Table B19 for
the weight of the left cauda epididymis) to obtain the spermdensity. The calculated value will vary by approximately 0.8%
from the Computer Automated sperm Analysis because the digital image evaluated is slightly smaller (4 pixels) than theactual
field causing a slight underestimate of the actual volume and an overestimate of the concentration.
418-028:PAGE B-28
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE B16 (PAGE 1) : SPERM MORPHOLOGY - SUMMARY - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY) RATS TESTED NORMAL DETACHED HEAD NO HEAD BROKEN FLAGELLUM BENT FLAGELLUM PERCENT ABNORMAL
N MEANS.D. MEANS.D . MEAN+S.D . MEANS.D . MEANS.D . MEANS.D .
I 0
10 192.3 3.1
3.7 2.4 3.4 1.7 0.4 0.5 0.2 0.4 3.8 1.5
II 0 .3
10 193.3 3.0
3.6 2.2 2.1 1.2 0.8 0.8 0.2 0.4 3.4 1.5
III 1
10 193.3 3.5
3.1 2.0 2.6 1.4 0.7 + 0.7 0.3 0.7 3.4 1.8
IV 3
10 173.8 + 59.8
6.8 11.0 10.5 + 23.1
8.5 24.8 0.4 1.3 13.1 29.9
V 10 10 193.3 3.1 3 .8 2.6 1.8 1.3 1.0 + 0.9 0.1 0.3 3.4 1.6
418-028:PAGE B-29
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770G.1)
TABLE B17 (PAGE 1) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DESCRIPTION
DOSAGE GROUP I
0 MG/KG/DAY
19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167
DS ( 25- 32) DS ( 43- 44) DS ( 23- 29)
NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS HEAD: SCAB (0.5 CM IN DIAMETER) INCISORS: MISSING/BROKEN DEHYDRATION
DOSAGE GROUP II
o.:) MG/KG/DAY
19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165
19171
DS ( 23 )
DS ( 36- 46) DS ( 6 ) DS ( 11 ) DS ( 17- 32)
NO ADVERSE FINDINGS CHROMORHINORRHEA NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS SOFT OR LIQUID FECES DRY, BROWN PERIORAL SUBSTANCE LOCALIZED ALOPECIA: HEAD
DS - DAY OF STUDY a. Observation confirmed at necropsy.
418-028:PAGE B-30
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770G.1)
TABLE B17 (PAGE 2) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DESCRIPTION
DOSAGE GROUP III
1 MG/KG/DAY
19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174
DS ( 43 ) DS { 11- 13) DS ( 41 )
DS ( 46- 47)
NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: NO ADVERSE FINDINGS CHROMODACRYORRHEA NO ADVERSE FINDINGS CHROMORHINORRHEA NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: NO ADVERSE FINDINGS
LIMBS a UNDERSIDE a
DOSAGE GROUP IV
3 MG/KG/DAY
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150
19156 19160 19162 19163 19166
DS ( 41 )
DS ( 34- 39) DS ( 34- 42) DS ( 34- 46)
DS ( 19- 32)
NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS CHROMORHINORRHEA NO ADVERSE FINDINGS NO ADVERSE FINDINGS INCISORS: MISSING/BROKEN CHROMODACRYORRHEA INCISORS: MISALIGNED a NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: HEAD NO ADVERSE FINDINGS NO ADVERSE FINDINGS
DS = DAY OF STUDY a. Observation confirmed at necropsy.
418-028:PAGE B-3
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B17 (PAGE 3) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP V
RAT #
19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158
19168 19169 19170
DS( 7- 8)
DS ( 34 )
DS ( 25 ) DS ( 25- 37) DS ( 34 )
DS = DAY OF STUDY
10 MG/KG/DAY
DESCRIPTION
NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS CHROMODACRYORRHEA NO ADVERSE FINDINGS LACRIMATION NO ADVERSE FINDINGS NO ADVERSE FINDINGS CHROMORHINORKHEA INCISORS: MISSING/BROKEN CHROMORHINORRHEA NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS
418-028 :PAGE B-32
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B18 (PAGE 1) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RAT NUMBER
DAY OF
DOSES
NECROPSY ADMINISTERED OBSERVATIONS a
I
0
19109
DS 43
42 ALL TISSUES APPEARED NORMAL.
19115
DS 43
42 ALL TISSUES APPEARED NORMAL.
19116 DS 44 43 KIDNEYS: BILATERAL, MOTTLED TAN AND RED. ALL OTHER TISSUES APPEARED NORMAL.
19119 DS 44 43 ALL TISSUES APPEARED NORMAL.
19122 DS 44 43 ALL TISSUES APPEARED NORMAL.
19125 DS 45 44 ALL TISSUES APPEARED NORMAL.
19131 DS 45 44 ALL TISSUES APPEARED NORMAL.
19132 DS 45 44 ALL TISSUES APPEARED NORMAL.
19134 DS 46 45 ALL TISSUES APPEARED NORMAL.
19135 DS 46 45 ALL TISSUES APPEARED NORMAL.
19143
DS 47
46 ALL TISSUES APPEARED NORMAL.
19151 DS 47 46 ALL TISSUES APPEARED NORMAL.
19157 DS 47 46 ALL TISSUES APPEARED NORMAL.
19161 DS 47 46 ALL TISSUES APPEARED NORMAL.
19167 DS 47 46 ALL TISSUES APPEARED NORMAL.
DS = DAY OF STUDY a. Refer to the individual clinical observations table (Table B17) for external observations confirmed at necropsy.
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B18 (PAGE 2) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RAT NUMBER
DAY OF
DOSES
NECROPSY ADMINISTERED OBSERVATIONS a
II 0.3 19102 DS 43 42 KIDNEYS: BILATERAL, MOTTLED TAN AND DARK RED.
ALL OTHER TISSUES APPEARED NORMAL.
19106 DS 43 42 ALL TISSUES APPEARED NORMAL. 19108 DS 44 43 ALL TISSUES APPEARED NORMAL. 19110 DS 44 43 ALL TISSUES APPEARED NORMAL.
19113 DS 44 43 KIDNEYS: LEFT, PELVIS, SLIGHT DILATION. ALL OTHER TISSUES APPEARED NORMAL.
19120 DS 45 44 ALL TISSUES APPEARED NORMAL. 19129 DS 45 44 ALL TISSUES APPEARED NORMAL.
19136 DS 45 44 KIDNEYS: BILATERAL, MOTTLED. ALL OTHER TISSUES APPEARED NORMAL.
19138 DS 46 45 ALL TISSUES APPEARED NORMAL. 19139 DS 46 45 ALL TISSUES APPEARED NORMAL. 19147 DS 47 46 ALL TISSUES APPEARED NORMAL. 19153 DS 47 46 ALL TISSUES APPEARED NORMAL. 19164 DS 47 46 ALL TISSUES APPEARED NORMAL. 19165 DS 47 46 ALL TISSUES APPEARED NORMAL. 19171 DS 47 46 ALL TISSUES APPEARED NORMAL.
DS = DAY OF STUDY a. Refer to the individual clinical observations table (Table B17) for external observations confirmed at necropsy.
418-028:PAGE B-34
PROTOCOL 4X8-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B18 (PAGE 3) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RAT NUMBER
DAY OF
DOSES
NECROPSY ADMINISTERED OBSERVATIONS a
III 1 19101 DS 43 42 ALL TISSUES APPEARED NORMAL. 19105 DS 43 42 ALL TISSUES APPEARED NORMAL. 19107 DS 43 42 ALL TISSUES APPEARED NORMAL. 19112 DS 44 43 ALL TISSUES APPEARED NORMAL. 19114 DS 44 43 ALL TISSUES APPEARED NORMAL. 19121 DS 45 44 ALL TISSUES APPEARED NORMAL. 19123 DS 45 44 ALL TISSUES APPEARED NORMAL. 19130 DS 46 45 ALL TISSUES APPEARED NORMAL. 19137 DS 46 45 ALL TISSUES APPEARED NORMAL. 19146 DS 46 45 ALL TISSUES APPEARED NORMAL. 19155 DS 47 46 ALL TISSUES APPEARED NORMAL. 19159 DS 47 46 ALL TISSUES APPEARED NORMAL. 19172 DS 47 46 ALL TISSUES APPEARED NORMAL. 19173 DS 47 46 ALL TISSUES APPEARED NORMAL. 19174 DS 47 46 ALL TISSUES APPEARED NORMAL.
DS = DAY OF STUDY a. Refer to the individual clinical observations table (Table B17) for external observations confirmed at necropsy.
418-028:PAGE B-35
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B18 (PAGE 4) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RAT NUMBER
DAY OF
DOSES
NECROPSY ADMINISTERED OBSERVATIONS a
IV
3 19100 DS 43 42 ALL TISSUES APPEARED NORMAL. 19103 DS 43 42 ALL TISSUES APPEARED NORMAL. 19104 DS 44 43 ALL TISSUES APPEARED NORMAL. 19118 DS 44 43 ALL TISSUES APPEARED NORMAL. 19133 DS 44 43 ALL TISSUES APPEARED NORMAL. 19141 DS 45 44 ALL TISSUES APPEARED NORMAL.
19142 DS 45 44 EPIDIDYMIDES: BILATERAL, SMALL; LEFT CAUDA, SMALL. TESTES: BILATERAL, SMALL. ALL OTHER TISSUES APPEARED NORMAL.
19144 DS 45 44 ALL TISSUES APPEARED NORMAL. 19148 DS 46 45 ALL TISSUES APPEARED NORMAL. 19150 DS 46 45 ALL TISSUES APPEARED NORMAL. 19156 DS 47 46 ALL TISSUES APPEARED NORMAL. 19160 DS 47 46 ALL TISSUES APPEARED NORMAL. 19162 DS 47 46 ALL TISSUES APPEARED NORMAL. 19163 DS 47 46 ALL TISSUES APPEARED NORMAL. 19166 DS 47 46 ALL TISSUES APPEARED NORMAL.
DS = DAY OF STUDY a. Refer to the individual clinical observations table (Table B17) for external observations confirmed at necropsy.
418-028:PAGE B-36
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B18 (PAGE 5) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RAT NUMBER
DAY OF
DOSES
NECROPSY ADMINISTERED OBSERVATIONS a
V
10 19111 DS 43 42 JEJUNUM: DIVERTICULUM (1.5 CM X 0 0.4 CM) ALL OTHER TISSUES APPEARED NORMAL.
19117 DS 43 42 ALL TISSUES APPEARED NORMAL.
19124 DS 43 42 ALL TISSUES APPEARED NORMAL. 19126 DS 44 43 ALL TISSUES APPEARED NORMAL. 19127 DS 44 43 ALL TISSUES APPEARED NORMAL. 19128 DS 45 44 ALL TISSUES APPEARED NORMAL.
19140 DS 45 44 ALL TISSUES APPEARED NORMAL. 19145 DS 46 45 ALL TISSUES APPEARED NORMAL.
19149 DS 46 45 ALL TISSUES APPEARED NORMAL. 19152 DS 46 45 ALL TISSUES APPEARED NORMAL. 19154 DS 47 46 ALL TISSUES APPEARED NORMAL. 19158 DS 47 46 ALL TISSUES APPEARED NORMAL. 19168 DS 47 46 ALL TISSUES APPEARED NORMAL. 19169 DS 47 46 ALL TISSUES APPEARED NORMAL. 19170 DS 47 46 ALL TISSUES APPEARED NORMAL.
DS = DAY OF STUDY a. Refer to the individual clinical observations table (Table B17) for external observations confirmed at necropsy
418-028:PAGE B-37
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B19 (PAGE 1) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP I
0 MG/KG/DAY
RAT TERMINAL BODY NUMBER WEIGHT
EPIDIDYMIS LEFT
ABS. REL. WT. % TBW
CAUDA EPIDIDYMIS LEFT
ABS. REL. WT. % TBW
TESTIS LEFT
ABS. REL. WT. % TBW
SEMINAL VESICLES WITH FLUID
ABS. REL. WT. % TBW
SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % TBW
EPIDIDYMIS RIGHT
ABS. REL. WT. % TBW
19109 19115 19116 19119 19122 19125 19131 19132 19134 19135
438 . 466 . 490 . 505. 451. 508 . 499 . 439. 419. 482 .
0.6013 0.6976a 0.6499 0.6541 0.6661 0.6160 0.6482 0.7103 0.6278 0.6052
0.14 0.15 0.13 0.13 0.15 0.12 0.13 0.16 0.15 0.12
0.2822 0.3438 0.3209 0.3489 0.3724 0.3260 0.3140 0.3684 0.3368 0.2942
0.06 0.07 0.06 0.07 0.08 0.06 0.06 0.08 0.08 0.06
1.5706 1.6971 1.6213 1.7174 1.6754 1.6621 1.6865 1.8079 1.4601 1.6728
0.36 0.36 0.33 0.34 0.37 0.33 0.34 0.41 0.35 0.35
1.3331 2.1021 1.5369 1.6464 1.9375 1.6300 1.5772 1.9409 1.8240 1.5266
0.30 0.45 0.31 0.33 0.43 0.32 0.32 0.44 0.44 0.32
0.7867 1.0227 0.6846 0.8014 0.9217 0.7377 0.7764 0.9312 0.9106 0.8672
0.18 0.22 0.14 0.16 0.20 0.14 0.16 0.21 0.22 0.18
0.6317a 0.7252 0.6497 0.6728 0.7436 0.6362 0.6767 0.7249 0.6540 0.6302
0.14 0.16 0.13 0.13 0.16 0.12 0.14 0.16 0.16 0.13
RAT TERMINAL BODY NUMBER WEIGHT
TESTIS RIGHT ABS. ]REL. WT. % TBW
PROSTATE
ABS. REL. WT. % TBW
BRAIN
ABS. REL. WT. % TBW
LIVER
ABS. REL. WT. % TBW
KIDNEY LEFT
ABS. REL. WT. % TBW
KIDNEY
RIGHT
ABS.
REL.
WT. % TBW
19109 19115 19116 19119 19122 19125 19131 19132 19134 19135
438 . 466. 490. 505 . 451. 508. 499. 439. 419 . 482 .
1.6529 1.6847 1.6820 1.6364 1.6956 1.6796 1.6534 1.8532 1.4818 1.7570
0.38 0.36 0.34 0.32 0.38 0.33 0.33 0.42 0.35 0.36
1.1854 1.4274 1.5838 0.7632 1.0942 1.1823 1.2496 1.8597 1.3858 1.1710
0.27 0.31 0.32 0.15 0.24 0.23 0.25 0.42 0.33 0.24
2.29 2.27 2.28 2.63 2.45 2.44 2.45 2.34 2.35 2.45
0.52 0.49 0.46 0.52 0.54 0.48 0.49 0.53 0.56 0.51
14.18 16.71 15.18 14.66 13.10 16.13 16.94 11.94 12.01 15.48
3.24 3.58 3.10 2.90 2.90 3.18 3.39 2.72 2.87 3.21
1.51 1.99 2.16 2.26 1.92 2.31 2.13 1.78 1.76 2.00
0.34 0.43 0.44 0.45 0.42 0.45 0.43 0.40 0.42 0.41
1.51 1.99 2.12 2.38 1.81 2.29 2.22 1.89 1.84 2.15
0.34 0.43 0.43 0.47 0.40 0.45 0.44 0.43 0.44 0.45
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. WT . = ORGAN WEIGHT.
a. Damaged during processing (weight not affected).
REL.. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100.
418-028:PAGE B-38
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE B19 (PAGE 2) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP I
0 MG/KG/DAY
RAT TERMINAL BODY NUMBER WEIGHT
ADRENAL LEFT
ABS. REL. WT. % TBW a
ADRENAL RIGHT
ABS. REL. WT. % TBW a
SPLEEN
ABS. REL. VT, % TBW
THYMUS
ABS. REL. WT. % TBW
HEART
ABS. WT.
REL. % TBW
19109 19115 19116 19119 19122 19125 19131 19132 19134 19135
438 . 466. 490. 505 . 451. 508. 499 . 439. 419. 482 .
0.027 0.041 0.035 0.048 0.033 0.034 0.041 0.036 0.024 0.031
6.16 8.80 7.14 9.50 7.32 6.69 8.22 8.20 5.73 6.43
0.027 0.040 0.035 0.046 0.031 0.031 0.036 0.038 0.025 0.030
6.16 8.58 7.14 9.11 6.87 6.10 7.21 8.66 5.97 6.22
0.56 0.77 0.95 0.79 0.79 0.76 1.03 0.73 0.60 0.90
0.13 0.16 0.19 0.16 0.18 0.15 0.21 0.17 0.14 0.19
0.37 0.41 0.49 0.30 0.33 0.70 0.47 0.27 0.44 0.33
0.08 0.09 0.10 0.06 0.07 0.14 0.09 0.06 0.10 0.07
1.41 1.62 1.51 1.62 1.68 1.54 1.67 1.40 1.46 1.63
0.32 0.35 0.31 0.32 0.37 0.30 0.33 0.32 0.35 0.34
ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Value was multiplied by 1000.
ABS. W T . = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100.
418-028:PAGE B-39
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770G.1)
TABLE B19 (PAGE 3) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP II
0.3 MG/KG/DAY
RAT TERMINAL BODY NUMBER WEIGHT
EPIDIDYMIS LEFT
ABS. REL. WT. % TBW
CAUDA EPIDIDYMIS LEFT
ABS. REL. WT. % TBW
TESTIS LEFT
ABS. REL. WT. % TBW
SEMINAL VESICLES WITH FLUID
ABS. REL. WT. % TBW
SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % TBW
EPIDIDYMIS RIGHT
ABS . REL. WT. % TBW
19102 19106 19108 19110 19113 19120 19129 19136 19138 19139
428 . 476. 474 . 453. 444 . 486. 435. 495 . 365. 432 .
0.6197 0.6623 0.6465 0.5411 0.6310 0.6180 0.6644 0.6785 0.6686 0.6280
0.14 0.14 0.14 0.12 0.14 0.13 0.15 0.14 0.18 0.14
0.2867 0.2962 0.3502 0.2779 0.3379 0.3209 0.3181 0.3219 0.3604 0.3114
0.07 0.06 0.07 0.06 0.08 0.07 0.07 0.06 0.10 0.07
1.5498 1.6495 1.8847 1.4915 1.7844 1.6588 1.8000 1.7629 1.7956 1.7773
0.36 0.35 0.40 0.33 0.40 0.34 0.41 0.36 0.49 0.41
1.7556 1.0913 1.2460 1.8646 1.7236 1.6952 1.7928 1.2650 1.5421 1.4625
0.41 0.23 0.26 0.41 0.39 0.35 0.41 0.26 0.42 0.34
0.9426 0.5991 0.7062 0.8697 0.8319 0.8335 0.8254 0.6950 0.8728 0.9423
0.22 0.12 0.15 0.19 0.19 0.17 0.19 0.14 0.24 0.22
0.6523 0.6675 0.6572 0.5439 0.6568 0.6724 0.6538 0.6914 0.6831 0.6675
0.15 0.14 0.14 0.12 0.15 0.14 0.15 0.14 0.19 0.15
RAT TERMINAL BODY NUMBER WEIGHT
TESTIS RIGHT ABS. REL. WT. % TBW
PROSTATE
ABS. WT.
REL. % TBW
BRAIN
ABS. REL. WT. % TBW
LIVER
ABS. REL. WT. % TBW
KIDNEY LEFT
ABS. REL. WT. % TBW
KIDNEY
RIGHT
ABS.
REL.
WT. % TBW
19102 19106 19108 19110 19113 19120 19129 19136 19138 19139
428 . 476. 474 . 453 . 444 . 486. 435 . 495 . 365 . 432 .
1.5930 1.6779 1.9171 1.4694 1.7350 1.6765 1.8164 1.8039 1.7840 1.8078
0.37 0.35 0.40 0.32 0.39 0.34 0.42 0.36 0.49 0.42
1.2374 1.0360 1.1892 1.1812 1.2130 1.4290 1.1232 1.3313 0.9939 1.2660
0.29 0.22 0.25 0.26 0.27 0.29 0.26 0.27 0.27 0.29
2.19 2.57 2.52 2.42 2.58 2.38 2.45 2.41 2.46 2.40
0.51 0.54 0.53 0.53 0.58 0.49 0.56 0.49 0.67 0.56
14.53 17.19 14.75 13.95 13.08 14.26 13.37 15.75 11.25 14.10
3.39 3.61 3.11 3.08 2.94 2.93 3.07 3.18 3.08 3.26
1.92 1.97 1.90 1.96 1.96a 1.72 1.89 1.83 1.58 1.88
0.45 0.41 0.40 0.43 0.44 0.35 0.43 0.37 0.43 0.44
1.95 2.00 1.98 2.00 2.11 1.76 1.90 1.69 1.66 1.93
0.46 0.42 0.42 0.44 0.48 0.36 0.44 0.34 0.45 0.45
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
ABS. WT . = ORGAN WEIGHT.
REL.. % TBW =: (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 300.
a. Rat 19113 had slight dilation of the pelvis of the left kidney. See the individual necropsy observations table (Table R18).
418-028-.PAGEB-40
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION /DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B19 (PAGE 4) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP II
0.3 MG/KG/DAY
RAT TERMINAL BODY NUMBER WEIGHT
ADRENAL LEFT
ABS. REL. WT. % TBW a
ADRENAL RIGHT
ABS. REL. WT. % TBW a
SPLEEN
ABS. REL. WT. % TBW
THYMUS
ABS. REL. WT. % TBW
HEART
ABS. WT.
REL. % TBW
19102 19106 19108 19110 19113 19120 19129 19136 19138 19139
428. 476. 474 . 453 . 444 . 486. 435. 495. 365. 432 .
0.041 0.024 0.030 0.037 0.046 0.042 0.037 0.033 0.028 0.032
9.58 5.04 6.33 8.17 10.36 8.64 8.50 6.67 7.67 7.41
0.038 0.024 0.030 0.038 0.044 0.038 0.034 0.034 0.027 0.032
8.88 5.04 6.33 8.39 9.91 7.82 7.82 6.87 7.40 7.41
0.89 0.86 0.73 0.85 0.81 0.83 0.76 0.72 0.73 0.92
0.21 0.18 0.15 0.19 0.18 0.17 0.17 0.14 0.20 0.21
0.52 0.42 0.47 0.41 0.48 0.40 0.34 0.58 0.30 0.54
0.12 0.09 0.10 0.09 0.11 0.08 0.08 0.12 0.08 0.12
1.38 1.56 1.64 1.59 1.47 1.56 1.55 1.71 1.30 1.46
0.32 0.33 0.34 0.35 0.33 0.32 0.36 0.34 0.36 0.34
ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Value was multiplied by 1000.
ABS. WT . = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100.
418-028:PAGE B-<
-P *
PROTOCOL 4X8-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-770G WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE B19 (PAGE 5) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP III
1 MG/KG/DAY
RAT TERMINAL BODY NUMBER WEIGHT
EPIDIDYMIS LEFT
ABS. REL. WT. % TBW
CAUDA EPIDIDYMIS LEFT
ABS. REL. WT. % TBW
TESTIS LEFT
ABS. REL. WT. % TBW
SEMINAL VESICLES WITH IFLUID
ABS. REL. WT. % TBW
SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % TBW
EPIDIDYMIS
RIGHT
ABS.
REL.
WT. % TBW
19101 19105 19107 19112 19114 19121 19123 19130 19137 19146
353 . 505. 437. 452 . 430 . 567. 464 . 434 . 443 . 473 .
0.6021 0.7012 0.5355a 0.6158 0.5678 0.6466 0.6675 0.6775 0.6420 0.6207
0.17 0.14 0.12 0.14 0.13 0.11 0.14 0.16 0.14 0.13
0.2993 0.3377 0.2667 0.3199 0.2915 0.3316 0.3384 0.3513 0.3467 0.3492
0.08 0.07 0.06 0.07 0.07 0.06 0.07 0.08 0.08 0.07
1.6371 2.0077 1.4816 1.6088 1.4232 1.8123 1.7221 1.7366 1.6457 1.6423
0.46 0.40 0.34 0.36 0.33 0.32 0.37 0 .40 0.37 0.35
1.1004 1.7433 2.2034 1.6734 1.6586 1.6481 1.7452 1.7430 1.3000 1.5693
0.31 0.34 0.50 0.37 0.38 0.29 0.38 0.40 0.29 0.33
0.5923 0.7941 0.9613 0.8909 0.7345 0.8330 0.9021 0.7931 0.7387 0.7248
0.17 0.16 0.22 0.20 0.17 0.15 0.19 0.18 0.17 0.15
0.6071 0.7481 0.5625 0.6460 0.6091 0.6559 0.6825 0.7227 0.6680 0.6320
0.17 0.15 0.13 0.14 0.14 0.12 0.15 0.17 0.15 0 .13
RAT TERMINAL BODY NUMBER WEIGHT
TESTIS RIGHT ABS. REL. WT. % TBW
PROSTATE
ABS. REL. WT. % TBW
BRAIN
ABS. REL. WT. % TBW
LIVER
ABS. REL. WT. % TBW
KIDNEY
LEFT
ABS.
REL.
WT. % TBW
KIDNEY
RIGHT
ABS.
REL.
WT. % TBW
19101 19105 19107 19112 19114 19121 19123 19130 19137 19146
353 . 505 . 437 . 452 . 430 . 567 . 464 . 434 . 443 . 473 .
1.5806 2.0016 1.5096 1.6041 1.4506 1.7745 1.8031 1.8184 1.6928 1.6866
0.45 0.40 0.34 0.35 0.34 0.31 0.39 0.42 0.38 0.36
0.8460 1.5220 1.5754 1.3786 1.1497 1.0712 0.9914 1.6000 1.0622 1.0704
0.24 0.30 0.36 0.30 0.27 0.19 0.21 0.37 0.24 0.23
2.22 2.40 2.35 2.41 2.36 2.54 2.43 2.37 2.45 2.26
0.63 0.48 0.54 0.53 0.55 0.45 0.52 0.55 0.55 0.48
11.34 17.13 13.84 14.51 14.34 23.98 19.27 13.79 14.59 16.57
3.21 3.39 3.17 3.21 3 .33 4.23 4.15 3.18 3.29 3 .50
1.50 2.37 1.71 2.09 1.84 2.20 2.17 1.88 1.88 1.94
0.42 0.47 0.39 0.46 0.43 0.39 0.47 0.43 0.42 0.41
1.56 2.29 1.71 1.97 1.92 2.25 2.22 1.98 2.14 2.01
0.44 0.45 0.39 0.44 0.45 0.40 0.48 0.46 0.48 0.42
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. W T . = ORGAN WEIGHT.
a. Damaged during processing (weight not affected).
REL. % TBW = (ORGAN WETGHT/TFRMINAL BODY WEIGHT) X 100.
418-028:PAGE B-42
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B19 (PAGE 6) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP III
1 MG/KG/DAY
RAT TERMINAL BODY NUMBER WEIGHT
ADRENAL LEFT
ABS. REL. WT. % TBW a
ADRENAL
RIGHT ABS. REL. WT. % TBW a
SPLEEN
ABS. REL. WT. % TBW
THYMUS
ABS. REL. WT. % TBW
HEART
ABS. REL. WT. % TBW
19101 19105 19107 19112 19114 19121 19123 19130 19137 19146
353 . 505. 437. 452430. 567. 464 . 434. 443 . 473 .
0.028 0.034 0.039 0.026 0.033 0.032 0.040 0.030 0.032 0.042
7.93 6.73 8.92 5.75 7.67 5.64 8.62 6.91 7.22 8.88
0.026 0.027 0.038 0.022 0.031 0.035 0.025 0.033 0.019 0.043
7.36 5.35 8.70 4.87 7.21 6.17 5.39 7.60 4.29 9.09
0.55 0.74 0.69 0.65 0.68 0.92 0.78 0.87 0.91 0.80
0.16 0.15 0.16 0.14 0.16 0.16 0.17 0.20 0.20 0.17
0.23 0.47 0.26 0.55 0.32 0.44 0.40 0.33 0.29 0.28
0.06 0.09 0.06 0.12 0.07 0.08 0.09 0.08 0.06 0.06
1.33 1.66 1.36 1.48 1.52 1.70 1.56 1.48 1.65 1.65
0.38 0.33 0.31 0.33 0.35 0.30 0.34 0.34 0.37 0.35
ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Value was multiplied by 1000.
ABS. W T . = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100.
418-028:PAGE B-43
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B19 (PAGE 7) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP IV
3 MG/KG/DAY
RAT TERMINAL BODY NUMBER WEIGHT
EPIDIDYMIS LEFT
ABS. REL. WT. % TBW
CAUDA EPIDIDYMIS LEFT
ABS . REL. WT. % TBW
TESTIS LEFT
ABS. REL. WT. % TBW
SEMINAL VESICLES WITH ]FLUID
ABS . REL. WT. % TBW
SEMINAL VESICLES
WITHOUT FLUID
ABS.
REL.
WT. % TBW
EPIDIDYMIS RIGHT
ABS. REL. WT. % TBW
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150
421. 487. 476. 442 . 448 . 545 . 479. 523 . 454 . 448 .
0.6712 0.6486 0.6201 0.5834 0.5667 0.6531 0.3058a 0.5626 0.6884 0.6161
0.16 0.13 0.13 0.13 0.13 0.12 0.06 0.11 0.15 0.14
0.3355 0.2909 0.2961 0.3022 0.2961 0.3098 0.1333a 0.2529 0.3851 0.3111
0.08 0.06 0.06 0.07 0.07 0.06 0.03 0.05 0.08 0.07
1.7129 1.6530 1.7770 1.5495 1.7262 1.7814 0.6988a 1.6357 1.8767 1.7049
0.41 0.34 0.37 0.35 0.38 0.33 0.14 0.31 0.41 0.38
2.0456 2.0607 1.4443 1.6316 1.7327 1.4610 1.1736 1.3813 1.3721 1.1701
0.48 0.42 0.30 0.37 0.39 0.27 0.24 0.26 0.30 0.26
1.0125 1.0014 0.7874 0.7381 0.8511 0.7077 0.6729 0.6369 0.6888 0.5734
0.24 0.20 0.16 0.17 0.19 0.13 0.14 0.12 0.15 0.13
0.6970 0.6457 0.5846 0.6169 0.5492 0.6801 0.3002a 0.6547 0.7389 0.6388
0.16 0.13 0.12 0.14 0.12 0.12 0.06 0 .12 0.16 0.14
RAT TERMINAL BODY NUMBER WEIGHT
TESTIS RIGHT ABS. REL. WT. % TBW
PROSTATE
ABS. REL. WT. % TBW
BRAIN
ABS. REL. WT. % TBW
LIVER
ABS. REL. WT. % TBW
KIDNEY LEFT
ABS. REL. WT. % TBW
KIDNEY RIGHT ABS. REL. WT. % TBW
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150
421. 487 . 476 . 442 . 448 . 545 . 479 . 523 . 454 . 448 .
1.7274 1.7657 1.7025 1.6129 1.7045 1.7406 0.6700a 1.6766 1.8681 1.7068
0.41 0.36 0.36 0.36 0.38 0.32 0.14 0.32 0.41 0.38
1.5079 1.4347 1.2209 1.3183 1.2429 1.0238 1.0863 1.1080 1.4524 1.3391
0.36 0.29 0.26 0.30 0.28 0.19 0.23 0.21 0.32 0.30
2.40 2.39 2.43 2.42 2.47 2.52 2.23 2.40 2.24 2.35
0.57 0.49 0.51 0.55 0.55 0.46 0.46 0.46 0.49 0.52
15.67 19.28 17.78 15.97 15.06 20.42 17.61 18.23 18.08 17.94
3 .72 3 .96 3.74 3.61 3 .36 3.75 3.68 3 .48 3 .98 4.00
1.82 2.40 1.98 1.90 2.08 2.18 2.00 2.21 1.91 1.97
0.43 0.49 0.42 0.43 0.46 0.40 0.42 0.42 0.42 0.44
1.91 2.39 2.16 2.12 2.24 2.20 2.07 2.36 1.92 1.92
0.45 0.49 0.45 0.48 0.50 0.40 0.43 0.45 0.42 0.43
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. WT . = ORGAN WEIGHT.
Rat 19142 had small testes, epididymides and left cauda epididymis.
(Table B18).
REL. % TBW := (ORGAN WEIGHT/TERMIHAL BODY WEIGHT) X: l o o. See the individual necropsy observations table
418-028 :PAGE B-44
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE B19 (PAGE 8) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP IV
3 MG/KG/DAY
RAT TERMINAL BODY NUMBER WEIGHT
ADRENAL
LEFT ABS. REL. WT. % TBW a
ADRENAL RIGHT
ABS. REL. WT. % TBW a
SPLEEN
ABS. REL. WT. % TBW
THYMUS
ABS. REL. WT. % TBW
HEART
ABS. REL. WT. % TBW
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150
421. 487. 476. 442 . 448. 545. 479 . 523 . 454 . 448 .
0.028 0.040 0.030 0.030 0.043 0.024 0.028 0.037 0.028 0.037
6.65 8.21 6.30 6.79 9.60 4.40 5.84 7.07 6.17 8.26
0.032 0.046 0.026 0.032 0.041 0.030 0.028 0.032 0.026 0.026
7.60 9.44 5.46 7.24 9.15 5.50 5.84 6.12 5.73 5.80
0.86 0.88 1.10 0.69 0.74 1.15 0.74 1.15 0.78 0.67
0.20 0.18 0.23 0.16 0.16 0.21 0.15 0.22 0.17 0.15
0.40 0.39 0.40 0.37 0.36 0.57 0.48 0.34 0.35 0.57
0.10 0.08 0.08 0.08 0.08 0.10 0.10 0.06 0.08 0.13
1.42 1.56 1.64 1.44 1.60 1.84 1.54 1.74 1.55 1.62
0.34 0.32 0.34 0.32 0.36 0.34 0.32 0.33 0.34 0.36
ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Value was multiplied by 1000.
ABS. WT. = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100.
418-028:PAGE B-45
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B19 (PAGE 9) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP V
10 MG/KG/DAY
RAT TERMINAL BODY NUMBER WEIGHT
EPIDIDYMIS LEFT
ABS. REL, WT. % TBW
CAUDA EPIDIDYMIS LEFT
ABS. REL. WT. % TBW
TESTIS LEFT
ABS. REL. WT. % TBW
SEMINAL VESICLES WITH FLUID
ABS. REL. WT. % TBW
SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % TBW
EPIDIDYMIS
RIGHT
ABS.
REL.
WT. % TBW
19111 19117 19124 19126 19127 19128 19140 19145 19149 19152
432 . 462 . 426. 426. 434 . 445. 442 . 441. 439. 461.
0.5886 0.5554a 0.7041 0.5648 0.5950 0.5787 0.6181 0.6705 0.6384 0.6200
0.14 0.12 0.16 0.13 0.14 0.13 0.14 0.15 0.14 0.13
0.2814 0.2921 0.3378 0.2550 0.3045 0.2725 0.2951 0.3537 0.3200 0.3288
0.06 0.06 0.08 0.06 0.07 0.06 0.07 0.08 0.07 0.07
1.7973 1.5902 1.9441 1.5950 1.7552 1.5509 1.6009 1.8102 1.9607 1.8784
0.42 0.34 0.46 0.37 0.40 0.35 0.36 0.41 0.45 0.41
1.4923 1.4692 1.6428 0.9950 1.6404 1.1019 1.5387 1.8705 1.4543 1.2190
0.34 0.32 0.38 0.23 0.38 0.25 0.35 0.42 0.33 0.26
0.7724 0.8619 0.8490 0.5749 0.7509 0.6009 0.8782 0.9316 0.8120 0.7403
0.18 0.19 0.20 0.13 0.17 0.14 0.20 0.21 0.18 0.16
0.6626 0.5723 0.6631 0.5576 0.5793 0.6242 0.6487 0.6428 0.6610 0.6498
0.15 0.12 0.16 0.13 0.13 0.14 0.15 0.14 0.15 0.14
RAT TERMINAL BODY NUMBER WEIGHT
TESTIS RIGHT ABS. REL. WT. % TBW
PROSTATE
ABS. REL. WT. % TBW
BRAIN
ABS. REL. WT. % TBW
LIVER
ABS. REL. WT. % TBW
KIDNEY LEFT
ABS. REL. WT. % TBW
KIDNEY
RIGHT
ABS.
REL.
WT. % TBW
19111 19117 19124 19126 19127 19128 19140 19145 19149 19152
432 . 462 . 426. 426 . 434 . 445 . 442 . 441. 439. 461.
1.7246 1.6160 1.8910 1.6044 1.7997 1.5952 1.6407 1.8340 1.9989 1.8997
0.40 0.35 0.44 0.38 0.41 0.36 0.37 0.42 0.46 0.41
1.0515 1.0954 1.5146 0.7260 1.4010 0.9706 1.2239 1.3756 1.2522 1.3077
0.24 0.24 0.36 0.17 0.32 0.22 0.28 0.31 0.28 0.28
2.48 2.43 2.38 2.28 2.62 2.31 2.42 2.40 2.38 2.34
0.57 0.52 0.56 0.54 0.60 0.52 0.55 0.54 0.54 0.51
24.36 24.11 25.72 22.94 27.38 21.74 20.21 23.20 20.06 18.58
5.64 5.22 6.04 5.38 6.31 4.88 4.57 5.26 4.57 4.03
2.00 2.22 2.21 2.04 1.90 1.78 1.93 2.27 1.76 1.97
0.46 0.48 0.52 0.48 0.44 0.40 0.44 0.51 0.40 0.43
2.13 2.26 2.18 2.04 1.95 1.82 1.88 2.16 1.92 2.07
0.49 0.49 0.51 0.48 0.45 0.41 0.42 0.49 0.44 0.45
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
ABS. WT . = ORGAN WEIGHT.
a. Damaged during processing (weight not affected).
REL.. % TBW == (ORGAN WEIGHT/TERM INAL BODY WEIGHT) X 100.
418-028:PAGE B-46
PROTOCOL 4X8-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVE LOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770G.1)
TABLE B19 (PAGE 10) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP V
10 MG/KG/DAY
RAT TERMINAL BODY NUMBER WEIGHT
ADRENAL LEFT
ABS. REL. WT. % TBW a
ADRENAL RIGHT
ABS. REL. WT. % TBW a
SPLEEN
ABS. REL. W T . % TBW
THYMUS
ABS. REL. W T . % TBW
HEART
ABS. ] WT. %
19111 19117 19124 19126 19127 19128 19140 19145 19149 19152
432 . 462 . 426. 426 . 434 . 445 . 442 . 441. 439 . 461.
0.025 0.030 0.035 0.029 0.031 0.036 0.036 0.034 0.029 0.036
5.79 6.49 8.22 6.81 7.14 8.09 8.14 7.71 6.60 7.81
ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Value was multiplied by 1000.
0.024 0.014 0.034 0.028 0.031 0.034 0.028 0.033 0.030 0.038
5.56 3.03 7.98 6.57 7.14 7.64 6.33 7.48 6.83 8.24
0.73 0.75 0.72 0.64 0.81 0.74 0.86 0.88 0.97 0.70
ABS. WT.. = ORGAN WEIGHT.
0.17 0.16 0.17 0.15 0.19 0.17 0.19 0.20 0.22 0.15
0.37 0.36 0.36 0.47 0.47 0 .40 0.44 0.38 0.43 0.51
0.08 0.08 0.08 0.11 0.11 0.09 0.10 0.09 0.10 0.11
1.38 1.60 1.40 1.38 1.43 1.42 1.50 1.36 1.46 1.47
0.32 0.35 0.33 0.32 0.33 0.32 0.34 0.31 0.33
0 . 32
REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100.
418-028 :PAGE B-47
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B20 (PAGE 1) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN
Fo GENERATION MALE RATS
DOSAGE GROUP I
0 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
EPIDIDYMIS LEFT
ABS. REL. WT. % BRW
CAUDA EPIDIDYMIS LEFT
ABS. REL. WT. % BRW
TESTIS LEFT
ABS. REL. WT. % BRW
SEMINAL VESICLES WITH FLUID ABS. REL. W T . % BRW
SEMINAL VESICLES WITHOUT FLUID ABS. REL. W T . % BRW
EPIDIDYMIS RIGHT
ABS. REL. W T . % BRW
19109 19115 19116 19119 19122 19125 19131 19132 19134 19135
2.29 2.27 2.28 2.63 2.45 2.44 2.45 2.34 2.35 2.45
0.6013 26.26 0.6976a 30.73 0.6499 28.50 0.6541 24.87 0.6661 27.19 0.6160 25.24 0.6482 26.46 0.7103 30.35 0.6278 26.71 0.6052 24.70
0.2822 0.3438 0.3209 0.3489 0.3724 0.3260 0.3140 0.3684 0.3368 0.2942
12.32 15.14 14.07 13.27 15.20 13.36 12.82 15.74 14.33 12.01
1.5706 1.6971 1.6213 1.7174 1.6754 1.6621 1.6865 1.8079 1.4801 1.6728
68.58 74.76 71.11 65.30 68.38 68.12 68.84 77.26 62.98 68.28
1.3331 2.1021 1.5369 1.6464 1.9375 1.6300 1.5772 1.9409 1.8240 1.5266
58.21 92.60 67.41 62.60 79.08 66.80 64.38 82.94 77.62 62.31
0.7867 1.0227 0.6846 0.8014 0.9217 0.7377
7764 9312 9106 8672
34.35 45.05 30.03 30.47 37.62 30.23 31.69 39.79 38.75 35.40
0.6317a 27.58
0.7252 31.95 0.6497 28.50 0.6728 25.58 0.7436 30.35 0.6362 26.07 0.6767 27.62 0.7249 30.98 0.6540 27.83 0.6302 25.72
RAT NUMBER
BRAIN WEIGHT
TESTIS RIGHT ABS. REL. WT. !i BRW
PROSTATE
ABS. REL. WT. % BRW
LIVER
ABS. REL. WT. % BRW
KIDNEY LEFT
ABS. REL. W T . % BRW
KIDNEY RIGHT ABS. REL. W T . % BRW
ADRENAL LEFT
ABS. REL. WT. % BRW
19109 19115 19116 19119 19122 19125 19131 19132 19134 19135
2.29 2.27 2.28 2.63 2.45 2.44 2.45 2.34 2.35 2.45
1.6529 1.6847 1.6820 1.6364 1.6956 1.6796 1.6534 1.8532 1.4818 1.7570
72.18 74.22 73.77 62.22 69.21 68.84 67.48 79.20 63.06 71.71
1.1854 1.4274 1.5838 0.7632 1.0942 1.1823 1.2496 1.8597 1.3858 1.1710
51.76 62.88 69.46 29.02 44.66 48.45 51.00 79.47 58.97 47.80
14.18 16.71 15.18 14.66 13.10 16.13 16.94 11.94 12.01 15.48
619.21 736.12 665.79 557.41 534.69 661.06 691.43 510.26 511.06 631.84
1.51
.99 .16 ,26 .92
31 2.13 1.78
1.76 2.00
65.94 87.66 94.74 85.93 78.37 94.67 86.94 76.07 74.89 81.63
1.51 1.99 2.12 2.38 1.81 2.29 2.22 1.89 1.84 2.15
65.94 87.66 92.98 90.49 73.88 93.85 90.61 80.77 78.30 87.76
0.027 0.041 0.035 0.048 0.033 0.034 0.041 0.036 0.024 0.031
1.18 1.81 1.54 1.82 1.35 1.39 1.67 1.54 1.02 1.26
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. WT. = ORGAN WEIGHT.
a. Damaged during processing (weight not affected).
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028 :PAGE B-48
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B20 (PAGE 2) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP I
0 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
19109 19115 19116 19119 19122 19125 19131 19132 19134 19135
2.29 2.27 2.28 2.63 2.45 2.44 2.45 2.34 2.35 2.45
ADRENAL RIGHT
ABS. REL. WT. % BRW
0.027 0.040 0.035 0.046 0.031 0.031 0.036 0.038 0.025 0.030
1.18 1.76 1.54 1.75 1.26 1.27 1.47 1.62 1.06 1.22
SPLEEN
ABS. REL. WT. % BRW
0.56 0.77 0.95 0.79 0.79 0.76 1.03 0.73 0.60 0.90
24.45 33.92 41.67 30.04 32.24 31.15 42.04 31.20 25.53 36.73
THYMUS
ABS. REL. WT. % BRW
0.37 0.41 0.49 0.30 0.33 0.70 0.47 0.27 0.44 0.33
16.16 18.06 21.49 11.41 13.47 28.69 19.18 11.54 18.72 13.47
HEART
ABS. REL. WT. % BRW
1.41 1.62 1.51 1.62 1.68 1.54 1.67 1.40 1.46 1.63
61.57 71.36 66.23 61.60 68.57 63.11 68.16 59.83 62.13 66.53
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. WT. = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028:PAGE B-49
PROTOCOL 418 028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B20 (PAGE 3) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP II
0.3 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
EPIDIDYMIS LEFT
ABS. REL. WT. % BRW
CAUDA EPIDIDYMIS LEFT
ABS. REL. WT. % BRW
TESTIS
LEFT
ABS.
REL.
WT. % BRW
SEMINAL VESICLES WITH FLUID ABS. REL. WT. % BRW
SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % BRW
EPIDIDYMIS RIGHT
ABS. REL. WT. % BRW
19102 19106 19108 19110 19113 19120 19129 19136 19138 19139
2.19 2.57 2.52 2.42 2.58 2.38 2.45 2.41 2.46 2.40
0.6197 0.6623 0.6465 0.5411 0.6310 0.6180 0.6644 0.6785 0.6686 0.6280
28.30 25.77 25.65 22.36 24.46 25.97 27.12 28.15 27.18 26.17
0.2867 0.2962 0.3502 0.2779 0.3379 0.3209 0.3181 0.3219 0.3604 0.3114
13.09 11.52 13.90 11.48 13.10 13.48 12.98 13.36 14.65 12.98
1.5498 1.6495 1.8847 1.4915 1.7844 1.6588 1.8000 1.7629 1.7956 1.7773
70.77 64.18 74.79 61.63 69.16 69.70 73.47 73.15 72.99 74.05
1.7556 1.0913 1.2460 1.8646 1.7236 1.6952 1.7928 1.2650 1.5421 1.4625
80.16 42.46 49.44 77.05 66.81 71.23 73.18 52.49 62.69 60.94
0.9426 0.5991 0.7062 0.8697 0.8319 0.8335 0.8254 0.6950 0.8728 0.9423
43.04 23.31 28.02 35.94 32.24 35.02 33.69 28.84 35.48 39.26
0.6523 0.6675 0.6572 0.5439 0.6568 0.6724 0.6538 0.6914 0.6831 0.6675
29.78 25.97 26.08 22.48 25.46 28.25 26.68 28.69 27.77 27.81
RAT NUMBER
BRAIN WEIGHT
TESTIS RIGHT ABS. REL. WT. % BRW
PROSTATE
ABS. REL. WT. % BRW
LIVER
ABS. REL. WT. % BRW
KIDNEY LEFT
ABS. REL. WT. % BRW
KIDNEY RIGHT ABS. REL. WT. % BRW
ADRENAL LEFT
ABS. REL. WT. % BRW
19102 19106 19108 19110 19113 19120 19129 19136 19138 19139
2.19 2.57 2.52 2.42 2.58 2.38 2.45 2.41 2.46 2.40
1.5930 1.6779 1.9171 1.4694 1.7350 1.6765 1.8164 1.8039 1.7840 1.8078
72.74 65.29 76.08 60.72 67.25 70.44 74.14 74.85 72.52 75.32
1.2374 1.0360 1.1892 1.1812 1.2130 1.4290 1.1232 1.3313 0.9939 1.2660
56.50 40.31 47.19
48.81 47.02 60.04 45.84 55.24 40.40 52.75
14.53 17.19 14.75 13.95 13.08 14.26 13.37 15.75 11.25 14.10
663.47 668.87 585.32 576.45 506.98 599.16 545.71 653.53 457.32 587.50
1.92 1.97 1.90 1.96 1.96a 1.72 1.89 1.83 1.58 1.88
87.67 76.65 75.40 80.99 75.97 72.27 77.14 75.93 64.23 78.33
1.95 2.00 1.98 2.00 2.11 1.76 1.90 1.69 1.66 1.93
89.04 77.82 78.57 82.64 81.78 73.95 77.55 70.12 67.48 80.42
0.041 0.024 0.030 0.037 0.04 6 0.042 0.037 0.033 0.028 0.032
1.87 0.93 1.19 1.53 1.78 1.76 1.51 1.37 1.14 1.33
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. WT. = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
a. Rat 19113 had slight dilation of the pelvis of the left kidney. See the individual necropsy observations table (Table B18 ).
418-028:PAGE B-50
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B20 (PAGE 4) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP II
0.3 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
19102 19106 19108 19110 19113 19120 19129 19136 19138 19139
2.19 2.57 2.52 2.42 2.58 2.38 2.45 2.41 2.46 2.40
ADRENAL RIGHT
ABS. REL. W T . % BRW
0.038 0.024 0.030 0.038 0.044 0.038 0.034 0.034 0.027 0.032
1.74 0.93 1.19 1.57 1.70 1.60 1.39 1.41 1.10 1.33
SPLEEN
ABS. REL. W T . % BRW
0.89 0.86 0.73 0.85 0.81 0.83 0.76 0.72 0.73 0.92
40.64 33.46 28.97 35.12 31.40 34.87 31.02 29.88 29.67 38.33
THYMUS
ABS. REL. W T . % BRW
0.52 0.42 0.47 0.41 0.48 0.40 0.34 0.58 0.30 0.54
23.74 16.34 18.65 16.94 18.60 16.81 13.88 24.07 12.20 22.50
HEART
ABS. REL. W T . % BRW
1.38 1.56 1.64 1.59 1.47 1.56 1.55 1.71 1.30 1.46
63.01 60.70 65.08 65.70 56.98 65.55 63 .26 70.95 52.84 60.83
ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. WT. = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028:PAGE B-
'J\
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF 1-1106 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770G.1)
TABLE B20 (PAGE 5) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP III
1 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
EPIDIDYMIS LEFT
ABS. REL. WT. % BRW
CAUDA EPIDIDYMIS LEFT
ABS. REL. WT. % BRW
TESTIS LEFT
ABS. REL. WT. % BRW
SEMINAL VESICLES WITH FLUID ABS. REL. WT. % BRW
SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % BRW
EPIDIDYMIS RIGHT
ABS. REL. WT. % BRW
19101 19105 19107 19112 19114 19121 19123 19130 19137 19146
2.22 2.40 2.35 2.41 2.36 2.54 2.43 2.37 2.45 2.26
0.6021 27.12 0.7012 29.22 0.5355a 22.79 0.6158 25.55 0.5678 24.06 0.6466 25.46 0.6675 27.47 0.6775 28.59 0.6420 26.20 0.6207 27.46
0.2993 0.3377 0.2667 0.3199 0.2915 0.3316 0.3384 0.3513 0.3467 0.3492
13.48 14.07 11.35 13.27 12.35 13.06 13.92 14.82 14.15 15.45
1.6371 2.0077 1.4816 1.6088 1.4232 1.8123 1.7221 1.7366 1.6457 1.6423
73.74 83.65 63.05 66.76 60.30 71.35 70.87 73.27 67.17 72.67
1.1004 1.7433 2.2034 1.6734 1.6586 1.6481 1.7452 1.7430 1.3000 1.5693
49.57 72.64 93.76 69.44 70.28 64.88 71.82 73.54 53.06 69.44
0.5923 0.7941 0.9613 0.8909 0.7345 0.8330 0.9021 0.7931 0.7387 0.7248
26.68 33.09 40.91 36.97 31.12 32.80 37.12 33.46 30.15 32.07
0.6071 0.7481 0.5625 0.6460 0.6091 0.6559 0.6825 0.7227 0.6680 0.6320
27,35 31.17 23.94 26.80 25.81 25.82 28.09 30.49 27.26 27.96
RAT NUMBER
BRAIN WEIGHT
TESTIS RIGHT ABS. REL. WT. % BRW
PROSTATE
ABS. REL. WT. % BRW
LIVER
ABS. REL. WT. % BRW
KIDNEY LEFT
ABS . REL. WT. % BRW
KIDNEY RIGHT ABS . REL. WT. % BRW
ADRENAL
LEFT
ABS.
REL.
WT. % BRW
19101 19105 19107 19112 19114 19121 19123 19130 19137 19146
2.22 2.40 2.35 2.41 2.36 2.54 2.43 2.37 2.45 2.26
1.5806 2.0016 1.5096 1.6041 1.4506 1.7745 1.8031 1.8184 1.6928 1.6866
71.20 83.40 64.24 66.56 61.47 69.86 74.20 76.72 69.09
74. 63
0.8460
1.5220 1.5754 1.3786
1.1497
1.0712 0.9914
1 . 6000
1.0622
1 . 0704
38.11 63.42 67.04 57.20 48.72 42.17
40. ao
67. 51
43.36 47.36
11.34 17.13 13.84 14.51 14.34 23.98 19.27 13.79 14.59 16.57
510.81 713.75 588.94 602.07 607.63 944.09 793.00 581.86 595.51 733.18
1.50 2.37
1.71 2.09
1.84
2.20 2.17
1 . 88
1.88
1 . 94
67.57 98.75 72.76 86.72 77.97 86.61 89.30 79.32 76.73
85. 84
1.56 2.29 1.71 1.97 1.92 2.25
2 . 22
1.98
2 . 14 2 . 01
70.27 '
95.42 72.76 81.74 81.36
88.58 91.36
83.54 87.35
88 . 94
0.028 0.034 0.039 0.026 0.033 0.032
0 . 040
0.030
0 . 032 0 . 042
3.26 1.42 1.66 1.08 1.40 1.26 1.65 1.26 1.31
1 . 86
ALL WEIGHTS WERE RECORDED IN GRAMS (G) . ABS. W T . = ORGAN WEIGHT. a. Damaged during processing (weight not affected).
REL. % TRW = (ORGAN WEIGHT/BRATN WEIGHT) X 100.
S-aaOVd:8CO-8lt
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B20 (PAGE 6) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP III
1 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
19101 19105 19107 19112 19114 19121 19123 19130 19137 19146
2.22 2.40 2.35 2.41 2.36 2.54 2.43 2.37 2.45 2.26
ADRENAL RIGHT
ABS. REL. WT. % BRW
0.026 0.027 0.038 0.022 0.031 0.035 0.025 0.033 0.019 0.043
1.17 1.12 1.62 0.91 1.31 1.38 1.03 1.39 0.78 1.90
SPLEEN
ABS. REL. WT. % BRW
0.55 0.74 0.69 0.65 0.68 0.92 0.78 0.87 0.91 0.80
24.77 30.B3 29.36 26.97 28.81 36.22 32.10 36.71 37.14 35.40
THYMUS
ABS. REL. WT. % BRW
0.23 0.47 0.26 0.55 0.32 0.44 0.40 0.33 0.29 0.28
10.36 19.58 11.06 22.82 13.56 17.32 16.46 13.92 11.84 12.3 9
HEART
ABS. REL. WT. % BRW
1.33 1.66 1.36 1.48 1.52 1.70 1.56 1.48 1.65 1.65
59.91 69.17 57.87 61.41 64.41 66.93 64.20 62.45 67.35 73.01
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. W T . = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028:PAGE B-53
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B20 (PAGE 7) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP IV
3 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
EPIDIDYMIS LEFT
ABS. REL. WT. % BRW
CAUDA EPIDIDYMIS LEFT
ABS. REL. WT. % BRW
TESTIS LEFT
ABS. REL. WT. % BRW
SEMINAL VESICLES WITH FLUID ABS. REL. WT. % BRW
SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % BRW
EPIDIDYMIS RIGHT
ABS. REL. WT. % BRW
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150
2.40 2.39 2.43 2.42 2.47 2.52 2.23 2.40 2.24 2.35
0.6712 27.97 0.6486 27.14 0.6201 25.52 0.5834 24.11 0.5667 22.94 0.6531 25.92 0.3058a 13.71 0.5626 23.44 0.6884 30.73 0.6161 26.22
0.3355 13.98 0.2909 12.17 0.2961 12.18 0.3022 12.49 0.2961 11.99 0.3098 12.29 0.1333a 5.98 0.2529 10.54 0.3851 17.19 0.3111 13.24
1.7129 71.37 1.6530 69.16 1.7770 73.13 1.5495 64.03 1.7262 69.89 1.7814 70.69 0.6988a 31.34 1.6357 68.15 1.8767 83.78 1.7049 72.55
2.0456 2.0607 1.4443 1.6316 1.7327 1.4610 1.1736 1.3813 1.3721 1.1701
85.23 86.22 59.44 67.42 70.15 57.98 52.63 57.55 61.25 49.79
1.0125 1.0014 0.7874 0.7381 0.8511 0.7077 0.6729 0.6369 0.6888 0.5734
42.19 41.90 32.40 30.50 34.46 28.08 30.17 26.54 30.75 24.40
0.6970 29.04 0.6457 27.02 0.5846 24 .06 0.6169 25.49 0.5492 22.23 0.6801 26.99 0 .3002a 13 .46 0.6547 27.28 0.7389 32.99 0.6388 27.18
RAT NUMBER
BRAIN WEIGHT
TESTIS RIGHT ABS. REL. WT. 1fc BRW
PROSTATE
ABS. WT.
REL. % BRW
LIVER
ABS. WT.
REL. % BRW
KIDNEY
LEFT
ABS.
REL.
WT. % BRW
KIDNEY RIGHT ABS. REL. WT. % BRW
ADRENAL LEFT
ABS . REL. WT. % BRW
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150
2.40 2.39 2.43 2.42 2.47 2.52 2.23 2.40 2.24 2.35
1.7274 71.98 1.7657 73.88 1.7025 70.06 1.6129 66.65 1.7045 69.01 1.7406 69.07 0.6700a 30.04 1.6766 69.86 1.8681 83.40 1.7068 72.63
1.5079 1.4347 1.2209 1.3183 1.2429 1.0238 1.0863 1.1080 1.4524 1.3391
62.83 60.03 50.24 54.48 50.32 40.63 48.71 46.17 64.84 56.98
15.67 19.28 17.78 15.97 15.06 20.42 17.61 18.23 18.08 17.94
652.92 806.69 731.69 659.92 609.72 810.32 789.69 759.58 807.14 763.40
1.82 2.40 1.98 1.90 2.08 2.18 2.00 2.21 1.91 1.97
75.8? 100.42
81.48 78.51 84.21 86.51 89.69 92.08 85.27 83.83
1.91 2.39 2.16 2.12 2.24 2.20 2.07 2.36 1.92 1.92
79.58 100.00
88.89 87.60 90.69 87.30 92.82 98.33 85.71 81.70
0.028 0.040 0.030 0.030 0.043 0.024 0.028 0.037 0.028 0.037
1.17 1.67 3.23 1.24 1.74 0.95 1.26 1.54 3 .25 1.57
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. W T . = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
a. Rat 19142 had small testes, epididymides and left cauda epididymis. See the individual necropsy observations table
(Table B18).
418-028:PAGE B-54
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE B20 (PAGE 8) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP IV
3 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150
2.40 2.39 2.43 2.42 2.47 2.52 2.23 2.40 2.24 2.35
ADRENAL RIGHT
ABS. REL. WT. % BRW
0.032 0.046 0.026 0.032 0.041 0.030 0.028 0.032 0.026 0.026
1.33 1.92 1.07 1.32 1.66 1.19 1.26 1.33 1.16 1.11
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
SPLEEN
THYMUS
HEART
ABS. REL. WT. % BRW
ABS. REL. WT. % BRW
ABS. REL. WT. % BRW
0.86 0.88 1.10 0.69 0.74 1.15 0.74 1.15 0.78 0.67
35.83 36.82 45.27 28.51 29.96 45.63 33.18 47.92 34.82 28.51
0.40 0.39 0.40 0.37 0.36 0.57 0.48 0.34 0.35 0.57
16.67 16.32 16.46 15.29 14.57 22.62 21.52 14.17 15.62 24.26
1.42 1.56 1.64 1.44 1.60 1.84 1.54 1.74 1.55 1.62
59.17 65.27 67.49 59.50 64.78 73.02 69.06 72.50 69.20 68.94
ABS. WT. = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028:PAGE B-55
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B20 (PAGE 9) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP V
10 MG/KG/DAY
RAT BRAIN NUMBER WEIGHT
EPIDIDYMIS LEFT
ABS. REL. WT. % BRW
CAUDA EPIDIDYMIS LEFT
ABS. REL. WT. % BRW
TESTIS LEFT
ABS. REL. WT. % BRW
SEMINAL VESICLES WITH FLUID ABS. REL. WT. % BRW
SEMINAL VESICLES WITHOUT FLUID ABS. REL. WT. % BRW
EPIDIDYMIS
RIGHT
ABS.
REL.
WT. % BRW
19111 19117 19124 19126 19127 19128 19140 19145 19149 19152
2.48 2.43 2.38 2.28 2.62 2.31 2.42 2.40 2.38 2.34
0.5886 23.73 0.5554a 22.86 0.7041 29.58 0.5648 24.77 0.5950 22.71 0.5787 25.05 0.6181 25.54 0.6705 27.94 0.6384 26.82 0.6200 26.50
0.2814 0.2921 0.3378 0.2550 0.3045 0.2725 0.2951 0.3537 0.3200 0.3288
11.35 12.02 14.19 11.18 11.62 11.80 12.19 14.74 13.44 14.05
1.7973 1.5902 1.9441 1.5950 1.7552 1.5509 1.6009 1.8102 1.9607 1.8784
72.47 65.44 81.68 69.96 66.99 67.14 66.15 75.42 82.38 80.27
1.4923 1.4692 1.6428 0.9950 1.6404 1.1019 1.5387 1.8705 1.4543 1.2190
60.17 60.46 69.02 43.64 62.61 47.70 63.58 77.94 61.10 52.09
0.7724 0.8619 0.8490 0.5749 0.7509 0.6009 0.8782 0.9316 0.8120 0.7403
31.14 35.47 35.67 25.21 28.66 26.01 36.29 38.82 34.12 31.64
0.6626 0.5723 0.6631 0.5576 0.5793 0.6242 0.6487 0.6428 0.6610 0.6498
26.72 23.55 27.86 24.46 22.11 27.02 26.80 26.78 27.77 27.77
RAT BRAIN NUMBER WEIGHT
TESTIS RIGHT ABS. REL. WT. i BRW
PROSTATE
ABS. REL. WT. % BRW
LIVER
ABS. WT.
REL. % BRW
KIDNEY LEFT
ABS. REL. W T . % BRW
KIDNEY RIGHT ABS. REL. WT. % BRW
ADRENAL
LEFT
ABS.
REL.
WT. % BRW
19111 19117 19124 19126 19127 19128 19140 19145 19149 19152
2.48 2.43 2.38 2.28 2.62 2.31 2.42 2.40 2.38 2.34
1.7246 1.6160 1.8910 1.6044 1.7997 1.5952 1.6407 1.8340 1.9989 1.8997
69.54 66.50 79.45 70.37 68.69 69.06 67.80 76.42 83.99 81.18
1.0515 1.0954 1.5146 0-.7260 1.4010 0.9706 1.2239 1.3756 1.2522 1.3077
42.40 45.08 63.64 31.84 53.47 42.02 50.57 57.32 52.61 55.88
24.36 24.11 25.72 22.94 27.38 21.74 20.21 23.20 20.06 18.58
982.26 992.18 1080.67 1006.14 1045.04 941.12 835.12 966.67 842.86 794.02
2.00 2.22 2.21 2.04 1.90 1.78 1.93 2.27 1.76 1.97
80.64 91.36 92.86 89.47 72.52 77.06 79.75 94.58 73.95 84.19
2.13 2.26 2.18 2.04 1.95 1.82 1.88 2.16 1.92 2.07
85.89 93.00 91.60 89.47 74.43 78.79 77.68 90.00 80.67 88.46
0.025 0.030 0.035 0.029 0.031 0.036 0.036 0.034 0.029 0.036
I .01 1.23 1.47 1.27 1.18 1.56 1.49 1.42 1.22 1.54
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. WT. = ORGAN WEIGHT.
a. Damaged during processing (weight not affected).
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028 :PAGE B-56
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B20 (PAGE 10) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP V
10 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
ADRENAL RIGHT
ABS. REL. W T . % BRW
SPLEEN
ABS. REL. W T . % BRW
THYMUS
ABS. REL. W T . % BRW
HEART
ABS. WT. <
19111 19117 19124 19126 19127 19128 19140 19145 19149 19152
2.48 2.43 2.38 2.28 2.62 2.31 2.42 2.40 2.38 2.34
0.024 0.014 0.034 0.028 0.031 0.034 0.028 0.033 0.030 0.038
0.97 0.58 1.43 1.23 1.18 1.47 1.16 1.38 1.26 1.62
0.73 0.75 0.72 0.64 0.81 0.74 0.86 0.88 0.97 0.70
29.44 30.86 30.25 28.07 30.92 32.03 35.54 36.67 40.76 29.91
0.37 0.36 0.36 0.47 0.47 0.40 0.44 0.38 0.43 0.51
14.92 14.81 15.13 20.61 17.94 17.32 18.18 15.83 18.07 21.79
1.38 1.60 1.40 1.38 1.43 1.42 1.50 1.36 1.46 1.47
55.64 65.84 58.82 60.53 54.58 61.47 61.98 56.67 61.34 62.82
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. W T . = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028:PAGE B-57
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B21 (PAGE 1) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DOSAGE GROUP I
0 MG/KG/DAY
DAY 1 2 3 4 5
19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157
19161 19167
322 . 357. 347. 350. 328 . 359. 341. 338. 332. 358. 338. 346. 331. 362 . 332 .
326. 361. 348. 356. 329. 364. 350 . 339. 330. 359. 334 . 350. 337. 373 . 340.
334 . 370. 360. 370. 320. 372 . 357. 343 . 342. 372. 344 . 362 . 344 . 385. 347.
342. 374 . 363 . 378. 312. 382. 362. 347. 345. 380. 347. 366. 350. 392. 351.
344 . 377. 372 . 388 . 336. 384 . 375 . 348. 350. 381. 357. 370 . 355 . 399. 359.
DAY 17 18 19 20 21
19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167
390. 429. 413 . 455 . 396. 435 . 417. 384 . 371. 426. 392 . 411. 394 . 463 . 410.
391. 442 . 422 . 463 . 399. 434 . 432 . 392 . 377 . 432. 393 . '413 . 397 . 468 . 409 .
392 . 443 . 420 . 470. 399. 442 . 425 . 393 . 377. 430 . 400. 408 . 396. 474 . 419.
398 . 451. 425. 476. 405 . 448 . 438. 410 . 380 . 440 . 406. 423 . 410 . 483 . 425.
400. 449 . 431. 478 . 406. 452 . 435. 415. 385 . 437. 408 . 424 . 405 . 488. 422 .
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation.
6
352 . 388. 378 . 394 . 346. 392 . 384 . 356. 356 . 391. 358. 378. 362. 411. 365 .
22
398 . 455 . 432 . 485. 409 . 452 . 440 . 406. 381. 440. 407 . 428 . 409. 499. 378 .
7
357 . 385 . 385 . 400 . 350 . 400 . 388 . 361. 358 . 393 . 363 . 380 . 363 . 417 . 372 .
23
396 . 458 . 442 . 483 . 413 . 465 . 447 . 407 . 381. 442 . 413 . 430. 411. 502 . 368 .
8
359. 393 . 388 . 414 . 354 . 409. 388 . 359. 358. 398. 366 . 387. 370. 424 . 373 .
24
403 . 460 . 448 . 492 . 420 . 471. 450 . 406. 387. 446. 414 . 434 . 420 . 508 . 363 .
9
355 . 402 . 389. 420 . 358 . 414 . 403 . 353 . 366. 395. 365. 389. 369. 425 . 382.
25
406 . 465. 448 . 494 . 419. 478 . 456 . 418 . 388 . 449. 417. 446. 424 . 517. 373 .
10
363 . 408 . 394 . 424 . 366 . 420 . 400 . 363 . 367. 398 . 374 . 392 . 377. 416. 382 .
26
409. 463 . 452 . 504 . 421. 482 . 458 . 420 . 394 . 453 . 426 . 445 . 429 . 518 . 389.
11
370. 412 . 402 . 431. 372 . 428 . 407. 363 . 370 . 408 . 381. 400 . 378 . 436. 388 .
27
420 . 462 . 461. 513 . 426 . 486 . 470 . 424 . 396 . 464 . 432 . 450 . 432 . 532 . 396 .
12
374 . 417 . 402 . 446. 379. 431. 407 . 369. 373 . 403 . 381. 404 . 384 . 433 . 391.
28
420 . 453 . 469511. 432 . 489. 470 . 426 . 404 . 465 . 440 . 452 . 409 . 539. 405 .
13
380 . 423 . 408 . 450 . 380 . 436 . 419 . 370 . 373 . 416 . 387. 407 . 394 . 436 . 391.
29b
421 . 472 . 462 . 504 . 432 . 491 . 479 . 428 . 404 . 468 . 435 . 463 . 438 . 546 . 406 .
14a
380 . 427 . 403 . 454 . 382 . 440 . 417 . 376 . 380 . 417. 390 . 406 . 393 . 446 . 399 .
30
427 . 469 . 466 . 510 . 434 . 493 . 479 . 428 . 406 . 469 . 440. 461 . 434 . 544 . 414 .
15
376. 422 . 410 . 449 . 389 . 435 . 418 . 376 . 357 . 416. 387 . 404 . 384 . 449. 396 .
31
430 . 479 . 476. 518 . 440 . 500 . 484 . 431. 415 . 470 . 444 . 457 . 439 . 548 . 398 .
16
384 . 430 . 416 . 452 . 396 . 435 . 418 . 376 . 378 . 424 . 388 . 408 . 392 . 457 . 401.
32
435 . 472 . 479 . 516 . 441. 498 . 494 . 438 . 419 . 477 . 453 . 464 . 441 . 555 . 421 .
418-028:PAGE B-58
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B21 (PAGE 2) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DOSAGE GROUP I
0 MG/KG/DAY
DAY 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47
19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167
442 . 439. 477. 521. 437 . 503 . 492 . 444 . 421. 485. 458 . 473 . 441. 557. 424 .
446. 482 . 485 . 532. 451. 509. 497. 446. 424 . 486. 456. 466. 443 . 561. 426 .
452. 485. 490. 538. 449. 517. 501. 446. 426. 493 . 466. 461. 447. 560. 438 .
443 . 476 . 491. 533 . 455 . 517. 513 . 448 . 433. 490. 468. 474 . 455. 566 . 441.
451. 490 . 490. 523 . 458 . 527 . 512 . 450 . 438 . 504 . 472 . 481. 458 . 567 . 445 .
447. 487. 492. 526. 467 . 517. 506. 439. 431. 494 . 470. 474 . 459. 571. 446 .
450. 491. 494 . 527. 467. 528. 514 . 454 . 434 . 496 . 477 . 481. 460 . 564 . 445 .
455 . 490 . 501. 529 . 468 . 528 . 516. 458. 436. 502. 478. 482 . 463 . 571. 451.
463 . 498. 501. 526. 468. 528 . 515. 465. 441. 502 . 476. 482 . 470 . 562 . 451.
466 . 499 . 503 . 537 . 475 . 534 . 520. 466 . 444 . 504 . 486 . 484 . 473 . 556 . 456 .
438 . 466. 509. 538 . 474 . 534 . 528 . 463 . 436. 504 . 491. 482 . 478. 559. 458 .
490 . 505 . 451 . 543 . 530 . 474 . 446 . 511. 493 . 490. 483 . 569 . 458 .
508 . 499 . 439 . 445 . 509 . 495 . 500. 491. 575. 462 .
419 . 482 . 499 . 503 . 486. 583 . 472 .
469 . 470 . 462 . 549. 441 .
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G).
418-028:PAGE B-59
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B21 (PAGE 3) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DOSAGE GROUP II
0.3 MG/KG/DAY
DAY 1 2 3 4 5 6 7 8 9 10 ii 12 13 14a 15 16
19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
315. 360. 340. 348. 328 . 355. 333 . 346. 314. 339. 331. 346. 338. 342. 348.
321. 356. 351. 356 . 340 . 358 . 340 . 352 . 323 . 343. 335 . 345 . 338 . 347 . 353 .
322. 369. 361. 358. 344. 368. 346. 367. 319. 348. 346. 337. 344. 355. 356.
328. 379. 371. 368. 352. 376. 354 . 370. 326. 350. 348 . 362 . 352 . 357 . 355 .
336. 383. 377. 372. 354 . 381. 361. 378. 326. 356. 356. 365. 360. 362. 363 .
339. 398 . 386 . 385 . 362 . 387 . 368. 389. 328 . 366. 362 . 371. 362 . 359. 367.
348, 400 , 389, 385, 368 , 389. 367. 392 . 331. 362 . 366. 375. 369. 367. 368 .
349. 405. 396. 389. 369. 396. 373 . 396. 330 . 369. 375 . 379. 379 . 371. 365 .
353 . 408 . 401. 391. 369 . 402 . 366. 402. 330 . 374 . 370. 381. 382. 382 . 366.
362 . 415 . 405 . 392 . 375. 404 . 377. 404 . 333. 378 . 379. 392 . 386 . 384 . 366.
367. 424 . 415. 400. 389. 412 . 386. 414 . 336. 381. 387. 392 . 395. 388 . 368.
370. 432 . 417. 404 . 388 . 414 . 387. 413 . 338. 385 . 389. 398 . 399. 392 . 372 .
365 . 433 . 422 . 410 . 396. 421. 392 . 426 . 344 . 388 . 397 . 405 . 404 . 400 . 378 .
366 . 438 . 427. 416 . 390 . 423 . 398 . 421. 348 . 391. 399 . 409 . 402 . 400 . 382 .
363 . 437. 428. 387.
391. 421. 388 . 414 . 334 . 385 . 397 . 404 . 407. 401 . 375 .
376. 441 . 426 . 390 . 396 . 433 . 391 . 414 . 336 . 388 . 397 . 417 . 414 . 409 . 385 .
DAY 17 18 19 20 21 22 23 24 25 26 27 28 29b 30 31 32
19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
375. 438. 429. 404 . 396. 433 . 402 . 420. 340. 385. 396. 418. 411. 406. 384 .
382 . 444. 435. 410. 396. 441. 408. 429. 343 . 392. 403 . 425. 423 . 412. 393 .
389. 443 . 436. 418 . 406. 438 . 408 . 435 . 346 . 395 . 412 . 423 . 429 . 411. 386 .
396. 446. 446. 422 . 408. 447. 411. 440. 353. 403 . 419. 433 . 433 . 422 . 399.
399. 452. 442 . 420. 412 . 451. 417. 446 . 358. 407. 420. 439. 442 . 429. 395.
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation.
396. 453 . 439. 423 . 410 . 454 . 417. 446. 352 . 406. 428. 444 . 439. 424 . 396.
403 . 457 . 444 . 437. 417. 458 . 424 . 454 . 353 . 410 . 430 . 444 . 453 . 434 . 401.
407 . 459 . 447 . 431. 423 . 457 . 425 . 455 . 360. 412 . 432 . 449. 454 . 434 . 406.
411. 467 . 451. 439. 421. 459. 429 . 458 . 360. 416. 434 . 450. 453 . 442 . 408 .
415. 469. 456 . 442 . 429 . 467 . 430 . 465 . 364 . 419. 445 . 457 . 451. 448. 411.
421. 470. 461. 444 . 433. 477. 433 . 472. 370. 424. 447. 463 . 463 . 454. 415.
413 . 476 . 464 . 447 . 434 . 479. 436 . 480 . 368 . 430 . 452 . 469 . 470 . 459 . 412 .
424 . 484 . 471 . 450 . 436 . 483 . 445 . 480 . 371. 427 . 459 . 473 . 472 . 460 . 419 .
426 . 485 . 466 . 453 . 442 . 481. 440 . 481 . 372 . 432 . 452 . 470 . 465 . 455 . 423 .
430 . 489 . 483 . 454 . 447 . 486. 449 . 487 . 372 . 433 . 462 . 480 . 476 . 462 . 423 .
431. 482 . 478 . 461 . 449 . 490 . 448 . 491 . 380 . 433 . 466 . 481 . 480 . 468 . 423 .
418-028:PAGE B-60
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B21 (PAGE 4) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DOSAGE GROUP ii
DAY 33 34 35 36
19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
431. 489. 483 . 465. 451. 491. 448. 503 . 375. 433. 466. 482. 487. 470. 426.
436. 488 . 484 . 464 . 453 . 496. 451. 506. 380. 442 . 474 . 486. 490 . 466. 420.
440. 488. 490. 464 . 453. 497. 451. 508. 379. 451. 471. 490. 497. 464 . 425.
443 . 486. 486. 461. 464 . 503 . 456. 511. 383 . 450. 475. 494 . 489. 468. 428 .
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
37
455. 499. 489. 462 . 458. 509. 450. 513 . 389. 451. 478. 495. 501. 470. 428 .
38
450 . 501. 479. 471. 456 . 493 . 440 . 504 . 382. 451. 469. 498 . 504 . 473 . 431.
0.3 MG/KG/DAY
39 40 41 42
455, 508 , 485 , 473 , 460. 506. 455. 524. 382 . 447. 478 . 498. 493 . 478. 424 ,
461. 502 . 485 . 474 . 463 . 508. 460. 523 . 387. 461. 480 . 500. 495 . 467 . 424 .
453 . 501. 488 . 474 . 466. 509. 461. 522. 386. 450 . 484 . 505. 500. 476. 427.
456. 506. 495. 481. 464 . 505. 463 . 528 . 390. 462. 497. 502 . 509. 480. 435.
43 44
428 . 476. 498 . 480. 468 . 517. 459. 534. 388. 458 . 481. 504 . 516. 486. 434 .
474 . 453 . 444 . 524. 466. 537. 389. 462 . 496. 511. 512 . 490. 443 .
45
486. 435. 495. 396. 464 . 499. 513 . 517. 489 . 444 .
46
365 . 432. 498. 506 . 521. 492 . 453 .
47
470. 487 . 484 . 455 . 421.
418-028:PAGE B-i
ON
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B21 (PAGE 5) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DOSAGE GROUP Ill
1 MG/KG/DAY
DAY 1 2 3 4 5 6 7 8 9 10 ii 12 13 14a 15 16
19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174
309 . 368 . 344 . 345 . 325 . 359. 337 . 345 . 329 . 354 . 337 . 346 . 350 . 351. 330 .
308. 372 . 350. 353 . 331. 368. 339. 346. 330. 357. 341. 351. 350. 355 . 334 .
312. 383 . 356. 360 . 334 . 381. 350. 354 . 342. 367. 347. 367 . 362 . 363 . 343 .
317 . 388. 367 . 363 . 338 . 389. 356. 356. 349. 374 . 354 . 368. 373 . 373 . 346 .
317. 395. 368. 371. 343. 403 . 365. 363. 353 . 379. 356. 376. 378 . 376. 353 .
320 . 404 . 380 . 374 . 348 . 409. 371 . 369. 355. 384 . 367. 385 . 388 . 383 . 360 .
322 . 411. 382 . 378 . 352. 403 . 375. 371. 364 . 393 . 371. 390. 398. 388. 362 .
324 . 399. 387. 381. 353 . 408 . 386. 374 . 367. 394 . 374 . 396. 402 . 393 . 369.
323 . 420. 393 . 386 . 356 . 433 . 384 . 378. 372. 396. 381. 390. 411. 395 . 374 .
318. 422 . 390 . 388 . 359. 428 . 386. 383 . 370 . 400 . 370 . 389 . 415 . 391. 377.
325. 418 . 395. 387 . 365 . 444 . 397. 385. 371. 407 . 376. 398 . 428 . 402 . 376.
327. 428 . 400. 393 . 364 . 452. 404 . 387. 383 . 408 . 380 . 408 . 430 . 405 . 383 .
333 . 432. 394 . 400 . 369. 452 . 411. 392 . 381. 412 . 388 . 403 . 420 . 410 . 389.
335 . 432 . 411. 405 . 371. 465 . 415 . 389 . 387 . 413 . 398 . 413 . 434 . 408 . 388 .
319. 429 . 403 . 406 . 363 . 445 . 407 . 384 . 386 . 405 . 383 . 401 . 414 . 409 . 373 .
326 . 439 . 414 . 398 . 361 . 477 . 415 . 386 . 393 . 412 . 396 . 409 . 437 . 413 . 386 .
DAY 17 18 19 20 21 22 23 24 25 26 27 28 29b 30 31 32
19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174
326 . 430 . 415 . 407. 366 . 474. 414 . 389 . 401. 409 . 401. 416 . 435. 426 . 388 .
337. 443 . 413 . 415 . 367. 480 . 418 . 393 . 402 . 419 . 405 . 409. 440. 430 . 388 .
333 . 454 . 415 . 415 . 374 . 488 . 426 . 397 . 404 . 426 . 409 . 417 . 447 . 432 . 396 .
340 . 453 . 424 . 423 . 370. 499 . 433 . 405 . 406. 428 . 416. 417 . 456 . 436 . 401.
343 . 455 . 432 . 424 . 381. 502 . 439. 406 . 410 . 435 . 418 . 428 . 461. 442 . 406.
335 . 462 . 428 . 433 . 379 . 511. 438 . 411. 417. 430. 422 . 428 . 464 . 441. 411.
345 . 461. 436. 433 . 389 . 522 . 439 . 415 . 421. 444 . 429 . 431. 470 . 443 . 414 .
341. 469 . 438 . 435 . 390 . 528 . 448 . 418 . 424 . 444 . 437. 435 . 479. 442 . 418 .
343 . 473 . 434 . 444 . 397 . 528 . 446. 419. 428 . 452 . 442 . 433 . 484 . 448 . 420 .
346 . 478 . 441. 445 . 400 . 533 . 454 . 421. 429. 449. 443 . 448 . 487 . 456 . 428 .
350 . 481. 439. 451. 407 . 538. 455 . 428 . 440 . 457 . 454 . 463 . 493 . 459 . 431.
353 . 491. 442 . 452 . 408 . 547 . 460 . 434 . 436 . 460 . 457. 458 . 500 . 459 . 433 .
355 . 497 . 447. 458 . 411 . 557.
461 . 433 . 443 . 462 . 458 . 462 . 505 . 463 . 437 .
359 . 500 . 451. 456 . 422 . 558 . 468 . 425 . 443 . 470 . 457 . 454 . 506 . 456 . 437 .
363 . 509. 450 . 458 . 422 . 568 . 466 . 438 . 452 . 471 . 467 . 460 . 506 . 460 . 444 .
365 . 509 . 450 . 461 . 423 . 571 . 468 . 438 . 449 . 473 . 471 . 463 . 514 . 466 . 447 .
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation.
418-028:PAGE B-62
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE B21 (PAGE 6) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DOSAGE GROUP Ill
1 MG/KG/DAY
DAY 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47
19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174
369. 515. 454 . 468. 428 . 573 . 472 . 449. 453 . 478 . 467. 470 . 514 . 467 . 449 .
370. 522 . 455. 463 . 430 . 576. 474 . 447 . 457. 478 . 474 . 466 . 508. 471. 453 .
374 . 519 . 461. 471. 435 . 579 . 481. 450 . 456. 479 . 475 . 476. 520 . 476 . 457 .
369. 528 . 457. 470 . 436. 584 . 483. 449. 462 . 481. 479 . 480. 528 . 486 . 460.
373 . 538. 458. 474 . 442 . 598. 478. 452 . 469. 481. 477 . 480. 534 . 485 . 457.
373 . 537 . 449. 473 . 442 . 590. 469. 454 . 465 . 483 . 481. 482 . 531. 483 . 462 .
374 . 536. 449. 480. 446. 602 . 482 . 448. 461. 475. 481. 485. 534 . 482 . 461.
379 . 535. 453 . 480 . 445 . 600 . 483 . 452 . 474 . 480 . 486 . 483 . 531. 466 . 457 .
375 . 533. 456. 480. 450 . 606. 489. 464. 474 . 493 . 492 . 484 . 532 . 477. 461.
379. 532. 460 . 478 . 451. 606. 491. 466. 471. 493 . 494 . 494 . 538 . 483 . 461.
353 . 505. 437. 482 . 454 . 603 . 497. 466 . 473 . 495. 493 . 494 . 541. 483 . 461.
452 . 430 . 616. 494 . 461. 473 . 496 . 502 . 484 . 547. 485 . 466 .
567 . 464 . 470 . 468 . 499 . 500 . 498 . 549 . 483 . 471.
434 . 443 . 473 . 504 . 506 . 556 . 486 . 473 .
481. 475 . 526 . 459 . 448 .
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
418-028:PAGE B-63
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER-, T-7706.1)
TABLE B21 (PAGE 7) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DOSAGE GROUP IV
3 MG/KG/DAY
DAY
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166
1
332 . 363 . 351. 342. 338. 363 . 334 . 348. 336. 356. 333 . 351. 331. 350. 356.
2
332. 363 . 360. 352 . 338. 374 . 338. 357 . 343 . 360. 330. 351. 333 . 356. 359.
3
341. 379. 366. 358. 339. 382 . 345. 368. 342 . 372 . 333 . 364 . 334 . 364 . 373 .
4
344 . 386. 375. 362 . 347 . 391. 354 . 378 . 355 . 377. 337. 375 . 338 . 368 . 385 .
5
348. 393. 383 . 363 . 354 . 396. 363 . 386. 360. 384 . 346. 376. 341. 379. 388.
6
356. 403 . 389. 370 . 357. 406 . 368. 393 . 366. 390 . 358 . 388 . 344 . 387 . 398 .
7
363 . 415 . 398 . 374 . 362 . 414 . 374 . 405. 376. 391. 361. 395. 347. 393 . 404 .
8
363 . 417. 401. 376. 364 . 422 . 379 . 410 . 378 . 396. 360 . 392 . 351. 394 . 396 .
9
366. 428 . 405 . 380 . 368. 426. 389. 418 . 388 . 399 . 368 . 392. 352. 401. 415.
10
366 . 425. 400 . 383 . 372 . 431. 387. 422 . 378 . 395. 366. 396 . 354 . 405 . 416.
11
378 . 434 . 408 . 389 . 384 . 438 . 391. 434 . 388 . 404 . 384 . 404 . 358 . 418 . 430 .
12
377 . 436. 412 . 394 . 393 . 451. 398 . 436. 389. 407 . 386. 401. 369. 412 . 430.
13
376 . 439 . 412 . 397 . 393 . 450 . 400 . 430 . 393 . 410 . 382 . 412 . 366 . 410 . 439 .
14a
381. 446 . 423 . 399 . 388 . 457 . 410 . 436. 398 . 411. 394 . 417. 369. 422 . 443 .
15
375 . 435. 426 . 399 . 386 . 452 . 407. 434 . 395. 406 . 385. 396 . 365 . 412 . 437 .
16
382 . 441 . 432 . 394 . 395 . 466 . 415 . 437 . 403 . 419 . 395 . 417 . 372 . 419 . 447 .
DAY 17 18 19 20 21
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166
390. 451. 438. 398 . 395. 462 . 420. 435. 405 . 418. 396 . 421. 377. 429. 456 .
391. 458 . 439. 406. 404 . 473 . 425 . 451. 412 . 427 . 392 . 424 . 376 . 434 . 460.
396. 457. 436 . 409. 410 . 476 . 431. 444 . 417 . 432 . 402 . 427 . 381. 438 . 465 .
400 . 470. 452 . 419 . 415 . 476 . 435 . 456 . 421. 441. 411. 434 . 382 . 453 . 473 .
403 . 468 . 454 . 425. 421. 486 . 441 . 459 . 421. 440 . 411. 437 . 390 . 455 . 480.
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation.
22
405 . 470 . 454 . 426 . 421. 490 . 438 . 462 . 424 . 436 . 409 . 431. 392 . 448 . 480 .
23
404 . 479 . 458 . 430 . 432 . 499. 448 . 471. 431. 448 . 416 . 446 . 397 . 462 . 480 .
24
408 . 489 . 461. 429. 427 . 502 . 450 . 474 . 434 . 442 . 417 . 442 . 402 . 463 . 487 .
25
411. 483 . 467 . 433 . 439. 505. 455 . 480. 437. 454 . 419 . 449 . 400. 459 . 488 .
26
414 . 486 . 464 . 434 . 440 . 512 . 463 . 494 . 438 . 450 . 423 . 450 . 408 . 463 . 493 .
27
418 . 488 . 471. 442 . 441. 519. 469 . 497 . 450 . 462 . 422 . 461 . 409 . 468 . 500 .
28
425 . 490 . 478 . 444 . 445 . 518 . 471 . 497 . 452 . 462 . 430 . 470 . 410 . 478 . 502 .
29b
428 . 492 . 479 . 446 . 449 . 531 . 472 . 509 . 455 . 464 . 436 . 464 . 415 . 484 . 503 .
30
428 . 498 . 481. 449 . 446 . 526 . 475 . 518 . 451 . 458 . 436 . 468 . 414 . 476 .
505 .
31
431. 497. 481 . 447 . 443 . 533 . 485 . 519 . 457 . 467 . 435 . 475 . 415 . 481 . 505 .
32
432 . 499 . 481. 451 . 451 . 539. 490 . 517 . 465 . 474 . 438 . 473 . 417 . 479 .
505 .
418-028:PAGE B-64
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B21 (PAGE 8) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DOSAGE GROUP IV
DAY 33 34 35 36
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166
435. 497. 484 . 448. 452. 537. 494. 524 . 460. 468 . 438. 473. 419. 491. 511.
438 . 502. 488. 452 . 453 . 537. 489. 524. 461. 463 . 442 . 475. 418. 483 . 511.
440 . 503 . 484 . 459. 454 . 543 . 491. 528. 469. 466. 441. 479. 426. 490. 517.
441. 499. 486. 458. 461. 545. 496. 531. 473 . 470. 448 . 479 . 424 . 492 . 513 .
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G).
37
445. 508 . 497. 457. 457. 556. 510. 539. 482. 470. 446. 485. 429. 494 . 519.
38
447. 513 . 499. 459 . 464 . 557. 497. 533 . 482. 472 . 450 . 488 . 427. 492. 525 .
3 MG/KG/DAY
39 40
448 . 516. 506. 464 . 470 . 566 . 501. 546. 481. 472 . 447 . 486 . 431. 497 . 525.
455. 509 . 506. 467 . 474 . 570 . 504 . 536. 489. 463 . 452 . 480. 433 . 492 . 520 .
41
449. 511. 502 . 464 . 470 . 567 . 500. 547. 485 . 478. 452 . 483 . 435 . 500 . 522 .
42
454 . 516. 506 . 469. 475 . 564 . 504 . 552. 486. 481. 457 . 481. 434 . 503 . 523 .
43 44
421. 487 . 509. 470 . 484 . 574 . 505. 547. 482 . 476. 453 . 478 . 435. 508 . 528.
476. 442 . 448. 585. 515. 553. 495. 472. 447 . 496. 441. 516. 535 .
45
545 . 479 . 523 . 495 . 479 . 455 . 493 . 449 . 513 . 531.
46
454 . 448 . 460 . 491. 445 . 512. 537 .
47
433 . 461. 415 . 486 . 506 .
418-028:PAGE B-65
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B21 (PAGE 9) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DOSAGE GROUP V
10 MG/KG/DAY
DAY 1 2 3 4 5 6 7 8 9 10 ii 12 13 14a 15 16
19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170
326. 363. 345. 344 . 329. 358. 331. 348. 325. 347. 346. 350. 329. 358 . 350.
334. 365. 346. 349. 335. 358. 328 . 349. 324 . 360. 346. 351. 329. 360. 353 .
339. 375. 354. 356. 342. 367. 347. 358. 331. 358. 354 . 362. 338. 365. 359.
346. 381. 360 . 360 . 351. 372 . 346. 366. 339. 367. 355. 368 . 341. 372. 365.
351. 382 . 365 . 365. 357. 376. 353 . 375. 339. 371. 363. 373 . 342 . 375 . 368.
360 . 387 . 372 . 370 . 366 . 382 . 359 . 375. 346. 378 . 369. 379. 352 . 379. 382 .
370 393 372 371 365 382 362 , 382, 352. 384 . 376. 384 . 356. 381, 382 .
370 . 393 . 379 . 371. 370. 385. 366. 386. 354. 385 . 371. 387 . 359. 388 . 386.
374 . 390. 382 . 377. 376 . 389. 373. 388 . 352. 382 . 378. 389. 360. 390. 386.
382 . 392 . 389. 377. 378. 394. 379. 393 . 359. 388. 381. 385. 369. 391. 390 .
390 . 404 . 389 . 384 . 379. 390 . 380. 395. 368 . 394 . 388 . 398 . 376 . 403 . 396.
389. 401. 379. 383 . 383 . 406. 387. 398. 367 . 396. 385. 395 . 378 . 403 . 395 .
391. 408 . 389. 391. 387 . 409. 388. 406. 367 . 401. 394 . 394 . 380. 409. 402 .
393 . 416. 393 . 389 . 395 . 408 . 393 . 406 . 369. 405 . 401. 401. 378. 410 . 402 .
389 . 405 . 385. 386. 362 . 411. 386 . 387 . 368 . 399 . 397 . 398 . 374 . 411. 400 .
396 . 416. 397 . 390 . 394 . 415 . 396 . 394 . 375 . 407 . 409 . 408 . 385 . 424 . 396.
DAY 17 18 19 20 21 22 23 24 25 26 27 28 29b 30 31 32
19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170
401. 410 . 403 . 394 . 388 . 414 . 401. 399 . 383 . 412 . 408 . 412 . 390 . 424 . 407 .
403 . 424 . 397. 393 . 382 . 425 . 407 . 401. 376. 415. 409. 412 . 394 . 429 . 412 .
407. 423 . 402 . 394. 384 . 429. 415 . 407. 383 . 416. 411. 414 . 388 . 431. 410.
410. 427. 409. 400. 398. 429. 417. 414 . 386. 418 . 412 . 422 . 391. 438. 418 .
412 . 428. 409. 402 . '402 . 430. 424 . 418 . 396. 426. 417 . 427 . 394 . 438 . 421 .
414 . 430. 410 . 400 . 405 . 434 . 417 . 414 . 399. 399 . 416 . 428 . 390. 436 . 420 .
426. 438. 415. 400. 464 ,C 436 . 420 . 421. 402 . 406 . 414 . 432 . 387. 446 , 424 ,
424 . 446 . 410 . 400. 417. 433 . 428 . 424 . 405 . 410. 415 . 431. 392 . 447 . 428 .
427. 444 . 413 . 406. 416 . 430 . 430. 424 . 406 . 417. 419 . 432 . 390 . 444 . 428 .
429 . 445 . 416 . 407 . 421. 440 . 436 . 430. 407 . 424 . 427 . 439. 396 . 447 . 433 .
437 . 456 . 419 . 415 . 432 . 439. 434 . 435 . 417 . 430 . 437 . 440 . 403 . 454 . 443 .
436 . 456 . 425 . 420 . 436 . 443 . 442 . 437. 417 . 432 . 437 . 447 . 404 . 456. 443 .
438 . 463 . 430 . 418 . 436 . 444 . 440. 440 . 422 . 430 . 443 . 447 . 405 . 463 . 446 .
440 . 460 . 429 . 422 . 435 . 444 . 446 . 440 . 422 . 440. 448 . 443 . 404 . 466 . 448 .
440 . 464 . 428 . 420 . 440 . 451. 450 . 447 . 433 . 445 . 452 . 446 . 409 . 461. 452 .
442 . 466 . 433 . 423 . 446 . 449 . 448 . 453 . 434 . 449. 463 . 450 . 414 . 468 . 455 .
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation. c. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses.
418-028.-PAGEB-66
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B21 (PAGE 10) : BODY WEIGHTS - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DOSAGE GROUP V
DAY 33 34 35 36
19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170
446. 465. 434 . 430. 448. 458. 452. 454. 443 . 450. 458. 449. 412. 471. 456.
456. 467. 437 . 436. 456. 457. 449 . 451. 442 . 455. 466. 448 . 414 . 469. 460 .
449. 473 . 443 . 431. 448 . 459. 456. 455 . 444 . 458. 468. 450. 418 . 472. 459.
449. 467. 438. 435 . 454 . 461. 453 . 455 . 451. 461. 472 . 453 . 414 . 484 . 465 .
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
37
457. 477 . 448. 429. 444 . 473 . 464 . 460 . 453 . 464 . 479. 461. 417. 485. 460.
38
456. 481. 445 . 438 . 454 . 463 . 454 . 463 . 460 . 463 . 477. 458 . 423 . 485 . 462 .
10 MG/KG/DAY
39 40 41
455 484 449 437 453 473 466 459 454 464 480 456 423 479. 466 .
461. 480. 445. 445 . 458 . 469. 465. 465. 463 . 476. 491. 460 . 420 . 471 . 457 .
468 . 486 . 448 . 446 . 455 . 472 . 466. 464 . 460. 479. 488 . 462 . 412. 474 . 452 .
42
466. 483 . 450. 452 . 470 . 470. 469. 471. 459. 483 . 496 . 469. 416 . 486 . 457 .
43
432. 462 . 426. 452 . 467 . 481. 473 . 473 . 462 . 485 . 490. 474 . 416 . 479 . 459.
44
426 . 434 . 486 . 486. 477. 466. 498 . 496. 461. 421. 477. 463 .
45
445 . 442 . 466 . 468 . 491. 498 . 478 . 421. 482 . 467 .
46
441 . 439 . 461. 498 . 471. 425 . 480 . 471.
47
466. 453 . 402 . 448 . 445 .
418-028:PAGE B-67
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B22 (PAGE 1): FEED CONSUMPTION VALUES - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DAYS 1- 8a 29b-36
RAT #
DOSAGE GROUP I
19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167
229. 187. 188. 236. 164. 212 . 213 . 169. 184 . 199. 196. 195 . 195 . 235. 187.
c 199. 209. 238 . 204 . 235. 222 . 189. 198. 208. 220. 190. 212 . 244 . 191.
RAT #
DOSAGE GROUP II
19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
193 . 212 . 222 . 199. 200. 200. 196. 212 . 169. 184 . 189 . 188*. 196 . 178 . 187.
200. 192 . 216. 202 . 203 . 195. 190. 226. 179. 201. 203 . 201. 246. 189. 178 .
DAY - DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation. c. Spilled feed precluded the calculation of this value.
0 MG/KG/DAY 0.3 MG/KG/DAY
418-028:PAGE B-68
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B22 (PAGE 2) : FEED CONSUMPTION VALUES - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DAYS 1- 8a 29b-36
RAT #
DOSAGE GROUP Ill
19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174
153. 207. 211. 209. 188 . 224 . 192 . 190. 207. 190. 194 . 251. 240. 206. 195 .
186. 219. 204 . 209. 199. 253 . 204 . 192 . 219. 194 . 208. 231. 222. 192 . 197.
RAT #
DOSAGE GROUP IV
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166
186 . 222 . 204 . 181. 194 . 233 . 195 . 227. 199. 214 . 176 . 214 . 171. 206 . 200 .
191. 218. 209. 188. 208. 236. 232 . 238 . 212 . 181. 177. 207. 181. 197 . 201.
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation.
1 MG/KG/DAY 3 MG/KG/DAY
418-028 :PAGE B-69
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B22 (PAGE 3) : FEED CONSUMPTION VALUES - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DAYS 1- 8a 29b-36
RAT #
DOSAGE GROUP V
19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170
193. 183. 191. 181. 198. 197. 177. 191. 170. 187. 198. 202. 175. 198. 189.
186. 206. 178. 188 . 198. 218 . 193. 194. 206. 200. 227 . 191. 168. 216. 198.
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. First value recorded after cohabitation.
10 MG/KG/DAY
418-028:PAGE B-70
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B23 (PAGE 1) : MATING AND FERTILITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DAYS IN COHABITATION
MATING STATUS
DOSAGE GROUP I
0 MG/KG/DAY
19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157a 19157b 19161 19167
7 2 3 2 4 4 3 1 4 3 3 2 4 7 2 4
DID NOT MATE M M M M M M M M M M M M M M M
DOSAGE GROUP II
0.3 MG/KG/DAY
19102 19106 191C8 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
4 i i 2 4 1 2 1 1 4
i
i 2 3 1
M M M M M M M M M M M M M M M
M MATED ( ) = FEMALE RAT NUMBER C - CONFIRMED P PREGNANT NP = NOT PREGNANT a. Result of first cohabitation period. b. Result of second cohabitation period.
MATING DATE
-
C
c c c c c c c c c c c c c c
c c c c c c c c c c c c c c c
FEMALE PREGNANCY STATUS
-(19010) P (19012) P(19019) P(19021) P (19023) P (19041) P (19042) P(19044) P(19050) P(19053) P(19065) P(19068) P (19072) P (19010) P (19074) P (19075)
P (19004) P(19009) P (19016) P(19018) P (19026) P(1903 6) P(19037) P (19043) P(1904 7) P{1904 8 P (19052) P {19055) P(19061) P (19067) P (19071)
418-028:PAGE B-71
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B23 (PAGE 2): MATING AND FERTILITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DAYS IN COHABITATION
MATING STATUS
DOSAGE GROUP III
1 MG/KG/DAY
19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174
3 3 4 2 1 4 1 4 2 3 1 4 4 2 4
M M M M M M M M M M M M M M M
DOSAGE GROUP IV
3 MG/KG/DAY
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156a 19156b 19160 19162 19163a 19163b 19166
7 4 4 2 4 1 1 7 3 1 4 6 2 4 2 7 1
DID NOT MATE M M M M M M DID NOT MATE M M
M M M M M DID NOT MATE M
M = MATED ( ) = FEMALE RAT NUMBER C = CONFIRMED P * PREGNANT NP = NOT PREGNANT a. Result of first cohabitation period. b. Result of second cohabitation period.
MATING DATE
C C C C C C C C C C C
c c c c
-
c c c c c c
-
c c c c c c c
-
c
FEMALE PREGNANCY STATUS
P (19003) P (19007) P(19008) P (19013) N P (19014) P (19015) P (19017) P (19024) P (19029) P (19034) N P (19038) P (19056) P (19057) P (19060) P (19064)
-(19002) P (19005) P (19035) P (1903 9) P (19040) P (19045) N P (19046) -(19051) P (19054) P {19058) P (19062) P (19002) P (19063) P (19066) P (19069) -(19051) P (19073)
418-028-.PAGE B-72
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B23 (PAGE 3) : MATING AND FERTILITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
DAYS IN COHABITATION
DOSAGE GROUP V
19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170
1 3 4 4 4 3 4 i 4 1 4 i i 1 1
M = MATED ( ) = FEMALE RAT NUMBER C = CONFIRMED P = PREGNANT NP = NOT PREGNANT
MATING STATUS
10 MG/KG/DAY
M M M M M M M M M M M M M M M
MATING DATE
C C C C C C
c c c c c c c c c
FEMALE PREGNANCY STATUS
P (19001) P (19006) P (19011) P(19020) P (19022) P (19025) P (19027) P (19028) P (19030) P (19031) P (19032) P (19033) P (19049) P (19059) P (19070)
418-028:PAGE B-73
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B24 (PAGE 1) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
.-P25-2.-STMl2P._I______ __ RAT #
19109
19115
19116
19119
19122
0 MG/KG/DAY
19125
19131
19132
19134
HOME CAGE BEHAVIOR
22 2 2 2 2 12 2
ALTERATIONS (HOME CAGE)
1 1 1 1 1 i 2a 1 1
REACTION TO REMOVAL
111 1 1 i 1i 1
REACTION TO HANDLING REARS IN OPEN FIELD
11 1 1 1 i1i 1 25 34 36 11 8
DEFECATION IN OPEN FIELD i 1 1 1 1 1 1 1 1
URINATION IN OPEN FIELD
2112 1 2 12 1
LEVEL OF AROUSAL
333 3 3 3 33 3
ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 i 1 1
GAIT PATTERN
1111 11 11 i
GAIT ABNORMALITY, SEVERITY
1
1
1
1
1
i
i
1
1
PALPEBRAL CLOSURE
1111 1i i1 1
PROMINENCE OF THE EYE
1111 1 1 111
LACRIMATION
111 1 1 i i1 1
SALIVATION
1111 11 i11
PILOERECTION
000 0 0 0 000
ABNORMAL RESPIRATION
0000 00 000
APPEARANCE
1 1 1 1 lb 1 1 1 1
VISUAL REACTION
22 22 2 2 222
TACTILE REACTION
2222 22
22
2
AUDITORY REACTION
3333 33 333
TAIL-PINCH REACTION
2222 2 2 222
AIR RIGHTING RESPONSE
11 1 1 1 1 11 1
PUPIL RESPONSE TO LIGHT
1i11 11 1i1
FORELIMB GRIP TEST #1 (G) 355 460 500 360 340 470 315 415 295
FORELIMB GRIP TEST #2 (G) 460 510 420 395 375 350 465 465 430
HINDLIMB GRIP TEST #1 (G) 450 320 620 315 315 490 255 300 280
HINDLIMB GRIP TEST #2 (G) 415 380 690 220 330 390 255 325 250
LANDING FOOT SPLAY #1 (CM)
6.7
9.8
8.8
7.9
4.5
8.5
7.8
8.0
7.7
LANDING FOOT SPLAY #2 (CM)
6.8
7.6
7.7
7.6
5.7
7.1
7.2
6.8
7.5
BODY WEIGHT (G)
452 487 495 527 464 529 507 445 433
VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEm "in"'t He'"b ATTERy7
a. Value appeared incorrectly recorded; value excluded from group averages and statistical analyses.
b . Chromorhinorrhea.
19135 1 1 1 1 0 1 1 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
315 370 345 275 8.4 8.4 503
418-028 :PAGE B-74
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B24 (PAGE 2) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT #
___________________________________ _________
19102
19106
19108
19110
HOME CAGE BEHAVIOR
2222
ALTERATIONS (HOME CAGE)
11i1
REACTION TO REMOVAL
11i1
REACTION TO HANDLING
11i1
REARS IN OPEN FIELD
11 8 3 11
DEFECATION IN OPEN FIELD 1 i 1 1
URINATION IN OPEN FIELD
2 i22
LEVEL OF AROUSAL
3333
ALTERATIONS (OPEN FIELD) 1 1 1 1
GAIT PATTERN
1111
GAIT ABNORMALITY, SEVERITY
1
1
1
1
PALPEBRAL CLOSURE
1111
PROMINENCE OF THE EYE
1 111
LACRIMATION
1111
SALIVATION
1111
PILOERECTION
0000
ABNORMAL RESPIRATION
0000
APPEARANCE
1111
VISUAL REACTION
2222
TACTILE REACTION
2222
AUDITORY REACTION
3333
TAIL-PINCH REACTION
2 222
AIR RIGHTING RESPONSE
1111
PUPIL RESPONSE TO LIGHT
1111
FORELIMB GRIP TEST #1 (G) 355 375 395 415
FORELIMB GRIP TEST #2 (G) 400 490 360 470
HINDLIMB GRIP TEST #1 (G) 345 435 610 365
HINDLIMB GRIP TEST #2 (G)
460
505
575
450
LANDING FOOT SPLAY #1 (CM)
11.6
9.5
7.6
8.0
LANDING FOOT SPLAY #2 (CM)
9.7
8.4
6.5
7.8
BODY WEIGHT (G)
444 489 490 467
19113 2 1 1 1 9 2 2 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
455 465 315 520 6.8 6.5 464
0.3 MG/KG/DAY 19120
221 1ii 11 1 1i1 443 211 222 333 i11 i11 111 i11 111 i11 111 000 000 111 222 222 333 222 1i1 1i1 245 250a 505 410 365 390 250 315 155 550 345b 220 6.2 12.5 7.6 4.8 12.7 7.8 496 443
i 1 i i 4 1 2 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1 215 465 435 365 8.0 9.2
VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY.
a. Vocalization and aggression observed during forelimb grip test.
b. Soft or liquid feces observed during hindlimb grip test.
1 1 1 1 5 1 2 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 i 435 550 465 335 9.9 11.5
418-028 :PAGE B-75
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B24 (PAGE 3) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP III
1 MG/KG/DAY
RAT #
19101 19105
19107
19112
19114
19121
19123
19130
HOME CAGE BEHAVIOR
22222 2 21 1
ALTERATIONS (HOME CAGE)
11 1 11 1 i1 1
REACTION TO REMOVAL
1111i 1 i11
REACTION TO HANDLING
1111i 1i1 1
REARS IN OPEN FIELD
33 72 2 3 25 6
DEFECATION IN OPEN FIELD 2 1 2 1 i 1 2 1 1
URINATION IN OPEN FIELD
222i 2 1 i1 1
LEVEL OF AROUSAL
33333 3 33 3
ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1
GAIT PATTERN
1111i 1 111
GAIT ABNORMALITY, SEVERITY
1
1
1
1
1
1
1
1
1
PALPEBRAL CLOSURE
11 11i 1 11 1
PROMINENCE OF THE EYE
11111 1 111
LACRIMATION
11 11 1 1 11 1
SALIVATION
11 111 1 11 1
PILOERECTION
00000 0 00 0
ABNORMAL RESPIRATION
00 000 0 00 0
APPEARANCE
1 1 la 1 i 1 1 1 1
VISUAL REACTION
22 222 2 22 2
TACTILE REACTION
22 222 2 22 2
AUDITORY REACTION
33 333 3 33 3
TAIL-PINCH REACTION
2 2 2 2 2 2 2b 2 2
AIR RIGHTING RESPONSE
11i11 1 111
PUPIL RESPONSE TO LIGHT
11 1i1 1 111
FORELIMB GRIP TEST #1 (G) 215 500 480 490 270 550 405 395 340
FORELIMB GRIP TEST #2 (G) 175 430 545 400 430 395 395 515 330
HINDLIMB GRIP TEST #1 (G)
520
480
540
415
395
465
375
280
305
HINDLIMB GRIP TEST #2 (G) 545 580 415 525 395 475 490 435 255
LANDING FOOT SPLAY #1 (CM)
B .2
8.7
9.7
6.8
9.0 11.8 8.5
9.7 11.1
LANDING FOOT SPLAY #2 (CM)
6.7
7.5 10.3 7.5
8.8 10.2 9.5
7.8 10.7
BODY WEIGHT (G)
375 532 459 482 439 601 476 457 467
VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERy"."
a. Localized alopecia: lower midline - right side (4.0 cm x 1.5 cm).
b. Soft or liquid feces observed during tail-pinch reaction.
c. Vocalization to touch and aggressive behavior observed during air righting response.
1 i 1 1 6 1 1 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 lc 1 570 360 220 280 8.7 7.6
418-028 :PAGE B-76
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B24 (PAGE 4) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP IV
3 MG/KG/DAY
RAT #
19100
19103
19104
19118
19133
19141
19142
19144
19148
HOME CAGE BEHAVIOR
2222 22122
ALTERATIONS (HOME CAGE)
i111 1111 1
REACTION TO REMOVAL
1111 11111
REACTION TO HANDLING
1111 11111
REARS IN OPEN FIELD
7614 4267 3
DEFECATION IN OPEN FIELD i 2 1 i i i 1 1 i
URINATION IN OPEN FIELD
2212 2i22 2
LEVEL OF AROUSAL
3333 3333 3
ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1
GAIT PATTERN
1111 11i11
GAIT ABNORMALITY, SEVERITY
1
1
1
1
1
1
1
1
1
PALPEBRAL CLOSURE
1111 11i11
PROMINENCE OF THE EYE
111 1 1111 1
LACRIMATION
1111 11i11
SALIVATION
1111 1111 1
PILOERECTION
0000 000 0 0
ABNORMAL RESPIRATION
000 0 0000 0
APPEARANCE
111 1 11i1 1
VISUAL REACTION
222 2 2222 2
TACTILE REACTION
2222 22222
AUDITORY REACTION
333 3 3333 3
TAIL-PINCH REACTION
2222 2222 2
AIR RIGHTING RESPONSE
1 1 1 1 1 1 lb 1 1
PUPIL RESPONSE TO LIGHT
111 1 i111 1
FORELIMB GRIP TEST #1 (G) 450 355 330 270 335 120 390 355 465
FORELIMB GRIP TEST #2 (G) 540 315 465 475 365 220 365 255 675
HINDLIMB GRIP TEST #1 (G)
425
520
450
380
350
270
215
200
405
HINDLIMB GRIP TEST #2 (G) 385 420 335 415 265 420 365 340 485
LANDING FOOT SPLAY #1 (CM)
7.6
10.8
6.6
9.0
6.6
6.8
9.7
8.5 11.9
LANDING FOOT SPLAY #2 (CM)
6.9
9.7
7.8
8.5
4.5
6.7
9.6
9.2 12.2
BODY WEIGHT (G)
441 505 494 472 459 563 506 538 481
VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY.
a. Chromodacryorrhea - right eye and incisors misaligned - upper bilateral.
b. Vocalization and aggression observed during air righting response.
19150 1 1 1 1 5 1 2 3 1 1 1 1 1 1 1 0 0 la 2 2 3 2 1 1
260 345 270 375 9 .4 9.6 473
418-028:PAGE B-77
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B24 (PAGE 5) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP V
10 MG/KG/DAY
RAT #
19111
19117
19124
19126
19127
19128
19140
19145
19149
HOME CAGE BEHAVIOR
22 212 2 222
ALTERATIONS (HOME CAGE)
1i111 i111
REACTION TO REMOVAL
1i 111 i11i
REACTION TO HANDLING
1 i 11 1 1 111
REARS IN OPEN FIELD
66 282 0 659
DEFECATION IN OPEN FIELD
1
1
11
2
1
1
1
1
URINATION IN OPEN FIELD
22 122 1222
LEVEL OF AROUSAL
33 333 3 333
ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1
GAIT PATTERN
11 1I1 1 111
GAIT ABNORMALITY, SEVERITY
1
1
1
1
1
1
1
1
1
PALPEBRAL CLOSURE
11 1111 111
PROMINENCE OF THE EYE
11 111 1 111
LACRIMATION
11 1111 111
SALIVATION
1 1 11 1 1 11 1
PILOERECTION
00 000 0 000
ABNORMAL RESPIRATION
00 000 0 000
APPEARANCE VISUAL REACTION
11 1111 111 22 222 2 222
TACTILE REACTION
2 2 222 2 22 2
AUDITORY REACTION
3 3 333 3 33 3
TAIL-PINCH REACTION
2 2222 2 222
AIR RIGHTING RESPONSE
11 1111 111
PUPIL RESPONSE TO LIGHT
11 111 1 111
FORELIMB GRIP TEST #1 (G) 355 335 320 580 415 300 285 165 165
FORELIMB GRIP TEST #2 (G) 365 450 350 470 470 450 450 155 275
HINDLIMB GRIP TEST #1 (G)'
500
420
510
485
440
430
430
500
250
HINDLIMB GRIP TEST #2 (G)
485
660
555
400
450
505
440
480
215
LANDING FOOT SPLAY #1 (CM)
8.1
7.5
8.1
8.8
9.1
5.3 13.0 8.1
5.8
LANDING FOOT SPLAY #2 (CM)
7.6
6.8
8.3
7.6
9.7
5.0 12.7 6.5
6.2
BODY WEIGHT (G)
458 475 440 439 463 470 462 473 466
VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY*."
19152 1 1 1 1 1 1 1 3 i 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
510 320 305 330 8.5 7.6 473
418-028:PAGE B-78
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B25 (PAGE 1): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP I
0 MG/KG/DAY
RAT NUMBER
19109
19115
19116
19119
19122
NUMBER OF MOVEMENTS
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
71 60 64 68 67
78 74 56 64 56
59 66 58 72 76
68 80 71 66 70
61 46 56 71 72
64 0 55 62 55
29 9 69 45 50
50 0 76 9 7
3 1 33 1 44
1 1 12 1 5
0 0 2 36 7
33 55
0
0 71
6 58 61 0 59
0 72 15 0 56
0 7 0 0 37
0 0 6 1 56
5 0 0 1 47
0 0 7 36 35
528 529 641 533 870
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19125
72 61 66 55 75 61 29 97 70 59 71 72 82 44 61 83 49 71 1178
19131
58 83 76 83 55 78 56 24 0 0 0 3 20 68 61 60 72 14 811
19132
62 67 76 70 47 52 50 62 40 31 47 46 73 50 12 25 44 53 907
19134
73 71 73 93 73 5 4' 0 30 73 20 43 0 0 5 0 16 8 587
19135
53 59 69 67 45 51 53 54 54 67 59 55 62 71 50 5 2 4 880
418-028-.PAGE B-79
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B25 (PAGE 2) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP I
0 MG/KG/DAY
RAT NUMBER
19109
19115
19116
19119
19122
TIME (SECONDS) SPENT IN MOVEMENT
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
185 217 193 169 161
182 182 133 186 191
161 115 110 181 149
144 127 106 166 190
106 54 113 132 129
91
0
125 111
71
70 6 140 82 125
99 0 87 8 10
0 0 31 0 113
0 0 11 1 4
0 0 0 36 6
38 91
0
0 84
9 90 60 0 95
0 67 9
0 151
0 5 0 0 105
0 0 5 0 79
4 0 0 0 100
0 0 6 46 44
1089
954
1129
1118
1807
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19125
194 201 162 88 140 158 48 124 118 122 169 114 116 127 118 102 57 125 2283
19131
229 188 183 139 92 133 65 18 0
0 0 1 21 104 99 106 72 23 1473
19132
219 184 178 129 69 135 80 165 53 43 58 72 126 90 10 24 70 56 1761
19134
224 217 173 134 94
1 2 0 50 122 12 62 0 0 3 0 16 2 1112
19135
220 210 143 191 78 87 84 102 75 186 121 119 152 108 51 3 1 3 1934
418-028 :PAGE B-80
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B25 (PAGE 3) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP II
0.3 MG/KG/DAY
RAT NUMBER
19102
19106
19108
19110
19113
NUMBER OF MOVEMENTS
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
64 55 64 64 71
69 55 61 60 56
68 59 47 66 24
63 68 65 73 15
44 60 61 59
0
32 24 51 70
0
5 54 71 65 0
3 45 60 57 2
34 77 37 64
0
6 75 60 37 51
0 53 3 0 16
1 64 0 51 1
5 58 65 0 12
14 61 64 22
0
51 53 39 20
0
36 81 51 65
0
64 78 52 46
0
63 58 41 40
0
622 1078 892 859 248
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19120
69 94 82 93 93 86 59 74 70 65 64 45 0 8 17 2 0 38 959
19129
52 58 67 67 61 77 70 59 48 56 72 66 74 59 27 2 3 6 924
19136
64 57 72 47 55 70 62 67 45 48 63 51 54 61 78 57 63 53 1067
19138
74 61 50 60 51 55 63 48 70 56 40 35 78 81 25 33 22 1 903
19139
66 65 63 61 63 63 51 52 47 77 40 37 84 68 45 49 64 44 1039
418-028 :PAGE B-:
OO
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B25 (PAGE 4) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP II
0.3 MG/KG/DAY
RAT NUMBER
19102
19106
19108
19110
19113
TIME (SECONDS) SPENT IN MOVEMENT
BLOCK I BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
215 133 150 116 35 40
1 1 33 4 0 0 1 26 113 57 93 111 1129
201 164 126 140 147 31 125 77 105 114 117 72 88 90 59 125 151 54 1986
192 152 71 162 166 103 136 81 99 78 4 0 86 120 60 63 66 37 1676
192 182 150 201 116 142 98 55 85 42
0 60 0 29 17 84 56 41 1550
176 138 24 16
0 0 0 0 0 94 49 0 7 0 0 0 0 0 504
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19120
197 160 211 144 171 135 148 162 117 94 135 90 0 2 26 0 0 43 1835
19129
19136
240 238 223 209 214 157 153 117 116 137 177 146 190 114 28 1 0 2 2462
216 209 203 129 197 125 102 146 63 95 123 181 135 152 146 121 117 139 2599
19138
191 170 144 143 83 76 71 69 125 75 58 62 207 122 15 28 21 1 1661
19139
198 198 101 123 182 88 68 129 66 133 51 60 155 102 67 76 121 46 1964
418-028:PAGE B-82
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B25 (PAGE 5) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP III
1 MG/KG/DAY
RAT NUMBER
19101
19105
19107
19112
19114
NUMBER OF MOVEMENTS
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
67 57 63 79 60
55 57 63 76 57
76 72 52 71 56
80 68 63 73 61
62 63 66 61 66
72 57 52 60 47
74 57 52 47 65
57 68 51 6 66
59 86 64 22 31
56 73 66 14 35
21 44 52 2 69
71 . 8
37 14
12
109 5 54 49
8
29 17 81 0 29
27 69 71
1
2
50 72
5
0
0
72 55 1 18 0
73 65
0 55
5
1110
993
893
648
669
TOTAL - SUM OF BLOCKS; EACH`BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19121
74 67 70 71 75 78 71 78 69 75 74 79 70 55 85 66 54 57 1268
19123
60 69 59 79 60 64 69 49 22 17 84 60 22 0 0 3 5 1 723
19130
51 55 57 43 71 52 28 43 31 47 73 60 37 53 65 47 13 42 868
19137
56 81 71 84 72 74 76 68 74 85 50 59 81 57 75 64 27 2 1156
19146
68 66 67 60 60 86 59 54 39 2 43 55 5 44 3 5 46 59 821
418-028:PAGE B-83
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B25 (PAGE 6) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP III
1 MG/KG/DAY
RAT NUMBER
19101
19105
19107
19112
19114
TIME (SECONDS) SPENT IN MOVEMENT
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
212 219 145 127 148 65 164 103 116 98 36 165 103 18 47 52 90 100 2008
226 224 156 125 191 110 79 139 154 120 76
8 1 20 135 100 81 156 2101
218 129 92 109 147 87 104 151 102 97 77 37 87 104 79 11
0 0 1631
207 144 160 138 134 93 60
2 18 6 0 11 54 0 0 0 16 76 1119
194 197 177 169 160 91 175 160 39 59 134 48
5 30 1 0 0 5 1644
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19121
201 198 197 138 157 164 112 161 208 153 170 180 113 95 139 152 162 85 2785
19123
228 220 203 141 115 139 146 73 25 11 125 138 34
0 0 5 3 0 1606
19130
236 230 187 167 151 99 29 51 82 99 99 109 24 136 140 71 18 43 1971
19137
219 202 202 188 166 201 141 132 116 131 81 in 98 65 138 211 23
1 2426
19146
207 195 206 122 134 135 92 127 76
0 62 110 2 73 1 i 76 97 1716
418-028:PAGE B-84
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B25 (PAGE 7) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP IV
3 MG/KG/DAY
RAT NUMBER
19100
19103
19104
19118
19133
NUMBER OF MOVEMENTS
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
80 55 61 54 47
84 74 72 73 69
54 69 87 87 81
57 57 75 86 78
67 43 85 71 37
29 67 62 79 41
47 60 66 62 71
62 43 64 44 12
55 53 69 27 14
32 69 65 85
0
1 50 76 74 8
1 46 89 60 18
3 14 77 77 54
58 69 63 10 71
75 63 71
3 40
54 74
61 70
0
72 62 63 72 20
67 16 57 61
5
898
984
1263
1095
666
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19141
63 69 69 71 74 66 56 63 69 51 58 54 73 69 54 57 48 47 1111
19142
73 76 67 55 77 59 49 71 83 50 65 66 56 80 54 56 66 34 1137
19144
66 75 54 48 71 64 70 80 60 49 70 57 62 53 49 67 65 74 1134
19148
54 70 74 63 42 74 66 69 63 58 68 69 53 61 67 45 67 63 1126
19150
68 73 74 64 64 58 59 62 60 41 47 31 35 58 37 25 0 0 856
418-028-.PAGE B-85
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B25 (PAGE 8) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP IV
3 MG/KG/DAY
RAT NUMBER
19100
19103
19104
19118
19133
TIME (SECONDS) SPENT IN MOVEMENT
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
198 136 83 120 120 30 59 87 82 30
0 0 0 106 113 58 146 108 1476
244 202 105 193 90 129 186 223 196 155 83 114 18 136 in 134 127 36 2482
235 171 159 156 131 109 187 108 114 94 155 136 100 102 97 100 95 88 2337
219 163 138 139 137 128 87 59 27 120 92 101 102 14
1 61 91 78 1757
171 200 138 181 55 57 141 43
9 0 3 14 87 107 43 0 13 2 1264
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19141
200 206 143 114 145 154 142 131 93 126 143 71 105 106 60 114 109 65 2227
19142
206 184 153 86 120 65 65 120 152 55 158 84 118 163 69 112 111 58 2079
19144
182 182 160 125 144 146 122 123 151 107 143 125 124 96 107 134 143 115 2429
19148
211 183 175 174 145 187 113 161 109 77 148 128 76 153 82 110 79 119 2430
19150
180 175 152 121 105 92 84 106 103 67 52 38 72 95 59 49
0 0 1550
418-028:PAGE B-86
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B25 (PAGE 9) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP V
10 MG/KG/DAY
RAT NUMBER
19111
19117
19124
19126
19127
NUMBER OF MOVEMENTS
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
62 69 57 61 72
68 66 67 72 63
67 56 63 76 61
58 50 73 63 68
62 49 65 42 25
39 50 59 51 67
59 63 62 62 30
55 74 24 61 12
46 37 42 35 75
73 40 47 51 64
44 0 45 50 33
28 39 57 37 67
44 31 64 30 86
77 0 29 64 66
75 0 39 62 57
43 0 66 61 3
71 0 72 49 56
65 1 58 31 63
1036
625
989
958
968
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19128
68 75 78 37 51 56 49 54 41 23 23 39 42 62 41 49 34 38 860
19140
64 87 72 41 62 55 54 78 87 47 82 43 21 16 61 69 6 1 946
19145
49 63 60 48 76 66 52 44 56 67 54 64 62 56 39 64 68 31 1019
19149
77 65 77 59 76 57 68 67 47 52 43 44 39 68 56 68 14 35 1012
19152
61 70 65 63 61 74 69 28 56 32 41 58 ` 11 0 0 2 3 19 713
418-028-.PAGEB-87
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE RE PRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B25 (PAGE 10) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
DOSAGE GROUP V
10 MG/KG/DAY
RAT NUMBER
19111
19117
19124
19126
19127
TIME (SECONDS) SPENT IN MOVEMENT
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
206 170 141 175 153 64 98 74 51 140 87 37 75 150 103 54 93 110 1981
161 174 110 169 75 67 81 101 63 64
0 94 54 0 0 0 0 0 1213
173 143 118 118 124 97 112 36 47 80 98 59 107 32 60 77 98 91 1670
169 116 141 115 111 96 102 64 47 47 102 65 40 66 74 95 86 21 1557
212 149 109 103 30 87 39
7 107 67 33 105 163 106 68
0 70 106 1561
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19128
192 205 128 42 65 134 104 116 81 27 17 37 48 90 66 132 42 69 1595
19140
181 176 197 86 108 64 107 90 125 49 126 42 29 14 100 142
5 0 1641
19145
243 233 231 220 158 196 195 100 196 165 80 138 135 155 95 203 108 69 2920
19149
230 158 146 126 173 94 121 98 129 87 60 57 38 120 76 68
6 55 1842
19152
181 177 166 155 141 128 120 34 90 42 69 95 16
0 0 0 2 20 1436
418-028:PAGE B-88
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B26 (PAGE 1) : SPERM MOTILITY, COUNT AND DENSITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS (See footnotes on the last page of this table.)
NUMBER
19115 19116 19119 19122 19125 19131 19132 19134 19135
19106 19108 19110 19113 19120 19129 19136 19138 19139
NUMBER MOTILE
276 254 323 328 210 256 375 302 235 332 11 232 367 333 257 334 469 293 338 223 228
MOTILE PERCENT 0 MG/KG/DAY
89 97 92 90 91 91 94 88 97 92 0.3 MG/KG/DAY 93 89 93 97 90 92 95 92 98 94
STATIC COUNT (NONMOTILE)
33 8 27 38 21 25 23 41 7 29
17 47 25 7 37 39 15 30 4 14
TOTAL COUNT a
309 262 350 366 231 281 398 343 242 361
249 414 358 264 371 508 308 368 227 242
SPERM
166 190 159 178 126 121 271 222 156
139 149 232 101 177 220 231 95 148 90
SPERM
1701.6 1598.6 1433.3 1475.8 978.7 1073.7 2496.6 1743.2 1339.9
1402.5 1455.1 1916.4 1051 .3 1515.3 1983.2 2100.6 853.7 1187.9
418-028:PAGE B-89
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCT ION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B26 (PAGE 2) : SPERM MOTILITY, COUNT AND DENSITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS (See footnotes on the last page of this table.)
RAT NUMBER DOSAGE GROUP III 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 DOSAGE GROUP IV
19103 19104 19118 19133 19141 19142 19144 19148 19150
NUMBER MOTILE
198 265 265 341 475 319 246 309 298 404
301 372 244 286 552 313 15 298 495 197
MOTILE PERCENT 1 MG/KG/DAY
89 87 90 95 97 96 90 93 92 96 3 MG/KG/DAY 91 86 95 95 97 23 90 92 88 98
STATIC COUNT (NONMOTILE)
25 38 31 19 16 12 26 23 25 16
28 60 14 16 46 17 49 32 36 29
TOTAL COUNT a
223 303 296 360 491 331 272 332 323 420
329 432 258 302 598 330 64 330 531 226
SPERM
163 186 121 173 130 248 164 190 114 121
141 171 131 86 143 217 33 88 119 117
SPERM
1575.4 1593.3 1312.4 1564.4 1290.1 2163.4 1401.9 1564.5 951.2
1215.7 1700.4 1279.8 823.2 1397.0 2026.2 716.1 1006.6 893.9
418-028'.PAGE B-90
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B26 (PAGE 3) : SPERM MOTILITY, COUNT AND DENSITY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
NUMBER GROUP V
NUMBER MOTILE
MOTILE
STATIC COUNT
PERCENT
(NONMOTILE)
10 MG/KG/DAY
TOTAL COUNT a
SPERM
SPERM
304 94 21 325 229 2354.1
19117
286
90
33
319 189 1871.7
19124
461
91
38
499 174 1490.0
19126
264
93
12 276 91 1032.3
19127
339
72
26
365 190 1805.0
19128
231
95
92
323 163 1730.3
19140
464
95
27
491 161 1578.2
19145
360
96
30 390 146 1194.1
19149
289
87
39
328 198 1789.9
19152
256
98
6 262 204
a. Sum of number motile and static count. Groups of five fields were evaluated until a sperm count of at least 200 was achieved or
20 fields were evaluated.
b. Sperm count used in the calculation of sperm density. Ten fields were evaluated.
c. The sperm density was calculated by dividing the sperm count by the volume in the image area (34.3 x 10 s mL) , multiplying by 2
(dilution factor) and multiplying by 10 to obtain the sperm concentration. The calculated sperm concentration value (rounded
to 1 decimal place) was multiplied by 50 (volume) and divided by the weight of the left cauda epididymis (see Table B19 for
the weight of the left cauda epididymis) to obtain the sperm density. The calculated value will vary by approximately 0.8%
from the Computer Automated Sperm Analysis because the digital image evaluated is slightly smaller (4 pixels) than the actual
field causing a slight underestimate of the actual volume and an overestimate of the concentration.
'9 39Vd;80*8lt7
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B27 (PAGE 1) : SPERM MORPHOLOGY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT NUMBER
NORMAL
DOSAGE GROUP I
19109 19115 19116 19119 19122 19125 19131 19132 19134 19135
186 194 189 190 192 195 194 193 196 194
DOSAGE GROUP II
19102 19106 19108 19110 19113 19120 19129 19136 19138 19139
189 196 195 192 196 190 189 196 195 195
DETACHED HEAD
0 MG/KG/DAY
6 2 7 8 3 2 3 2 1 3
0.3 MG/KG/DAY
5 i i 3 3 8 6 3 3 3
NO HEAD
7 4 4 2 5 2 2 4 2 2
4 i 2 3 1 2 4 1 i 2
BROKEN FLAGELLUM
i 0 0 0 0 1 0 0 1 1
2 1 1 2 0 0 i 0 1 0
BENT FLAGELLUM
0 0 0 0 0 0 1 1 0 0
0 1 X 0 0 0 0 0 0 0
PERCENT ABNORMAL
7.0 3.0 5.5 5.0 4.0 2 .5 3.0 3.5 2.0 3.0
5.5 2.0 2.5 4.0 2.0 5.0 5.5 2.0 2 .5 2.5
418-028-.PAGE B-92
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B27 (PAGE 2) : SPERM MORPHOLOGY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT NUMBER
NORMAL
DOSAGE GROUP III
19101 19105 19107 19112 19114 19121 19123 19130 19137 19146
198 197 189 197 191 196 192 188 192 193
DOSAGE GROUP IV
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150
196 192 198 188 192 192
4 184 194 198
DETACHED HEAD
1 MG/KG/DAY
1 1 5 1 6 2 2 5 3 5
3 MG/KG/DAY
0 4 2 4 3 5 37 10 3 0
NO HEAD
1 1 3 1 3 2 5 4 4 2
3 4 0 7 3 2 76 6 2 2
BROKEN FLAGELLUM
0 1 1 1 0 0 1 2 1 0
1 0 0 1 2 1 79 0 1 0
BENT FLAGELLUM
0 0
2
0 0 0 0 1 0 0
0 0 0 0 0 0 4 0 0 0
PERCENT ABNORMAL
1.0 1.5 5.5 1.5 4.5 2.0 4.0 6.0 4.0 3.5
2.0 4.0 1.0 6.0 4.0 4.0 98.0
3.0 1.0
418-028:PAGE B-93
O
CD
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE B27 (PAGE 3) : SPERM MORPHOLOGY - INDIVIDUAL DATA - Fo GENERATION MALE RATS
RAT NUMBER
NORMAL
DOSAGE GROUP V
19111 19117 19124 19126 19127 19128 19140 19145 19149 19152
198 197 192 196 189 191 191 196 192 191
DETACHED HEAD
10 MG/KG/DAY
1 1 6 2 6 2 8 2 3 7
NO HEAD
i i i 2 2 5 i i 3 1
BROKEN FLAGELLUM
0 1 1 0 3 2 0 1 1 1
BENT FLAGELLUM
0 0 0 0 0 0 0 0 1 0
PERCENT ABNORMAL
1.0 1.5 4.0 2 .0 5.5 4.5 4 .5 2 .0 4 .0 4.5
APPENDIX C REPORT TABLES - Fo GENERATION FEMALE RATS
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE Cl (PAGE 1) : CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II 0 0.3
III IV 13
PRECOHABITATION (DAY 1 OF STUDY TO THE DAY OF COHABITATION) :
MAXIMUM POSSIBLE INCIDENCE
210/ 15
210/ 15
210/ 15
210/ 15
MORTALITY
0 0 00
BROWN PERIORAL SUBSTANCE
RALES
LOCALIZED ALOPECIA: TOTAL HEAD LIMBS
0/ 0
0/ 0
0/ 0 0/ 0 0/ 0
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/ 1 0/ 0 4/ 1
URINE-STAINED ABDOMINAL FUR
0/ 0
0/ 0
0/ 0
0/ 0
MIOSIS
0/ 0
0/ 0
0/ 0
0/ 0
ABDOMINAL DISTENTION
0/ 0
0/ 0
0/ 0
0/ 0
EMACIATION COLD TO TOUCH
0/ 0 0/ 0
0/ 0 0/ 0
0/ 0 0/ 0
0/ 0 0/ 0
STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS. MAXIMUM POSSIBLE INCIDENCE = (DAYS X RATS)/NUMBER OF RATS EXAMINED PER GROUP. N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION.
V 10
210/ 15 0
7/ 1 7/ 1 4/ 1 4/ 1 0/ 0 3/ 1 2/ 1 2/ 1 2/ 1 1/ 1
418-028:PAGE C-
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE Cl (PAGE 2) : CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
PRESUMED GESTATION: a
I II III IV
0 0.3
13
MAXIMUM POSSIBLE INCIDENCE
330/ 15
329/ 15
338/ 15
312/ 14
MORTALITY
0 0 00
LOCALIZED ALOPECIA: TOTAL LIMBS HEAD
0/ 0 0/ 0 0/ 0
0/ 0 0/ 0 0/ 0
2/ 1 2/ 1 0/ 0
30/ 2 30/ 2
0/ 0
NOSE: SWOLLEN BACK: SCAB
0/ 0 13/ 1
0/ 0 0/ 0
0/ 0 0/ 0
1/ 1 0/ 0
BACK: ULCERATION
1/ 1
0/ 0
0/ 0
0/ 0
STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS. MAXIMUM POSSIBLE INCIDENCE = (DAYS X RATS)/NUMBER OF RATS EXAMINED PER GROUP. N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION, a. Restricted to rats with a confirmed mating date.
V 10
330/ 15 0
21/ 1 14/ 1
V1 0/ 0 0/ 0 0/ 0
418-028 :PAGE C-2
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE Cl (PAGE 3) : CLINICAL OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
MAXIMUM POSSIBLE INCIDENCE
LACTATION:
I 0
330/ 15
II 0.3
330/ 15
III 1
286/ 13
IV 3
286/ 13
MORTALITY
0 0 00
LOCALIZED ALOPECIA:
TOTAL LIMBS HEAD BACK
39/ 3 30/ 2
9/ 1 0/ 0
20/ 1 20/ 1
0/ 0 0/ 0
28/ 2 22/ 1
7/ 2 0/ 0
32/ 3 28/ 2
0/ 0 4/ 1
ABDOMINAL DISTENTION
0/ 0
0/ 0
0/ 0
0/ 0
RALES
0/ 0
0/ 0
0/ 0
0/ 0
EMACIATION
0/ 0
0/ 0
0/ 0
0/ 0
BACK OR HEAD: SCAB
13/ 3
23/ 2
0/ 0
0/ 0
DEHYDRATION
0/ 0
0/ 0
0/ 0
0/ 0
TIP OF TAIL MISSING
0/ 0
0/ 0
0/ 0
6/ 1
STATISTICAL ANALYSES OF CLINICAL OBSERVATION DATA WERE RESTRICTED TO THE NUMBER OF RATS WITH OBSERVATIONS. MAXIMUM POSSIBLE INCIDENCE = (DAYS X RATS)/NUMBER OF RATS EXAMINED PER GROUP. N/N = TOTAL NUMBER OF OBSERVATIONS/NUMBER OF RATS WITH OBSERVATION.
V 10 330/ 15
0 27/ 2 21/ 1
6/ 1 0/ 0 16/ 1 9/ 1 7/ 1 6/ 1 1/ 1 0/ 0
418-028:PAGE C-3
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C2 (PAGE 1) : NECROPSY OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III IV
0 0.3
13
RATS EXAMINED a
N 15
15
15 15
MORTALITY
N0 0 0 0
APPEARED NORMAL
N 15
15
14 13
KIDNEYS:
RIGHT, CORTEX ADHERED TO RIGHT
LATERAL LIVER LOBE
N0
0
10
OVARIES: LEFT, SMALL N 0 0 0 1
SPLEEN :
OMENTUM ADHERED TO THE LENGTH
OF THE OUTER CAPSULE
N0
0
01
LARGE AND SMALL INTESTINES:
DISTENDED WITH GAS
N0
0
00
THYMUS : SMALL
N0 0 0 0
SPLEEN: SMALL
N0 0 0 0
ADRENALS:
BILATERAL, LARGE
N0
0
00
STOMACH:
FUNDIC MUCOSAL SURFACE CONTAINED
APPROXIMATELY 12 BLACK AREAS N
0
0
00
a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy
V 10 15
0 14
0 0
0 1 1 1 1
1
418-028 :PAGE C-4
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C3 (PAGE 1) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND PRIMORDIAL FOLLICLE COUNT - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I 0
TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS
RATS TESTED
N 15
PREGNANT
N IS
TERMINAL BODY WEIGHT
MEANS.D .
306.3 26.0
BRAIN LIVER KIDNEY LEFT KIDNEY RIGHT ADRENAL LEFT ADRENAL RIGHT SPLEEN THYMUS OVARY LEFT
MEANS.D. MEANS.D. MEANS.D. MEANS.D. MEAN+S.D. MEANS.D. MEANS.D. MEANS.D . MEANS.D .
2.16 0.08 ( 10] a
14.38 2.24
[ 10] a 1.39 0.14
[ 10] a 1.47 0.12
[ 10] a 0.052 0.009
( 10] a 0.043 0.007
t 10] a 0.63 0.08
[ 10] a 0.21 0.07
[ 10] a 0.055 0.014
OVARY RIGHT
MEANS.D .
0.062 0.015
UTERUS WITH CERVIX
MEANS.D.
0.53 0.09
HEART
MEANS.D.
1.40 0.17 [ 10] a
ALL WEIGHTS WERE RECORDED IN GRAMS (G) . [ ] = NUMBER OF VALUES AVERAGED a. Only ten rats were tested.
II 0.3
15
15
324.3 27.1
2.11 0.09 [ 10] a
15.98 + 2.71 ( 10] a
1.47 0.14 ( 10] a
1.52 0.16 [ 10] a
0.051 + 0.009 [ 10] a
0.041 0.010 [ 10] a
0.65 0.09 [ 10] a
0.21 0.06 [ 10] a
0.056 0.020
0.060 0.019
0.56 0.12
1.26 0.13 [ 10] a
III 1
15
13
311.2 35.0
2 .10 0 .09 [ 10] a
14 .70 2 .92 [ 10] a
1 .38 0 .14 [ 10] a
1 .45 0 .13 [ 10] a
0. 051 0 .009 [ 10] a
0. 050 0 .Oil [ 10] a
0 -60 0 .11 [ 10] a
0 18 0 .04 [ 10] a
0 .053 0. 014
0.1060 0.1021
0 .50 0 .13
1 .35 0 .11 [ 10] a
IV 3
15
13
319.6 40.4
2 .08 0 .18 [ 10] a
15 .11 3 .28 [ 10 ]a
1 .49 0 .19 [ 10] a
1 .52 0 .13 ( 10] a
0 .053 0 .012 t io:1a
0 .04 9 0 .006 [ io:1a
0 .75 0 .31 t io;1a
0 .20 0 .10 ( 10]ta
0 .053 0. 012
0.1054 0.1012
0 .62 0 .15
1 .40 0 .13 [ 10] a
V 10
15
15
303.5 37.9
2 .12 + 0 .10 [ 10] a
13 .64 3 .18 [ 10] a
1 39 0 .10 [ 10] a
1 41 0 .15 [ 10] a
0 .053 0 .009 [ 10] a
0 .046 o .008 [ 10] a
0 .54 0 .10 [ 10] a
0 .18 + 0 .04 [ 10] a
0.1054 0.1015
0.1054 0.1018
0 .56 0 .16
1 .33 0 .25 [ 10] a
418-028:PAGE C-5
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C3 (PAGE 2) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND PRIMORDIAL FOLLICLE COUNT - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I 0
PRIMORDIAL FOLLICLE COUNT
RATS TESTED
N 15
PREGNANT
N 15
OVARY #1 OVARY #2
MEANS.D . MEANS.D.
12.58 11.01 ( 10] a
12.94 9.01 [ 10] a
ALL WEIGHTS WERE RECORDED IN GRAMS (G). [ ] = NUMBER OF VALUES AVERAGED a. Only ten rats were tested.
II 0.3
III 1
IV V 3 10
15
15
12.40 + 6.24 [ 10] a
10.14 + 2.29 [ 10] a
418-028 :PAGE C-6
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-770G WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C4 (PAGE 1) : RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I 0
RATS TESTED
N 15
PREGNANT
N 15
TERMINAL BODY WEIGHT
MEANS.D.
306.3 26.0
BRAIN LIVER KIDNEY LEFT KIDNEY RIGHT ADRENAL LEFT b ADRENAL RIGHT b SPLEEN THYMUS OVARY LEFT b
MEANS.D . MEANS.D. MEANS .D . MEANS.D . MEANS .D . MEANS.D . MEANS.D . MEANS.D. MEANS.D .
0.711 + 0.062 [ 10) a
4.703 0.450 [ 10] a
0.459 0.049 [ 10] a
0.482 0.043 [ 10] a
17.095 2.132 [ 10] a
13.984 1.612 [ 10] a
0.208 0.024 ( 10] a
0.070 0.022 [ 10] a
18.005 4.064
OVARY RIGHT b
MEANS.D . 20.307 4.390
UTERUS WITH CERVIX
MEANS.D .
0.175 0.031
HEART
MEANS.D.
0.459 0.067 [ 10] a
ALL WEIGHTS WERE RECORDED IN GRAMS (G) . [ ] = NUMBER OF VALUES AVERAGED a. Only ten rate were tested. b. Value was multiplied by 1000.
II 0.3
15
15
324.3 27.1
0.659 0.055 [ 10] a
4.947 0.703 C 10] a
0.460 0.053 [ 10] a
0.472 0.052 [ 10] a
15.856 2.913 [ 10] a
12.842 3.379 [ 10]a
0.205 0.028 [ 10] a
0.065 0.018 [ 10] a
17.632 6.782
18.514 5.844
0.175 0.042
0.392 0.057 [ 10] a
III IV 13
V 10
15 15
15
13 13
15
311.2 35.0
319.6 40.4
303.5 37.9
0.684 0.082 ( 10] a
4.697 0.512 [ loia
0.446 0.054 [ 10]a
0.467 0.042 [ 10] a
16.799 4.091 [ 10] a
16.479 4.381 [ 10]a
0.194 0.035 [ 10] a
0.059 0.016 [ 10]a
17.053 3.559
0.675 0.099 [ 10] a
4.795 0.517 [ 10]a
0.479 0.070 [ 10] a
0.492 0.058 [ 10]a
16.867 3.532 [ 10] a
15.743 2.727 l 10] a
0.238 0.076 [ 10] a
0.065 0.037 [ 10] a
16.883 4.629
0.732 0.102 ( 10] a
4.582 0.541 [ 10]a
0.477 0.040
[ 10] a 0.484 0.043
[ 10] a 18.402 4.737
[ 10] a 15.959 4.763
l io] a 0.181 0.026
[ 101 a 0.059 0.016
[ 10] a 17.611 3,620
19.152 6.400
17.025 3.632
17.529 5.247
o o U1 cn
0.162 0.046
0.198 0.063
0.185
0.436 0.054 [ 10]a
0.457 0.073 [ 10] a
0.453 + 0.056 ( 10] a
RATIOS (%) = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100.
418-028:PAGE C-7
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C5 (PAGE 1) : RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II 0 0 .3
RATS TESTED
N 10
10
BRAIN WEIGHT LIVER KIDNEY LEFT KIDNEY RIGHT ADRENAL LEFT ADRENAL RIGHT SPLEEN THYMUS OVARY LEFT OVARY RIGHT UTERUS WITH CERVIX
MEANS.D . MEANS.D . MEANS.D. MEANS.D . MEANS.D. MEANS.D . MEANS.D. MEANS.D . MEANS.D. MEANS.D. MEANS.D.
2.16 0.08 664.58 96.72
64.31 5.18 67.75 4.49
2.42 0.42 1.98 0.31 29.20 3.42 9.72 3.12 2.68 0.75 2.83 0.72 26.20 4.17
2.11 0.09 757.16 127.78
69.72 4.89 71.72 6.50
2.40 0.35 1.95 0.46 30.95 4.47 9.96 2.95 2.85 0.84 3.09 0.93 28.44 + 4.18
HEART
MEANS.D.
64.52 7.00
59.50 6.15
ALL WEIGHTS WERE RECORDED IN GRAMS (G) . * Significantly different from the Group I value (p<0.05).
III IV 13
V 10
10 10
10
2.10 0.09
2.08 0.18
2.12 0.10
701.88 155.49
729.66 165.57
641.86 141.49
65.73 6.72
71.48 6.75*
65.57 3.88
68.95 7.09
73.35 5.96
66.53 5.96
2.44 0.39
2.54 0.58
2.49 0.40
2.39 0.48
2.36 0.40
2.15 0.40
28.56 5.09
36.15 15.02
25.16 4.18
8.43 1.96
9.68 + 4.96
8.35 2.13
2.47 0.43
2.55 0.58
2.58 0.78
2.82 0.98
2.55 0.57
2.37 0.89
24.14 6.72
31.96 7.43
27.71 6.59
64.03 5.41
67.44 6.68
62.58 10.73
RATIOS (%) = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028 :PAGE C-8
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C6 (PAGE 1) : HEMATOLOGY - SUMMARY - Fo GENERATION FEMALE RATS (See abbreviations on the last page of this table.)
I
DOSAGE (MG/KG/DAY)
0
N 10
II 0.3 10
WBC (THSN/CU MM)
MEAN S.D. 9.0 3.09
13.8 5.73*
RBC (MILL/CU MM)
MEAN S.D. 6.51 0.461
6.22 0.423
HGB (GRAMS/DL)
MEAN S.D. 15.5 0.95
15.0 0.77
HCT (%)
MEAN S.D. 40.5 2.93
39.3 2.72
MCV (CU MICRONS)
MEAN S.D. 62.2 1.19
63.3 2.01
MCH (PICO GRAMS)
MEAN S.D. 23.9 0.55
24.2 0.76
MCHC (%)
MEAN S.D. 38.4 0.76
38.3 0.94
PLAT (THSN/CU MM)
MEAN S.D. 1419 153.0
1240 208.1
MPV (CU MICRONS)
MEAN S.D. 8.3 0.49
8.0
* Significantly different from the Group I value (p<0.05).
0.84
hi
i 10
ii.i 2.98 6.40 0.554 15.2 0.91 39.5 3.24 61.8 1.50 23.9 0.88 38.7 1.29 1274 226.3 8.3 0.82
IV 10 10.8 3 .14 6.39 0.532 15,2 0.90 40.1 3.02 62.9 2.04 23.8 1.25 37.8 1.22 1305 207.2 8.0 0.63
V 10 8.9 3.48 6.42 0.538 15.3 0.77 40.4 3.15 63.0 1.60 23.8 1.05 37.8 1.37 1355 176.8
418-028 :PAGE C-9
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C6 (PAGE 2) : HEMATOLOGY - SUMMARY - Fo GENERATION FEMALE RATS (See abbreviations on the last page of this table.)
DOSAGE (MG/KG/DAY)
I 0 N 10
II 0.3 10
PT (SECONDS)
MEAN S.D. 13.2 0.41
13.4 0.29
APTT (SECONDS)
MEAN S.D. 21.7 2.36
23.9 3.19
NRBC COUNT
MEAN S.D. 0
0.0
0 0.0
Lymphocytes (THSN/CU MM) MEAN S.D. 6.6 2.44
9.8 3.44*
Segmented (THSN/CU MM)
MEAN S.D. 2.2 0.90
3.6 3.69
Bands (THSN/CU MM)
MEAN S.D. 0.0 0.00
0.0 0.00
Monocytes (THSN/CU MM)
MEAN S.D. 0.1 0.15
0.3 0.49
Eosinophils (THSN/CU MM) MEAN S.D. 0.1 0.10
0.1 0.13
Basophils (THSN/CU MM)
MEAN S.D. 0.0 0.00
0.0 0.00
Abnormal L (THSN/CU MM) MEAN S.D. 0.0 0.05
0.0 0.00
Other (THSN/CU MM)
MEAN S.D. 0.0 0.00
0.0
* Significantly different from the Group I value (p<0.05).
0.00
III 1 10
13.2 0.37 23.5 2.35
0 0.0 8.4 2.60 2.4 0.93 0.0 0.00 0.2 0.13 0.1 0.13 0.0 0.00 0.1 0.07 0.0 0.00
IV 10 13.5 0.42 25.2 2.45 0 0.0 8.2 2.52 2.4 0.96 0.0 0.09 0.2 0.11 0.1 0.10 0.0 1 0.00 0.0 0.10 0.0 0.00
V 10 13.8 1.12 25.2 3.81 0 0.6 6.0 2.77 2.6 0.82 0.0 0.00 0.2 0.14 0.1 0.15 0.0 0.00 0.0 0.05
418-028 :PAGE C-10
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C6 (PAGE 3) : HEMATOLOGY - SUMMARY - Fo GENERATION FEMALE RATS
RBC HGB HCT MCV MCH MCHC PLAT MPV PT APTT NRBC Segmented Abnormal L Other
TERMINOLOGY white Blood Cells (Leukocytes) Red Blood Cells (Erythrocytes) Hemoglobin Hematocrit (Packed Cell Volume) Mean Corpuscular Volume Mean Corpuscular Hemoglobin Mean Corpuscular Hemoglobin Concentration Platelet Count Mean Platelet Volume Prothrombin Time Activated Partial Thromboplastin Nucleated Red Blood Cell Count Segmented Neutrophils Abnormal Lymphocytes Other Cells
418-028:PAGE C - ll
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C7 (PAGE 1) : CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION FEMALE RATS (See abbreviations on the last page of this table.)
DOSAGE (MG/KG/DAY)
N
TP (G/DL)
MEAN S.D.
A (G/DL)
MEAN S.D.
GLU (MG/DL)
MEAN S.D.
CHOL (MG/DL)
MEAN S.D.
TBILI (MG/DL)
MEAN S.D.
BUN (MG/DL)
MEAN S.D.
CREAT (MG/DL)
MEAN S.D.
CK (U/L)
MEAN S.D.
ALT (U/L)
MEAN S.D.
I 0 10
6.1 0.52 4.1 0.42 152 19.8 77 27.8 0.2 0.07 28 4.4 0.4 0.05 202 54.1 129 i 31.7
II 0.3 10
5.5 0.50 4.0 0.34 162 20.0 72 14.0 0.2 0.03 24 4.7 0.4 0.05 250 85.6 133 23.0
III 1 10
5.9 0.41 4.1 0.24 155 18.7 71 20.0 0.2 0.05 28 t 6.7 0.3 0.05 192 21.7 142 34.2
IV 10 5.8 0.32 4.0 0.29 146 16.2 62 14.2 0.1 0.05 25 4.4 0.4 0.08 213 80.4 127 24.7
V 10 5.8 0.29 4.0 0.31 140 35.5 61 19.8 0.1 0.05 30 15.4 0.3 0.06 252 101.6
418-028:PAGE C-12
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C7 (PAGE 2) : CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION FEMALE RATS (See abbreviations on the last page of this table.)
DOSAGE GROUP
I ii III IV
DOSAGE (MG/KG/DAY)
0 0.3 1 3
RATS TESTED
N 10
10
10 10
V 10 10
AST (U/L)
MEAN S.D.
142 22.8
135 21.6
137 11.8
124 12.1
156 40.7
ALK (U/L)
MEAN S.D.
145 t 88.7
159 81.7
CA (MG/DL)
MEAN t S.D.
10.6 0.72
11.2 0.63
PHOS (MG/DL)
MEAN S.D.
8.8 1.33
7.9 1.94
TRI (MG/DL)
MEAN S.D.
54 19.9
50 10.2
NA (MMOL/L)
MEAN S.D.
143 6.3
143 2.4
K (MMOL/L)
MEAN S.D.
5.8 0.67
5.6 0.58
CL (MMOL/L)
MEAN S.D.
96 3.4
94 2.7
G (G/DL)
MEAN S.D.
1.9 0.22
1.6 0.26**
A/G (NONE)
MEAN S.D.
2.2 0.28
2.6
** Significantly different from the Group I value (p<0.01).
0.43**
136 107.3 10.4 0.87 9.0 2.80
49 29.4 142 2.5 5.6 0.32 95 3.8 1.8 0.21 2.2 0.21
178 131.0 10.4 0.46 8.7 2.88
45 19.5 142 2.6 6.1 0.70 95 3.4 1.7 0.13 2.4 0.26
128 44.7 10.4 0.82 10.1 1.64
44 18.3 142 2.6 6.2 0.90 94 3.1 1.8 0.21 2.3 0.37
418-028 :PAGE C-13
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C7 (PAGE 3) : CLINICAL CHEMISTRY - SUMMARY - Fo GENERATION FEMALE RATS
KEY TO CLINICAL CHEMISTRY TABLE
A GLU CHOL TBILI BUN CREAT ALT AST ALK CA PHOS TRI NA K CL G A/G
TERMINOLOGY Total Protein Albumin Glucose Cholesterol Total Bilirubin Blood Urea Nitrogen Creatinine Alanine Aminotransferase Aspartate Aminotransferase Alkaline Phosphatase Calcium Phosphorus Triglycerides Sodium Potassium Chloride Globulin Albumin/Globulin Ratio
418-028:PAGE C-14
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C8 (PAGE 1) : BODY WEIGHTS - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS
418-028:PAGE C-15
o CO
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RATS TESTED
N
I 0
15
BODY WEIGHT (G)
DAY 1 DAY 2
MEANS.D . MEANS .D .
228.6 228.2 + 8.7
DAY 3
MEANS.D.
233.5 7.2
DAY 4
MEANS.D.
236.6 7.7
DAY 5
MEANS.D .
239.0 10.0
DAY 6
MEAN+S.D .
241.2 10.8
DAY 7
MEANS.D .
245.3 10.4
DAY 8
MEANS.D .
250.5 11.5
DAY 9
MEANS.D .
250.4 12.1
DAY 10
MEANS.D.
251.6 14.3
DAY 11
MEANS.D .
256.4 14.6
DAY 12
MEANS.D.
256.9 14.0
DAY 13
MEANS.D .
256.3 16.3
DAY 14a
MEANS.D .
258.5 16.1
DAY = DAY OF STUDY a. Last value recorded before cohabitation.
II 0.3
15
224.7 8.1 226.2 9.1 228.5 + 9.5 233.8 9.4 234.6 11.0 235.4 11.2 238.5 + 10.7 243.4 10.6 244.1 10.8 243.4 + 12.6 246.1 12.2 250.8 12.4 250.4 + 12.8 250.7 12.6
III 1
15
226.3 7.7 227.3 + 9.2 231.1 10.1 234.2 9.8 236.9 9.8 241.0 10.8 244 .3 10.8 246.5 + 11.6 248.3 11.8 250.0 + 12.8 254.9 13.3 254.8 12.5 255.0 13.2 257.9 i 13.6
IV 3
15
226.8 7.9 227.3 7.6 231.5 8.0 234.5 8.3 235.3 9.3 237.7 9.1 241.0 9.4 245.8 9.6 245.8 10.5 246.3 + 12.5 248.6 11.5 252.1 11.3 252.9 12.8 253.0 13.2
V 10 15
226.9 8.0 228.3 10.0 231.5 10.0 235.7 10.5 235.1 12.3 236.3 + 14.9 238.4 15.2 243.5 18.4 242.3 20.8 243.3 20.9 248.3 19.3 252.0 18.4 251.9 17.9 251 .1 18.0
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C9 (PAGE 1) : BODY WEIGHT CHANGES - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS
OH I
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RATS TESTED
N 15
BODY WEIGHT CHANGE (G)
DAYS 1 - 8
MEANS.D.
+21.9 8.3
DAYS 8 - 14a
MEANS.D .
+7.9 + 7.4
DAYS 1 - 14a
MEANS.D .
+29.9 13.7
DAYS = DAYS OF STUDY a. Last value recorded before cohabitation.
II 0.3
15
+18.7 6.3 +7.3 4.2
+25.9 7.2
III 1
15
+20.3 5.7 +11.3 6.1 +31.6 8.4
IV 3
15
+19.0 4.3 +7.2 6.4
+26.2 8.3
V 10 15
+16.7 16.0 +7.5 8.9
+24.2 + 14.4
418-028:PAGE C-16
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVE LOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE CIO (PAGE 1): MATERNAL BODY WEIGHTS - iGESTATION - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RATS TESTED
N
PREGNANT
N
MATERNAL BODY WEIGHT (G)
DAY 0
MEANS.D.
DAY 1
MEANS.D .
DAY 2
MEANS.D.
DAY 3
MEAN+S.D .
DAY 4
MEANS.D.
DAY 5
MEANS.D.
DAY 6
MEANS.D.
DAY 7
MEANS.D .
DAY 8
MEANS.D.
DAY 9
MEANS.D.
DAY 10
MEANS.D.
DAY = DAY OF GESTATION
I 0 15 15
270.1 14.3 273.7 19.9 280.5 20.2 283.4 20.6 286.5 22.2 291.3 + 20.3 294.1 + 18.7 298.0 16.1 303.3 18.0 307.9 16.8 314.1 17.2
II 0 .3
15 15
259.4 12.0 264.7 11.5 269.9 12.8 274.3 12.4 278.9 12.9 283.1 13.9 287.3 14.2 290.4 14.9 294.6 13.2 299.3 15.3 304.2 15.5
III 1
15 13
270.9 15.6 274.6 13.4 278.2 14.7 284.5 14.0 285.7 + 16.6 290.2 + 17.3 292.2 + 18.0 295.2 18.4 300.5 18.6 305.3 20.1 311.7 20.5
IV 3
15 13
265.6 15.4 270.9 14.5 275.4 15.6 278.8 16.0 282.7 17.7 286.3 16.8 288.5 18.1 291.3 + 19.1 296.2 + 22.1 301.0 22.3 306.3 22.6
V 10 15 15
260.9 18.2 266.9 19.2 269.1 18.1 275.7 18.0 277.7 20.8 280.9 19.4 283.7 19.8 287.7 20 .6 292.2 21.0 295.9 20.6 302.1 22.1
418-028:PAGE C-17
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE CIO (PAGE 2) : MATERNAL BODY WEIGHTS - GESTATION - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RATS TESTED
N
PREGNANT
N
MATERNAL BODY WEIGHT (G)
DAY 11
MEANS.D.
DAY 12
MEANS.D.
DAY 13
MEANS.D .
DAY 14
MEAN+S.D .
DAY 15
MEANS.D.
DAY 16
MEANS.D .
DAY 17
MEANS.D .
DAY 18
MEANS.D.
DAY 19
MEANS.D .
DAY 20
MEANS .D .
DAY = DAY OF GESTATION
I 0 15 15
320.7 19.6 325.6 + 19.8 331.1 19.0 338.8 17.9 345.7 18.4 353.1 23.8 365.3 26.7 383.5 27.1 398.1 31.0 412.0 35.0
II 0 .3
15 15
311.7 16.5 318.3 16.8 321.3 16.9 328.5 + 16.8 336.1 17.7 345.1 17.8 357.7 19.8 370.3 21.5 380.3 27.4 397.4 27.8
III 1
15 13
318.5 20.6 325.1 19.8 328.3 21.6 334.2 20.7 342.5 20.6 350.1 20.8 364.8 19.4 380.4 20.8 393.0 22.7 412.1 21.7
IV 3
15 13
313.6 + 22.0 319.6 26.0 323.2 25.8 329.2 26.1 335.2 26.3 342.8 29.0 356.0 30.6 365.2 25.2 380.4 24.7 398.8 + 27.6
V 10 15 15
308.6 23.3 315.0 23.9 319.3 23.3 324.1 23 .1 331.2 + 24.1 337.7 24.6 353.3 24.6 365.0 25.9 378.0 27.8 395.1 28.1
418-028:PAGE C-18
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE Cll (PAGE 1) : MATERNAL BODY WEIGHT CHANGES - GESTATION - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RATS TESTED
N
PREGNANT
N
MATERNAL BODY WEIGHT CHANGE (G)
DAYS 0 - 7
MEANS.D.
DAYS 7 - 10
MEANS.D.
DAYS 10 - 12
MEANS.D.
DAYS 12 - 15
MEANS.D.
DAYS 15 - 18
MEANS.D .
DAYS 18 - 20
MEANS.D.
DAYS 0 - 20
MEANS.D .
DAYS = DAYS OF GESTATION
I 0 15 15
+27.9 6.7 +16.1 4.9 +11.5 4.2 +20.1 4.3 +37.9 10.6 +28.5 + 16.6 +141.9 29.0
II 0.3
15 15
+31.0 7.4 +13.8 3.4 +14.1 3.3 +17.7 3.6 +34.2 7.9 +27.1 13.2 +138.0 27.4
III 1
15 13
+24.3 6.3 +16.5 5.3 +13.4 + 4.2 +17.4 + 4.0 +37.9 5.2 +31.7 6.7 +141.2 14.1
IV 3
15 13
+25.7 10.3 +15.0 6.1 +13.3 5.8 +15.5 5.5 +30.0 12.5 +33.6 9.2 +133.2 21.9
V 10 15 15
+26.9 5.8 +14.4 3.7 +12.9 6.2 +16.2 4.1 +33.8 5.7 +30.1 + 8.9 +134,2 16.9
418-028:PAGE C-19
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C12 (PAGE 1) : MATERNAL BODY WEIGHTS - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III
0 0.3
1
IV 3
V 10
RATS TESTED PREGNANT DELIVERED A LITTER MATERNAL BODY WEIGHT (G)
N N N
15 15 15
15 15 15 15 13 13 15 13 13
15 15 15
DAY i DAY 2
MEANS.D . MEANS.D .
313.1 22.6 313.1 24.6
302.2 + 16.8 300.1 17.2
309.5 20.6 305.4 18.9
304.7 23.2 304.2 22.2
296.3 19.9 298.9 19.8
DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 DAY 8 DAY 9 DAY 10 DAY 11
MEANS.D. MEANS.D . MEAN+S.D . MEAN+S.D. MEAN+S .D . MEANS.D. MEAN+S.D. MEANS.D. MEANS.D.
316.1 22.6
321.5 22.7
326.0 20.5
332.7 26.1
340.4 20.8
342.3 19.8
349.9 25.6 [ 14] a
353.6 17.9 [ 13 ]a
354.4 18.5 ( 14] a
300.2 18.6 [ 13] a
303.4 17.2* [ 13] a
307.3 14.2
312.9 11.9*
321.4 12.6*
320.7 12.6*
331.7 11.9 ( 14] a
334.9 17.5
331.9 25.7*
310.4 18.1 [ 11] a
314.2 19.8 [ 12] a
314.9 + 21.1 [ 12] a
323.9 18.2 [ 12] a
331.2 18.3
333.6 19.6 [ 12 ]a
337.4 17.3
345.5 18.2
349.2 20.3 t 12 ]a
305.0 23.1 [ 12] a
310.2 22.5 [ 12] a
311.5 23.0 [ 12 ]a
316.9 16.1 [ 111a
317.7 21.6** [ 12] a
322.2 21.5*
331.8 21.2
333.5 23.0 [ 12]a
336.4 24.6 [ 12 ]a
300.3 20.0 [ 14] a
299.3 19.7* [ 13 ]a
308.4 15.7 [ 13] a
306.0 26.9**
315.2 + 25.4**
318.1 + 26.0**
324.7 29.7**
327.4 38.3
330.2 30.8*
DAY = DAY OF LACTATION [ ) - NUMBER OF VALUES AVERAGED
a. Excludes values that appeared incorrectly recorded, as well as those associated with interrupted water access. * Significantly different from the Group I value (p<0.05).
** Significantly different from the Group I value (p<0.01).
418-028:PAGE C-20
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE C12 (PAGE 2) : MATERNAL BODY WEIGHTS - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III IV
V
0 0.3 1 3 10
RATS TESTED
N 15 15 15 15 15
PREGNANT
N 15 15 13 13 15
DELIVERED A LITTER
N
15
15
13
13
15
MATERNAL BODY WEIGHT (G)
DAY 12 DAY 13 DAY 14 DAY 15 DAY 16 DAY 17 DAY 18 DAY 19 DAY 20 DAY 21 DAY 22
MEANS.D. MEANS.D . MEANS.D . MEANS.D . MEANS.D . MEANS.D . MEANS.D . MEANS.D. MEANS.D. MEANS.D. MEANS.D .
355.7 20.2
364.1 18.5 [ :14] a
359.8 21.5
355.3 31.2
360.7 22.0
351.7 21.4
360.3 21.5
360.1 21.4
359.6 19.0
350.1 26.9 [ 14]1a
306.3 26.0
344.2 13.6 [ 14] a
342.9 17.2* [ 14] a
342.7 14.5 [ 14] a
342.4 10.4 [ 14] a
345.7 12.9
341.1 16.9
346.4 15.6
347.9 15.1
344.6 16.1
335.7 + 18.7 [ 14] a
324.3 27.1
352.6 20.1 [ 12] a
353.5 20.2 [ 12] a
353.1 17.3
343.2 17.2 [ 12] a
353.2 18.0
346.5 17.8 ( 12] a
352.2 21.5
355.0 19.6
348.8 20.6
343.4 +19.8
311.2 35.0
347.5 24.4 [ 12] a
352.0 21.8 [ 12] a
345.1 19.5
348.7 21.4 [ 12] a
348.4 21.3
339.3 26.4
352.2 21.8
357.5 25.1
352.9 24.0
344.4 25.8
319.6 40.4
334.2 32.5 [ 14] a
340.1 30.8*
335.2 32.2** f 13] a
333.4 33.6 ( 14] a
337.8 34 .3 [ 14] a
333.0 33.4
340.6 34.3
339.5 32.3 [ 14] a
338.9 34.9
334.4 35.9
303.5 37.9
DAY = DAY OF LACTATION ( ] = NUMBER OF VALUES AVERAGED a. Excludes values that appeared incorrectly recorded, as well as those associated with interrupted water access.
* Significantly different from the Group I value (p<0.05). ** Significantly different from the Group I value (p<0.01).
418-028:PAGE C-2
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C13 (PAGE 1) : MATERNAL BODY WEIGHT CHANGES - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II XIX
0 0.3
1
RATS TESTED
N 15 15 15
PREGNANT
N 15 15 13
DELIVERED A LITTER
N
15
15
13
MATERNAL BODY WEIGHT CHANGE (G)
IV 3
15
13
13
V 10
15
15
15
DAYS 1 - 5 DAYS 5 - 8 DAYS 8 - 11 DAYS 11 - 15 DAYS 15 - 18 DAYS 18 - 22
MEANS.D . MEANS.D . MEANS.D. MEAN+S.D . MEANS.D. MEAN+S.D.
+12.9 10.2
+16.3 9.6
+13.9 7.1 [ 14] a
-0.7 22.4 [ 14] a
+4.9 21.8
-54.0 25.3
+5.1 10.7
+13.5 7.4
+11.1 19.2
+12.8 19.9 [ 14] a
+2.2 11.9 [ 14] a
-22.1 26.7
+7.2 12.7 [ 12] a
+17.3 7.6 [ H]a
+14.4 5.6 [ 11] a
-3.7 + 13.2
[ 11] a +7.9 18.0
[ 12] a -41.1 33.6
+7.7 14.8 [ 12] a
+11.0 11.0 [ 12] a
+13.6 10.6 [ 12] a
+13.8 9.7 [ 11] a
+4.1 6.3 [ 12 ]a
-32.5 28.2
+7.8 15.1 [ 13 ]a
+16.5 10.1 [ 133a
+12.1 10.8
+3.7 + 11.2 [ 14 ]a
+7.4 11.4 [ 14 ]a
-37.1 29.8
DAYS 1 - 22
MEANS.D.
-6.9 28.4
+22.1 + 26.0
+1.7 28.0
+14.9 31.8
+7.3 29.3
DAYS = DAYS OF LACTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that appeared incorrectly recorded, as well as those associated with interrupted water access.
418-028:PAGE C-22
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-770S WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C14 (PAGE 1) : ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III
0 0.3
1
RATS TESTED
N 15
15 15
FEED CONSUMPTION (G/DAY)
DAYS 1 - 8
MEANS.D.
20.4 1.8 [ 13] a
19.5 l.S
20.7 2.0
DAYS = DAYS OF STUDY [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that were not recorded, as well as those associated with spillage.
IV 3
15
19.5 1.8
V 10 15
19.6 3.0
418-028:PAGE C-23
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C15 (PAGE 1) : RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - PRECOHABITATION - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RATS TESTED
N
FEED CONSUMPTION (G/KG/DAY)
I 0
15
II 0.3
15
III 1
15
DAYS 1 - 8
MEANS.D.
- 5.5 13] a
83.4 5.6
87.9 7.0
DAYS = DAYS OF STUDY [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that were not recorded, as well as those associated with spillage.
IV 3
15
83.0 5.2
V 10 15
83 .3
418-028:PAGE C-24
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C16 (PAGE 1) : MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - GESTATION - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I 0
RATS TESTED
N 15
PREGNANT
N 15
MATERNAL FEED CONSUMPTION (G/DAY)
DAYS 0 - 7
MEANS.D .
25.4 3.3
DAYS 7 - 10
MEANS.D.
27.7 2.8
DAYS 10 - 12 DAYS 12 - 15
MEANS.D. MEANS.D .
32.0 10.5 ( 14] a
28.4 2.8
DAYS 15 - 18
MEANS.D.
25.4 4.0
DAYS 18 - 20
MEAN+S.D .
26.6 5.7
DAYS 0 - 20
MEAN+S.D.
26.9 3.2
DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that were associated with spillage.
II 0.3
15
15
25.0 26.8 27.0 27.5 26.7 22.8 25.9
2.5 2.8 3.2 2.4 3.1 6.2 2.4
III 1
15 13
24.3 2.7 26.3 3.4 28.0 3.2 27.5 2.1 25.9 2.1 25.8 3.2 25.8 2.0
IV 3
15 13
25.2 + 3.6 26.3 5.0 26.6 + 3.9 26.7 3.9 25.3 3 .6 25.0 3.7 25.7 3.0
V 10
15
15
24.0 25.8 27.0 27.5 26.0 26.1 25.6 +
2.1
2 .5 2.8 2.6 3.3 4.8 2.3
418-028 :PAGE C-25
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C17 (PAGE 1) : MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - GESTATION - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I 0
RATS TESTED
N 15
PREGNANT
N 15
MATERNAL FEED CONSUMPTION (G/KG/DAY)
CO co 00 H-
DAYS 0 - 7
MEANS.D.
8.4
DAYS 7 - 10
MEANS.D .
90.5 7.4
DAYS 10 - 12 DAYS 12 - 15
MEANS .D . MEANS.D .
99.0 28.7 [ 14] a
84.9 7.3
DAYS 15 - 18
MEANS.D.
70.0 8.5
DAYS 18 - 20
MEANS.D.
66.4 12.4
DAYS 0 - 20
MEANS .D .
83.3 6.6
DAYS = DAYS OF GESTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that were associated with spillage.
II 0.3
15 15
90.4 7.1 90.0 7.0 86.5 8.0 84.4 5.8 75.6 + 6.9 59.3 15.4 82.6 5.6
III 1
15 13
85.6 6.9 86.4 7.4 87.9 + 6.1 82.7 4.9 72.3 + 6.2 65.4 7.9 80.5 3.1
IV 3
15 13
89.8 9.3 87.7 12.7 84.8 7.0 81.5 6.9 72.2 7.4 66.1 11.8 81.6 5.4
V 10 15 15
86.8 + 5.5 87.6 5.4 87.3 4 .3 85.6 7.2 75.1 8 .3 68.7 + 10.7 82.5 4.0
418-028-.PAGEC-26
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770G.1)
TABLE C18 (PAGE 1) : MATERNAL ABSOLUTE FEED CONSUMPTION VALUES (G/DAY) - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
i ii 0 0.3
RATS TESTED
N 15
15
PREGNANT
N 15
15
DELIVERED A LITTER
N
15
15
MATERNAL FEED CONSUMPTION (G/DAY)
DAYS 1 - 5 DAYS 5 - 8
MEANS.D. MEAN+S.D.
38.5 61.2
7.1 6.4
27.6 8.7** [ 14] a
53.7 6.6
DAYS 8 - 15
MEAN+S.D.
71.6 8.6
68.3
DAYS 1 - 15
MEAN+S.D.
59.9 7.0
54.3 +
DAYS = DAYS OF LACTATION [ ] = NUMBER OF VALUES AVERAGED a. Excludes values that were associated with spillage. * Significantly different from the Group I value (p<0.05). ** Significantly different from the Group I value (p<0.01).
8.3* 7.1
III 1
15 13 13
33.2 4.0 [ 12] a
55.9 4.4 69.2 4.0 56.9 4.9
IV V 3 10
15 15
13 15
13 15
31.4 + 5.5* 49.4 10.2 69.6 9.5** 54.4 7.2
34.4 7.9 [ 14 ]a
5 2 . 3 + 9.0
68.2 9.4**
55.7 8.2
418-028:PAGE C-27
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.X)
TABLE C19 (PAGE 1) : MATERNAL RELATIVE FEED CONSUMPTION VALUES (G/KG/DAY) - LACTATION - SUMMARY - Fo GENERATION FEMALE RATS
1 1
11
1
1
1
1
111 >
1
1
1
i
1
o H
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III
0 0.3
1
RATS TESTED
N 15 IS 15
PREGNANT
N 15 15 13
DELIVERED A LITTER
N
15
15
13
MATERNAL FEED CONSUMPTION (G/KG/DAY)
IV 3
15
13
13
15 15 15
DAYS 1 - 5 DAYS 5 - 8 DAYS 8 - 11 DAYS 11 - 15 DAYS 1 - 15
MEANS.D. MEANS.D . MEANS.D . MEANS.D . MEANS.D .
121.1 21.3
183.0 20.6
176.1 134.6 [ 14] a
222.6 97.5 [ 14] a
176.7 19.5
91.8 + 27.8** [ 14] a
170.4 23.5
176.1 109.9
225.3 64.3 [ 14] a
166.9 22.6 [ 14] a
107.6 15.0 [ 12] a
170.6 12.2 [ 11] a
101.9 97.9
[ 11] a 276.0 76.3
[ 11] a 172.4 11.5
[ 12] a
102.7 21.2 t 12] a
155.2 32.4** [ 12] a
155.4 134.0 [ 12] a
245.4 89.7 [ 11] a
166.6 20.2 [ 12] a
118.7 22.1 ( 12 ]a
168.2 + 20.0 [ 12 ]a
138.4 127.0
248.7 81.6 [ 14 ]a
175.1 14.9 ( 14 ]a
DAYS = DAYS OF LACTATION [ ] = NUMBER OF VALUES AVERAGED
a. Excludes values that appeared incorrectly recorded, as well as those associated with interrupted water access or spillage. ** Significantly different from the Group I value (p<0.01).
418-028:PAGE C-28
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C20 (PAGE 1) : MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - SUMMARY - Fo GENERATION FEMALE RATS
1
1
1
1
1
1
1
111 >
1
(
1
l
1
1
DOSAGE GROUP DOSAGE (MG/KG/DAY)
ESTROUS CYCLING OBSERVATIONS
RATS EVALUATED
N
ESTROUS STAGES/ 13 DAYS
MEANS.D .
RATS WITH 6 OR MORE CONSECUTIVE DAYS OF DIESTRUS
N
RATS WITH 6 OR MORE CONSECUTIVE DAYS OF ESTRUS
N
i 0
15 2.7 0.9
1
0
II 0.3
15 2.8 0.9
0
0
III 1
15 3.3 0.6
0
0
IV 3
15 2.9 + 0.8
0
1
o fl
15 2.1 1.2
1 0
418-028:PAGE C-29
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C20 (PAGE 2) : MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III
0 0.3
1
RATS IN COHABITATION
N 15
15
15
DAYS IN COHABITATION a
MEAN+S.D . 3.7 3.0
1.9 1. 2
2.8 1.2
RATS THAT MATED
N(%)
15(100.0)
15(100.0)
15(100.0)
FERTILITY INDEX b
N/N 15/ 15 (%) (100.0)
15/ 15 (100.0)
13/ 15 ( 86.7)
RATS WITH CONFIRMED
MATING DATES
N 15 15 15
MATED BY FIRST MALE c DAYS 1-7
N (%)
14( 93.3)
15(100.0)
15(100.0)
MATED BY SECOND MALE c DAYS 8-14
N (%)
1( 6.7)
0( 0.0)
0( 0.0)
RATS PREGNANT/RATS IN COHABITATION
N/N 15/ 15 <%) (100.0)
15/ 15 (100.0)
13/ 15 ( 86.7)
a. Restricted to rats with a confirmed mating date and rats that did not mate. b. Number of pregnancies/number of rats that mated.
c. Restricted to rats with a confirmed mating date.
IV 3
15 4 . 0 + 4.0 14 ( 93.3)
13/ 14 ( 92.8)
14
13( 92.8)
M 7.2)
13/ 15 ( 86.7)
v 10 15 2.5 1.4 15(100.0) 15/ 15 (100.0)
15
15(100.0)
0( 0.0)
15/ 15 (100.0)
e-3 39Vd:8cO-8lfr
O
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C21 (PAGE 1) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS
iiiitiiiiiiiiiiiii -
iiiiiiiiiiii
|> 2 11111111
DOSAGE GROUP
I II III
DOSAGE (MG/KG/DAY!
0 0.3
1
FEMALE RATS
N 10
10
10
10
10
HOME CAGE BEHAVIOR 1: Sleeping 2: Awake, Immobile 3: Normal movement 4 : Unusual posture 5: Unusual behavior
N N N N N
1 1 8 0 0
4 2 4 0 0
4 1 5 0 0
4 3 3 0 0
i 4 5 0 0
ALTERATIONS (HOME CAGE) 1: None 2 : Stereotyped behavior 3: Bizarre behavior 4 : Limb twitches/tremor 5: Whole body tremor/spasm 6: Unusual posture 7: Tonic-clonic seizure
N N N N N N N
10 0 0 0 0 0 0
10 0 0 0 0 0 0
10 0 0 0 0 0 0
10 0 0 0 0 0 0
10 0 0 0 0 0 0
REACTION TO REMOVAL di Sits quietly (2) Vocalization (3) Runs or freezes (4) Tail or throat rattles
N N N N MEAN SCORE
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0 1.0
REACTION TO HANDLING
di No resistance
KT 10
(2) Vocalization
N0
(3) Tense
N0
(4) Squirming
N0
MEAN SCORE
1.0
n: - Category number for descriptive test item.
10 0 0 0 1.0
10 0 0 0 1.0
10 0 0 0
10 0 0 0
n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score and then dividing the sum of the products by the total number of rats
418-028:PAGE C-31
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
<! 1 1 t t <1 1 1 1 11
TABLE C21 (PAGE 2) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY) FEMALE RATS
N
REARS IN OPEN FIELD
MEANS.D.
DEFECATION IN OPEN FIELD 1: None 2 : Feces normal 3: Soft or liquid feces
N N N
URINATION IN OPEN FIELD (1) None ( 2 ) Normal urination (3) Excess urination
N N N MEAN SCORE
LEVEL OF AROUSAL (1) Stuporous ( 2 ) Sluggish (3) Apparently normal (4) Sudden darting (5) Freezing, vocalization
N N N N N MEAN SCORE
I 0 10
12.0 3.6
8 2
0
6
4 0 1.4
0 0 10 0 0 3.0-
II
10
13.0 2.7
10 0 0
7 3 0 1.3
0 0 10 0 0 3.0
III
10
11.6 3.5
6
1 1
7 3 0 1.3
0 0 10 0 0 3.0
IV
10
10.7 2.3
8
1 1
10 0 0 1.0
0 0 10 0 0 3.0
10
10.9 2.6
8
2
0
8
2 0 1.2
0 0 10 0 0 3.0
S
ALTERATIONS (OPEN FIELD)
1: None 2 : Stereotyped behavior 3 : Bizarre behavior 4 : Limb twitches/tremor 5: Whole body tremor/spasm 6 : Unusual posture 7; Tonic-clonic seizure
N N N N N N N
10 0 0 0 0 0 0
10 0 0 0 0 0 0
10 0 0 0 0 0
10 0 0 0 0 0
10 0 0 0 0 0
n : = Category number for descriptive test item.
(n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score and then dividing the sum of the products by the total number of rats
418-028:PAGE C-32
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C21 (PAGE 3) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS
i> 2
DOSAGE (MG/KG/DAY) FEMALE RATS
i 0 N 10
II 10
III 10
IV 10
10
GAIT PATTERN 1: Apparently normal 2: Ataxic 3: Limbs splay or drag 4: Spastic, tip-toe 5: Duck-walk 6: Scissors gait
N N N N N N
10 0 0 0 0 0
10 0 0 0 0 0
10 0 0 0 0 0
10 0 0 0 0 0
8 0 0 2 0 0
GAIT ABNORMALITY, SEVERITY
(1) Normal gait
N 10
10
10
10
(2) Slight
N0
0
0
0
(3) Moderate
N0
0
0
0
(4) Extreme
N0
0
0
0
MEAN SCORE
1.0
1.0
1.0
1.0
8 2 0 0 1.2
PALPEBRAL CLOSURE
(1) Wide open
N 10
10
10
10
(2) Slightly drooping
N
0
0
0
0
(3) Half-closed
N0
0
0
0
(4) Completely shut
N
0
0
0
0
MEAN SCORE
1.0
1.0
1.0
1.0
10 0 0 0 1.0
PROMINENCE OF THE EYE
1: Normal
N 10
10
10
10
2 : Exophthalmos
N0
0
0
0
3: Enophthalmos
N0
0
0
n: Category number for descriptive test item
10 0
(n) Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score and then dividing the sum of the products by the total number of rats
418-028.-PAGE C-33
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
<! 1 1 1 1 1( 1 1 1 1 1
TABLE C21 (PAGE 4): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS
i i i i i i i i i i i i i i
j>
i t i i i i
i
i i i i i i i i i i i i
DOSAGE GROUP DOSAGE (MG/KG/DAY)
LACRIMAI ION
(1) No excess
N
(2) Excess at eyelid margin
N
(3) Margin persistently damp (4) Extends beyond margin
N N
MEAN SCORE
I 0
10 0 0 0 1.0
h
10
10 0 0 0 1.0
III
10
10 0 0 0 1.0
SALIVATION
(1) No excess
N
(2) Margin of mouth wet
N
(3) 1/4 to 1/2 submandibular (4) Entire submandibular
N N
MEAN SCORE
10 0 0 0
1.0
10
0 0 0 1.0
10 0 0 0 1.0
PILOERECTION
N0 0 0
ABNORMAL RESPIRATION
N
0
0
0
APPEARANCE
(1) Clean and groomed (2) Unkempt
N N
10 0
10 0
9
1
(3) Urine and/or fecal stain N MEAN SCORE
0 1.0
0 1.0
0 1.1
10
10 0 0 0 1.0
10 0 0 0 1.0
0
0
9
0 1
1.2
10
10 0 o 0 1.0
10 0 o 0 1.0
0
1
10 0 0 1.0
S
VISUAL REACTION
(1) None
N0
(2) Orienting
N 10
(3) Startle (4) More energetic reaction
N N
0
0
(5) Attacks
N0
MEAN SCORE
2.0
n: Category number for descriptive test item.
0
10 0 0
0 2.0
0 10 0 0 0 2.0
0
10 0 0 0
0
10
0
0 0
(n) Score assigned to graded test items; mean score was calculated by multiplying each score b y t h e n u m b e r o f r a t s w i t h t h a t s c o r e and then dividing the sum of the products by the total number of rats
418-028:PAGE C-34
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C21 (PAGE 5) : FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS
s <i 1 1 1 1 1 1 1 1 1 1
DOSAGE GROUP DOSAGE.(MG/KG/DAY) FEMALE RATS
I 0 N 10
II 0.3 10
III 1 10
IV 10
10
' TACTILE REACTION
t u None
N0
0
0
0
(2) Orienting
N 10
10
10
10
(3) Startle
N0
0
0
0
(4) More energetic reaction
N
0
0
0
0
(5) Attacks
N0
0
0
0
MEAN SCORE
2.0
2.0
2.0
2.0
0 10 0 0 0 2.0
AUDITORY REACTION
d i None
N0
0
0
0
(2) Orienting
N0
0
0
1
(3) Startle (4) More energetic reaction
N N
10 0
10 0
10 0
9 0
(5) Intense vocalization
N
0
0
0
0
MEAN SCORE
3.0
3.0
3.0
2.9
0 1 9 0 0 2.9
TAIL'-PINCH REACTION
d i None
N0
0
0
0
(2) Orienting
N8
9
8 10
(3) Startle
N2
1
2
0
(4) More energetic reaction
N
0
0
0
0
(5) Attacks
N0
0
0
0
0 9 1 0 0
MEAN SCORE
2.2
2.1
2.2
2.0
n: = Category number for descriptive test item.
2.1
(n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score
and then dividing the sum of the products by the total number of rats
418-028:PAGE C-35
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C21 (PAGE 6): FUNCTIONAL OBSERVATIONAL BATTERY - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY) FEMALE RATS
I 0 N 10
ii III 10 10
IV 10
V 10
AIR RIGHTING RESPONSE
(1) All feet land on ground
N
(2) Lands on side (3) Lands on back
N N
MEAN SCORE
10 0 0 1.0
10 0 0 1.0
10 0 0 1.0
10 0 0 1.0
10 0 0 1.0
PUPIL RESPONSE TO LIGHT
N
10
10
10
10
10
FORELIMB GRIP TEST Maximum (G) Average (G)
MEANS.D. 509.5 161.7 MEANiS.D. 455.9 136.7
396.5 125.7 319.8 100.6
492.5 257.7 423.9 207.3
493.0 112.3 452.5 103.4
518.5 460.3
161.9 166.4
HINDLIMB GRIP TEST Maximum (G) Average (G)
MEAN+S.D. 462.0 + 111 .3 MEANS.D. 423.0 113.7
412.5 104.7 366.5 77.3
455.5 + 87.7 418.3 79.4
397.0 67.5 362.8 79.8
485.5 427.3
+ 71.5 52.2
LANDING FOOT SPLAY Average (CM)
MEANS.D .
7.7 1.8
6.7 1.0
7.7 1.5
7.1 + 1.4
8.1 1.7
BODY WEIGHT (G)
MEANS.D. 353.4 22.0
n: Category number for descriptive test item.
347.2 14.8
350.6
22.8
(n) = Score assigned to graded test items; mean score was calculated by multiplying each score by the number of rats with that score and then dividing the sum of the products by the total number of rats
418-028:PAGE C-36
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C22 (PAGE 1) : MOTOR ACTIVITY - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
NUMBER OF FEMALE RATS
NUMBER OF MOVEMENTS
N
i 0
10
II 0.3
10
BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK TOTAL
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
MEAN MEAN MEAN MEAN MEAN MEAN t MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN
72.0 53.8 50.4 28.6 27.5 23.9 11.6 19.3 21.4 19.6
9.2 18.1 12.1 16.0 22.2 23.2 32.2 25.9 487.0
6.9 25.7 26.5 34.7 24.0 26.5 16.0 18.1 21.0 22.1 10.6 25.5 18.3 19.0 30.6 27.2 33.8 28.5 244.9
67.1 53.6 41.2 30.7 21.2 19.4 17.8 13.2 10.5 6.5
7.0 5.9 15.0 19.0 13.0 15.0 11.7 10.8 378.6
7.6 20.8 34.2 25.5 23.6 20.7 23.2 18.6 24.3 7.2 16.6 i 5.3 22.1 19.6 15.7 16.7 18.6 + 14.7 202.4
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
III 1
10
68.3 66.6 50.2 43.9 43.6 42.6 44.5 38.0 28.1 29.4 26.9 21.1 24.3 24.4 23.6 24.5 24.7 17.9 642.6
6.8 12.4 17.0 26.8 26 -4 29.5 21.3 20.5 25.4 29.3 28.2 26.2 26.3 30.8 25.9 28.2 27.9
18.9 295.6
IV V 3 10
10 10
65.7 57.1 49.3 39.0 33.9 35.0 38.3 44.5 34.0 25.9 23.5 21.8 19.8 24.4 19.8 27.2 21.9 19.0 600.1
9.7 18.2 21.4 25.1 + 24.2 26.8 29.4 18.0 19.0 23.5 + 22.7 + 20.4 + 25.0 26.2 24.9 29.0 + 23.2 25.3 292.0
68.4 42.5 31.1 20.5 18.6 19.7 14.0 32.6 27.9 15.5 19.7 29.7 22.1 16.8 15.1 19.2 18.3 22.6 454.3
9.8 19.9 24.6 + 22.9 + 22.4 + 18.0 17 .3 26.2 24.6 16.5 22.6 + 21.4
25.5 18.3 + 20.2
18.9 25 .6 + 20.9 261.4
418-028:PAGE C-37
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C22 (PAGE 2) : MOTOR ACTIVITY - SUMMARY - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
NUMBER OF FEMALE RATS
N
TIME (SECONDS) SPENT IN MOVEMENT
I 0
10
II III 0.3 1
10 10
BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK BLOCK TOTAL
1 2 3 4 5 6 7 S 9 10 11 12 13 14 15 16 17 18
MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN MEAN
154.8 27.4 95.3 50.4 65.7 + 36.2 30.6 41.4 33 .6 36.5 27.5 37.9 11.7 18.4 25.4 29.0 25.5 28.6 25.2 30.0 11.8 14.7 22.9 35.7 14.0 23.3 14.8 20.2 30.1 46.0 27.0 33.9 40.7 46.3 38.2 45.8
694.8 331.8
141.5 94.0 60.1 48.0 27.5 31.0 21.4 15.5 13.8 6.2 8.3 4.2 14.7 24.1 15.5 17.6 13.7 9.6
566.7
46.3 54.4 48.0 48.9 30.6 41.8 31.9 26.5 37.1 9.6 21.8 3.7 21.0 + 27.9 23.7 24.1 27.6
14.8 350.6
154.4 32.2 114.4 24.2
88.5 + 56.9 70.2 + 52.2 63.4 42.7 56.1 41.1 69.0 46.5 60.7 36.2 37.9 41.2 38.7 44.1 39.7 44.2 34.4 48.6 38.4 + 52.5 34.5 48.1 36.4 44.5
36.1 42.1 37.8 48.8 18.1 23.2 1028.7 477.6
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
IV V 3 10
10 10
181.0 36.4 119.5 56.0
94.4 55.9 73.0 61.1 52.0 47.4 56.7 47.1 65.3 59.7 70.1 26.6 66.6 58.8 41.6 49.9 37.2 46.8 26.6 25.8 33.4 49.6 33.1 + 42.5
33.0 54.3 38.6 40.7 34.9 46.8 29.3 48.7 1086.3 711.3
146.2 26.1 96.6 63.6 52.3 51.5 34.6 45.9 27.6 35.5 31.0 30.6 16.5 29.0 41.7 38.3 40.1 38.6 14.1 + 16.3 24.6 33.0 38.7 34 .5 32.7 43 .3 25.6 30 .6 17.3 + 25.7 18.5 23.1 21.7 33.6 27.6 30.1
707.4 442.6
418-028:PAGE C-38
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE C23 (PAGE 1) : NATURAL DELIVERY OBSERVATIONS - SUMMARY - Fo GENERATION FEMALE RATS
1 11111 1 (-* 1 O < >1 1 1 < t1 11 1
DOSAGE GROUP DOSAGE (MG/KG/DAY)
I II III
0 0.3
1
IV 3
RATS ASSIGNED TO
NATURAL DELIVERY
N
15
15
15
15
15
PREGNANT
N (%)
15(100.0)
15(100.0)
13( 88.7)
13( 88.7)
15(100.0)
DELIVERED LITTERS
N (%)
15(100.0)
15(100.0)
13(100.0)
13(100.0)
15(100.0)
DURATION OF GESTATION a MEANS.D.
22.5 0.5
22.7 0.4
22.7 0.5
22.8 0.4
22.6 0.5
IMPLANTATION SITES
N
PER DELIVERED LITTER MEANS.D.
251 16.7 1.3
230 15.3 2.9
206 15.8 1.3
192 14.8 2.8
231 15.4 2.3
DAMS WITH STILLBORN PUPS N (%)
0( 0.0)
0( 0.0)
M 7.7)
3 ( 23.1)
2 ( 13.3)
DAMS WITH NO LIVEBORN PUPS N
0( 0.0)
0( 0.0)
0( 0.0)
0( 0.0)
0 ( 0.0)
GESTATION INDEX b
% N/N
100.0 15/ 15
100.0 15/ 15
100.0 13/ 13
100.0 13/ 13
100.0 15/ 15
DAMS WITH ALL PUPS DYING DAYS 1-4 POSTPARTUM
N(%)
0( 0.0)
0( 0.0)
0( 0.0)
0( 0.0)
0( 0.0)
DAMS WITH ALL PUPS DYING DAYS 5-22 POSTPARTUM
N (%)
0( 0.0)
0( 0.0)
0( 0.0)
0( 0.0)
0( 0.0)
a. Calculated as the time (in days) elapsed between confirmed mating (arbitrarily defined as day 0) and the time (in days) the first pup was delivered.
b. Number of rats with live offspring/number of pregnant rats.
418-028:PAGE C-39
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C24 (PAGE 1) : LITTER OBSERVATIONS (NATURALLY DELIVERED PUPS) - SUMMARY - FI GENERATION LITTERS
418-028:PAGE C-40
111 > o 1 1 1 1 1 1 1
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)
I 0
DELIVERED LITTERS WITH ONE OR MORE LIVEBORN PUPS
N
15
PUPS DELIVERED (TOTAL)
N
MEAN+S.D.
235 15.7 1.7
LIVEBORN
MEANS.D. N (%)
15.7 1.7 235(100.0)
STILLBORN
MEANS.D . N(%)
0.0 0.0 0( 0.0)
UNKNOWN VITAL STATUS
N
0
PUPS FOUND DEAD OR PRESUMED CANNIBALIZED
II 0.3
15
214 14.3+ 3.2
14.3 3.2 214(100.0)
0.0 0.0 0( 0.0)
0
III 1
13
201 15.5 1.4
15.4 1.6 200( 99.5)
0.1 0.3 M 0.5)
0
DAY 1 DAYS 2 - 8 DAYS 9-15 DAYS 16-22
N / N (%) N / N (%) N / N (%) N/N (%)
1/235( 6/234( 0/228( 0/228(
0.4) 2.6) 0.0) 0.0)
2/214( 6/212( 2/206( 0/204(
0.9) 2.8) 1.0) 0.0)
0/200( 3/200( 1/197( 0/196(
0 .0) 1 .5) 0 .5) 0 .0)
VIABILITY INDEX a
%
97.0
N/N 228/235
96.3 206/214
98.5 197/200
LACTATION INDEX b
%
100.0
N/N 228/228
99.0 204/206
99.5 196/197
DAY(S) = DAY(S) POSTPARTUM a. Number of live pups on day 8 postpartum/number of liveborn pups on day 1 postpartum. b. Number of live pups on day 22 postpartum/number of live pups on day 8 postpartum.
IV 3
13
181 13.9 3.1
13.6 3.2 177( 97.8)
0.2 + 0.4 3( 1.6)
1
2/177 ( 1.1) 2/175 ( 1.1) 1/173 ( 0.6) 0/172 ( 0.0)
97.7 173/177
99.4 172/173
15
220 14.7 2.5
14.5 2.4 218( 99.1)
0.1 0.4 2( 0.9)
0
3/218( 3/215 ( 1/212 { 0/211(
1.4) 1.4) 0.5) 0.0)
97.2 212/218
99.5 211/212
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C24 (PAGE 2) : LITTER OBSERVATIONS (NATURALLY DELIVERED PUPS) - SUMMARY - FI GENERATION LITTERS
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)
i II III
0 0 .3
1
DELIVERED LITTERS WITH
ONE OR MORE LIVEBORN PUPS
N
15
15
13
SURVIVING PUPS/LITTER a
DAY 1 DAY 8 DAY 15 DAY 22 PERCENT MALE PUPS PER NUMBER OF PUPS SEXED
MEANS.D . MEANS.D . MEANS.D . MEANS.D.
15.7 + 1.7 15.2 1.8 15.2 1.8 15.2 1.8
14.3 3.2 13.7 2.9 13.6 2.8 13.6 2.8
15.4 1.6 15.2 1.5 15.1 1.3 15.1 1.3
DAY 1
MEANS.D .
45.2 12.4
51.9 13.1
51.6 6.8
DAY 8
MEANS.D .
45.2 13.0
52.7 + 12.0
51.8 6.3
DAY 15
MEANS.D.
45.2 13.0
53.1 11.8
52.0 6.2
DAY 22
MEANS.D .
45.2 13.0
53.1 11.8
52.0 6.2
DAY = DAY POSTPARTUM a. Average number of live pups per litter, including litters with no surviving pups. b. Includes pups born alive, found dead day 1 postpartum.
IV 3
13
13.6 3 .2 13.3 + 3 .3 13.2 3 .2 13.2 3 .2
43.6 + 13.4 42.9 + 13.1 43.1 13.0 43.1 13.0
V 10
15
14.5 14.1 14.1 14.1
51.4 51.4 51.8 + 51.8
418-028:PAGE C-
-b -
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C24 (PAGE 3) : LITTER OBSERVATIONS (NATURALLY DELIVERED PUPS) - SUMMARY - FI GENERATION LITTERS
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)
DELIVERED LITTERS WITH ONE OR MORE LIVEBORN PUPS
N
LIVE LITTER SIZE AT WEIGHING
DAY 1
MEANS.D.
DAY 8
MEANS.D .
DAY 15
MEANS.D .
DAY 22
MEANS.D.
PUP WEIGHT/LITTER (GRAMS)
DAY 1
MEAN+S.D .
DAY 8
MEANS.D .
D A Y 15
M E A N S .D .
D A Y 22
MEANS.D.
DAY = DAY POSTPARTUM
I 0
15
15.6 1.8 15.2 1.8 15.2 1.8 15.2 1.8
6.3 0.3 14.3 1.6
26.2 + 2.8
3 7 . 4 4 .7
II 0.3
15
14.1 3.1 13.7 2.9 13.6 2.8 13.6 + 2.8
6.3 0.5 13.3 + 1.7 2 6 . 3 3 .9 3 9 . 3 + 6 .9
13
15.4 1.6 15.2 1.5 15.1 1.3 15.1 1.3
6.4 0.3 13.8 1.0
25.9 2.6 38.0 5.7
13
13.5 3.3 13.3 3 .3 13.2 3.2 13.2 3.2
6.5 0.7 1 4 . 1 3 .1 2 7 . 4 5 .7 4 0 . 0 7 .9
15
14.3 2.2 14.1 2.1 14.1 2.2 14.1 2.2
6.3 + 0.5
13.1 1.5
2 5 . 1 3 .3 3 6 . 2 7 .7
418-028:PAGE C-42
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C25 (PAGE 1) : CLINICAL OBSERVATIONS FROM BIRTH TO DAY 22 POSTPARTUM - SUMMARY - FI GENERATION PUPS
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY) LITTERS EXAMINED (N)
I II Ill
0 0.3
1
15 15 13
IV 3
13
TRANSIENT CLINICAL OBSERVATIONS : a
TOTAL FREQUENCY (DAYS X PUPS)/LITTERS WITH OBSERVATIONS
NOT NURSING
N/N 0/0 1/1 0/0 0/0
EMACIATION
N/N 0/0 0/0 0/0 0/0
DEHYDRATION
N/N 0/0
4/1 2/2
0/0
WHOLE BODY, EXCLUDING HEAD,
DISCOLORATION, PURPLE
N/N
0/0
0/0
0/0
0/0
SCAB b
N/N 0/0 0/0 0/0 6/1
COLD TO TOUCH N/N 0/0 2/2 0/0 0/0
LEFT EYE, PERIORBITAL
DISCOLORATION, PURPLE
N/N
0/0
0/0
0/0
8/1
RIGHT EYE, ENLARGED
N/N 0/0
0/0
0/0
3/1
RIGHT HINDLIMB, LACERATION N/N
0/0
0/0
0/0
1/1
BACK, BRUISE
N/N 2/1 4/1 0/0 0/0
NOT NESTING
N/N 0/0 1/1 0/0 0/0
PALE IN APPEARANCE
N/N 3/2
0/0
0/0
0/0
RIGHT EYE, CORNEAL OPACITY N/N
5/1
0/0
0/0
0/0
a. Tabulation restricted to adverse observations,- all other pups appeared normal. b. Right hindlimb or head.
V 10 15
13/1 13/1 13/1
6/1 3/1 1/1
0/0 0/0 0/0 0/0 0/0 0/0 0/0
418-028.-PAGE C-43
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C26 (PAGE 1) NECROPSY OBSERVATIONS - SUMMARY - FI GENERATION PUPS
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)
I II 0 0.3
LITTERS EXAMINED (N)
15 15
TOTAL PUPS STILLBORN, OR FOUND DEAD a,b
STILLBORN FOUND DEAD
N6 N0 N6
5 0 5
NO MILK IN STOMACH c
N (%) 2 ( 33.3)
5(100.0)
PUPS SACRIFICED AND NECROPSIED ON DAYS 5 AND 22 POSTPARTUM c
III 1
13
2 1 1
0( 0.0)
IV 3
13
4 2 2
1( 50.0)
V 10
15
3
2
1
0( 0.0)
LITTERS EVALUATED PUPS EVALUATED
APPEARED NORMAL LITTER INCIDENCE PUP INCIDENCE
KIDNEYS: RIGHT, PELVIS, MODERATE DILATION LITTER INCIDENCE PUP INCIDENCE
N 15 N 228
N(%) 15(100.0) N (%) 228(100.0)
N (%) 0( 0.0) N(t) 0( 0.0)
15 204
14( 93.3) 203( 99.5)
M 6.7) M 0.5)
13 196
13(100.0) 196(100.0)
0( 0.0) 0( 0.0)
13 172
13(100.0) 172(100.0)
0( 0.0) 0( 0.0)
15 211
15(100.0) 211(100.0)
0( 0.0) 0( 0.0)
a. Restricted to pups in which complete necropsies were performed. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation.
b. Refer to the individual pup clinical observations table (Table C44) for external clinical observations confirmed at necropsy c. Analysis restricted to pups found dead and necropsied.
418-028-.PAGE C-44
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C27 (PAGE 1) : PUP LIVER WEIGHTS - SUMMARY - FI GENERATION PUPS
i i11 > or-t 1 1 1l 111
DOSAGE GROUP DOSAGE (MG/KG/DAY) LITTERS EXAMINED TERMINAL BODY WEIGHT
WEIGHT/LITTER MALE PUPS FEMALE PUPS
I 0
N 10
MEAN+S.D . MEAN+S.D . MEAN+S.D .
37.42 + 4.53 38.17 + 4.72 36.67 + 4.44
LIVER WEIGHT/LITTER MALE PUPS FEMALE PUPS
MEAN+S.D . MEAN+S.D . MEAN+S.D.
1.54 + 0.24 1.48 + 0.26 1.59 + 0.24
RATIOS (%) OF LIVER TO TERMINAL BODY WEIGHT
WEIGHT/LITTER
MEAN+S.D.
4.10 + 0.24
MALE PUPS
MEAN+S.D .
3.86 + 0.27
FEMALE PUPS
MEAN+S.D .
4.33 + 0.24
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ii III 0.3 1
IV 3
10 10 10 10
40.00 + 8.08 41.57 + 8.53 38.35 + 7.94
38.56 + 4.78 40.27 + 4.60 36.86 + 5.30
40.11 + 8.35 41..04 + 8.18 39.22 + 8.57
34.70 + 8.26 35.33 + 8.27 34.07 + 8.30
1.65 + 0.41 1.64 + 0.43 1.65 + 0.40
1.60 + 0.28 1.62 + 0.31 1.58 + 0.31
1.70 + 0.38 1.65 + 0.40 1.75 + 0.39
1.40 + 0.40 1.37 + 0.40 1.44 + 0.40
4.10 0.28 3.91 + 0.33 4.28 + 0.26
4.14 + 0.33
4.23 + 0.37
3.98 + 0.34
4.02 + 0.44
4.01 + 0.4 7
3.79 + 0.37
4.26 + 0.34
4.46 + 0.35
4.17 + 0.36
RATIOS (%) = (LIVER WEIGHT/TERMINAL BODY WEIGHT) X 100.
418-028:PAGE C-45
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C2 8 (PAGE 1) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP I
0 MG/KG/DAY
RAT #
DESCRIPTION
19010 19012
19019 19021
19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
DG ( DG ( DL ( DL( DL (
9) 9- 21)
1- 2) 9- 13) 9- 22)
DL ( 9- 13) DL ( 14- 22) DL ( 22 )
DL ( 7- 22)
NO ADVERSE FINDINGS BACK: ULCERATION (1.5 CM X 1.0 CM) BACK: SCAB (DID NOT EXCEED 2.0 CM X 1.0 CM) BACK: SCAB (2.0 CM X 1.0 CM) BACK: SCAB (2.0 CM X 0.5 CM) LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS HEAD: SCAB (0.2 CM IN DIAMETER) LOCALIZED ALOPECIA: HEAD a HEAD: SCAB (0.2 CM X 0.4 CM)b NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS
DS = DAY OF STUDY
DG = DAY OF PRESUMED GESTATION
a. Observation confirmed at necropsy.
b. First observed at necropsy.
DL = DAY OF LACTATION
418-028:PAGE C-46
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C28 (PAGE 2) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP II
0.3 MG/KG/DAY
RAT #
DESCRIPTION
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055
19061 19067 19071
DL ( 5- 21)
DL ( 3- 22) DL ( 17- 22)
NO ADVERSE FINDINGS NO ADVERSE FINDINGS HEAD: SCAB (0.3 CM X 1.0 CM) NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS a TAIL: SCAB (3.0 CM X 0.8 CM)a NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS
DS = DAY OF STUDY
DG = DAY OF PRESUMED GESTATION
a. Observation confirmed at necropsy.
DL = DAY OF LACTATION
418-028:PAGE C-47
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C28 (PAGE 3) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP III
1 MG/KG/DAY
RAT #
DESCRIPTION
19003 19007 19008 19013 19014 19015 19017 19024 19029
19034 19038 19056 19057 19060 19064
DL ( 17- 22)
DG ( 20- 21) DL ( 1- 22) DL( 22 )
NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: NO ADVERSE FINDINGS NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LOCALIZED ALOPECIA: LOCALIZED ALOPECIA: NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS
HEAD a
LIMBS LIMBS a HEAD b
DS = DAY OF STUDY
DG = DAY OF PRESUMED GESTATION
a. Observation confirmed at necropsy.
b. First observed at necropsy.
DL = DAY OF LACTATION
418-028.-PAGE C-48
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C28 (PAGE 4) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP IV
3 MG/KG/DAY
RAT #
DESCRIPTION
19002 19005 19035 19039 19040 19045
19046
19051 19054 19058 19062 19063 19066 19069 19073
DL ( 19- 22)
DG ( 14 ) DG ( 18- 21) DL ( 1- 22) DS ( 11- 14) DG ( 0- 25)
DL ( 17- 22)
DL ( 17- 22)
LOCALIZED ALOPECIA: BACK a NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NOSE : SWOLLEN LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS a LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS LOCALIZED ALOPECIA: LIMBS a NO ADVERSE FINDINGS TIP OF TAIL MISSING a NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS
DS = DAY OF STUDY
DG - DAY OF PRESUMED GESTATION
a. Observation confirmed at necropsy.
DL = DAY OF LACTATION
418-028:PAGE C-49
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C28 (PAGE 5) : CLINICAL OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP V
10 MG/KG/DAY
RAT #
DESCRIPTION
19001 19006 19011 19020
19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
DS ( 6- 12) DS ( 6- 12) DS ( 10- 12) DS ( 11 ) DS ( 11- 12) DS ( 11- 12) DS ( 11- 12) DS ( 11- 17) DG( 0- 6) 1X3( 7- 20) DL ( 2- 22) DL ( 7- 22) DL ( 14- 15) DL ( 14- 22) DL ( 17 ) DL ( 18- 22)
DL ( 17- 22) DL ( 17- 22)
NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS BROWN PERIORAL SUBSTANCE RALES URINE-STAINED ABDOMINAL FUR COLD TO TOUCH MIOSIS ABDOMINAL DISTENTION EMACIATION LOCALIZED ALOPECIA: HEAD LOCALIZED ALOPECIA: HEAD LOCALIZED ALOPECIA: LIMBS LOCALIZED ALOPECIA: LIMBS a ABDOMINAL DISTENTION a EMACIATION RALES DEHYDRATION EMACIATION a NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS HEAD: SCAB (0.3 CM X 0.3 CM)a LOCALIZED ALOPECIA: HEAD a NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS NO ADVERSE FINDINGS
DS = DAY OF STUDY
DG = DAY OF PRESUMED GESTATION
a. Observation confirmed at necropsy.
DL = DAY OF LACTATION
418-028:PAGE C-50
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C29 (PAGE 1) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RAT NUMBER
DAY OF PREGNANCY DOSES NECROPSY STATUS ADMINISTE
OBSERVATIONS a
I
0
19010
DL 22
P
70 ALL TISSUES APPEARED NORMAL.
19012
DL 22
P
58 ALL TISSUES APPEARED NORMAL.
19019
DL 22
P
59 ALL TISSUES APPEARED NORMAL.
19021
DL 22
P
58 ALL TISSUES APPEARED NORMAL.
19023
DL 22
P
60 ALL TISSUES APPEARED NORMAL.
19041
DL 22
P
59 ALL TISSUES APPEARED NORMAL.
19042
DL 22
P
58 ALL TISSUES APPEARED NORMAL.
19044
DL 22
P
56 ALL TISSUES APPEARED NORMAL.
19050
DL 22
P
60 ALL TISSUES APPEARED NORMAL.
19053
DL 22
P
59 ALL TISSUES APPEARED NORMAL.
19065
DL 22
P
58 ALL TISSUES APPEARED NORMAL.
19068
DL 22
P
57 ALL TISSUES APPEARED NORMAL.
19072
DL 22
P
58 ALL TISSUES APPEARED NORMAL.
19074
DL 22
P
59 ALL TISSUES APPEARED NORMAL.
19075
DL 22
P
59 ALL TISSUES APPEARED NORMAL.
II
0.3
19004
DL 22
P
59 ALL TISSUES APPEARED NORMAL.
19009
DL 22
P
57 ALL TISSUES APPEARED NORMAL.
19016
DL 22
F
57 ALL TISSUES APPEARED NORMAL.
19018
DL 22
P
57 ALL TISSUES APPEARED NORMAL.
19026
DL 22
P
60 ALL TISSUES APPEARED NORMAL.
19036
DL 22
P
57 ALL TISSUES APPEARED NORMAL.
19037
DL 22
P
58 ALL TISSUES APPEARED NORMAL.
19043
DL 22
P
57 ALL TISSUES APPEARED NORMAL.
19047
DL 22
P
57 ALL TISSUES APPEARED NORMAL.
19048
DL 22
P
60 ALL TISSUES APPEARED NORMAL.
19052
DL 22
P
56 ALL TISSUES APPEARED NORMAL.
19055
DL 22
P
57 ALL TISSUES APPEARED NORMAL.
19061
DL 22
P
56 ALL TISSUES APPEARED NORMAL.
19067
DL 22
P
58 ALL TISSUES APPEARED NORMAL.
19071
DL 22
P
57 ALL TISSUES APPEARED NORMAL.
DG = DAY OF PRESUMED GESTATION P = PREGNANT NP = NOT PREGNANT
DL = DAY OF LACTATION
a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy
418-028:PAGE C-5
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C29 (PAGE 2) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RAT NUMBER
DAY OF PREGNANCY DOSES NECROPSY STATUS ADMINISTERED OBSERVATIONS a
19003
DL 22
P
58 ALL TISSUES APPEARED NORMAL.
19007
DL 22
P
59 KIDNEYS: RIGHT, CORTEX ADHERED TO RIGHT LATERAL LIVER LOBE. ALL OTHER TISSUES APPEARED NORMAL.
19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
DL 22 DL 22 DG 25 DL 22 DL 22 DL 22 DL 22 DL 22 DG 25 DL 22 DL 22 DL 22 DL 22
P P NP P P P P P NP P P P P
59 ALL TISSUES APPEARED NORMAL.
58 ALL TISSUES APPEARED NORMAL.
39 ALL TISSUES APPEARED NORMAL. 59 ALL TISSUES APPEARED NORMAL. 57 ALL TISSUES APPEARED NORMAL. 59 ALL TISSUES APPEARED NORMAL. 58 ALL TISSUES APPEARED NORMAL. 58 ALL TISSUES APPEARED NORMAL. 39 ALL TISSUES APPEARED NORMAL. 59 ALL TISSUES APPEARED NORMAL. 59 ALL TISSUES APPEARED NORMAL. 57 ALL TISSUES APPEARED NORMAL. 60 ALL TISSUES APPEARED NORMAL.
DG = DAY OF PRESUMED GESTATION P = PREGNANT NP = NOT PREGNANT
DL = DAY OF LACTATION
Refer to the individual clinical observations table (Table C27) for external observations confirtned at necropsy.
418-028:PAGE C-52
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE C29 (PAGE 3) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RAT NUMBER
DAY OF PREGNANCY DOSES NECROPSY STATUS ADMINISTERED OBSERVATIONS a
IV
3
19002
DL 22
P
69 ALL TISSUES APPEARED NORMAL.
19005
DL 22
P
59 ALL TISSUES APPEARED NORMAL.
19035
DL 22
P
59 ALL TISSUES APPEARED NORMAL.
19039
DL 22
P
57 ALL TISSUES APPEARED NORMAL.
19040
DL 22
P
58 ALL TISSUES APPEARED NORMAL.
19045
DL 22
P
57 ALL TISSUES APPEARED NORMAL.
19046
DG 25
NP
39 ALL TISSUES APPEARED NORMAL.
19051
DG 25
NP
52 OVARIES: LEFT, SMALL (0.003 G ) . ALL OTHER TISSUES APPEARED NORMAL.
19054 19058 19062
DL 22 DL 22 DL 22
P P P
59 ALL TISSUES APPEARED NORMAL. 57 ALL TISSUES APPEARED NORMAL. 59 ALL TISSUES APPEARED NORMAL.
19063
DL 22
P
58 SPLEEN: OMENTUM ADHERED TO THE LENGTH OF THE OUTER CAPSULE. ALL OTHER TISSUES APPEARED NORMAL.
19066 19069 19073
DL 22 DL 22 DL 22
P P P
59 ALL TISSUES APPEARED NORMAL. 58 ALL TISSUES APPEARED NORMAL. 57 ALL TISSUES APPEARED NORMAL.
DG = DAY OF PRESUMED GESTATION P = PREGNANT NP _ NOT PREGNANT
DL DAY OF LACTATION
a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy.
418-028:PAGE C-53
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-770G WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C29 (PAGE 4) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP DOSAGE (MG/KG/DAY)
RAT NUMBER
DAY OF PREGNANCY DOSES NECROPSY STATUS ADMINISTERED OBSERVATIONS a
V
10
19001
DL 22
P
57 ALL TISSUES APPEARED NORMAL.
19006
DL 22
P
58 ALL TISSUES APPEARED NORMAL.
19011
DL 22
P
59 ALL TISSUES APPEARED NORMAL.
19020
DL 22
P
59 LARGE AND SMALL INTESTINES: DISTENDED WITH GAS. THYMUS : SMALL. SPLEEN : SMALL. ADRENALS : BILATERAL, LARGE. STOMACH: FUNDIC MUCOSAL SURFACE CONTAINED APPROXIMATELY 12 BLACK AREAS (PINPOINT TO 0.3 CM IN DIAMETER) . ALL OTHER TISSUES APPEARED NORMAL.
19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
DL 22 DL 22 DL 22 DL 22 DL 22 DL 22 DL 22 DL 22 DL 22 DL 22 DL 22
P P P P P P P P P P P
60 ALL TISSUES APPEARED NORMAL.
59 ALL TISSUES APPEARED NORMAL.
59 ALL TISSUES APPEARED NORMAL. 57 ALL TISSUES APPEARED NORMAL. 60 ALL TISSUES APPEARED NORMAL. 56 ALL TISSUES APPEARED NORMAL. 59 ALL TISSUES APPEARED NORMAL. 56 ALL TISSUES APPEARED NORMAL. 57 ALL TISSUES APPEARED NORMAL. 56 ALL TISSUES APPEARED NORMAL. 57 ALL TISSUES APPEARED NORMAL.
DG > DAY OF PRESUMED GESTATION
DL = DAY OF LACTATION
P = PREGNANT NP - NOT PREGNANT
a. Refer to the individual clinical observations table (Table C27) for external observations confirmed at necropsy.
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C30 (PAGE 1) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP I
0 ]MG/KG/DAY
RAT TERMINAL BODY NUMBER WEIGHT
19012 19019 19021 19023 19041 19042 19044 19050 19053 19065
P P P P P P P P P P
335 . 309. 270. 280 . 305 . 302 . 360. 290. 299. 301.
RAT TERMINAL BODY NUMBER WEIGHT
19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
P P P P P P P P P P P P P P P
299 . 335 . 309. 270 . 280 . 305 . 302 . 360. 290 . 299 . 301. 360. 292 . 297. 295 .
BRAIN
ABS. REL. WT. % TBW
2.22 2.22 2.21 2.11 2.09 2.25 2.17 2.11 2.25 2.00
0.66 0.72 0.82 0.75 0.68 0.74 0.60 0.73 0.75 0.66
SPLEEN
ABS. REL. WT. % TBW
0.78 0.64 0.58 0.53 0.54 0.64 0.67 0.74 0.61 0.54
0.23 0.21 0.21 0.21 0.18 0.21 0.19 0.26 0.20 0.18
LIVER
ABS. REL. WT. % TBW
16.17 15.21 14.21 13.09 12.15 14.31 19.73 12.84 13.17 12.97
4.83 4.92 5.26 4.68 3.98 4.74 5.48 4.43 4.40 4 .31
THYMUS
ABS. REL. WT. % TBW
0.23 0.31 0.11 0.16 0.16 0.33 0.27 0.20 0.17 0.17
0.07 0.10 0.04 0.06 0.05 0.11 0.08 0.07 0.06 0.06
KIDNEY LEFT
ABS. REL. WT. % TBW
1.53 1.43 1.50 1.23 1.24 1.60 1.51 1.32 1.26 1.30
0.46 0.46 0.56 0.44 0.41 0.53 0.42 0.46 0.42 0.43
OVARY LEFT
ABS . REL. WT. % TBW a
0.035 0.092 0.044 0.044 0.039 0.062 0.059 0.070 0.044 0.058 0.068 0.048 0.051 0.057 0.059
11.70 27.46 14.24 16.30 13.93 20.33 19.54 19.44 15.17 19.40 22.59 13.33 17.46 19.19 20.00
KIDNEY RIGHT ABS. REL. WT. % TBW
1.66 1.46 1.55 1.39 1.35 1.57 1.60 1.41 1.34 1.33
0.50 0.47 0.57 0.50 0.44 0.52 0.44 0.49 0.45 0.44
OVARY RIGHT ABS. REL. WT. % TBW a
0.042 0.073 0.064 0.040 0.062 0.037 0.057 0.081 0.048 0.085 0.066 0.075 0.060 0.073 0.073
14.05 21.79 20.71 14.81 22.14 12.13 18.87 22.50 16.55 28.43 21.93 20.83 20.55 24.58 24.74
ADRENAL
LEFT
ABS.
REL.
WT. % TBW a
0.050 0.055 0.045 0.054 0.048 0.056 0.076 0.048 0.049 0.042
14.92 17.80 16.67 19.28 15.74 18.54 21.11 16.55 16.39 13.95
UTERUS WITH CERVIX ABS. REL. WT. % TBW
0.48 0.57 0.51 .53 0.62 0.46 0.68 0.56 0.56 0.47 0.69 0.55 0.36 0.53 0.44
0.16 0.17 0.16 0.20 0.22 0.15 0.22 0.16 0.19 0.16 0.23 0.15 0.12 0.18 0.15
ADRENAL
RIGHT
ABS.
REL.
WT. V TBW a
0.047 0.047 0.040 0.028 0.044 0.046 0.053 0.036 0.043 0.044
14.03 15.21 14 .81 10 .OO 14.43 15.23 14 .72 12.41 14.38 14.62
HEART
ABS. REL. WT . % TBW
1.32 1.55 1.31 1.62 1.35 1.64 1.45 1.19 1.41 1.13
0.39 0.50 0.48 0.58 0.44 0.54 0.40 0.41 0.47 0.38
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. W T . * ORGAN WEIGHT.
P = PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. Value was multiplied by 1000.
REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100
418-028:PAGE C-55
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C30 (PAGE 2) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP II
0.3 MG/KG/DAY
RAT TERMINAL BODY NUMBER WEIGHT
BRAIN
ABS. REL. VJT. % TBW
LIVER
ABS. REL. WT. % TBW
KIDNEY LEFT
ABS. REL. WT. % TBW
KIDNEY RIGHT ABS. REL. WT. % TBW
ADRENAL LEFT
ABS. REL. WT. % TBW a
ADRENAL RIGHT
ABS. REL. WT. % TBW a
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048
P P P P P P P P P P
276. 346. 314 . 338. 296 . 359. 309. 356. 325. 306.
1.99 2.11 2.17 2.04 2.12 2.13 2.09 2.23 2.00 2.24
0.72 0.61 0.69 0.60 0.72 0.59 0.68 0.63 0.62 0.73
11.23 16.15 18.06 19.18 15.44 16.63 18.25 18.19 14.85 11.85
4.07 4.67 5.75 5.67 5.22 4.63 5.91 5.11 4.57 3.87
1.34 1.38 1.41 1.41 1.65 1.45 1.43 1.77 1.35 1.55
0.48 0.40 0.45 0.42 0.56 0.40 0.46 0.50 0.42 0.51
1.40 1.37
1.43 1.42 1.70 1.54 1.53 1.87 1.47 1.42
0.51 0.40 0.46 0.42 0.57 0.43 0.50 0.52 0.45 0.46
0.043 0.038 0.059 0.052 0.054 0.042 0.056 0.065 0.044 0.055
15.58 10.98 18.79 15.38 18.24 11.70 18.12 18.26 13.54 17.97
0.049 0.033 0.048 0.041 0.045 0.044 0.047 0.053 0.027 0.024
17.75 9.54
15.29 12.13 15.20 12.26 15.21 14.89
8.31 7.84
RAT TERMINAL BODY NUMBER WEIGHT
SPLEEN
ABS. REL. WT. % TBW
THYMUS
ABS. WT.
REL. % TBW
OVARY LEFT
ABS. REL. WT. % TBW a
OVARY RIGHT ABS. REL. WT. % TBW a
UTERUS WITH CERVIX ABS. REL. WT. % TBW
HEART
ABS.
REL.
WT. % TBW
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
P P P P P P P P P P P P P P P
276. 346. 314. 338 . 296. 359. 309. 356 . 325. 306 . 320. 336. 315. 294. 374 .
0.60 0.61 0.53 0.74 0.70 0.74 0.74 0.77 0.55 ' 0.55
0.22 0.18 0.17 0.22 0.24 0.21 0.24 0.22 0.17 0.18
0.24 0.31 0.16 0.21 0.18 0.28 0.21 0.10 0.21 0.19
0.09 0.09 0.05 0.06 0.06 0.08 0.07 0.03 0.06 0.06
0.083 0.067 0.063 0.064 0.048 0.077 0.062 0.052 0.057 0.024 0.093 0.032 0.038 0.061 0.026
30.07 19.36 20.06 18.93 16.22 21.45 20.06 14.61 17.54
7.84 29.06
9.52 12.06 20.75
6.95
0.071 0.072 0.081 0.068 0.075 0.095 0.046 0.056 0.059 0.026 0.055 0.052 0.025 0.059 0.058
25.72 20.81 25.80 20.12 25.34 26.46 14.89 15.73 18.15
8.50 17.19 15.48
7.94 20.07 15.51
0.65 0.51 0.70 0.64 0.73 0.58 0.45 0.63 0.55 0.56 0.45 0.28 0.53 0.50 0.71
0.24 0.15 0.22 0.19 0.25 0.16 0.14 0.18 0.17 0 .18 0.14 0.08 0.17 0.17 0.19
1.35 1.51 1.23 1.16 1.35 1.20 1.15 1.31 1.05 1.25
0.49 0.44 0.39 0.34 0.46 0.33 0.37 0.37 0.32 0.41
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. WT. = ORGAN WEIGHT,
P * PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. Value was multiplied by 1000.
REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100 .
418-028:PAGE C-56
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C30 (PAGE 3) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP III
1 MG/KG/DAY
RAT TERMINAL BODY NUMBER WEIGHT
BRAIN
ABS. REL. W T . % TBW
LIVER
ABS. REL. WT. % TBW
KIDNEY LEFT
ABS . REL. W T . % TBW
KIDNEY RIGHT ABS. REL. W T . % TBW
ADRENAL LEFT
ABS. REL. WT. % TBW a
ADRENAL RIGHT
ABS. REL. WT. % TBW a
19003 19007 19008 19013 19015 19017 19024 19029 19034 19056
P P P P P P P P P P
284 . 303. 292 . 389 . 274 . 350. 309. 332. 287. 292 .
2.13 2.16 2.01 2.05 2.21 2.15 2.23 1.98 2.10 2.02
0.75 0.71 0.69 0.53 0.81 0.61 0.72 0.60 0.73 0.69
12.51 13.07 12.76 19.40 12.50 16.49 14.95 19.93 12.83 12.62
4.40 4.31 4.37 4.99 4.56 4.71 4.84 6.00 4.47 4.32
1.31 1.62 1.24 1.44 1.14 1.45 1.53 1.28 1.34 1.47
0.46 0.53 0.42 0.37 0.42 0.41 0.50 0.38 0.47 0.50
1.37 1.66b 1.31 1.64 1.24 1.45 1.45 1.45 1.41 1.50
0.48 0.55 0.45 0.42 0.45 0.41 0.47 0.44 0.49 0.51
0.054 0.067 0.045 0.050 0.066 0.039 0.053 0.049 0.051 0.040
19.01 22.11 15.41 12.85 24.09 11.14 17.15 14.76 17.77 13.70
0.060 0.071 0.041 0.049 0.058 0.038 0.042 0.049 0.056 0.040
21.13 23.43 14.04 12.60 21.17 10.86 13.59 14.76 19.51 13.70
RAT TERMINAL BODY NUMBER WEIGHT
19003 19007 19008 19013 19015 19017 19024 19029 19034 19056 19057 19060 19064
p P P P P P P P p P P P P
284 . 303 . 292 . 389. 274 . 350 . 309. 332. 287 . 292 . 287. 357. 289 .
SPLEEN
ABS. REL. WT. % TBW
0.62 0.82 0.49 0.65 0.42 0.60 0.61 0.60 0.54 0.65
0.22 0.27 0.17 0.17 0.15 0.17 C .20 0.18 0.19 0.22
THYMUS
ABS. REL. WT. % TBW
0.14 0.12 0.17 0.22 0.24 0.13 0.19 0.16 0.18 0.22
0.05 0.04 0.06 0.06 0.09 0.04 0.06 0.05 0.06 0.08
OVARY LEFT
ABS. REL. WT. % TBW a
0.054 0.053 0.050 0.068 0.043 0.053 0.043 0.041 0.062 0.051 0.034 0.089 0.051
19.01 17.49 17.12 17.48 15.69 15.14 13.92 12.35 21.60 17.46 11.85 24.93 17.65
OVARY RIGHT ABS. REL. WT. % TBW a
0.079 0.086 0.055 0.080 0.048 0.048 0.020 0.058 0.074 0.043 0.041 0.092 0.051
27.82 28.38 18.84 20.56 17.52 13.71
6.47 17.47 25.78 14.73 14.28 25.77 17.65
UTERUS WITH CERVIX ABS . REL. WT. % TBW
0.48 0.79 0.53 0.58 0.48 0.35 0.42 0.34 0.44 0.66 0.35 0.61 0.44
0.17 0.26 0.18 0.15 0.18 0.10 0.14 0.10 0.15 0.23 0.12 0.17 0 .15
HEART
ABS.
REL.
WT. % TBW
1.29 1.30 1.17 1.35 1.51 1.36 1.40 1.48 1.21 1.39
0.45 0.43 0.40 0.35 0.5 5 0.39 0.45 0.44 0.42 0.48
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. WT. = ORGAN WEIGHT.
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
REL. % TBW = (ORGAN WEIGHT/TEP.MINAL BODY WEIGHT) X 100 .
a. Value was multiplied by 1000.
b. Dam 19007 had the cortex of the right kidney adhered to the right lateral lobe of the liver . See the individual necropsy
observations table (Table C28).
418-028'.PAGE C-57
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C30 (PAGE 4) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP IV
RAT TERMINAL BODY NUMBER WEIGHT
19005 19035 19039 19040 19045 19054 19058 19062 19063 19066
P P P P P P P P P P
285. 261. 315. 294 . 385. 287. 350. 290. 369. 292 .
RAT TERMINAL BODY NUMBER WEIGHT
BRAIN
ABS. REL. WT. % TBW
1.81 2.04 2.09 2.05 2.15 2.49 2.15 2.13 2.03 1.91
0.64 0.78 0.66 0.70 0.56 0.87 0.61 0.73 0.55 0.65
SPLEEN
ABS. REL. WT. % TBW
3 MG/KG/DAY
LIVER
ABS. REL. WT. % TBW
13.80 12.06 16.01 13.33 17.71 11.54 19.11 13.59 21.27 12.70
4.84 4.62 5.08 4.53 4.60 4.02 5.46 4.69 5.76 4.35
THYMUS
ABS. REL. WT. % TBW
KIDNEY
LEFT
ABS.
REL.
WT. % TBW
1.16 1.54 1.27 1.54 1.63 1.65 1.61 1.58 1.67 1.26
0.41 0.59 0.40 0.52 0.42 0.57 0.46 0.54 0.45 0.43
OVARY LEFT
ABS. REL. WT. % TBW a
KIDNEY RIGHT ABS. REL. WT. % TBW
1.26 1.56 1.40 1.48 1.66 1.55 1.57 1.61 1.69 1.47
0.44 0.60 0.44 0.50 0.43 0.54 0.45 0.56 0.46 0.50
OVARY RIGHT ABS. REL. WT. % TBW a
ADRENAL LEFT
ABS. REL. WT. % TBW a
0.044 0.064 0.055 0.052 0.063 0.041 0.064 0.04 6 0.067 0.031
15.44 24.52 17.46 17.69 16.36 14.28 18.28 15.86 18.16 10.62
UTERUS WITH CERVIX ABS. REL. WT. % TBW
ADRENAL
RIGHT
ABS.
REL.
WT. % TBW a
0.046 0.055 0.055 0.051 0.042 0.038 0.049 0.046 0.059 0.045
16.14 21.07 17.46 17.35 10.91 13.24 14.00 15.86 15.99 15.41
HEART
ABS. REL. WT. % TBW
418-028:PAGE C-58
19002 19005 19035 19039 19040 19045 19054 19058 19062 19063 19066 19069 19073
P P P P P P P P P P P P P
302. 285 . 261. 315. 294 . 385 . 287 . 350. 290 . 369. 292 . 362 . 363 .
0.54 0.66 0.71 0.64 0.61 0.84 0.77 0.62 1.59b 0.55
0.19 0.25 0.22 0.22 0.16 0.29 0.22 0.21 0.43 0.19
0.14 0.16 0.25 0.24 0.13 0.36 0.12 0.14 0.09 0.39
0.05 0.06 0.08 0.08 0.03 0.12 0.03 0.05 0.02 0.13
0.058 0.049 0.051 0.079 0.058 0.046 0.064 0.052 0.058 0.049 0.028 0.057 0.040
19.20 17.19 19.54 25.08 19.73 11.95 22.30 14.86 20.00 13.28
9.59 15.74 11.02
0.052 0.056 0.055 0.062 0.046 0.057 0.048 0.066 0.058 0.057 0.025 0.076 0.046
17.22 19.65 21.07 19.68 15.65 14.80 16.72 18.86 20.00 15.45
8.56 20.99 12.67
0.46 0.80 0.71 0.46 0.50 0.53 0.75 0.74 0.78 0.56 0.78 0.57 0.37
0.15 0.28 0.27 0.15 0.17 0.14 0.26 0.21 0.27 0.15 0.27 0.16 0.10
1.16 1.45 1.20 1.55 1.47 1.48 1.39 1.41 1.39 1.51
0.41 0.56 0.38 0.53 0.38 0.52 0.40 0.49 0.38 0.52
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. WT. = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100.
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. Value was multiplied by 1000. b. Dam 19063 had omentum adhered to the entire length of the outer capsule of the spleen. See the individual necropsy
observations table (Table C28).
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C30 (PAGE 5) : TERMINAL BODY WEIGHTS AND ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO TERMINAL BODY WEIGHT INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP V
10 MG/KG/DAY
RAT TERMINAL BODY NUMBER WEIGHT
BRAIN
ABS. REL. WT. % TBW
LIVER
ABS. WT.
REL. % TBW
KIDNEY LEFT
ABS. REL. WT. % TBW
KIDNEY RIGHT ABS. REL. WT. % TBW
ADRENAL
LEFT
ABS.
REL.
WT. % TBW a
ADRENAL RIGHT
ABS. REL. WT. % TBW a
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031
P P P P P P P P P P
278 . 304 . 283 . 210 . 294 . 291. 266. 339. 314 . 361.
2.00 2.13 2.05 2.00 2.18 2.13 2.27 2.02 2.18 2.24
0.72 0.70 0.72 0.95 0.74 0.73 0.85 0.60 0.69 0.62
12.11 14.39 14.24
7.01 12.61 13.99 12.11 15.89 14.52 19.51
4.36 4.73 5.03 3.34 4.29 4.81 4.55 4.69 4.62 5.40
1.36 1.44 1.41 1.14 1.45 1.36 1.38 1.38 1.46 1.52
0.49 0.47 0.50 0.54 0.49 0.47 0.52 0.41 0.46 0.42
1.35 1.55 1.36 1.09 1.63 1.40 1.35 1.41 1.50 1.47
0.48 0.51 0.48 0.52 0.55 0.48 0.51 0.42 0.48 0.41
0.041 0.057 0.045 0.058b 0.064 0.061 0.053 0.044 0.062 0.042
14.75 18.75 15.90 27.62 21.77 20.96 19.92 12.98 19.74 11.63
0.031 0.055 0.045 0.056 0.041 0.055 0.047 0.041 0.046 0.038
11.15 18.09 15.90 26.67 13.94 18.90 17.67 12.09 14.65 10.53
RAT TERMINAL BODY NUMBER WEIGHT
SPLEEN
ABS. WT.
REL. % TBW
THYMUS
ABS. WT.
REL. % TBW
OVARY LEFT
ABS. REL. WT. % TBW a
OVARY RIGHT ABS. REL. WT. % TBW a
UTERUS WITH CERVIX ABS. REL. WT. % TBW
HEART
ABS. REL. WT. % TBW
19001 19006 19C11 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
P p p P P P P P P p p P p P P
278. 304. 283 . 210. 294. 291. 266. 339. 314 . 361. 287. 328. 330. 317. 351.
0.57 0.54 0.50 0.28b 0.53 0.56 0.61 0.54 0.58 0.64
0.20 0.18 0.18 0.13 0.18 0.19 0.23 0.16 0.18 0.18
0.18 0.15 0.15 0.11b 0.14 0.25 0.23 0.23 0.17 0.16
0.06 0.05 0.05 0.05 0.05 0.08 0.09 0.07 0.05 0.04
0.048 0.056 0.046 0.036 0.060 0.053 0.039 0.087 0.045 0.076 0.031 0.069 0.050 0.061 0.051
17.27 18.42 16.25 17.14 20.41 18.21 14.66 25.66 14.33 21.05 10.80 21.04 15.15 19.24 14.53
0.047 0.074 0.036 0.047 0.035 0.058 0.018 0.053 0.048 0.087 0.043 0.076 0.073 0.063 0.045
16.91 24.34 12.72 22.38 11.90 19.93
6.77 15.63 15.29 24.10 14.98 23.17 22.12 19.87 12.82
0.64 0.46 0.68 0.50 0.74 0.53 0.44 0.37 0.78 0.74 0.33 0.82 0.50 0.39 0.47
0.23 0.15 0.24 0.24 0.25 0.18 0.16
0.11
0.25
0.20
0.11 0.25 0.15
0.12
0.13
0.92 1.57 1.24 0.90 1.54 1.38 1.32 1.56 1.37 1.50
0.33 0.52 0.44 0.43 0.52 0.47 0.50 0.46 0.44 0.42
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS.. WT. = ORGAN WEIGHT.
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. Value was multiplied by 1000.
b. Dam 19020 had a large left adrenal, small spleen, and small thymus.
(Table C28),
REL. % TBW = (ORGAN WEIGHT/TERMINAL BODY WEIGHT) X 100 . See the individual necropsy observations table
418-028:PAGEC-59
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C31 (PAGE 1): ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP I
0 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
LIVER
ABS. REL. WT. % BRW
KIDNEY LEFT
ABS. REL. WT. % BRW
KIDNEY RIGHT ABS . REL. WT. % BRW
ADRENAL LEFT
ABS. REL. WT . % BRW
ADRENAL
RIGHT
ABS.
REL.
WT. % BRW
SPLEEN
ABS. WT.
REL. % BRW
19012 19019 19021 19023 19041 19042 19044 19050 19053 19065
P P P P P P P P P P
2.22 2.22 2.21 2.11 2.09 2.25 2.17 2.11 2.25 2.00
16.17 15.21 14.21 13.09 12.15 14.31 19.73 12.84 13.17 12.97
728.38 685.14 642.99 620.38 581.34 636.00 909.22 608.53 585.33 648.50
1.53 1.43 1.50 1.23 1.24 1.60 1.51 1.32 1.26 1.30
68.92 64.41 67.87 58.29 59.33 71.11 69.58 62.56 56.00 65.00
1.66 1.46 1.55 1.39 1.35 1.57 1.60 1.41 1.34 1.33
74.77 65.76 70.14 65.88 64.59 69.78 73.73 66.82 59.56 66.50
0.050 0.055 0.045 0.054 0.048 0.056 0.076 0.048 0.049 0.042
2.25 2.48 2.04 2.56 2.30 2.49 3.50 2.27 2.18 2.10
0.047 0.047 0.040 0.028 0.044 0.046 0.053 0.036 0.043 0.044
2.12 2.12 1.81 1.33 2.10 2.04 2.44 1.71 1.91 2.20
0.78 0.64 0.58 0.58 0.54 0.64 0.67 0.74 0.61 0.54
35.14 28.83 26.24 27.49 25.84 28.44 30.88 35.07 27.11 27.00
RAT NUMBER
BRAIN WEIGHT
THYMUS
ABS. REL. WT. % BRW
OVARY LEFT
ABS. REL. WT. % BRW
OVARY RIGHT ABS. REL. WT. %; BRW
UTERUS WITH CERVIX
ABS . REL. WT. % BRW
HEART
ABS.
REL.
WT. % BRW
19012 19019 19021 19023 19041 19042 19044 19050 19053 19065
P P P P P P P P P P
2.22 2.22 2.21 2.11 2.09 2.25 2.17 2.11 2.25 2.00
0.23 0.31 0.11 0.16 0.16 0.33 0.27 0.20 0.17 0.17
10.36 13.96
4.98 7.58 7.66 14.67 12.44 9.48 7.56 8.50
0.092 0.044 0.044 0.039 0.062 0.059 0.070 0.044 0.058 0.068
4.14 1.98 1.99 1.85 2.97 2.62 3.22 2.08 2.58 3.40
0.073 0.064 0.040 0.062 0.037 0.057 0.081 0.048 0.085 0.066
3.29 2.88 1.81 2.94 1.77 2.53 3.73 2.27 3.78 3.30
0.57 0.51 0.53 0.62 0.46 0.68 0.56 0.56 0.47 0.69
25.68 22.97 23.98 29.38 22.01 30.22 25.81 26.54 20.89 34.50
1.32 1.55 1.31 1.62 1.35 1.64 1.45 1.19 1.41 1.13
59.46 ` 69.82 59.28 76.78 64.59 72.89 66.82 56.40 62.67 56.50
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. WT. = ORGAN WEIGHT.
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
418-028 :PAGE C-60
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C31 1[PAGE 2) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP II
0.3 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
LIVER
ABS. REL. WT. % BRW
KIDNEY LEFT
ABS. REL. WT. 'fc BRW
KIDNEY RIGHT ABS. REL. WT. % BRW
ADRENAL
LEFT
ABS.
REL.
WT. % BRW
ADRENAL
RIGHT
ABS.
REL.
WT. % BRW
SPLEEN
ABS. WT.
REL. % BRW
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048
P P P P P P P P P P
1.99 2.11 2.17 2.04 2.12 2.13 2.09 2.23 2.00 2.24
11.23 16.15 18.06 19.18 15.44 16.63 18.25 18.19 14.85 11.85
564.32 765.40 832.26 940.20 728.30 780.75 873.20 815.70 742.50 529.02
1.34 1.38 1.41 1.41 1.65 1.45 1.43 1.77 1.35 1.55
67.34 65.40 64.98 69.12 77.83 68.08 68.42 79.37 67.50 69.20
1.40 1.37 1.43 1.42 1.70 1.54 1.53 1.87 1.47 1.42
70.35 64.93 65.90 69.61 80.19 72.30 73.20 83.86 73.50 63.39
0.043 0.038 0.059 0.052 0.054 0.042 0.056 0.065 0.044 0.055
2.16 1.80 2.72 2.55 2.55 1.97 2.68 2.91 2.20 2.46
0.049 0.033 0.048 0.041 0.045 0.044 0.047 0.053 0.027 0.024
2.46 1.56 2.21 2.01 2.12 2.06 2.25 2.38 1.35 1.07
0.60 0.61 0.53 0.74 0.70 0.74 0.74 0.77 0.55 0.55
30.15 28.91 24.42 36.27 33.02 34.74 35.41 34.53 27.50 24.55
RAT NUMBER
BRAIN WEIGHT
THYMUS
ABS. WT.
REL. % BRW
OVARY LEFT
ABS . REL. WT. % BRW
OVARY RIGHT ABS. REL. WT. %; BRW
UTERUS WITH CERVIX
ABS. REL. WT. % BRW
HEART
ABS. WT.
REL. % BRW
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048
P P P P P P P P P P
1.99 2.11 2.17 2.04 2.12 2.13 2.09 2.23 2.00 2.24
0.24 0.31 0.16 0.21 0.18 0.28 0.21 0.10 0.21 0.19
12.06 14.69
7.37 10.29
8.49 13.14 10.05
4.48 10.50
8.48
0.083 0.067 0.063 0.064 0.048 0.077 0.062 0.052 0.057 0.024
4.17 3.18 2.90 3.14 2.26 3.62 2.97 2.33 2.85 1.07
0.071 0.072 0.081 0.068 0.075 0.095 0.046 0.056 0.059 0.026
3.57 3.41 3.73 3.33 3.54 4.46 2.20 2.51 2.95 1.16
0.65 0.51 0.70 0.64 0.73 0.58 0.45 0.63 0.55 0.56
32.66 24.17 32.26 31.37 34.43 27.23 21.53 28.25 27.50 2 5 .00
1.35 1.51 1.23 1.16 1.35 1.20 1.15 1.31 1.05 1.25
67.84 71.56 56.68 56.86 63.68 56.34 55.02 58.74 5 2 .50 5 5 .80
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. WT. = ORGAN WEIGHT.
P = PREGNANT NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
REL. % TBW = (ORGAN WEIGHT/BRATN WEIGHT) X 100.
418-028:PAGE C-61
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE C31 (PAGE 3): ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP III
1 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
LIVER
ABS. REL. WT. % BRW
KIDNEY LEFT
ABS. REL. WT. % BRW
KIDNEY RIGHT ABS. REL. WT. % BRW
ADRENAL LEFT
ABS. REL. WT. % BRW
ADRENAL
RIGHT
ABS.
REL.
WT. % BRW
SPLEEN
ABS. WT.
REL. % BRW
19003 19007 19008 19013 19015 19017 19024 19029 19034 19056
P P P P P P P P P P
2.13 2.16 2.01 2.05 2.21 2.15 2.23 1.98 2.10 2.02
12.51 13.07 12.76 19.40 12.50 16.49 14.95 19.93 12.83 12.62
587.32 605.09 634.82 946.34 565.61 766.98 670.40 1006.56 610.95 624.75
1.31 1.62 1.24 1.44 1.14 1.45 1.53 1.28 1.34 1.47
61.50 75.00 61.69 70.24 51.58 67.44 68.61 64.65 63.81 72.77
1.37 1.66a 1.31 1.64 1.24 1.45 1.45 1.45 1.41 1.50
64.32 76.85 65.17 80.00 56.11 67.44 65.02 73.23 67.14 74.26
0.054 0.067 0.045 0.050 0.066 0.039 0.053 0.049 0.051 0.040
2.54 3.10 2.24 2.44 2.99 1.81 2.38 2.47 2.43 1.98
0.060 0.071 0.041 0.049 0.058 0.038 0.042 0.049 0.056 0.040
2.82 3.29 2.04 2.39 2.62 1.77 1.88 2.47 2.67 1.98
0.62 0.82 0.49 0.65 0.42 0.60 0.61 0.60 0.54 0.65
29.11 37.96 24.38 31.71 19.00 27.91 27.35 30.30 25.71 32.18
RAT NUMBER
BRAIN WEIGHT
THYMUS
ABS. REL. WT. % BRW
OVARY LEFT
ABS. REL. WT. % BRW
OVARY RIGHT ABS. REL. WT. % BRW
UTERUS WITH CERVIX
ABS . REL. WT. % BRW
HEART
ABS. REL. WT. % BRW
19003 19007 19008 19013 19015 19017 19024 19029 19034 19056
P P P P P P P P P P
2.13 2.16 2.01 2.05 2.21 2.15 2.23 1.98 2.10 2.02
0.14 0.12 0.17 0.22 0.24 0.13 0.19 0.16 0.18 0.22
6.57 5.56 8.46 10.73 10.86 6.05 8.52 8.08 8.57 10.89
0.054 0.053 0.050 0.068 0.043 0.053 0.043 0.041 0.062 0.051
2.54 2.45 2.49 3.32 1.94 2.46 1.93 2.07 2.95 2.52
0.079 0.086 0.055 0.080 0.048 0.048 0.020 0.058 0.074 0.043
3.71 3.98 2.74 3.90 2.17 2.23 0.90 2.93 3.52 2.13
0.48 0.79 0.53 0.58 0.48 0.35 0.42 0.34 0.44 0.66
22.54 36.57 26.37 28.29 21.72 16.28 18.83 17.17 20.95 32.67
1.29 1.30 1.17 1.35 1.51 1.36 1.40 1.48 1.21 1.39
60.56 60.18 58.21 65.85 68.32 63.26 62.78 74.75 57.62 68.81
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. WT. = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/BRA IN WEIGHT) X 100.
P = PREGNANT NP NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. Dam 19007 had the cortex of the right kidney adhered to the right lateral lobe of the liver . See the individual nccropr-.y
observations table (Table C28).
418-028'.PAGE C-62
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C31 (PAGE 4) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP IV
3 MG/KG/DAY
RAT NUMBER
BRAIN WEIGHT
LIVER
ABS. REL. WT. % BRW
KIDNEY LEFT
ABS. REL. WT. % BRW
KIDNEY RIGHT ABS. REL. WT. % BRW
ADRENAL LEFT
ABS. REL. WT. % BRW
ADRENAL
RIGHT
ABS.
REL.
WT. % BRW
SPLEEN
ABS. WT.
REL. % BRW
19005 19035 19039 19040 19045 19054 19058 19062 19063 19066
P P P P P P P P P P
1.81 2.04 2.09 2.05 2.15 2.49 2.15 2.13 2.03 1.91
13.80 12.06 16.01 13.33 17.71 11.54 19.11 13.59 21.27 12.70
762 .43 591.18 766.03 650.24 823.72 463.45 888.84 638.03 1047.78 664.92
1.16 1.54 1.27 1.54 1.63 1.65 1.61 1.58 1.67 1.26
64.09 75.49 60.76 75.12 75.81 66.26 74.88 74.18 82.27 65.97
1.26 1.56 1.40 1.48 1.66 1.55 1.57 1.61 1.69 1.47
69.61 76.47 66.98 72.20 77.21 62.25 73.02 75.59 83.25 76.96
0.044 0.064 0.055 0.052 0.063 0.041 0.064 0.046 0.067 0.031
2.43 3.14 2.63 2.54 2.93 1.65 2.98 2.16 3.30 1.62
0.046 0.055 0.055 0.051 0.042 0.038 0.049 0.046 0.059 0.045
2.54 2.70 2.63 2.49 1.95 1.53 2.28 2.16 2.91 2.36
0.54 0.66 0.71 0.64 0.61 0.84 0.77 0.62 1.5 9a 0.55
29.83 32.35 33.97 31.22 28.37 33.73 35.81 29.11 78.32 28.80
RAT NUMBER
BRAIN WEIGHT
THYMUS
ABS. REL. WT. % BRW
OVARY LEFT
ABS. REL. WT. % BRW
OVARY RIGHT ABS. REL. WT. %; BRW
UTERUS WITH CERVIX
ABS. REL. WT. % BRW
HEART
ABS. REL. WT. % BRW
19005 19035 19039 19040 19045 19054 19058 19062 19063 19066
P P P P P P P P P P
1.81 2.04 2.09 2.05 2.15 2.49 2.15 2.13 2.03 1.91
0.14 0.16 0.25 0.24 0.13 0.36 0.12 0.14 0.09 0.39
7.73 7.84 11.96 11.71 6.05 14.46 5.58 6.57 4.43 20 .42
0.049 0.051 0.079 0.058 0.046 0.064 0.052 0.058 0.049 0.028
2.71 2.50 3.78 2.83 2.14 2.57 2.42 2.72 2.41 1.46
0.056 0.055 0.062 0.046 0.057 0.048 0.066 0.058 0.057 0.025
3.09 2.70 2.97 2.24 2.65 1.93 3.07 2.72 2.81 1.31
0.80 0.71 0.46 0.50 0.53 0.75 0.74 0.78 0.56 0.78
44.20 34.80 22.01 24.39 24.65 30.12 34.42 36.62 27.59 40.84
1.16 1.45 1.20 1.55 1.47 1.48 1.39 1.41 1.39 1.51
64.09 71.08 57.42 75.61 68.37 59.44 64.65 66.20 68.47 79.06
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
ABS. WT. = ORGAN WEIGHT.
REL. % TBW = (ORGAN WEIGHT/BRAIN WEIGHT) X 100.
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. Dam 19063 had omentum adhered to the entire length of the outer capsule of the spleen. See the individual necropsy
observations table (Table C28).
418-028:PAGE C-63
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVE LOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C31 (PAGE 5) : ORGAN WEIGHTS AND RATIOS (%) OF ORGAN WEIGHT TO BRAIN WEIGHT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP V
RAT NUMBER
BRAIN WEIGHT
LIVER
ABS. REL. WT. % BRW
10 MG/KG/DAY
KIDNEY LEFT
ABS. REL. WT. % BRW
KIDNEY RIGHT ABS. REL. WT. % BRW
ADRENAL
LEFT
ABS.
REL.
WT. % BRW
ADRENAL RIGHT
ABS. REL. WT. % BRW
SPLEEN
ABS.
REL.
WT. % BRW
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031
P p P P P p P P p p
2.00
2.13 2.05 2.00 2.18 2.13 2.27 2.02 2.18 2.24
12.11 14.39 14.24
7.01 12.61 13.99 12.11 15.89 14.52 19.51
605.50 675.59 694.63 350.50 578.44 656.81 533.48 786.63 666.06 870.98
1.36 1.44 1.41 1.14 1.45 1.36 1.38 1.38 1.46 1.52
68.00 67.60 68.78 57.00 66.51 63.85 60.79 68.32 66.97 67.86
1.35 1.55 1.36 1.09 1.63 1.40 1.35 1.41 1.50 1.47
67.50 72.77 66.34 54.50 74.77 65.73 59.47 69.80 68.81 65.62
0.041 0.057 0.045 0.058a 0.064 0.061 0.053 0.044 0.062 0.042
2.05 2.68 2.20 2.90 2.94 2.86 2.33 2.18 2.84 1.88
0.031 0.055 0.045 0.056 0.041 0.055 0.047 0.041 0.046 0.038
1.55 2.58 2.20 2.80 1.88 2.58 2.07 2.03 2.11 1.70
0.57 0.54 0.50 0.28a 0.53 0.56 0.61 0.54 0.58 0.64
28.50 25.35 24.39 14.00 24.31 26.29 26.87 26.73 26.60 28.57
RAT NUMBER
BRAIN WEIGHT
THYMUS
ABS. REL. WT. % BRW
ABS. WT.
REL. % BRW
OVARY RIGHT ABS. REL. WT. % BRW
UTERUS
WITH CERVIX
ABS.
REL.
WT. % BRW
HEART
ABS. REL. WT. % BRW
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031
P P P P P P P P P P
2.00
2.13 2.05
2.00 2.18 2.13 2.27 2.02 2.18 2.24
0.18 0.15 0.15 0.11a 0.14 0.25 0.23 0.23 0.17 0.16
9.00 7.04 7.32 5.50 6.42 11.74 10.13 11.39 7.80 7.14
048 056 0.046 0.036 0.060 0.053 0.039 0.087 0.045 0.076
2.40 2.63 2.24 1.80 2.75 2.49 1.72 4.31 2.06 3.39
0.047 0.074 0.036 0.047 0.035 0.058 0.018 0.053 0.048 0.087
2.35 3.47 1.76 2.35 1.60 2.72 0.79 2.62 2.20 3.88
0.64 0.46 0.68 0.50 0.74 0.53 0.44 0.37 0.78 0.74
32.00 21.60 33.17 25.00 33.94 24.88 19.38 18.32 35.78 33.04
0.92 1.57 1.24 0.90 1.54 1.38 1.32 1.56 1.37 1.50
46.00 73.71 60.49 45.00 70.64 64.79 58.15 77.23 62.84 66.96
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
AB IT. = ORGAN WEIGHT.
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES)
a. Dam 19020 had a large left adrenal, small spleen, and small thymus
(Table C28).
REL . % TBW =: (ORGAN WEIGHT/BRAIN WEIGHT) X 100. See the individual necropsy observations table
418-028:PAGE C-64
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C32 (PAGE 1) : PRIMORDIAL FOLLICLE COUNT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP I RAT # 19012
AVERAGE
OVARY #1 31 37 46 33 34
36.2
0 MG/KG/DAY OVARY M 2 21 46 34 36 36 34.6
RAT M 19042
AVERAGE
OVARY M l 1
0 1 6 3 2.2
OVARY #2 18 9 9 16 13
13.0
19019 AVERAGE
4 1 2 0 1 1.6
0 5 2 2 7 3.2
19044 AVERAGE
3 11 9 13 51 17.4
5 8 8 9 17 9.4
19021 AVERAGE
16 16 21 20 14 17.4
4 4 12 17 30 13.4
19050 AVERAGE
3 5 2 4 3 3.4
1 5 3 6 10 5.0
19023 AVERAGE
7 14 10 14 ii 11.2
22 ii 13 27 6 15.8
19053 AVERAGE
24 11 27 27 25 22.8
3 ii 16 20 38 17.6
418-028:PAGE C-65
19041 AVERAGE
7 14 2 5 7 7.0
4 3 4 6 9 5.2
19065 AVERAGE
4 3 9 3 14 6.6
7 15 11 12 16 12.2
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OP T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C32 (PAGE 2): PRIMORDIAL FOLLICLE COUNT - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP V RAT # 19001
AVERAGE
OVARY #1 3 4 9 6 23
9.0
OVARY #2 6 5 6 17 20
10.8
10 MG/KG/DAY
RAT # 19025
AVERAGE
OVARY #1 11 12 6 6 7 8.4
OVARY #2 4 6 15 25 12
12.4
19006 AVERAGE
27 11 23 26 21 21.6
5 6 19 20 20 14.0
19027 AVERAGE
6 6 17 13 43 17.0
0 5 8 12 8 6.6
19011 AVERAGE
6 16 8 16 37 16.6
1 0 12 24 8 9.0
19028 AVERAGE
3 2 2 5 7 3.8
1 7 13 13 10 8.8
19020 AVERAGE
5 4 15 8 20 10.4
2 1 2 12 20 7.4
19030 AVERAGE
9 21 24 22 26 20.4
3 13 6 7 20 9.8
418-028:PAGE C
19022 AVERAGE
9 2 5 i 7 4.8
9 4 ii 17 19 12.0
19031 AVERAGE
11 15 11 9 14 12.0
7 4 14 11 17 10.6
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C33 (PAGE 1) : BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14a
RAT #
19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
RAT #
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
DOSAGE GROUP I
0 MG/KG/DAY
213 . 235. 230. 231. 219. 245. 227. 231. 220 . 234. 223 . 232. 222. 235. 232 .
218. 239. 232 . 236. 213 . 239. 225. 230. 222. 238 . 223 . 229. 217. 238. 224 .
223 . 238. 240 . 237. 222 . 247. 232 . 233 . 226. 243 . 230. 236 . 228 . 238 . 229.
225. 236 . 242 . 240 . 227. 252 . 236 . 235 . 229. 244 . 232 . 247. 229. 241. 234 .
224 . 247 . 244 . 244 . 223 . 252 . 238 . 242 . 229. 246 . 234 . 256 . 228 . 244 . 234 .
229. 246. 251. 248 . 222 . 249. 236. 238 . 232 . 255 . 241. 260 . 228 . 247. 236 .
235 . 250 . 254 . 245 . 228 . 258 . 236. 240 . 236 . 260. 245. 265 . 239. 246 . 242 .
237. 251. 261. 250. 232. 264 . 244 . 247. 245. 262. 247 . 277. 244 . 253 . 244 .
238 . 261. 256 . 253 . 229 . 266 . 247 . 249 . 243 . 262 . 244 . 275 . 238 . 251. 244 .
239. 261. 263 . 258 . 224 . 260. 248. 243 . 240. 269. 250 . 281. 238 . 254 . 246 .
246. 267. 269. 258 . 233 . 268 . 248 . 246. 245. 272. 255 . 291. 247. 254 . 247.
251. 258 . 269 . 260 . 235 . 272 . 242 . 245 . 251. 274 . 255 . 288 . 250 . 258 . 246 .
246 . 270 . 272 . 264 . 235 . 268 . 249 . 249. 246 . 271. 254 . 288 . 242 . 263 . 227 .
249 . 267 . 277. 266 . 234 . 264 . 250 . 250 . 247 . 277 . 261. 293 . 240 . 260 . 242 .
DOSAGE GROUP II
0.3 MG/KG/DAY
205. 231. 222 . 222. 221. 230. 217. 227. 219. 228 . 228. 235 . 219 . 237 . 230.
203 . 234 . 224 . 228 . 227. 235 . 217. 228 . 213 . 230. 228. 231. 225. 238. 232.
214. 236 . 225. 228 . 232. 239 . 222 . 233 . 207. 235 . 226. 228 . 225. 245. 232 .
215 . 246. 227. 233 . 236. 243 . 228 . 237. 217. 240. 235. 239 . 227. 246 . 238 .
214 . 248 . 231. 232 . 231. 247 . 228 . 238. 211. 239. 240 . 249. 233 . 240 . 238 .
216 . 252 . 232 . 230 . 233 . 249 . 227 . 237. 212 . 240. 234 . 243 . 238 . 246 . 242 .
220 . 252 . 234 . 240 . 237 . 249. 236 , 245 . 213 . 246. 236 , 241, 237. 251. 241.
226. 263 . 234 . 239. 239. 255 . 241. 248 . 223 . 244 . 245 . 253 . 241. 252 . 248 .
222 . 257 . 240. 244 . 236. 260. 244 . 246. 224 . 245 . 246 . 258 . 244 . 245 . 251.
219 . 260 . 238 . 241. 241. 262 . 237 . 244 . 217 . 245 . 244 . 253 . 248 . 250 . 252 .
226 . 260 . 239. 241. 246 . 263 . 240 . 253 . 219. 253 . 247 . 255 . 242 . 258 . 250 .
228 . 265 . 247 . 246 . 251. 269 . 240 . 253 . 229 . 255 . 254 . 264 . 241 . 259 . 261.
226 . 264 . 243 . 246 . 249 . 271 . 242 . 252 . 228 . 252 . 255 . 266 . 246. 254 . 262 .
223 . 265 . 244 . 247. 249 . 268 . 249 . 252 . 227 . 253 . 251. 262 . 250 . 259 . 261 .
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation.
418-028:PAGE C-67
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770 6.1)
TABLE C33 (PAGE 2) : BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14a
RAT #
DOSAGE GROUP III
1 MG/KG/DAY
19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
213 . 244 . 224 . 229. 221. 228. 226. 234. 219. 231. 219. 230 . 224 . 233 . 219.
218. 248 . 222 . 233 . 219. 227. 221. 242 . 219. 234 . 220. 229. 226. 233 . 218.
220. 254 . 223 . 237. 226. 227. 231. 241. 214 . 239. 223 . 238. 234 . 236. 224 .
218. 258. 233 . 240. 228. 231. 234 . 244. 221. 239. 227. 240. 234. 238. 228 .
219 . 256. 239. 243. 229. 235. 236. 253 . 229. 243 . 227. 240. 236. 240. 228 .
227 . 262 . 244 . 251. 231. 239. 233 . 259. 233. 250 . 230 . 240 . 238. 247. 231.
230. 269 . 242 . 249. 237. 237 . 239. 262 . 234 . 252 . 237 . 245 . 242 . 252. 237.
229. 273 . 243 . 256 . 241. 236 . 246. 265 . 234 . 250 . 238. 250 . 245. 250 . 242 .
227. 270. 250 . 262. 240 . 237. 246. 267 . 242. 255. 237. 251. 246. 253 . 241.
234 . 274 . 254 . 261. 240 . 239. 243. 276 . 246 . 257 . 236. 249 . 246 . 254 . 241.
234 . 280 . 261. 264 . 246. 241. 249. 282 . 250. 261. 243 . 257. 251. 256. 249.
229. 276. 254 . 264 . 250 . 244 . 257 . 278. 246. 264 . 244 . 258 . 251. 256. 251.
232 . 281. 254 . 271. 245 . 239 . 259 . 269 . 250. 266 . 240 . 256 . 253 . 260 . 250 .
236 . 285 . 264 . 272 . 250 . 240 . 250 . 273 . 256 . 266 . 244 . 258 . 253 . 270 . 251.
RAT ft
DOSAGE GROUP IV
3 MG/KG/DAY
19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
224 . 239. 225. 224. 218. 231. 214 . 237 . 219 . 224. 222 . 240 . 223 . 235. 227.
220. 238. 226. 222. 220. 227. 217. 234 . 223 . 233 . 220. 241. 223 . 237. 229.
22B . 248 . 233 . 223 . 226 . 230 . 221. 240. 224 . 231. 229. 244 . 226 . 240 . 229.
232 . 250. 237. 227. 227. 236. 227. 244 . 223 . 235. 229. 248. 227. 241. 234 .
238. 246. 230 . 233 . 226 . 240 . 227. 249. 229. 228. 224 . 249. 225. 248. 238.
241. 248 . 231. 234. 231. 237. 228 . 255. 241. 229. 229. 248. 226. 250 . 237 .
246. 251. 242 . 230 . 234 . 243 . 232 . 258 . 234 . 238 . 235 . 254 . 227. 251. 240 .
251. 255 . 243 . 236. 240 . 250 . 235 . 262 . 236. 241. 241. 265. 236. 252 . 244 .
251. 252 . 243 . 241. 236. 250 . 237. 265. 241. 239. 234 . 260 . 230 . 261. 247.
250 . 256. 240 . 242 . 238 . 250 . 237. 270 . 244 . 232 . 237 . 264 . 227 . 264 . 243 .
255. 260. 248. 242. 243 . 256. 237. 271. 245. 235. 242 . 263 . 230. 258. 244 .
257. 260 . 251. 242. 251. 261. 237. 276 . 244 . 240 . 246 . 266. 238 . 261. 251.
258 . 256 . 247. 245 . 245 . 262 . 247 . 281. 244 . 248 . 240. 269. 232 . 268 . 252 .
256 . 259 . 249 . 248 . 246 . 262 . 242 . 283 . 246 . 242 . 242 . 268 . 232 . 269 . 251.
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Last value recorded before cohabitation.
418-028:PAGE C-68
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE C33 (PAGE 3) : BODY WEIGHTS - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DAY 1
2
3
4
5
6
7
8
9 10 11 12 13 14a
RAT #
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
DOSAGE GROUP V
215 . 231. 228 . 226. 221. 229. 218 . 232. 220. 245. 227. 225. 226. 240. 220.
214 . 234 . 230. 224 . 221. 236. 220. 232 . 220. 252 . 229. 224. 228. 242. 218.
217. 238. 234 . 222. 227 . 240. 224 . 232. 227. 255. 234. 228. 234 . 243 . 218.
217. 235 . 238. 229. 230. 244 . 228 . 241. 230. 262 . 240. 231. 237. 246. 227.
208 . 236. 236. 231. 226 . 239 . 226 . 242 . 228 . 264 . 239. 234 . 237 . 250 . 231.
212 . 241. 243 . 203 . 230 . 249. 229. 244 . 232 . 262 . 243 . 231. 240. 252 . 233 .
10 MG/KG/DAY
218. 242 244 199. 239. 259 231 243, 237. 255. 251. 233 . 245 250 230
220 . 246. 248. 192. 240 . 267. 235. 250. 242 . 263 . 258 . 245. 254 . 254 . 239.
215 . 250 . 242 . 186 . 236 . 271. 231. 253 . 238. 264 . 255 . 244 . 254 . 256 . 239.
214 . 258 . 241. 188. 236. 272 . 235 . 251. 241. 266. 256. 241. 252. 258 . 241.
218 . 258. 249. 203 . 247. 283 . 238. 252 . 249. 268. 262 . 246 . 257. 256. 238 .
221. 257. 249. 212 . 247. 285 . 240 . 258. 253 . 272 . 266. 250. 262 . 262 . 246.
218 . 259 . 245 . 220 . 241. 280 . 238. 259 . 249. 277. 263 . 256. 264 . 263 . 246.
213 . 266 . 243 . 221. 243 . 282 . 238 . 259. 251. 269. 264 . 252 . 257. 260 . 248 .
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation.
418-028 :PAGE C-69
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE C34 (PAGE 1) : MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
RAT #
DOSAGE GROUP I
0 MG/KG/DAY
PREGNANCY STATUS DAY 0 1 2 3 4 5 6
19010 P 19012 P 19019 P 19021 P 19023 P 19041 P 19042 P 19044 P 19050 P 19053 P 19065 P 19068 P 19072 P 19074 P 19075 P
293 . 273 . 267. 276. 250. 291. 259. 256 . 258 . 284 . 279. 287. 254 . 268 . 257 .
304 . 281. 284 . 279. 244 . 290 . 265. 265 . 248 . 299. 286. 290 . 257 . 273 . 240 .
309. 281. 286 . 283 . 257 . 304 . 271. 270. 270. 300. 289. 302 . 268 . 285 . 232 .
312 . 291. 293 . 285 . 261. 312 . 270 . 280 . 269 . 303 . 289 . 297 . 272 . 284 . 233 .
313 . 295 . 301. 291. 262 . 308. 276. 277. 272 . 310. 293 . 307. 272 . 290. 230 .
312. 301. 310. 291. 267. 314 . 285. 283 . 274 . 309. 300. 312 . 273 . 294 . 244 .
310 . 300. 309 . 296 . 265. 318 . 293 . 288 . 280. 311. 298 . 320 . 268 . 295. 261.
DAY 13 14 15 16 17 18 19
19010 P 19012 P 19019 P 19021 P 19023 P 19041 P 19042 P 19044 P 19050 P 19053 P 19065 P 19068 P 19072 P 19074 P 19075 P
344 . 338 . 336. 331. 299. 354 . 338 . 325. 316. 350 . 346. 354 . 310 . 332 . 294 .
350 . 343 . 348 . 337. 305 . 358 . 348 . 340 . 320 . 359. 348 . 359. 321. 340 . 306.
358 . 350. 357. 347. 314 . 366 . 354 . 337. 328 . 366 . 360 . 365 . 327 . 345 . 311.
365 . 355 . 365 . 354 . 318 . 371. 374 . 349 . 305. 373 . 376 . 382 . 335 . 356 . 318 .
378 . 369 . 379 . 365 . 298 . 392 . 378 . 362 . 338 . 391. 386 . 394 . 350 . 370 . 329.
398 . 386 . 396. 373 . 325. 416. 397 . 380 . 360. 415 . 411. 410 . 369. 377 . 340 .
416 . 408 . 420 . 352 . 341. 425 . 414 . 392 . 374 . 429. 432 . 434 . 384 . 397. 353 .
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
7
313 . 308 . 304 . 302 . 271. 320 . 294 . 291. 282 . 313 . 300. 320 . 280 . 300 . 272 .
20
436. 424 . 426 . 344 . 357. 449 . 430. 420 . 388 . 449 . 446 . 441. 403 . 408 . 359 .
8
313. 312. 308. 304 . 273 . 324. 306. 297. 290. 323. 314 . 331. 289. 298. 268.
21
453 . 445. 445. 385. 366.
443 .
403 . 458 .
424 . 382 .
9 324 . 315 . 311. 301. 280 . 332 . 314 . 303 . 292 . 318 . 318 . 333 . 291. 306 . 280 .
22
419.
10
328 . 321. 316 . 314 . 283 . 337. 320. 306 . 300 . 329 . 325. 338 . 301. 311. 282 .
23
11
336. 327 . 324 . 320 . 286 . 343 . 329 . 312 . 305 . 342 . 334 . 345 . 307. 319 . 281.
24
12
339 . 333 . 331 . 330 . 287 . 347 . 337 . 321 . 307 . 338 . 340 . 352 . 308 . 326 . 288 .
25
418-028:PAGE C-70
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C34 (PAGE 2) : MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
RAT #
DOSAGE GROUP II
0.3 MG/KG/DAY
PREGNANCY STATUS DAY 0 1 2 3 4 5 6
19004 P 19009 P 19016 P 19018 P 19026 P 19036 P 19037 P 19043 P 19047 P 19048 P 19052 P 19055 P 19061 P 19067 P 19071 P
239. 269. 249. 255. 268. 271. 260. 255 . 232. 271. 259. 267. 259 . 273 . 264 .
DAY 13
245. 275 . 250. 262 . 259. 281. 268. 265. 244. 273 . 269 . 277 . 259 . 270 . 274 .
14
252 . 278. 258. 266. 273 . 288. 274. 275. 241. 282. 262 . 284 . 266. 268 . 281.
15
262 . 281. 260. 269. 273 . 292. 272 . 274 . 248 . 287. 274 . 289. 264 . 283 . 286.
16
265 . 283 . 266. 278. 285. 296. 280. 278 . 248 . 288. 272. 294 . 271. 288 . 292 .
17
269. 286. 260 281 288 301 287 285 251, 291 285. 300 278. 289 295
18
270 . 291. 269. 286. 290 . 304 . 290 . 295. 255. 295. 288 . 306. 278 . 289. 304 .
19
19004 P 19009 P 19016 P19018 P 19026 P 19036 P 19037 P 19043 P 19047 P 19048 P 19052 P 19055 P 19061 P 19067 P 19071 P
310.
320.
321.
321.
299.
310.
326.
332 .
336 .
349.
343 .
348 .
321.
325 .
329.
338 .
280 .
289 .
321.
329.
322 . ' 330.
341.
349.
308.
315.
324 .
325.
339.
348.
325. 330 . 312. 339. 346. 357. 328 . 346. 297. 336. 338 . 358. 325. 340. 364 .
334 . 335. 325 . 348. 361. 367 . 342 . 357. 304 . 336. 350. 371. 338. 344 . 365.
349. 343 . 338. 363. 378. 383 . 351. 372 . 314 . 348 . 366. 384 . 345. 351. 380.
361 349 348 373 394 398 364 387 329 358 377 401 351 370 394
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY - DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
383 . 326 . 361. 391. 418 . 410 . 377 . 389 . 334. 358. 391. 411. 367. 379 . 409 .
7
276. 294 . 270 . 292 . 298 . 313 . 292 . 292. 256. 303 . 288. 307. 279. 294 . 302 .
20
396 . 334 . 380. 408 . 432 . 424 . 393 . 405 . 364 . 375 . 409. 433 . 382 . 395. 431.
8
280 . 298 . 281. 295. 296. 321. 296. 295. 264 . 299. 293 . 305. 288. 299. 309 .
21
361. 395. 422 . 452 . 422 . 399. 417. 380. 382 .
452 .
414 . 444 .
9
288 . 299. 277. 299 . 302 . 324 . 301. 305 . 264 . 306 . 299. 318. 291. 300. 316 .
22
10
292 . 304 . 282 . 309. 311. 330 . 302 . 310 . 270 . 309 . 305 . 322 . 290 . 308 . 319 .
23
11
301. 310 . 291. 318. 327. 332 . 310 . 318 . 274 . 312. 309 . 334 . 296 . 312 . 331.
24
12
306 . 315 . 296 . 322 . 329. 342 . 319 . 328 . 279 . 317 . 318 . 339 . 306 . 321 . 338 .
25
418-028 :PAGE C-71
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C34 (PAGE 3) : MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
RAT #
DOSAGE GROUP III
1 MG/KG/DAY
PREGNANCY STATUS DAY 0 1 2 3 4 5 6
19003 P 19007 P 19008 P 19013 P 19014 NP 19015 P 19017 P 19024 P 19029 P 19034 P 19038 NP 19056 P 19057 P 19060 P 19064 P
244 . 293 . 283 . 291. 250. 250. 258 . 291. 266. 266. 237. 272 . 269. 276. 263 .
252 . 297. 282. 289. 259. 259. 262 . 294 . 267. 274 . 243 . 277. 271. 271. 275.
252 . 302 . 293 . 294 . 263 . 262 . 261. 292 . 278. 280. 254 . 282. 269 . 278. 274 .
258 . 304 . 296. 296. 264 . 264 . 275. 304 . 275. 284 . 262 . 285 . 281. 288 . 238 .
258. 312. 302. 304 . 270. 266. 269. 305. 277. 289. 261. 290. 279. 277. 286.
260. 310. 310. 311. 276. 265. 275. 311. 283 . 292 . 265. 287. 282 . 295. 291.
262 . 315. 312 . 310. 281. 259. 278. 309. 284 . 294 . 273. 292. 289. 301. 294 .
DAY 13 14 15 16 17 18 19
19003 P 19007 P 19008 P 19013 P 19014 NP 19015 P 19017 P 19024 P 19029 P 19034 P 19038 NP 19056 P 19057 P 19060 P 19064 P
291. 354 . 352. 350. 297 . 290. 314 . 341. 317. 340. 294 . 324. 318. 346. 331.
301. 360 . 358. 358. 298 . 298 . 323 . 345 . 317. 346 . 294 . 326. 328 . 347 . 337.
308 . 369 . 368 . 361. 303 . 310. 332 . 355 . 323 . 359. 288. 338 . 333 . 353 . 343 .
320 . 380. 370 . 372 . 306. 315 . 338. 358 . 336. 364 . 284 . 342 . 337. 371. 348.
335. 391. 389. 386. 312. 329. 358. 374 . 355 . 369. 287. 355. 357. 379. 366.
354. 412 . 411. 398. 310. 346. 364 . 388. 363 . 390. 288 . 368 . 375. 392 . 384 .
365 . 431. 423 . 409. 310. 360. 385. 368. 376. 400. 281. 384 . 388. 409. 411.
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G).
7
264 . 318 . 317. 310 . 280 . 264 . 283 . 318 . 284. 300 . 278 . 293 . 290. 302 . 295.
20
386 . 444 . 439. 432 . 310. 374 . 406. 416 . 393 . 413 . 282 . 395 . 402 . 425 . 432 .
8
267. 324 . 323 . 320. 290. 275 . 288. 316. 280. 308 . 281. 299. 296. 306. 305 .
21
420 .
450. 316. 386. 421. 400. 403 . 432 . 281. 420. 424 .
445 .
9
269 . 332. 327 . 317. 291. 275 . 292 . 329 . 285 . 313 . 282 . 308. 301. 314 . 307 .
22
313 .
286 .
10
271. 340 . 335 . 328 . 295 . 287 . 298 . 330 . 290 . 321. 285 . 313 . 307 . 320 . 312 .
23
305 .
288 .
ii
287 . 345 . 344 . 333 . 295 . 291. 301. 340. 294 . 334 . 291. 315 . 310 . 329 . 317 .
24
293 .
288 .
12
286 . 350 . 345 . 341 . 299 . 298 . 316 . 342 . 306 . 339 . 296 . 318 . 318 . 334 . 333 .
25
287 .
302 .
418-028 :PAGE C-72
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C34 (PAGE 4) : MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
RAT #
DOSAGE GROUP IV
3 MG/KG/DAY
PREGNANCY STATUS DAY 0 1 2 3 4 5 6
19002 P 19005 P 19035 P 19039 P 19040 P 19045 P 19046 NP 19051 NP 19054 P 19058 P 19062 P 19063 P 19066 P 19069 P 19073 P
295.
294 .
299 .
276.
276.
286 .
264.
270.
273 .
249.
253 .
253 .
266.
270.
274 .
269.
279.
282 .
247.
254.
258 .
MATING NOT CONFIRMED
248.
260.
260.
258.
266.
271.
256.
266.
268 .
284 .
289 .
294 .
246.
244 .
254 .
284 .
289 .
298 .
258.
266 .
268 .
299. 284 . 272 . 256. 277. 288. 269.
258. 280 . 274 . 300. 258 . 304 . 275.
305 . 284 . 273 . 256. 281. 293 . 267.
262 . 283 . 278. 308. 262 . 311. 279 .
306. 285. 280. 260. 283 . 294 . 268.
267. 293 . 279. 310. 267. 314 . 284 .
307. 284 . 281. 264 . 288. 290. 273 .
264. 293 . 289. 314 . 266 . 322 . 288.
19002 P 19005 P 19035 P 19039 P 19040 P 19045 P 19046 NP 19051 NP 19054 P 19058 P 19062 P 19063 P 19066 P 19069 P 19073 P
DAY 13 14 15
338 .
341.
352 .
306.
316.
319.
296.
297.
306 .
291.
296.
303 .
320.
329.
337 .
336.
342.
347.
290.
294.
293 .
MATING NOT CONFIRMED
296.
302 .
299 .
329.
340 .
346 .
322.
332 .
336 .
362.
368 .
369.
301.
302 .
314 .
375.
378.
387.
330.
336.
342 .
16
350 . 326. 307 . 314 . 343 . 363 . 288 .
307. 350. 340. 383 . 321. 404 . 349.
17
371. 338 . 323 . 324 . 357. 382 . 284 .
304 . 365. 356. 392. 335 . 413 . 368 .
18
380. 357. 336. 329. 370. 392. 283 .
316. 383 . 376. 393 . 351. 384 . 380.
19
394 . 372. 354 . 348 . 390 . 402 . 284 .
328 . 396. 391. 407. 368 . 408. 387.
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
7
310. 287. 282 . 264 . 292 . 296. 275.
268. 300. 292 . 318. 264 . 324 . 290.
20
406. 389. 383. 362 . 412 . 423 . 279.
337 . 414 . 415 . 424 . 381. 436 . 402 .
8
316. 290. 273 . 267. 294 . 313 . 281.
276. 303. 292 . 326. 268 . 336. 296.
21
429. 400. 390.
441. 274 .
344 . 424 .
440. 394 . 454 . 420.
9 320 . 292 . 277. 269. 298. 313 . 274 .
280 . 313 . 304 . 330 . 274 . 341. 302 .
22
281.
304 .
10
325 . 297 . 282 . 274 . 306 . 320 . 282 .
284 . 320 . 307 . 335 . 278 . 346 . 308 .
23
280.
ii
323 . 303 . 296 . 281. 313 . 324 . 280 .
291. 322 . 316. 345 . 290 . 358 . 315 .
24
284 .
12
333 . 300 . 293 . 287 . 317 . 340 . 296 .
296 . 328 . 320 . 355 . 290 . 370 . 326 .
25
274 .
418-028:PAGE C-73
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7705.1)
TABLE C34 (PAGE 5) : MATERNAL BODY WEIGHTS - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
RAT #
DOSAGE GROUP V
10 MG/KG/DAY
PREGNANCY STATUS DAY 0 1 2 3 4 5 6
19001 P 19006 P 19011 P 19020 P 19022 P 19025 P 19027 P 19028 P 19030 P 19031 P 19032 P 19033 P 19049 P 19059 P 19070 P
223. 268 . 254 . 236. 267. 293 . 248. 265. 273 . 281. 281. 249. 256. 267. 252.
229. 280. 261. 234 . 271. 303 . 252 . 271. 271. 290. 279. 260. 267 . 276 . 259 .
233 . 281. 260. 249. 266 . 303 . 251. 278 . 272 . 285. 292. 258 . 278 . 271. 259.
237. 282 . 263 . 254 . 282 . 307. 260 . 283 . 286 . 297 . 292 . 263 . 281. 278 . 270 .
235 . 292 . 264 . 256. 290. 314. 256 . 283 . 278. 298. 299. 262. 287 . 286. 266.
242 . 293 . 264 . 259. 293 . 313 . 260. 288. 284 . 303. 300 . 267. 284 . 289. 275.
239. 296. 275 . 257. 293 . 316. 269. 292. 284 . 303 . 301. 272 . 295. 291. 272 .
DAY 13 14 15 16 17 18 19
19001 P 19006 P 19011 P 19020 P 19022 P 19025 P 19027 P 19028 P 19030 P 19031 P 19032 P 19033 P 19049 P 19059 P 19070 P
271. 336. 308. 293 . 321. 359. 296. 324 . 314. 348. 344. 303 . 332. 329. 311.
278 . 347. 305 . 300 . 328. 354 . 299. 327 . 321. 357. 350. 312. 338. 333. 313 .
283 . 353 . 309. 303. 337 . 364 . 303 . 338. 328. 366. 355. 324 . 338. 344 . 323 .
289. 366 . 320. 306. 345. 372 . 308 . 344 . 332 . 371. 355 . 328 . 346. 352. 332 .
303. 379. 340 . 321. 361. 384 . 326. 354 . 345. 389. 375 . 344 . 369. 363 . 347.
309. 397. 354 . 332 . 369. 401. 341. 365. 354 . 398. 390. 358 . 373 . 376. 358.
P - PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAY = DAY OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
320. 422 . 375. 349 . 389 . 409. 353 . 377. 368 . 414 . 404 . 370 . 386. 383 . 351.
7
243 . 298 . 278 . 263 . 294 . 324 . 270. 289. 288 . 313. 309. 278 . 296. 297. 276.
20
334 . 436. 386. 362. 416. 413 . 373 . 394 . 382 . 436. 417. 390. 410 . 405 . 372 .
8
251. 306. 275 . 269. 298. 329. 272. 297. 286. 322. 310. 279. 302 . 301. 286.
21
343 . 451. 406.
391. 425. 386 . 411. 397 .
447.
425. 427 . 404 .
9
250 . 311. 287 . 276. 303 . 333 . 274 . 301. 292 . 318 . 315 . 285 . 307 . 299. 287.
22
10
251. 318 . 297 . 283 . 311. 342 . 282 . 304 . 299. 327 . 323 . 288 . 309 . 308 . 290 .
23
ii
255 . 323 . 289. 311. 316. 351. 287. 308 . 307. 337. 331. 292 . 312 . 314 . 296 .
24
12
266 . 333 . 292 . 293 . 320 . 352 . 290 . 318 . 315 . 346 . 341 . 304 . 329 . 325 . 301.
25
418-028:PAGE C-74
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE C35 (PAGE 1) : MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
RAT #
DOSAGE GROUP I
0 MG/KG/DAY
DAY 1 2 3 4 5 6 7 8 9 10
19010 19012 19019 19021 19023 19041 19C42 19044 19050 19053 19065 19068 19072 19074 19075
334. 316. 324 . 302. 279. 337. 335 . 301. 285 . 324. 332. 338 . 311. 313. 266.
DAY 14
330. 319. 309 . 266 . 294 . 347 . 334 . 300. 285. 327 . 340 . 344 . 298. 319. 284 .
15
332 . 322 . 320 . 289. 299. 346 . 329. 303. 285 . 338 . 337 . 349. 300. 313 . 279 .
16
334. 327. 337 . 288 . 302 . 352 . 340 . 312. 290. 336 . 345 . 348. 305. 320. 287 .
17
341. 323 . 337 . 310. 310. 358 . 338. 321. 300. 339. 343 . 347. 299. 336 . 288 .
18
344 . 331. 342. 272 . 319 . 371. 346 . 319. 305. 359. 351. 360 . 324 . 345 . 303 .
19
351. 347. 343. 324. 316. 363 . 346. 330. 304. 367. 362 . 362. 334 . 352. 305.
20
351. 346. 340 . 320 . 318 . 367 . 344 . 340. 313 . 367 . 361. 371. 337 . 348 . 311.
21
368. 349. 360. 291. 331. 383. 350. 339. 330. 374. 364. 381. 288.a 358. 321.
22b
353 . 295 .a 360 . 326 . 338. 371. 354 . 341. 327 . 377 . 377 . 366. 340 . 367 . 297 .a
19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
352 . 365 . 388 . 347 . 335. 378 . 370 . 368 . 337 . 374 . 385 . 382 . 363 . 337. 316.
353 . 381. 371. 352 . 331. 396. 370 . 354 . 339. 378 . 393 . 382 . 294 . 338. 298 .
362 . 386. 384 . 355 . 323 . 385 . 371. 367 . 343 . 360 . 376 . 386 . 348 . 346. 318 .
359 . 362 . 363 . 331. 322 . 376. 346. 327. 329. 367. 346 . 398 . 355. 365. 330 .
360 . 378 . 394 . 344 . 329. 359. 382 . 354 . 338 . 381. 370. 382 . 351. 363 . 319.
349 . 356. 379. 346. 338 . 367 . 365 . 359. 337 . 377 . 371. 403 . 364 . 376 . 314 .
347. 354 . 384 . 354. 332 . 375 . 365. 376. 336. 366. 356 . 388 . 354 . 380 . 327.
353 . 373 . 372 . 307 .a 317 . 362 . 355 . 366 . 341. 285 . 345 . 386 . 367. 359. 320 .
299. 335. 309. 270. 280. 305. 302. 360. 290. 299. 301. 360. 292. 297. 295.
DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses.
b. Dams were fasted prior to sacrifice.
ii
360 . 353 . 365 . 328 . 345 . 381. 354 . 352 . 335 . 312 .a 377 . 377 . 345 . 369 . 321 .
12
356. 359. 352 . 316. 336 . 380 . 362 . 352 . 335 . 380 . 365 . 379. 360 . 378 . 325 .
13
345 . 366 . 374 . 350 . 340 . 390 . 362 . 356 . 342 . 392 . 391 . 380 . 359 . 350 . 280 .a
418-028 :PAGE C-75
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C35 (PAGE 2) : MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
RAT #
DOSAGE GROUP II
0.3 MG/KG/DAY
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
DAY 1
2
290. 286. 295. 302. 318. 304 . 267. 314. 281. 306. 302. 320. 309. 305. 334.
293 . 306. 297. 308. 296. 294 . 272 . 314. 269. 300 . 297. 326. 290. 306 . 334 .
DAY 14
15
349. 349. 342 . 336. 360 . 344 . 310. 355. 323 . 355. 315 .C 331. ' 338 . 344 . 362 .
337 . 348 . 341. 337. 354 . 355 . 326 . 342 . 321. 346 . 352. 348. 335. 352 . 316 .a
3
296. 273 . 298. 311. 273 .a 297. 277. 311. 271. 305. 261.a 320. 297. 311. 335.
16
345. 343. 336. 341. 356. 356. 332. 338. 330. 349. 353. 363 . 322. 352 . 369.
4
301. 251.a 306. 311. 320. 296. 269. 316. 276. 302 . 264 .a 332 . 293 . 310. 312 .
17
317. 341. 330 . 341. 355 . 343 . 312. 333. 318 . 338. 349. 366 . 348 . 360 . 365.
5
303. 301. 310 . 318. 314 . 296. 288 . 316. 287. 307 . 285 . 332. 309 . 314 . 329 .
18
332 . 345 . 327. 353 . 341. 345. 332 . 344 . 324 . 356. 345. 372 . 338 . 371. 371.
6
317. 312. 320. 320. 311. 309. 292. 321. 284. 315. 315. 332. 307 , 319, 320 ,
19
344 349 329 349 353 358 326 349 317 365 351 367 337 358 367
7
310. 324 . 323 . 325. 326. 319. 296. 332. 304 . 320. 316. 348. 315 . 331. 332 .
20
325. 342. 324. 340. 358. 344. 342. 344 . 319. 368. 346. 368 . 334 . 343 . 372 .
8
316. 318. 321. 327. 331. 303 . 301. 325. 296. 327. 317. 332. 323 . 335. 339.
21
304 . 336. 308. 343. 360. 351. 321. 348. 308. 350. 346. 350 . 327. 308.a 348.
9
330. 325. 323 . 336. 333. 318. 318. 342. 311. 336. 331. 353. 277.a 346. 342.
22b
276. 346. 314. 338. 296. 359. 309. 356. 325. 306. 320. 336. 315. 294. 374.
10
331. 331. 318. 347 . 347. 334 . 321. 349. 312 . 343 . 330 . 363 . 297 . 352. 348 .
DAY - DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses.
b. Dams were fasted prior to sacrifice. c. Water access was interrupted; value excluded from group averages and statistical analyses.
11
333 . 329 . 324 . 339 . 341. 335 . 251. 346 . 318 . 336 . 339 . 354 . 319 . 350 . 364 .
12
334. 342. 328 . 332. 338. 347. 230 .a 354 . 318. 351. 350. 364 . 340 . 356. 365.
13
330 . 343 . 329 . 342 . 355 . 352 . 298 . 352 . 264 .a 345 . 340 . 360 . 332 . 367 . 356 .
418-028`.PAGE C-76
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C35 (PAGE 3) : MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
RAT #
DOSAGE GROUP III
1 MG/KG/DAY
DAY 1 2 3 4 5 6 7 8 9 10
19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
285.
284.
303 .
309.
331.
326.
346.
334 .
NOT PREGNANT
281.
266.
320 .
307.
295.
312.
282.
284.
311.
320.
NOT PREGNANT
317.
311.
305.
294.
336 .
318.
311.
305.
287. 316. 328. 315.a
283 . 310. 321. 281. 323 .
316. 278 .a 330 . 319.
293. 316. 335. 348 .
288 . 312 . 327. 283 . 322 .
282 .a 300. 328. 318.
300. 316. 316.a 349.
277. 313 . 332 . 290. 328 .
321. 311. 342 . 300.
308 . 337. 341. 354 .
295 . 322 . 332 . 301. 309.a
319. 320 . 345. 313 .
312 . 339. 350. 350.
302 . 324. 342 . 305. 354.
331. 324. 353. 319.
317. 348 . 355 . 357.
296. 339. 344 . 309. 345.
311.a 324 . 348 . 321.
316. 347. 351. 359.
313 . 341. 354 . 309. 338 .
339. 321. 358. 340.
330 . 354 . 361. 372 .
321. 352 . 361. 309. 345.
339. 339. 366. 342 .
DAY 14 15 16 17 18 19 20 21 22b
19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
344 .
336.
369 .
331.
361.
370.
391.
379.
NOT PREGNANT
339.
323 .
336.
343 .
364 .
326.a
323 .
326.
359.
352.
NOT PREGNANT
347.
341.
351.
337.
362 .
350.
344 .
330.
335. 359. 358. 387.
322 . 366. 368 . 332 . 358 .
343 . 343 . 371. 349.
333 . 354 . 340 . 369 .
304 . 343 . 351. 299.a 339.
346. 352 . 373 . 354 .
330. 377. 360 . 380.
312. 363 . 366. 321. 371.
348 . 337. 351. 363 .
335 . 369. 356. 386 .
323 . 373 . 369. 332 . 356 .
329. 356. 372 . 359.
315 . 352 . 350. 381.
316. 358 . 367. 317. 358 .
350. 354 . 351. 366 .
338 . 355. 350 . 374.
312 . 360 . 354 . 322 . 352 .
338 . 305 . 352 . 352 .
284 . 303 . 292 . 389 .
274 . 350. 309. 332 . 287.
292 . 287 . 357 . 289 .
DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses. b. Dams were fasted prior to sacrifice.
ii
274 .a 364 . 368 . 372 .
311. 350 . 368 . 318. 349.
346 . 336. 369. 340 .
12
281 .a 363 . 361. 389 .
310. 356 . 369. 326. 351.
352 . 350 . 360. 344 .
13
320. 373 . 358. 390 .
344 . 363 . 348 . 323 . 355 .
343 . 352 . 373 . 302 .a
418-028:PAGE C-77
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C35 (PAGE 4) : MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
RAT #
DOSAGE GROUP IV
3 MG/KG/DAY
DAY 1 2 3 4 5 6 7 8 9 10
19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
335.
330.
328.
337.
284 .
295.
297.
307.
271.
267.
276.
285.
271.
269.
265.
270.
321.
299.
299.
314 .
315 .
315 .
315.
318.
NOT PREGNANT
NOT PREGNANT; MATING NOT CONFIRMED
280.
296.
291.
296.
309.
320.
276.a 268.a
304.
308.
318.
317.
331.
332.
341.
348.
290 .
280.
288 .
292.
332 .
329.
332 .
332.
318.
315.
310.
306.
338. 317. 289. 272 . 315. 304 .a
297. 300. 326. 354. 297. 330. 303 .
340. 322. 286 . 254 .a 323 . 315.
304 . 309 . 322 . 341. 303 . 288 .a 321.
345 . 320. 292. 283 . 328 . 310 .
303 . 313. 332. 357. 301. 275.a 328.
356. 325. 292 . 278 . 339. 318 .
312 . 319. 334. 351. 314 . 320. 330.
338. 328. 309. 292. 350 . 352.
312 . 329. 347. 370. 313 . 333 . 340.
348 . 328 . 309. 288. 350 . 346.
313. 340. 351. 368. 315. 288.a 346.
DAY 14 15 16 17 18 19 20 21 22b
19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
361.
358.
360.
369.
341.
342.
351.
320 .
315 .
322.
314 .
306.
311.
310.
310.
296.
360.
355.
350.
334.
349.
377.
361.
353 .
NOT PREGNANT
NOT PREGNANT; MATING NOT CONFIRMED
335 .
332.
333 .
313.
331.
302 .c 345.
350 .
369 .
358 .
356.
335.
377.
380 .
383 .
370.
338 .
332 .
332 .
325.
349.
361.
366.
365.
350.
357.
368.
375.
358. 344 . 322 . 320. 365. 380 .
328 . 345. 352. 384 . 336 . 373 . 371.
376. 352 . 326 . 317. 361. 402 .
326. 364 . 355. 388 . 341. 375. 364.
378 . 350. 315. 313 . 367. 386 .
322 . 363 . 354. 377. 340 . 358. 365.
359 . 333 . 312 . 317. 356. 398 .
323 . 324. 342 . 385 . 328 . 352 . 348 .
302. 285. 261. 315 . 294 . 385 .
287. 350. 290. 369. 292 . 362 . 363 .
DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Value appeared incorrectly recorded and was excluded from group averages and statistical analyses. b. Dams were fasted prior to sacrifice. c. Water access was interrupted; value excluded from group averages and statistical analyses.
11
357. 328 . 305. 293 . 348 . 348 .
306 . 337 . 348 . 378 . 304 .a 337. 352 .
12
368 . 340 . 316 . 300 . 356. 368 .
290 .a 351. 349 . 385 . 322 . 353 . 362 .
13
367. 336. 332 . 306 . 356 . 376 .
333 . 353 . 368 . 381. 351. 365. 290.a
418-028:PAGE C-78
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7708.1)
TABLE C35 (PAGE 5) : MATERNAL BODY WEIGHTS - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
RAT #
DOSAGE GROUP V
10 MG/KG/DAY
DAY 1 2 3 4 5 6 7 8 9 10
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
256 . 308. 291. 260. 278. 310. 281. 313 . 307. 316. 317. 295 . 310. 312 . 290 .
257. 308. 286. 268 . 300 . 318. 283 . 302 . 301. 324 . 330. 292. 304 . 313 . 297.
254 . 313 . 290. 279. 310. 326 . 278 . 307. 304 . 289.a 327. 292 . 308 . 314 . 302 .
254 . 317 . 302 . 274 . 314 . 315.a 274 . 310. 309 . 286.a 319. 299. 305. 312. 302 .
234 .a 322 . 303 . 271. 317. 331. 242 .a 310 . 318 . 319. 309. 305 . 286 .a 313 . 305 .
262. 324. 308 . 243 . 322 . 349. 276. 311. 320. 329. 307 . 308. 302 . 317. 312.
261. 328 . 302 . 269. 335 . 358 . 294 . 315. 327. 340. 326 . 320 . 318. 322 . 313 .
265. 330. 321. 266. 343 . 347. 283 . 315 . 331. 340. 335. 326. 320. 327. 323 .
259 . 331. 321. 268 . 344 . 361. 291. 325. 348. 354 . 339. 329. 326. 338. 337.
273 . 346. 331. 262 . 361. 365 . 238. 331. 340. 362 . 343 . 342 . 339. 348 . 330 .
DAY 14 15 16 17 18 19 20 21 22b
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
287 . 367. 332 . 270 . 360 . 384 . 317. 318. 357. 316.c
351. 347. 348. 320. 303 .c
288. 366. 294 .a 246. 348. 373 . 312. 335. 355 . 362. 336. 341. 346. 322. 337.
286. 366. 318 . 252. 352 . 358 . 309. 294. c 353 . 365. 359. 338. 358 . 357. 358.
278 . 356. 326 . 246 . 352 . 355. 306. 329. 344 . 364. 343 . 332. 341. 358. 365.
304 , 373 , 338 . 252 . 359, 392, 302 , 340 , 346, 375, 356, 329 347 345 351
302 . 373 . 350 . 251. 363 . 363 . 321. 348. 346. 373 . 319.a 332 . 334 . 339. 358.
296 . 378 . 330. 246 . 349. 358. 315 . 330. 365 . 381. 341. 323 . 349 . 360 . 363 .
292 . 373 . 330. 228 . 349. 346. 315. 346. 355. 371. 344 . 323 . 349. 343 . 352 .
278 . 304 . 283 . 210. 294 . 291. 266. 339. 314 . 361. 287. 328. 330. 317. 351.
DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a . Value appeared incorrectly recorded and was excluded from group averages and statistical analyses.
b. Dams were fasted prior to sacrifice. c. Water access was interrupted; value excluded from group averages and statistical analyses.
11
281. 344 . 338 . 253 . 341. 368 . 296 . 334 . 346. 366. 328 . 339. 335. 347. 337 .
12
278 . 339. 326 . 268 . 360. 381. 304 . 331. 346. 371. 284 .a 335 . 331. 352 . 357 .
13
286 . 348 . 345 . 259 . 355 . 379 . 322 . 338 . 348 . 371 . 354 . 344 . 348 . 350 . 355 .
418-028:PAGE C-79
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770G.1)
TABLE C36 (PAGE 1): FEED CONSUMPTION VALUES - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DAYS 1- 8a
RAT #
DOSAGE GROUP I
19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
140. 142. 162. 147. 124 .
b 138. 144 . 123.
c 151. 167. 132. 146. 138.
RAT #
DOSAGE GROUP II
19004 19009 19016 19018 19026 19036 19037 19043 19047 19043 19052 19055 19061 19067 19071
132. 156. 126. 137. 144 . 136. 138. 153 . 110. 131. 123 . 147. 134 . 139. 139.
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation. b. Spilled feed precluded the calculation of this value. c. Value was not recorded.
0 MG/KG/DAY 0.3 MG/KG/DAY
418-028:PAGE C-80
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C36 (PAGE 2) : FEED CONSUMPTION VALUES - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DAYS 1- 8a
RAT #
DOSAGE GROUP III
19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
124 . 150. 155. 150. 136. 142. 127. 169. 153 . 149. 130. 141. 143. 174. 138.
RAT #
DOSAGE GROUP IV
19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
145. 150. 125. 118. 133 . 134. 132. 160. 13 5. 128. 129. 153 . 124 . 153 . 134 .
DAY - DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation.
1 MG/KG/DAY 3 MG/KG/DAY
418-028:PAGEC-81
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C36 (PAGE 3) : FEED CONSUMPTION VALUES - PRECOHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DAYS 1- 8a
RAT #
DOSAGE GROUP V
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
107. 119. 139.
92. 133. 151. 135. 163. 136. 180. 147. 148. 141. 138. 132.
DAY = DAY OF STUDY ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Last value recorded before cohabitation.
10 MG/KG/DAY
8-0 39Vd:8^0-8Ifr
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C37 (PAGE 1) : MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
PREGNANCY STATUS DAYS 0 - 7
7 - 1 0 10 - 12 12 - 15 15 - 18 18 - 20
RAT #
DOSAGE GROUP I
0 MG/KG/DAY
19010 P 19012 P 19019 P 19021 P 19023 P 19041 P 19042 P 19044 P 19050 P 19053 P 19065 P 19068 P 19072 P 19074 P 19075 P
184. 85. 50. 77. 76. 53 .
178. 82. 55. 83 . 81. 59.
188. 90. 82 . 95. 75. 56.
182 .
85.
58.
93.
78.
21.
140. 66. 44 . 76. 47. 51.
190. 82. 127. 81. 83 . 58.
192. 91. 69. 101. 88 . 66.
189. 91. 59. 93 . 90. 54 .
158. 70. 49. 73 . 56. 53 .
188. 77. 64. 84. 76. 58.
203. 92. 73. 94. 88. 68.
191. 93 . 57. 86. 86. 55.
171.
75.
a
77. 74. 58.
193. 89. 63 . 90. 82. 51.
117. 78. 46. 77. 65. 36.
RAT #
DOSAGE GROUP II
0.3 MG/KG/DAY
19004 P 19009 P 19016 P 19018 P 19026 P 19036 P 19037 P 19043 P 19047 P 19048 P 19052 P 19055 P 19061 P 19067 P 19071 P
186. 83. 58. 86. 81. 60.
178 .
79.
49.
91.
82.
17.
137. 65. 45. 70. 71. 42.
176. 85. 59. 90 . 85. 55.
179. 81. 58. 90. 86. 59.
193. 93 . 56. 82. 78. 40.
185. 83 . 59. 77. 67. 39.
170.
84 . 57.
84 . 95.
54.
150.
67.
43 .
70.
72 . 46.
164.
67.
44 .
76.
69.
46.
162. 79. 49. 77. 79. 46.
198. 91. 63. 90. 97 . 49.
170. 80. 51. 86. 81. 52 .
173 .
79.
58.
80.
69.
22 .
203 .
90.
60.
90.
88.
57.
P - PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Spilled feed precluded the calculation of this value.
418-028:PAGE C-83
PROTOCOL 4X8-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C37 (PAGE 2) : MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
PREGNANCY STATUS DAYS 0 - 7
7 - 1 0 10 - 12 12 - 15 15 - 18 18 - 20
RAT #
DOSAGE GROUP III
1 MG/KG/DAY
19003 P 19007 P 19008 P 19013 P 19014 NP 19015 P 19017 P 19024 P 19029 P 19034 P 19038 NP 19056 P 19057 P 19060 P 19064 P
144 .
65.
49.
77.
66.
50.
179.
83.
60.
86.
78 .
53.
213. 94. 64. 86. 79. 60.
160 .
78.
64 . 85.
86.
54 .
175. 83. 50. 73. 78 . 41.
142. 71. 49. 73 . 79. 55.
149. 70. 50. 74 . 86. 51.
181. 91. 56. 84 . 75. 46.
175. 63 . 49. 89. 80. 45.
182 .
87.
65.
90.
76.
36.
153 .
76.
53 . 68 . 71.
65.
167 .
76.
53 . 77 . 71.
54 .
174. 80. 53 . 79. 80. 53 .
172. 92. 64. 92. 86. 59.
177 .
74.
53.
79 . 69.
55.
RAT #
DOSAGE GROUP IV
3 MG/KG/DAY
19002 P 19005 P 19035 P 19039 P 19040 P 19045 P 19046 NP 19051 NP 19054 P 19058 P 19062 P 19063 P 19066 P 19069 P 19073 P
167. 62. 49.
165. 68. 48 .
155. 56. 44 .
142. 65. 44 .
187 .
79.
57 .
186. 91. 59.
170. 72. 52.
MATING NOT CONFIRMED
160. 75. 49.
196 .
92.
51.
181. 80. 56.
224 .
95.
63.
149. 66. 47.
220.
106.
70.
164. 91. 56.
70. 75. 63. 71. 87. 83 . 73 .
68. 81. 81. 97. 76 . 104 . 86.
79. 70. 62. 70. 77 . 94 . 54 .
56 . 88. 72 . 81. 74 . 74 . 90.
47. 55. 51. 54 . 59. 52 . 27.
52 . 49. 55 . 48. 51. 28. 49.
P - PREGNANT NP - NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS - DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
418-028:PAGE C-84
4'
PROTOCOL 418-028:
g" **
C*
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C37 (PAGE 3) : MATERNAL FEED CONSUMPTION VALUES - PRESUMED GESTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
PREGNANCY STATUS DAYS 0 - 7 7 - 10 10 - 12 12 - 15 15 - 18 18 - 20
RAT #
DOSAGE GROUP V
10 MG/KG/DAY
19001 P 19006 P 19011 P 19020 P 19022 P 19025 P 19027 P 19028 P 19030 P 19031 P 19032 P 19033 P 19049 P 19059 P 19070 P
127. 165. 146. 162 . 185. 202 . 144 . 184 . 175 . 182. 180. 164. 176. 169. 156.
63. 74. 69. 77. 75. 88. 73. 82. 71. 91. 84. 82. 83. 75. 75.
42. 55. 48. 53. 57. 65 . 47. 56. 54. 59. 59. 57. 54 . 54 . 50.
71. 85. 69. 79. 88. 73 . 81. 93 . 78. 94. 93. 89. 81. 84 . 82.
70. 72. 75. 64 . 81. 64 . 65. 84. 73. 89. 94. 85. 81. 86. 88.
41. 61. 56. 51. 69. 50. 41. 55. 57. 54 . 62 . 55 . 52 . 50 . 30.
P = PREGNANT NP = NOT PREGNANT (VALUES EXCLUDED FROM AVERAGES) DAYS = DAYS OF PRESUMED GESTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
418-028:PAGE C-85
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C38 (PAGE 1) : MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DAY 1 - 5 5 - 8 8 - 1 5
RAT #
DOSAGE GROUP I
0 MG/KG/DAY
19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
131. 155. 137.
99. 158. 176. 137. 196. 144 . 165. 191. 149. 125 . 202 . 144 .
158 . 178. 186. 181. 168. 183 . 150. 207. 182 . 206. 203 . 184 . 161. 216. 191.
387. 498. 540. 478. 488. 549. 468. 628. 506. 511. 579. 502 . 427. 521. 433 .
RAT #
DOSAGE GROUP II
0.3 MG/KG/DAY
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
158 . 85 .
140 . 120 .
25 . 101.
85 . 138 . 114 . 114 .
82 . 145 .
99. 142 .
a
165 . 141. 167 . 167. 173 . 145 . 211. 180. 154 . 13 7. 154 . 172 . 138. 170. 142 .
513 . 400 . 495. 486. 374 . 533 . 561. 516. 460. 447. 497. 493 . 366. 520. 512 .
DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Spilled feed precluded the calculation of this value.
418-028:PAGE C-86
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-770S WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C38 (PAGE 2) : MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DAY 1 - 5 5 - 8 8 - 15
RAT #
DOSAGE GROUP III
1 MG/KG/DAY
19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
155 .
164.
156 .
181.
a 183.
120 .
183.
NOT PREGNANT
117 .
158.
114.
166.
135.
163.
138 .
148.
14 9.
143.
NOT PREGNANT
113 .
169.
117 .
168.
138 .
185.
143 .
168.
439. 508 . 527. 517.
474 . 475. 461. 473 . 470.
513 . 471. 513 . 455.
RAT #
DOSAGE GROUP IV
3 MG/KG/DAY
19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
113 .
132.
427.
175 .
159.
497.
108 .
112 .
438 .
14 6 .
145.
436.
140 .
189.
542.
130 .
160.
584 .
NOT PREGNANT
NOT PREGNANT; MATING NOT CONFIRMED
113 .
125.
360.
98 . 184 . 496.
147 .
175 .
560 .
131.
160 .
568.
110.
13 9.
453 .
106 .
81. 451.
114 .
167 .
523 .
DAY - DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G) . a. Spilled feed precluded the calculation of this value.
418-028:PAGE C-87
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C3 8 (PAGE 3) : MATERNAL FEED CONSUMPTION VALUES - LACTATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DAY 1 - 5 5 - 8 8 - 15
RAT #
DOSAGE GROUP V
10 MG/KG/DAY
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
87. 154 . 114 . 137 . 191. 187 .
99 . 126 . 154 .
92 . 147. 143 .
a 144 . 150.
119. 178. 157.
91. 184 . 195. 132 . 143 . 158 . 178. 149. 166. 169. 167. 167 .
381. 558 . 445 . 319. 520 . 553 . 427. 454 . 503 . 559. 481. 499. 474 . 494 . 492 .
DAY = DAY OF LACTATION ALL WEIGHTS WERE RECORDED IN GRAMS (G). a. Spilled feed precluded the calculation of this value.
418-028 :PAGE C-88
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C39 (PAGE 1) : MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
RAT #
ESTROUS STAGES/ 13 DAYS
DAYS IN COHABITATION
MATING STATUS
DOSAGE GROUP I
0 MG/KG/DAY
19010
2
14
19012
2
2
19019
3
3
19021
3
2
19023
4
4
19041
4
4
19042
i
3
19044
2
1
19050
4
4
19053
2
3
19065
3
3
19068
2a
2
19072
2
4
19074
3
2
19075
3
4
M M M M M M M M M M M M M M M
DOSAGE GROUP II
0.3 MG/KG/DAY
19004
4
4
M
19009
3
1M
19016
3
i
M
19018
3
2
M
19026
1
4
M
19036
2
1
M
19037
3
2
M
19043
4
1M
19047
2
1
M
19048
4
4
M
19052
2
iM
19055
2
1
M
19061
3
2
M
19067
3
3
M
19071
3
1
M
M - MATED C - CONFIRMED P = PREGNANT NP = NOT PREGNANT a. Six or more consecutive days of diestrus were observed.
MATING DATE
c c c c c c c c c c c c c c c
c c c c c c c c c c c c c c c
PREGNANCY STATUS
P P P P P P P P P P P P P P P
P P P P P P P P P P P P P P P
418-028:PAGE C-89
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C39 (PAGE 2) : MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
R A T ft
ESTROUS STAGES/ 13 D A Y S
DAYS IN COHABITATION
MATING STATUS
DOSAGE GROUP III
19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
3 3 3 3 4 2 3 3 3 3 3 4 4 4
4
1 MG/KG/DAY
3 3 4 2 1 4 1 4 2 3 1 4 4 2 4
M
M M M M M
M
M M M M M M M M
DOSAGE GROUP IV
3 MG/KG/DAY
19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
4 13
34
34
32
44 31 2i la 14 33 21 44 32 34 32 31
M =. M A T E D
C = CONFIRMED
P = PREGNANT
NP = NOT PREGNANT
a. Six or more consecutive days of estrus were observed.
M
M
M
M M M M
DID NOT MATE
M M M M M M M
MATING DATE
C C C C C C C C c c c c c c c
c
c
c
c c c c
-
c c c c c c c
PREGNANCY
STATUS
p P P
P
' NP P
P
P P P NP P P P P
P P P
P P P
NP -
P P P P P P P
418-028:PAGE C-90
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C3 9 (PAGE 3) : MATING AND FERTILITY, ESTROUS CYCLING AND DAYS IN COHABITATION - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
RAT #
ESTROUS STAGES/ 13 DAYS
DAYS IN COHABITATION
MATING STATUS
DOSAGE GROUP V
10 MG/KG/DAY
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
3 2 3 0 3 la 3 1 0 1 3 3 2 3 3
1 3 4 4 4 3 4 i 4 1 4 i i 1 1
M M M M M M M M M M M M M M M
M MATED C = CONFIRMED P = PREGNANT NP = NOT PREGNANT a Six or more consecutive days of diestrus were observed.
MATING DATE
c c c c c c c c c c c c c c c
PREGNANCY STATUS
P P P p P P P p P p P P P p P
rjjoYd-m-m
\o
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C40 (PAGE 1) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP I
0 MG/KG/DAY
RAT #
19012
19019
19021
19023
19041
19042
19044
19050
19053
HOME CAGE BEHAVIOR
3233 3 3333
ALTERATIONS (HOME CAGE)
11i1 1 111i
REACTION TO REMOVAL
11i1 11111
REACTION TO HANDLING
1111 11111
REARS IN OPEN FIELD
10 12 12 19 7 13 15 7 14
DEFECATION IN OPEN FIELD 1 1 1 2 i 1 2 1 1
URINATION IN OPEN FIELD
1122 1 2 211
LEVEL OF AROUSAL
3 3333 3 333
ALTERATIONS (OPEN FIELD) 1 i 1 1 1 1 1 1 1
GAIT PATTERN
1i111 1111
GAIT ABNORMALITY, SEVERITY
1
i
1
1
1
1
1
1
1
PALPEBRAL CLOSURE
1 i 11 1 1 11 1
PROMINENCE OF THE EYE
1 1 11 1 1 111
LACRIMATION
1 1 11 1 1 111
SALIVATION
1 1 11 1 1 111
PILOERECTION
0 0 00 0 0 00 0
ABNORMAL RESPIRATION
0 000 0 0000
APPEARANCE
1 1 la 1 lb 1 1 1 1
VISUAL REACTION
2 2 22 2 2 222
TACTILE REACTION
2 2 22 2 2 22 2
AUDITORY REACTION
3 3 33 3 3 33 3
TAIL-PINCH REACTION
2 2 23 2 3 222
AIR RIGHTING RESPONSE
1 1 11 1 1 111
PUPIL RESPONSE TO LIGHT
I 1 11 1 1 111
FORELIMB GRIP TEST #1 (G) 410 325 240 550 370 655 330 275 505
FORELIMB GRIP TEST #2 (G) 465 650 345 500 355 845 375 350 545
HINDLIMB GRIP TEST #1 (G)
245
365
450
335
675
565
520
295
405
HINDLIMB GRIP TEST #2 (G) 335 445 420 300 670 475 350 350 530
LANDING FOOT SPLAY #1 (CM)
12.1
8.8
8.0
4.4
6.4
6.5
9.5
4.0
9.3
LANDING FOOT SPLAY #2 (CM)
9.6
8.0
8.3
6.0
5.7
5.7
8.0
6.4
9.4
BODY WEIGHT (G)
372 374 314 327 382 366 342 342 351
"v a l u e 's ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY.
a. Localized alopecia: head (1.0 cm x 0.4 cm).
b. Localized alopecia: left forepaw and forelimb (1.5 cm x 0.6 cm) and right forelimb (0.6 cm x 0.7 cm).
c. Ears torn: both pinnae.
19065 1 1 .1 1 11 1 1 3 1 1 1 1 1 1 1 0 0 lc 2 2 3 2 1 1
430 600 315 415 7.0 7.7 364
418-028 :PAGE C-92
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C40 (PAGE 2): FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP II
0 .3 MG/KG/DAY
RAT #
19004
19009
19016
19018
19026
19036
19037
19043
19047
HOME CAGE BEHAVIOR
313 2 1 321 3
ALTERATIONS (HOME CAGE)
11 1 1 1 111 i
REACTION TO REMOVAL
11 1 1 1 1i1 1
REACTION TO HANDLING
1111 11111
REARS IN OPEN FIELD
10 12 12 9 11 14 14 15 18
DEFECATION IN OPEN FIELD 1 1 1 1 1 1 1 1 1
URINATION IN OPEN FIELD
12 1 1 1 i12 1
LEVEL OF AROUSAL
33 3 3 3 333 3
ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1
GAIT PATTERN
1111 1 111 1
GAIT ABNORMALITY, SEVERITY
1
1
1
1
1
11
1
1
PALPEBRAL CLOSURE
1111 11111
PROMINENCE OF THE EYE
11 11 1 111 1
LACRIMATION
11 11 1 111 1
SALIVATION
11 11 1 1111
PILOERECTION
00 00 0 0000
ABNORMAL RESPIRATION
00 00 0 0000
APPEARANCE
1 1 la 1 1 1 1 1 1
VISUAL REACTION
22 2 2 2 222 2
TACTILE REACTION
22 2 2 2 222 2
AUDITORY REACTION
3333 3 333 3
TAIL-PINCH REACTION
2222 2 222 3
AIR RIGHTING RESPONSE
i111 1 111 1
PUPIL RESPONSE TO LIGHT
11 11 1 111 1
FORELIMB GRIP TEST #1 (G) 165 510 285 275 325 155 120 400 220
FORELIMB GRIP TEST #2 (G) 390 333 140 450 530 145 475 535 325
HINDLIMB GRIP TEST #1 (G) 335 365 375 385 365 270 420 255 .320
HINDLIMB GRIP TEST #2 (G) 315 380 525 355 285 365 665 375 240
LANDING FOOT SPLAY #1 (CM)
6.0
8.7
7.9
5.2
6.3
6.2
6.5
5.2
6.2
ON CO
LANDING FOOT SPLAY #2 (CM)
7.9
9.0
6.9
7.4 6.7 7.0 5.4 5.7
BODY WEIGHT (G)
317 356 352 350 334 362 335 356 34 5
VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY,
a. Localized alopecia: head (0.4 cm x 0.5 cm).
19048 1 1 1 1 15 1 2 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
305 310 410 325 5.8 6.5 365
418-028-.PAGE C-93
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C40 (PAGE 3) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP III
1 MG/KG/DAY
RAT #
19003
19007
19008
19013
19015
19017
19024
19029
19034
HOME CAGE BEHAVIOR ALTERATIONS (HOME CAGE)
33 1313312 111 11111 1
REACTION TO REMOVAL
11 1 11 111 1
REACTION TO HANDLING REARS IN OPEN FIELD
1111 14 9 10 8
1111 1 6 13 14 10 16
DEFECATION IN OPEN FIELD i 1 1 1 1 1 1 3 1
URINATION IN OPEN FIELD
i1 1 12 1 1 1 2
LEVEL OF AROUSAL
333 33333 3
ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1
GAIT PATTERN
111111111
GAIT ABNORMALITY, SEVERITY
1
1
1
1
1
1
1
i
1
PALPEBRAL CLOSURE
11 1 111 11 1
PROMINENCE OF THE EYE
1111111i1
LACRIMATION
1 1 1 11 1 11 i
SALIVATION
1111111i1
PILOERECTION
0 0 0 00 0 00 0
ABNORMAL RESPIRATION
00 0 00 0 00 0
APPEARANCE
1 1 la 1 lb 2 1 lc 1
VISUAL REACTION
222222222
TACTILE REACTION
2 2 2 22 2 22 2
AUDITORY REACTION TAIL-PINCH REACTION
33 3333333 2 2 2 2 2 3 4*,* 2 2
AIR RIGHTING RESPONSE
111i111i1
PUPIL RESPONSE TO LIGHT
i1 1 11 1 11 1
FORELIMB GRIP TEST #1 (G) 325 975 85 200 420 330 695 320 610
FORELIMB GRIP TEST #2 (G) 245 535 75 365 455 720 665 395 505
HINDLIMB GRIP TEST #1 (G) 295 280 370 495 445 450 465 435 455
HINDLIMB GRIP TEST #2 (G) 445 315 320 470 375 530 440 520 605
LANDING FOOT SPLAY #1 (CM)
5.4
7.0
6.2 10.8 6.8
7.7
8.8
6.2
7.4
LANDING FOOT SPLAY #2 (CM)
6.3
8.5
5.8 10.6 7.2
6.4 10.4 8.0
7.5
BODY WEIGHT (G)
323 365 360 386 325 369 359 316 344
VtCl UeV "aeTe "th"e ~QUAOTi"t y """cATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY.
a . Chromorhinorrhea.
b. Localized alopecia: head (0.3 cm in diameter).
c. Localized alopecia: both forepawa and forelimba (2.8 cm x 0.5 cm) and head (0.3 cm x 0.5 cm).
19056 1 1 1 i 16 2 2 3 1 1 1 1 1 1 1 0 0 1 2 2 3 3 1 1
255 300 290 365 8.3 8.4 359
418-028:PAGE C-94
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C4 0 (PAGE 4) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP IV
3 MG/KG/DAY
RAT #
19005
19035
19039
19040
19045
19054
19058
19062
19063
HOME CAGE BEHAVIOR
3 12 3 12 32 1
ALTERATIONS (HOME CAGE)
1 11 1 1 1 11 1
REACTION TO REMOVAL
1 11 1 i1 1i 1
REACTION TO HANDLING
1 11 1i111 1
REARS IN OPEN FIELD
11 7 15 12 13 10 10 11 8
DEFECATION IN OPEN FIELD 3 i 1 1 2 i 1 1 1
URINATION IN OPEN FIELD
1 i11 1i11 1
LEVEL OF AROUSAL
3 333 3333 3
ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1
GAIT PATTERN
11i1 11 11 1
GAIT ABNORMALITY, SEVERITY
1
1
i
1
1
1
1
1
1
PALPEBRAL CLOSURE
1 11 1 11 1 1 1
PROMINENCE OF THE EYE
1 1i11111 1
LACRIMATION SALIVATION
1 1i11111 1 1 1i111 11 1
PILOERECTION ABNORMAL RESPIRATION APPEARANCE VISUAL REACTION TACTILE REACTION AUDITORY REACTION TAIL-PINCH REACTION AIR RIGHTING RESPONSE PUPIL RESPONSE TO LIGHT
0 00000 00 0 0 0000000 0 1 1 1 1 la 3b 1 lc 1 2 22 2 22 2 2 2 2 22 2 22 2 2 2 3 332 33 33 3 222222 222 1 i1 1 1 1 1 1 1 1 i11 1 1 1 1 1
FORELIMB GRIP TEST #1 (G)
415
355 445
490
560
525
260
310
545
FORELIMB GRIP TEST #2 (G)
685
360 395
465
555
605
435
225
530
HINDLIMB GRIP TEST #1 (G) 465 255 190 355 340 350 220 400 465
HINDLIMB GRIP TEST #2 (G) 470 295 315 430 435 325 365 460 485
LANDING FOOT SPLAY #1 (CM)
8.0
5.5
5.4
6.5
8 .0
7.5
7.4
7.5
7.0
LANDING FOOT SPLAY #2 (CM)
8.3
5.8 6.3
7.2
9.4
9.6
9.0
7.0
7.5
BODY WEIGHT (G)
330 322 317 353 380 339 355 351 368
"W^uFs"afTe "to~QUM^t"t Y , CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY.
a. Localized alopecia: left axilla (4.0 cm x 3.0 cm).
b. Localized alopecia: right forepaw and forelimb (1.7 cm x 0.6 cm).
c. Tip of tail missing.
19066 1 1 1 1 10 1 1 3 1 1 1 1 1 1 1 0 0 1 2 2 3 2 1 1
495 390 270 365 4 .0 5.0 337
418-028:PAGE C-95
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST IN RATS (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C40 (PAGE 5) : FUNCTIONAL OBSERVATIONAL BATTERY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP V
10 MG/KG/DAY
RAT #
19001
19006
19011
19020
19022
19025
19027
19028
19030
HOME CAGE BEHAVIOR
222323133
ALTERATIONS (HOME CAGE)
1111 i1111
REACTION TO REMOVAL
1111 i1111
REACTION TO HANDLING
1111 11111
REARS IN OPEN FIELD
12 9 9 9 9 10 14 8 15
DEFECATION IN OPEN FIELD 1 1 1 1 1 1 1 2 1
URINATION IN OPEN FIELD
1111 1 122 1
LEVEL OF AROUSAL
3333 3333 3
ALTERATIONS (OPEN FIELD) 1 1 1 1 1 1 1 1 1
GAIT PATTERN
4a 1
1 4a
1
1
1
1
1
GAIT ABNORMALITY, SEVERITY
2
1
1
2
1
1
1
1
1
PALPEBRAL CLOSURE
i1111111 1
PROMINENCE OF THE EYE
111111111
LACRIMATION
i1111111 1
SALIVATION
111111111
PILOERECTION
0000 0000 0
ABNORMAL RESPIRATION
0 0 0 lc 0 0 0 0 0
APPEARANCE
1 lb 1 Id 1 1 1 1 le
VISUAL REACTION
22222222 2
TACTILE REACTION
22222222 2
AUDITORY REACTION
2333 33333
TAIL-PINCH REACTION
2222 2222 2
AIR RIGHTING RESPONSE PUPIL RESPONSE TO LIGHT
1111 i1111 1i11 i1111
FORELIMB GRIP TEST #1 (G)
170
785
525
205
560
535
315
270
595
FORELIMB GRIP TEST #2 (G)
290
735
465
240
645
540
600
525
495
HINDLIMB GRIP TEST #1 (G)
385
410
330
435
385
520
265
305
405
HINDLIMB GRIP TEST #2 (G)
380
530
490
370
630
430
410
480
530
LANDING FOOT SPLAY #1 (CM)
4.8
6.3
9.0
8.8
10.5
10.0
6.3
8.7
6.2
LANDING FOOT SPLAY #2 (CM)
5.8
7.0
9.4
8.7
8.5
9.0
6.5
9.2
7.0
BODY WEIGHT (G)
250 365 320 254 366 362 318 343 332
"VALUES ARE THE QUANTITY, CATEGORY NUMBER, QUANTAL RESPONSE OR SCORE RECORDED FOR EACH ITEM IN THE BATTERY.
a. Tip-toe walk.
b. Ear torn: right pinna.
c. Rales.
d. Localized alopecia: both forepaws and forelimbs (1.0 cm x 0.4 cm); Dehydration; Abdominal distention.
e. Scab: head (0.3 cm in diameter); Localized alopecia: head (0.5 cm in diameter).
19031 3 1 i i 14 2 i 3 1 1 1 1 1 1 1 0 0 1 2 2 3 3 i 1
270 440 410 445 10.4 9.2 373
418-028:PAGE C-96
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCT ION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C41 (PAGE 1) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP I
0 MG/KG/DAY
RAT NUMBER
19012
19019
19021
19023
19041
NUMBER OF MOVEMENTS
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
84 77 76 63 74
86 17 67
0 66
83 30 65
0 72
70 7 25 2 23
65 3 43 2 49
76 3 11 0 57
39 41 20 0 4
32 53 23 0 0
12 37
7
0 13
20 41 4 20 1
17 4 10 1 2
71 5 10 2 1
57 4 21 1 1
40 1 9 0 37
67 2 2 1 75
83 2 3 0 47
81 4
5 37 79
59 12 10 0 36
1042
343
411
129
637
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19042
73 52 64 3 4 2 i 11 55 5 0 1 1 2 6 5 4 4 293
19044
73 61 18 33 54 34 3 24 54 71 30 19 2 8 3 1 0 0 488
19050
69 59 64 9 9 10 4 1 29 8 0 9 2 4 3 39 70 59 448
19053
60 65 63 108 33 6 4 10 1 1 23 59 27 8 7 22 39 74 610
19065
71 65 45 6 13 40 0 39 6 25 5 4 5 51 56 30 3 5 469
418-028:PAGE C-97
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C41 (PAGE 2) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP I
0 MG/KG/DAY
RAT NUMBER
19012
19019
19021
19023
19041
TIME (SECONDS) SPENT IN MOVEMENT
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
191 138 161 108 167
157 34 147 0 116
119 41
75
0
96
113 7 25 3 17
83 4 48 0 43
111 i 6 0 75
37 50 23
0
1
35 93 28
0
0
5 60 6
0 14
26 50 5 36 0
22 6 10 2
4
74 3 10 3
0
68 2 21 0 2
42 1 9 0 36
77 i 0 0 119
71 1 0 0 74
100 2
3 38 92
114 21
7
0 40
1445
515
584
190
896
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19042
180 84 98 2 1 1 1 8 67 4 0 1 0 1 5 4 3 6 466
19044
157 100 29 27 105 37
2 31 62 95 29 18 0 5 i 0 0 0 698
19050
185 147 81 10
8 12 1 0 41 7 0 12 0 1 4 79 113 106 807
19053
125 85 71 101 31 1 2 12 0 0 43 103 42 1 5 17 56 84 779
19065
136 83 47 1 13 31 0 47 0 29 2 5 5 52 89 24 0 4 568
418-028:PAGE C-98
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C41 (PAGE 3) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP II
0.3 MG/KG/DAY
RAT NUMBER
19004
19009
19016
19018
19026
NUMBER OF MOVEMENTS
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
65 68 53 60 75
36 75 61 55 55
31 104
3
6 57
49 41 7 1 54
29 46 0 9 30
22 45
1
7
3
3 18 4 22 3
13 59
2
2
0
0 79 0 1 1
1 22 4 12 5
0 1 6 1 54
7 1 5 ii 10
4 6 1 7 38
40 2 14 8 41
30 3 0 6 17
42 32 1 6 3
4 63 13 13 0
6 41 3 1 0
382 706 178 228 446
TOTAL = SUM OF BLOCKS; EACH-BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19036
73 64 58 20 12 0 29 2 3 2 0 0 12 0 5 4 4 27 315
19037
73 68 50 27 8 30 9 29 10 14 1 7 4 30 50 42 6 25 483
19043
65 27 3 16 5 28 12 8 5 2 4 2 6 0 2 3 2 0 190
19047
77 16 22 10 0 0 0 0 2 0 0 0 2 4 10 9 10 4 166
19048
62 79 78 82 73 58 78 17 4 -3 3 16 70 51 7 8 2 1 692
418-028 :PAGE C-99
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C41 (PAGE 4): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP II
0.3 MG/KG/DAY
RAT NUMBER
19004
19009
19016
19018
19026
TIME (SECONDS) SPENT IN MOVEMENT
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
131 213
85
76 152
41 168 93 49 96
47 135
3
7 82
67 56
4
0 116
32 55 0 9 51
20 76
0
7
0
1 11 3 31 3
12 84
2
1
0
0 119 0 0 1
0 29 1 11 4
0 0 6 3 70
6 0479
2 3 0 4 42
33 0 17 13 72
43 1 0 3 22
62 36
0
4
1
2 91 12 11 0
4 40 0 0 0
503 1117 230 236 721
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19036
181 136 92 12 15
0 46 2 1 1 0 0 19 0 1 2 3 28 539
19037
120 140 91 60 19 60
8 36 12 15 2 6 3 36 71 55 11 22 767
19043
120 41 1 18 1 25 9 4 3 0 0 1 10 0 1 0 0 0 234
19047
133 19 35 8 0 0 0 0 0 0 0 0 2 1 8 9 6 1 222
19048
204 157 108 139 93 122 102 14
2 i 2 9 62 69 5 7 1 1 1098
418-028:P
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C41 (PAGE 5) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP III
1 MG/KG/DAY
RAT NUMBER
19003
19007
19008
19013
19015
NUMBER OF MOVEMENTS
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
76 74 55 71 69
61 40 63 70 68
65 65 70 19 30
40 60 48 3 61
18 27 89 5 64
37 49 78 1 84
46 50 70 1 74
49 57 64 2 40
9 53 57 2
8
5 85 74 0
2
0 57 64 1
1
3 1 71 10 3
45 9 78 0
3
58 1 77 0
2
52 7 59 1
1
43 1 85 19 6
51 7 60 0
8
47 4 42 1
5
705 647 1204 206 529
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19017
70 59 37 19 25 36 40 38 51 27 29 16 27 32 61 39 43 10 659
19024
74 85 59 61 60 58 55 53 24 24 58 59 26 6 10 1 1 28 742
19029
69 81 48 56 70 65 44 38 65 38 53 41 50 64 39 46 70 39 976
19034
58 68 48 6 43 9 22 34 10 27 1 2 1 1 4 0 1 1 336
19056
67 71 61 85 35 9 43 5 2 12 5 5 4 3 2 5 6 2 422
418-028:PAGE C-
O
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C41 (PAGE 6): MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP III
1 MG/KG/DAY
RAT NUMBER
19003
19007
19008
19013
19015
TIME (SECONDS) SPENT IN MOVEMENT
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
180 153 118 150
96 69 139 109
128 109 143
19
64 99 85 2
23 27 136 11
59 75 102 0
65 55 140 0
69 90 123 0
13 68 109 0
4 122 112 0
0
77 100
1
3 0 93 10
71 7 158 0
60 0 125 0
80 9 109 0
69 0 116 24
91 9 138 0
56 1 52 0
1131 970 2098 326
153 138 21 78 123 119 154 78
7 1 0 i 2 1 0 9 12 0 897
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19017
201 129 66 22 49 53 63 65 87 36 41 22 29 47 97 57 47
7 1118
19024
174 123 176 98 84 81 70 56 14 27 93 136 24
4 ii 0 0 22 1193
19029
97 85 30 66 88 59 61 49 71 47 84 73 90 106 56 83 77 42 1264
19034
186 119 136
9 53 2 24 69 10 26 0 4 0 0 2 0 0 1 641
19056
132 137 57 179 40 11 58
8 0 12 1 2 3 2 0 3 4 0 649
418-028:P
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C41 (PAGE 7) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP IV
3 MG/KG/DAY
RAT NUMBER
19005
19035
19039
19040
19045
NUMBER OF MOVEMENTS
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
59 82 75 62 55
63 77 58 18 66
52 51 63 11 67
51 33 64 2 79
54 37 73 1 50
64 7 15 15 56
78 5 4 57 66
66 34 2B 29 44
57 27
9
1 52
55 0 9 0 59
50 6 5 0 59
54 3 3 32 53
68 1 0 3 55
60 0
9 11 53
46 5 3 1 69
58 4 39 2 50
54 19 17 4 57
50 3 2 0 76
1039
394
4 76
249 1066
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19054
68 75 75 62 52 56 48 75 43 43 35 6 37 52 25 4 2 0 758
19058
67 48 27 13 5 2 2 22 39 18 3 16 3 3 1 1 0 14 284
19062
49 69 41 40 33 54 57 49 55 49 47 35 21 53 44 31 10 24 761
19063
71 37 32 32 6 12 11 36 33 22 26 14 7 3 1 81 52 17 49?
19066
69 60 74 14 28 69 55 62 24 4 4 2 3 O 3 2 4 4 481
418-028:P
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C41 (PAGE 8) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP IV
3 MG/KG/DAY
RAT NUMBER
19005
19035
19039
19040
19045
TIME (SECONDS) SPENT IN MOVEMENT
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
241 163 158 215 236
167 129 110 23 188
106 63 100 26 196
130 42
89
1 192
108 29
87
0 140
120 5 29 22 131
117 2
2 79 150
108 42 45 37 76
112 31
14
0 194
83 0 10 0 154
83 2 3 0 137
63 1
2 38 66
135 0 0 0 112
100 0 4 6 101
58 4 0 0 150
83 2 54 1 81
105 23
13
1 119
73 1 1 0 152
1992
539
721
449 2575
TOTAL = SUM OF BLOCKS; EACH. BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19054
181 184 155 133 58 64 73 73 65 39 31
2 33 40 9 1 0 0 1141
19058
154 67 45 23 16 5 i 60 56 29 5 24 ii 6 i 2 0 24 529
19062
143 158 69 52 60 82 149 98 109 79 77 47 36 73 107 62 10 27 1438
19063
150 63 41 43 4 20 12 56 68 21 31 22 5 1 0 98 77 14 726
19066
169 106 143 25 18 89 68 106 17
1 3 1 2 0 1 2 1 1 753
418-028:PAGE C-104
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C41 (PAGE 9) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP V
10 MG/KG/DAY
RAT NUMBER
19001
19006
19011
19020
19022
NUMBER OF MOVEMENTS
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
72 76 61 75 63
30 4 59 28 59
20 8 63 3 63
7 2 52 0 56
5
1 64
0 46
6 18 59 0 39
6 1 57 1 23
61 1 61 48 63
57 4 61 3 44
43 2 30 35 28
43 4 65 1 41
52 7 64 48 38
46 4 62 5 46
16 4 38 1 47
7 3 44 0 40
5 1 52 39 36
1 2 67 50 46
6 24 52 44 39
483 166 1011 381 817
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19025
83 45 9 5 27 29 7 49 54 4 1 1 1 2 3 32 10 47 409
19027
52 27 41 42 31 17 23 19 0 4 7 34 1 0 0 2 0 1 301
19028
78 45 7 1 2 6 16 3 9 7 24 30 51 40 48 17 2 5 391
19030
65 64 58 5 4 10 3 3 14 2 5 9 2 3 0 6 2 4 259
19031
59 64 39 35 6 13 3 18 33 0 6 14 3 17 6 2 3 4 325
418-028:PAGE C-105
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C41 (PAGE 10) : MOTOR ACTIVITY - INDIVIDUAL DATA - Fo GENERATION FEMALE RATS
DOSAGE GROUP V
10 MG/KG/DAY
RAT NUMBER
19001
19006
19011
19020
19022
TIME (SECONDS) SPENT IN MOVEMENT
BLOCK 1 BLOCK 2 BLOCK 3 BLOCK 4 BLOCK 5 BLOCK 6 BLOCK 7 BLOCK 8 BLOCK 9 BLOCK 10 BLOCK 11 BLOCK 12 BLOCK 13 BLOCK 14 BLOCK 15 BLOCK 16 BLOCK 17 BLOCK 18 TOTAL
162 128 132 104 152
17 1 120 16 157
13 14 122 0 125
6 1 60 0 126
3 3 87 0 86
6
25 100
0
49
1 1 94 0 21
52 0 84 54 106
78 5 94 2 81
34 0 39 19 35
54 2 98 0 53
90 7 81 65 68
49 4 121 4 86
28 2 51 0 89
3 2 58 0 54
1 0 65 27 34
0 i 86 61 61
1 34 78 35 50
598 230 1570 387 1433
TOTAL = SUM OF BLOCKS; EACH BLOCK CONSISTS OF A 5 MINUTE PERIOD.
19025
151 119
6 1 29 56 2 76 72 1 0 0 0 0 0 45 4 69 631
19027
148 121 58 66 55 35 25 23
0 2 5 39 0 0 0 0 0 0 577
19028
147 104
4 0 0 6 20 1 3 11 17 20 55 47 51 9 2 3 500
19030
134 123 107
2 2 14 1 2 16 0 4 4 1 1 0 3 1 3 418
19031
204 188 74 84 11 19
0 19 50 0 13 13 7 38 5 1 1 3 730
418-028:PAGE C-106
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C4 2 (PAGE 1) : NATURAL DELIVERY, IMPLANTATION SITES, AND PUP VIABILITY AND SEX - INDIVIDUAL DATA Fo GENERATION FEMALE RATS/F1 GENERATION LITTERS
RAT/ LITTER NUMBER
DURATION OF GESTATION (DAYS) N
LITTER DELIVERED LIVE STILL- TOTAL BORN BORN BORN
NNN
1 MF
NUMBER OF LIVE PUPS AT
COMPLETION OF DAY POSTPARTUM
8 15 22
MF
MF
MF
MATERNAL DOSAGE GROUP I
0 MG/KG/DAY
19010 19012 . 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
23 23 23 23 22 22 23 22 22 23 22 22 22 23 23
14 16 15 14 13 18 15 17 15 16 20 15 16 15 (1) 16
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
14 16 15 14 13 18 15 17 15 16 20 15 16 15 16
4 10 5 11 87 95 76 6 12 69 89 5 10 97 9 11 69 88 4 10 11 5
49 5 11 87 95 75 6 12 69 88 5 10 87 9 10 59 88 4 10 11 5
49 5 11 87 95 75 6 12 69 88 5 10 87 9 10 59 88 4 10 11 5
49 5 11 87 95 75 6 12 69 88 5 10 87 9 10 59 88 4 10 11 5
MATERNAL DOSAGE GROUP II
0.3 MG/KG/DAY
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
22 23 23 23 23 22 23 23 23 23 22 23 22 23 23
18 7
15 14 19 16(1) 16 13 13
9 17 16(1) 13 14 14
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
18 7
15 14 19 16 16 13 13
9 17 16 13 14 14
8 10 25 12 3 86 10 9 69 88 76 76 54 6 11 10 5 85 68 86
89 25 12 3 86 10 8 68 88 76 76 54 6 10 10 5 75 67 86
89 25 12 3 86 10 8 67 87 76 76 54 6 10 10 5 75 67 86
89 25 12 3 86 10 8 67 87 76 76 54 6 10 10 5 75 67 86
M = MALE F FEMALE ( ) - NUMBER OF PUPS DYING PRIOR TO WEIGHING ON DAY 1 POSTPARTUM.
TOTAL IMPLANTATIONS
N
15 17 17 16 16 18 17 18 17 16 20 15 16 17 16
19 8
15 16 20 16 17 15 14 12 18 16 13 16 15
418-028:PAGE C-107
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C42 (PAGE 2) : NATURAL DELIVERY, IMPLANTATION SITES, AND PUP VIABILITY AND SEX - INDIVIDUAL DATA FO GENERATION FEMALE RATS/F1 GENERATION LITTERS
RAT/ LITTER NUMBER
DURATION OF GESTATION (DAYS) N
LITTER DELIVERED LIVE STILL- TOTAL BORN BORN BORN
NNN
1 MF
NUMBER OF LIVE PUPS AT
COMPLETION OF DAY POSTPARTUM
8 15 22
MF
MF
MF
MATERNAL DOSAGE GROUP III
1 MG/KG/DAY
19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
22 22 22 23 NOT PREGNANT 23 23 23 23 23 NOT PREGNANT 23 23 22 23
16 18 15 15
15 14 15 16 13
14 17 14 18
0 16 0 18 0 15 0 15
0 15 0 14 0 15 0 16 1 14
0 14 0 17 0 14 0 18
88 7 11 78 96
96 68 96 97 67
77 98 86 99
88 7 10 77 96
96 68 96 87 67
77 98 86 99
88 7 10 77 96
96 68 96 87 67
77 98 86 98
88 7 10 77 96
96 68 96 87 67
77 98 86 98
MATERNAL DOSAGE GROUP IV
3 MG/KG/DAY
19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
23
10(1) 1
il
23 16 0 16
23 14 0 14
22 15 0 15
22 17 0 17
23 15 0 16 [1]
NOT PREGNANT
NOT PREGNANT; MATING NOT CONFIRMED
23 5 0 5
23 13 0 13
22 15 0 15
23 13 1 14
23
13 (1) 1
14
23 17 0 17
23 14 0 14
36 6 10 68 69 7 10 69
32 85 96 2 11 57 6 il 86
36 6 10 68 59 7 10 69
32 85 96 2 11 57 6 11 76
36 6 10 68 59 7 10 69
32 85 96 2 11 57 6 10 76
36 6 10 68 59 7 10 69
32 85 96 2 11 57 6 10 76
M = MALE F a FEMALE ( ) = NUMBER OF PUPS DYING PRIOR TO WEIGHING ON DAY 1 POSTPARTUM. [ ) a NUMBER OF PUPS IN WHICH CANNIBALIZATION AND/OR AUTOLYSIS PRECLUDED THE DETERMINATION OF VIABILITY.
TOTAL IMPLANTATIONS
N
17 18 16 15
15 14 16 17 15
14 17 15 17
14 16 16 15 17 16
6 14 15 16 15 17 15
418-028:PAGE C-108
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C42 (PAGE 3) : NATURAL DELIVERY, IMPLANTATION SITES, AND PUP VIABILITY AND SEX - INDIVIDUAL DATA Fo GENERATION FEMALE RATS/F1 GENERATION LITTERS
RAT/ LITTER NUMBER
DURATION OF GESTATION (DAYS) N
LITTER DELIVERED LIVE STILL- TOTAL BORN BORN BORN
N NN
1 MF
NUMBER OF LIVE PUPS AT
COMPLETION OF DAY POSTPARTUM
8 15 22
MF
MF
MF
MATERNAL DOSAGE GROUP V
10 MG/KG/DAY
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
23 23 23 22 23 22 23 23 22 22 23 22 23 23 22
il 19(1) 13 13 16(1) 20 14 12 13 15 14 14 15 15 14 (1)
0 1 0 0 0 0 0 1 0 0 0 0 0 0 0
11 20 13 13 16 20 14 13 13 15 14 14 15 15 14
47 6 12 76 85 96 13 7 4 10 57 67 87 77 68 11 4 10 5 85
47 5 12 76 85 95 13 7 4 10 57 67 77 77 68 11 4 10 5 85
47 5 12 76 85 95 13 7 4 10 57 67 77 77 68 11 4 10 5 84
47 5 12 76 85 95 13 7 4 10 57 67 77 77 68 11 4 10 5 84
M = MALE F = FEMALE ( ) = NUMBER OF PUPS DYING PRIOR TO WEIGHING ON DAY 1 POSTPARTUM.
TOTAL IMPLANTATIONS
N
11 20 14 14 16 20 14 15 16 15 17 14 16 15 14
418-028:PAGE C-109
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C43 (PAGE 1) : PUP BODY WEIGHT LITTER AVERAGES FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION LITTERS
RAT/ LITTER NUMBER
DAY 1 MFT
DAY 8 MFT
DAY 15 MFT
DAY 22 M FT
MATERNAL DOSAGE GROUP I
C) MG/KG/DAY
19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
6.8 6.6 6.6 16.4 15.9 16.1 28.4 27.7 27.9 41.9 40.0 40.6 6.6 6.4 6.5 13.8 13.6 13.7 26.5 25.5 25.8 42.7 40.6 41.2 6.6 6.2 6.4 15.4 14.4 14.9 28.6 26.5 27.6 40.0 37.2 38.7 6.4 5.9 6.2 12.7 11.9 12.4 23.4 22.1 22.9 35.8 33.8 35.1 6.3 6.2 6.2 16.8 16.5 16.7 32.8 32.1 32.5 46.1 44.4 45.4 6.2 6.0 6.1 13.0 13.0 13.0 24.1 23.8 23.9 32.6 32.5 32.5 6.5 6.4 6.4 14.1 13.6 13.8 26.4 26.3 26.4 36.4 35.6 35.9 5.7 6.0 5.8 13.8 13.0 13.4 26.8 25.2 26.0 42.6 40.5 41.5 6.6 6.2 6.3 14.6 13.7 14.0 27.1 25.7 26.2 36.4 35.1 35.6 6.4 6.4 6.4 15.6 15.4 15.5 29.3 28.2 28.8 35.9 35.5 35.7 6.0 5.7 5.8 13.2 12.2 12.7 24.8 23.4 24.0 32.4 30.8 31.6 6.8 6.4 6.6 17.2 15.8 16.3 29.7 27.4 28.2 47.7 45.1 46.0 5.9 5.5 5.7 12.3 11.9 12.1 22.7 21.6 22.2 31.7 30.0 30.8 7.1 6.7 6.8 17.7 16.8 17.0 27.4 27.4 27.4 35.2 34.0 34.4 6.2 6.3 6.2 12.9 13.0 12.9 22.3 23.1 22.6 36.1 36.1 36.1
MATERNAL DOSAGE GROUP II
0.3 MG/KG/DAY
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
5.7 5.4 5.5 13.5 11.9 12.7 24.5 22.3 23.3 31.1 28.8 29.9 7.2 7.0 7.0 15.4 15.5 15.5 34.4 33.5 33.8 56.4 53.2 54.1 6.4 6.1 6.4 14.6 12.9 14.2 27.7 23.1 26.8 46.3 38.1 44.6 7.1 6.5 6.8 15.3 14.4 14.9 28.3 25.6 27.2 45.6 41.6 43.8 7.1 6.5 6.8 13.7 12.1 13.0 25.0 22.7 24.0 31.8 29.4 30.7 6.2 5.6 5.8 11.6 9.6 10.4 26.9 24.1 25.4 41.1 36.8 38.8 5.6 5.4 5.5 11.5 11.2 11.4 18.3 18.0 18.2 31.2 29.2 30.3 6.6 6.2 6.4 14.0 13.4 13.7 29.4 28.3 28.9 46.4 43.7 45.2 7.2 6.8 7.0 15.3 14.4 14.9 28.2 27.0 27.6 38.2 37.3 37.8 6.4 6.2 6.3 16.1 16.2 16.1 33.1 32.4 32.8 49.0 46.4 47.8 6.2 5.9 6.0 11.0 10.8 10.8 22.6 22.8 22.8 35.8 35.9 35.9 6.7 6.4 6.6 14.3 13.1 13.9 26.4 25.1 26.0 39.8 37.2 38.9 5.8 5.6 5.7 13.8 12.8 13.4 24.8 24.6 24.8 32.2 33.8 32.8 7.0 6.5 6.7 13.7 13.3 13.5 29.4 28.1 28.7 40.2 38.8 39.4 6.5 6.7 6.6 11.4 11.7 11.5 24.8 24.5 24.7 40.0 39.7 39.9
M = MALE F = FEMALE T = TOTAL (SUM OF PUP WEIGHTS/NUMBER OF LIVE PUPS) DAY = DAY POSTPARTUM
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
418-028:PAGE C-110
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C4 3 (PAGE 2) : PUP BODY WEIGHT LITTER AVERAGES FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION LITTERS
RAT/ LITTER NUMBER
DAY 1 M FT
DAY 8 MFT
DAY 15 M FT
DAY 22 M FT
MATERNAL DOSAGE GROUP III
1 MG/KG/DAY
19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
6.6 6.0 6.3 6.3 5.8 6.0 6.2 5.7 6.0 7.0 6.4 6.8 NOT PREGNANT 6.7 6.2 6.5 7.4 6.9 7.1 6.2 5.8 6.1 6.3 5.8 6.1 6.8 6.4 6.6 NOT PREGNANT 6.8 6.6 6.7 6.6 6.4 6.5 6.9 6.4 6.7 6.7 6.2 6.5
13.5 13.7 14.7 15.2
12.1 12.3 14.1 13.9
12.8 12.9 14.4 14.7
14.0 14.8 14.5 14.1 15.3
13.1 14.4 13.4 12.2 14.3
13.7 14.5 14.1 13.2 14.8
15.1 13.1 14.8 12.1
14.8 12.9 13.4 11.5
14.9 13.0 14.2 11.8
23.2 24.5 29.2 27.9
21.3 21.7 28.1 25.1
22.2 22.9 28.6 26.8
26.3 27.6 27.4 26.3 30.4
24.9 25.8 25.4 22.2 28.6
25.8 26.6 26.6 24.4 29.4
29.6 23.6 29.2 22.8
28.8 23.2 26.4 22.2
29.2 23.4 28.0 22.5
30.4 33.6 41.5 47.0
28.1 30.5 39.0 42.3
29.2 31.8 40.2 45.1
38.4 45.8 40.0 43.7 41.2
35.9 44.2 37.5 34.6 39.0
37.4 44.9 39.0 39.5 40.0
41.4 32.7 46.6 27.8
39.8 32.0 42.8 30.2
40.6 32.4 45.0 28.9
MATERNAL DOSAGE GROUP IV
3 MG/KG/DAY
19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
7.6 7.1 7.3 19.1 17.9 18.3 6.5 5.8 6.0 13.2 13.0 13.1 7.2 6.7 6.9 12.9 12.5 12.6 5.9 5.4 5.6 11.1 10.2 10.6 5.4 5.1 5.2 11.6 10.9 11.2 6.5 6.6 6.6 11.7 12.0 11.9 NOT PREGNANT
NOT PREGNANT; MATING NOT CONFIRMED
7.4 7.5 7.4 20.1 21.2 20.6 6.6 6.5 6.6 14.9 14.6 14.8 6.9 6.6 6.8 16.7 15.8 16.3 7.0 6.9 6.9 14.6 15.2 15.1 6.5 6.3 6.4 15.8 15.9 15.9 5.9 5.7 5.8 10.3 9.7 9.9 7.2 6.8 7.0 13.9 12.8 13.4
35.5 24.2 23.3 22.9 25.2 24.0
33.1 23.7 22.5 21.2 23.4 23.6
33.9 23.9 22.8 21.8 24.1 23.8
41.2 27.8 30.7 29.8 30.9 19.3 27.7
40.4 27.2 29.4 30.0 30.8 20.4 25.6
40.9 27.6 30.2 29.9 30.8 20.0 26.8
48.0 33.2 33.8 35.1 31.7 37.6
45.4 31.7 32.3 32.4 29.3 36.2
46.3 32.2 32.9 33.4 30.3 36.7
57.1 46.4 42.4 47.6 43.8 30.1 44.3
56.6 45.1 40.1 46.2 43.0 33.4 40.9
56.9 45.9 41.4 46.4 43.3 32.2 42.8
M - MALE F = FEMALE T = TOTAL (SUM OF PUP WEIGHTS/NUMBER OF LIVE PUPS) DAY = DAY POSTPARTUM
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
418-028-.PAGE C-lll
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C43 (PAGE 3) : PUP BODY WEIGHT LITTER AVERAGES FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION LITTERS
RAT/ LITTER NUMBER
DAY 1 M FT
DAY 8 M FT
DAY 15 M FT
DAY 22 M FT
MATERNAL DOSAGE GROUP V
10 MG/KG/DAY
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
6.8 6.6 6.6 14.0 14.3 14.2 26.6 26.6 26.6 44.1 44.0 44.1 6.5 6.1 6.2 13.8 13.1 13.3 25.4 23.7 24.2 35.2 32.7 33.4 6.9 6.6 6.8 13.9 13.6 13.8 26.2 25.5 25.9 36.4 35.5 36.0 5.8 5.5 5.7 9.2 9.1 9.2 15.7 15.4 15.6 15.4 15.5 15.5 6.0 5.7 5.9 15.3 14.9 15.2 29.0 27.0 28.3 36.3 34.5 35.7 5.4 5.0 5.3 12.9 11.0 12.3 24.2 20.4 22.9 30.8 26.8 29.4 7.3 6.5 6.8 12.6 12.1 12.2 23.6 21.9 22.4 33.0 31.1 31.6 6.7 6.3 6.4 13.1 13.2 13.2 25.9 25.9 25.9 39.8 40.1 40.0 6.4 6.1 6.2 15.0 14.3 14.6 29.5 28.1 28.7 40.1 38.2 39.1 5.9 5.7 5.8 12.3 11.9 12.1 27.6 25.7 26.6 44.8 41.1 43.0 7.3 6.9 7.1 14.6 13.2 13.9 25.9 24.4 25.2 35.9 34.2 35.1 6.6 6.0 6.2 13.8 12.6 13.1 27.4 25.2 26.2 44.1 41.0 42.4 6.7 6.2 6.6 12.6 11.0 12.2 25.4 22.8 24.7 36.8 32.9 35.7 7.0 6.5 6.9 12.3 11.0 11.9 24.9 21.3 23.7 34.6 30.4 33.2 6.5 6.3 6.4 15.4 14.8 15.2 29.8 28.0 29.2 49.6 46.8 48.7
M * MALE F = FEMALE T = TOTAL (SUM OF PUP WEIGHTS/NUMBER OF LIVE PUPS)
DAY = DAY POSTPARTUM
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
418-028:PAGE C-112
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C44 (PAGE 1) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
PUP #
12
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
RAT/ LITTER #
MATERNAL DOSAGE GROUP I
0 MG/KG/DAY
POSTPARTUM DAY 1
19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
6.8 7.0 7.4 6.0 6.9 6.8 7.3 6.9 5.1 6.5 6.8 7.0 6.3 6.0 6.5 6.3 6.5 6.9 7.0 6.4 6.1 6.5 6.8 6.2 6.6 6.2 6.7 6.6 6.1 6.4
6.8 6.2 6.5 6.6 6.4 6.9 6.7 6.8 6.3 6.4 6.3 6.0 6.2 6.3 6.0
6.7 6.4 6.5 6.7 6.7 6.1 6.4 6.4 6.2 5.6 5.5 6.1 6.2 6.0
6.9 6.2 6.2 5.8 6.1 6.2 6.5 6.0 6.1 6.2 6.1 6.2 6.3 6.3 5.8 6.1 6.3 6.1 6.6 6.5 5.9 6.0 6.6 6.4 6.3 5.9 5.8 6.0 6.0 5.4 5.6 6.2 7.2 6.9 6.3 6.5 6.1 6.3 6.4 6.4 7.0 6.5 6.1 6.3 6.5 6.1 5.8 5.0 5.7 5.8 5.9 6.1 6.1 5.3 5.4 6.3 6.1 6.7 6.0 6.6 6.3 5.4 5.1 6.9 6.6 6.9 6.5 6.2 5.9 6.3 5.7 6.2 6.5 6.0 6.1 6.1 6.4 6.5 6.5 6.6 6.5 6.1 6.2 6.9 6.5 6.8 6.0 6.2 6.5 6.4 6.3 6.6 6.3 6.3 5.9 5.8 5.6 5.9 6.0 5.9 6.1 6.0 6.7 5.2 5.7 6.0 6.2 5.8 5.4 5.4 5.9 5.7 5.6 5.7 7.0 6.6 6.6 7.0 6.8 7.0 6.2 6.8 6.7 6.3 6.5 6.0 6.0 6.6 6.7 5.9 5.7 6.1 6.0 5.5 6.0 6.1 6.0 5.5 5.7 5.5 5.4 5.6 5.6 5.2 5.5 6.9 7.2 7.3 7.0 MD 1 7.0 6.8 7.1 6.6 7.1 7.0 6.0 6.6 6.3 6.7 6.4 6.1 5.5 6.4 5.8 6.4 6.4 6.3 6.5 6.5 6.2 6.4 6.3 6.3 6.0 6.3
RAT/ LITTER #
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
MATERNAL DOSAGE GROUP II
0.3 MG/KG/DAY
POSTPARTUM DAY i
5.6 5.9 5.9 5.8 5.9 5.2 5.5 5.8 5.0 5.5 5.7 5.3 6.1 5.2 5.3 4.9 5.8 5.4 7.5 7.0 6.7 6.9 7.1 6.8 7.4 6.6 6.3 6.5 6.1 6.9 6.7 6.4 6.7 6.3 6.0 5.9 6.8 5.7 6.2 6.5 7.2 6.7 7.2 6.9 7.2 7.2 7.7 6.9 6.1 6.6 6.4 6.4 6.9 6.5 6.7 7.1 7.3 7.3 6.9 6.7 7.4 7.1 7.4 7.0 6.7 6.9 6.6 6.4 6.1 6.7 5.7 6.6 6 .5 6.1 6.4 6.6 6.0 6.2 5.6 6.6 5.7 4.9 5.8 4.6 5.5 5.6 5.9 5.7 FD 1 5.7 5.9 5.6 5.6 5.9 5.6 5.6 4.9 5.1 5.8 5.9 5.3 5.0 5.4 5.3 5.4 6.8 6.7 6.1 6.9 6.8 6.7 6.6 6.3 5.8 6.2 6.4 6.2 6.0 7.1 7.7 7.9 7.6 6.6 6.5 7.1 6.8 6.5 6.8 6.7 6.7 7.5
6.7 6.6 6.4 6.3 5.9 6.2 6.2 6.4 5.9 6.0 6.1 6.3 6.3 6.3 6.1 6.1 5.6 5.8 6.5 5.4 6.3 6.1 5.6 6.0 5.7 5.7 6.8 6.5 7.2 6.6 7.0 6.8 6.4 6.6 6.7 6.4 MD 1 6.8 6.6 6.2 6.3 6.0 5.9 5.9 5.8 5.6 5.7 6.3 5.7 5.6 5.8 5.6 5.7 5.6 5.3 7.2 6.8 7.3 6.9 7.1 7.0 6.5 7.0 6.2 6.2 6.6 6.8 6.5 6.2 6.6 6.3 5.4 7.4 6.6 6.9 6.7 6.4 7.0 6.5 6.5 6.5 6.9 6.9
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
418-028:PAGE C-113
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C44 (PAGE 2) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
RAT/ LITTER #
MATERNAL DOSAGE GROUP h i
1 MG/KG/DAY
POSTPARTUM DAY 1
19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
7.2 7.0 6.8 6.5 6.5 6.6 6.3 5.8 6.7 6.0 6.1 6.3 5.8 5.1 5.7 5.9 6.4 6.3 6.5 5.8 6.3 6.6 6.2 6.6 5.6 5.6 5.6 5.9 5.7 6.1 5.4 5.9 5.6 5.6 6.4 6.0 6.0 6.5 5.9 6.3 6.6 6.1 5.6 6.2 6.2 6.1 6.3 5.7 3.5 7.4 7.1 6.8 7.3 7.3 7.0 6.5 7.0 6.8 6.5 7.3 5.9 6.1 6.5 6.4 NOT PREGNANT 6.5 7.2 6.6 6.5 6.4 6.7 6.9 6.8 6.5 6.2 6.3 6.2 6.3 6.3 5.9 7.1 7.2 7.8 7.7 7.3 7.2 6.7 7.1 6.7 7.2 6.5 8.1 7.4 5.7 5.7 6.4 6.2 5.8 6.5 6.2 6.3 6.4 6.8 5.4 5.6 6.3 5.7 5.6 6.4 6.6 6.2 6.4 6.5 6.1 6.4 6.8 6.1 5.8 6.0 5.9 6.0 5.7 5.4 6.3 5.7 7.1 6.9 6.6 6.8 6.8 6.6 6.4 6.4 6.9 7.1 5.9 6.2 6.3 FS NOT PREGNANT 6.8 6.9 6.4 6.9 6.7 6.7 7.5 6.7 6.1 6.3 6.4 6.9 6.9 6.6 6.8 6.5 6.5 6.9 6.6 6.7 6.1 6.6 6.6 6.1 6.3 6.8 6.5 6.8 6.2 5.8 6.6 7.0 6.8 6.4 6.5 7.1 7.3 7.2 6.8 6.1 5.8 6.6 6.8 6.5 6.4 6.8 6.9 6.6 6.9 6.8 6.1 6.5 6.9 7.0 6.0 6.5 6.2 6.4 6.7 6.1 5.9 6.4 6.1
RAT/ LITTER #
MATERNAL DOSAGE GROUP IV
3 MG/KG/DAY
POSTPARTUM DAY 1
19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
7.7 7.6 7.5 MS 7.2 7.1 6.9 7.2 7.3 7.1 FD 1 6.9 6.2 7.0 5.9 6.4 6.4 6.2 5.9 5.6 5.4 5.6 6.0 5.7 6.0 6.0 5.7 7.3 7.3 7.4 7.2 6.9 6.9 6.6 6.6 6.6 7.0 6.7 6.5 6.7 6.8 6.4 5.8 5.4 5.9 5.7 6.4 5.4 5.9 5.5 5.5 5.5 4.8 5.4 6.0 5.1 5.5 5.1 5.8 4.9 5.7 5.3 5.3 5.2 5.1 5.2 5.3 5.4 5.4 5.4 4 .8 4.8 4.5 6.5 7.1 6.5 7.1 5.4 6.5 6.2 6.7 6.5 6.8 6.8 6.3 6.3 6.4 7.2 UU NOT PREGNANT NOT PREGNANT; MATING NOT CONFIRMED
7.0 7.5 7.7 7.6 7.4 6.2 7.0 ' 6.9 6.3 6.6 6.6 6.3 7.1 6.7 6.4 6.1 6.8 6.6 7.2 6.9 6.9 6.9 6.9 6.9 7.0 7.3 6.4 6.1 6.6 6.6 6.6 6.7 6.7 6.7 7.3 7.6 6.8 6.5 6.5 6.8 6.6 6.5 7.3 6.7 7.1 7.4 FS 6.4 7.2 6.6 6.1 6.2 6.3 MD 1 6.2 5.9 6.0 6.7 6.3 6.5 FS 6.1 5.8 6.1 5.1 6.1 6.0 6.3 5.7 5.2 5.8 5.7 6.2 4.5 5.8 5.8 5.8 5.8 7.2 7.0 6.8 7.8 6.9 7.2 7.7 7.4 7.0 6.7 6.4 6.6 7.1 6.7
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
20
t7ll-3H0V(T-8O-8lt
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C44 (PAGE 3) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
RAT/ LITTER #
MATERNAL DOSAGE GROUP V
10 MG/KG/DAY
POSTPARTUM DAY 1
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
6.9 6.4 6.8 7.0 6.7 6.1 6.5 6.6 6.8 6.5 6.7 7.0 6.3 6.6 7.0 6.1 5.8 5.9 6.1 6.4 6.5 5.6 6.5 6.2 6.0 6.7 5.9 6.0 5.9 FD 1 FS 7.4 7.3 6.3 7.0 6.9 6.7 6.8 7.1 6.7 6.5 6.2 6.6 6.3 6.3 6.0 6.1 6.7 4.5 5.4 5.7 5.6 4.9 5.2 5.5 5.4 6.3 6.2 6.0 5.8 6.1 5.7 6.5 5.9 6.0 6.1 MD 1 5.4 5.5 5.4 5.9 5.9 6.0 5.1 5.0 5.2 5.4 5.4 5.4 5.6 6.1 5.1 5.6 5.7 5.5 4.8 5.2 4.8 5.2 5.2 4.9 5.0 5 .0 7.3 6.9 8.1 6.9 7.2 6.0 6.4 6.8 6.8 6.6 5.9 6.3 6.9 6.5 6.8 7.1 6.1 6.8 6.6 6.2 5.9 6.6 6.5 6.5 6.5 5.9 FS 6.6 5.9 6.8 6.9 6.0 6.4 5.9 6.3 4.9 6.5 6.3 6.1 6.7 6.2 6.3 6.2 5.0 5.9 5.8 5.9 5.9 6.1 5.7 5.5 5.5 5.5 5.9 5.9 7.6 7.4 7.2 7.4 7.2 7.1 7.4 6.9 6.9 7.2 7.0 7.1 6.7 6.7 6.4 6.7 6.5 6.9 6.4 6.6 6.0 5.9 5.9 6.1 6.0 5.8 6.4 5.9 7.0 6.4 7.0 6.4 7.3 6.6 6.8 6.4 6.7 6.3 7.2 6.8 6.0 6.1 5.9 7.2 7.0 6.6 6.8 7.2 7.0 7.4 7.0 7.3 6.8 6.5 6.5 6.4 6.5 6.8 6.8 6.6 6.0 6.5 6.5 6.4 6.3 6.7 6.2 5.7 6.6 6.7 6.4 FD 1
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBOEN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
SlI-3 3DVr.8Z0-8tt
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C44 (PAGE 4) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
RAT/ LITTER #
MATERNAL DOSAGE GROUP I
0 MG/KG/DAY
POSTPARTUM DAY 8
19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
15.9 14.2 15.2 13.3 16.5 10.5 13.9 14.5 13.8 15.6 14.7 17.7
10.9 16.7 14.1
16.5 14.2 15.1 13.2 18.1 14.9 15.7 13.2 13.9 14.6 14.8 17.0 11.8 18.1 13.3
15.9 13.3 15.7 13.1 17.2 12.5 13.8 15.2 14.6 15.7 13.4 17.0 12.4 18.2 13.3
17.3 14.4 15.1 13.5 16.9 13.5 12.9 13.5 15.2 16.5 12.4 16.9 13.2 17.8 10.8
17.0 12.9 16.2 12.0 15.7 13.9 14.9 15.1 15.7 14.9 11.8 17.4 13.2 MD 1 13.0
14.7 13.7 15.9 13.0 17.2 12.8 13.5 15.6 12.6 16.0 15.1 MD 2 11.2 17.5 14.2
18.2 13.1 14.7 13.3 16.0 12.7 13.7 12.2 11.6 15.6 13.2 16.9 12.8 16.2 10.8
12.1 13.4 15.0 11.8 16.3 14.1 14.9 10.9 12.6 16.0 13.0 15.7 13.1 16.6 13.5
16.2 13.3 13.8 11.4 15.8 13.7 13.5 12.1 15.1 MD 5 10.0 16.4 11.6 17.8 12.5
16.0 13.9 14.5 12.5 16.1 14.1 13.9 13.4 15.0 15.3 12.9 15.6 11.1 15.3 14.2
16.7 13.7 15.3 12.0 17.3 12.9 12.9 11.7 15.6 15.7 12.6 T5.6 12.0 17.4 11.9
16.1 14.1 14.9 11.8 17.1 11.6 12.7 13.8 13.4 16.6 14.9 15.3 12.6 17.5 10.7
16.3 12.1 12.9 11.6 FD 4 11.4 13.2 14.2 14.4 14.8 10.6 15.0 11.8 15.9 13.4
FD 3 14.1 14.7 11.7
13.4 14.8
13.4 13.4 14.0 12.8 15.2 11.7 15.8 12.5 18.2 13.5
15.8 13.9 10.7 13.6 15.5 10.4 16.1 11.9 15.4 13.8
14.8
11.8 13.8 14.8 12.7 11.4 13.5
11.6 FM 2
12 .1
13.5 11.3
13.2
FD 5
RAT/ LITTER #
MATERNAL DOSAGE GROUP ii
0.3 MG/KG/DAY
POSTPARTUM DAY 8
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
15.2 15.3 15.9 15.9 14.4 12.1 12.0 13.5 14.5 16.6 11.5 14.0 14.3 13.5 10.1
11.5 15.5 15.2 15.6 12.8 11.3
9.3 14.1 16.0 17.2 10.3 13.4 13.7 14.6
9.2
14.9 16.9 15.5 14.5 14.3 12.5 11.2 13.0 14.0 16.3 10.2 14.3 13.5 14.3 11.6
11.8 15.4 13.2 15.2 13.2 10.1 12.2 14.7 15.5 15.4 11.9 13.8 12.8 12.6 10.8
13.6 15.3 14.5 15.5 15.8 11.5 12.5 13.9 16.1 15.2 11.1 13.8 13.9 13.8 12.0
14.5 15.4 15.0 15.0 13.4 11.8 11.7 14.0 15.3 16.4 10.8 14.2 13.9 13.4 11.3
13.8 14.6 14.8 15.4 13.3 10.5 10.7 14.6 15.7 15.8 10.7 16.1 14.3 12.5 13.4
13.0
13.0 15.2 13.9
7.5 12.7 14.2 11.4 16.2 11.4 14.3 MD 3 13.5 12.9
12.3
13.8 15.7 12.1 11.3 12.1 13.6 14.5 16.2 11.6 15.4 13.2 13.3 12.1
12.6
14.3 13.1 13.4 13.3 10.8 13.2 14.3
10.5 13.7 12.1 13.2 10.4
12.4 13.3
14.8 13.8 13.9
6.4 11.8 13.6 15.6
15.0 15.8 12.0
8.6 10.7 12.3 16.0
10.4 MD 1 13.0 13.1 12.5
11.0 11.4 12.7 13.5 13.2
12.3
14.0 13.9 12.1
7.6 11.4 13.3 14.5
11.0 14.2 12.8 14.1
9.5
10.0
14.7 13.8 11.7 11.5
9.3
10.6 14.2
FD 8 12.5
13.6 10.1 11.4 FD 2 11.7
11.6 12.9
10.6
12.6 FD 1 12.0
9.0 13.0
10.3 11.2
FD 5
FM 6 11.6
FD 8
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
418-028:PAGE C-116
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C44 (PAGE 5) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
RAT/ LITTER #
MATERNAL DOSAGE GROUP III
1 MG/KG/DAY
POSTPARTUM DAY 8
19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
13.9 13.6 14.3 14.1 13.7 13.3 13.7 14.8 15.4 15.8 14.9 14.0 NOT PREGNANT 13.9 14.5 14.3 14.1 15.7 15.7 14.6 14.2 14.7 14.3 14.1 13.5 15.1 15.0 15.5 NOT PREGNANT 15.0 14.9 16.0 13.2 13.1 12.6 16.1 14.9 16.2 11.1 11.6 14.3
11.1 13.7 15.6 15.1
14.2 14.4 13.8 14.3 15.4
14.6 13.5 14.9 10.1
13.5 12.5 15.1 15.1
15.2 15.0 14.3 14.4 15.7
15.4 12.8 13.2 10.8
14.1 14.8 14.7 15.3
13.5 13.6 14.9 13.7 15.0
14.3 13.0 14.1 10.9
13.5 13.9 13.7 15.9
14.1 13.6 14.0 13.8 14.1
15.4 13.2 14.0 13.8
13.7 11.7 14.8 15.4
12.9 15.3 15.1 14.9 12,7
14.1 12.4 14.6 11.7
11.7 13.5 14.0 15.6
13.9 12.3 14.9 MM 2 14.6
15.4 13.8 12.9 14.9
12.9 11.2 13.6 14.2
li.i 15.3 13.6 12.7 14.8
14.5 14.0 12.2
9.7
12.3 12.7 14.6 12.6
13.2 15.1 12.7 10.9 15.2
15.5 14.2 14.5 11.5
li.i 11.9 15.2 15.3
13.8 15.2 13.3 12.6 14.0
15.2 12.1 13.0 10.7
10.9 12.2 14.0 12.7
13.8 14.2 15.5 11.7 14.8
14.5 11.9 15.8 11.3
11.5 12.9 12.5 13.4
13.3 13.8 13.5 13.0
FS
14.3 12.1 12.0 13.8
14.2 11.7 FM 2 15.0
13.2
12.1 11.8
12.0
9.3
12.5 12.8
12.7 13.9 13.6
12.5
12.8 10.3
FD 2 13.4
RAT/ LITTER #
19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
MATERNAL DOSAGE GROUP IV
3 MG/KG/DAY
POSTPARTUM DAY 8
19.8 19.2 18.4 MS 18.3 17.9 13.6 11.9 14.8 12.2 12.5 14.0 13.0 13.2 12.9 13.2 12.3 12-.6 10.4 11.2 12.1 11.6 10.1 MD 2 12.5 10.5 11.8 13.0 9.7 12.0 12.0 12.8 11.5 11.7 9.8 12.4 NOT :PREGNANT NOT :PREGNANT; MATING NOT CONFIRMED 20.7 20.4 19.2 21.5 21.0 14.4 13.9 14.8 14.6 16.6 14.8 16.2 17.3 17.3 17.1 16.7 17.4 15.7 13.4 15.3 14.0 16.3 15.9
16.6 15.7 15.5 15.9 15.5 16.5 10.6 10.2 11.4 10.1 8.3 11.0 15.4 13.4 13.6 13.5 13.5 14.5
17.3 13.4 12.2
9.0 11.8 12.3
14.6 16.4 16.7 MD 1
9.8 13.6
17.9 12.2 11.0
8.9 9.8 12.7
15.2 15.0 13.4 15.7 10.1 MM 3
17.9 12.8 13.5 11.5 11.3 11.9
15.9 16.7 14.8 17.1 10.4 12.9
18.2 13.9 12.7
9.8 8.5 11.1
14.2 15.7 15.3 16.3
8.4 13.3
FD 1 13.3 12.1
9.9 11.2 11.3
13.9 13.6
9.9 12.8 13.1
14.2 16.9 15.1 15.3 10.8 12.4
13.7 16.2 16.1 15.0 10.3 13.3
13.1 12.9 10.8
9.9 12.9
15.1 15.5 13.8 15.4 10.7 12.7
12.9 11.8 11.2 12.7 11.8
15.6 FS FS 6.2
11.9
12.3 11.3 12.0 11.0
15.2
9.4
12.7 1 1 .1
UU
10.0
10.1 1 0 .4
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
19
20
418-028:PAGE C-117
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE C44 (PAGE 6) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
RAT/ LITTER #
MATERNAL DOSAGE GROUP V
10 MG/KG/DAY
POSTPARTUM DAY 8
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
14.3 12.9 13.9
8.5 15.8 12.5 12.0 13.1 15.6 12.7 13.6 13.5 11.5 10.3 15.8
13.6 13.5 14.2
9.3 15.3 10.6 13.2 13.7 14.5 10.7 15.2 13.9 13.7 11.5 13.2
13.2 13.8 13.8
9.1 16.2 14.5 13.1 13.3 14.9 12.4 15.0 13.5 13.1 12.8 14.3
14.8 14.8 14.3
8.8 14.8 12.7 12.2 11.7 15.7 11.3 14.6 14.7 11.0 13.1 15.2
14.4 14.2 13.3
8.6 15.3 12.3 10.8 13.8 13.7 13.6 15.2 14.0 14.1 12.5 16.1
14.3 MD 2 14.1
8.4 15.2 13.7 11.8 13.2 15.3 12.9 13.4 13.3 12.8 13.0 16.4
14.0 13.4 13.7 10.8 14.8 12.6 11.8 12.9 15.0 12.6 14.9 12.7 12.5 12.3 15.8
15.3 14.0 13.0
9.8 15.6 15.0 11.6 13.7 14.4 MM 2 12.5 12.3 12.1 13.0 16.0
14.1 13.0 13.4
7.7 14.5
9.9 12.2 12,6 14.5 13.1 14.0 13.5 14.8 12.1 14.7
14.3 12.7 13.2
8.3 MD 1 12.1 13.5 14.5 11.9 11.8 14.1 12.2 12.7 12.4 16.9
13.7 12.8 14.9
9.4 14.5 12.4 12.6 13.4 13.3 11.0 13.0 12.6 10.4
9.9 14.8
12.1 13.2
9.5 15.7 15.3 12.8 12.4 15.5 13.8 12.5 12.1 12.5 11.5 14.9
13.7 14.1 10.8 14.1 14.4 12.6
FS 15.4 12.4 13.4 13.0 12.7 11.4 12.9
11.5 12.8
14.3 16.0 11.5 11.9 10.9
10.3 13.1 12.4
9.3 11.9 FD 1
10.8
9.4 10.5
15.4
FM 2 12.3
12.8 10.5
13.4 10.5
FD 1 10.3
FS 10 .2
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
418-028:PAGE C-118
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C44 (PAGE 7) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 1 7 18 19 20
RAT/ LITTER #
19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
MATERNAL DOSAGE GROUP I
0 MG/KG/DAY
POSTPARTUM DAY 15
28.0 26.2 28.9 23.3 31.0 26.0 26.9 23.6 26.3 29.0 29.2 29.4 20.6 29.1 23.7
28.9 25.8 29.3 23.1 31.6 21.6 26.5 30.7 26.8 31.0 25.1 29.5 23.4 28.3 23.8
26.7 26.8 25.2 24.8 34.7 22.9 28.3 22.2 28.3 28.4 23.3 28.3 21.2 27.6 21.6
29.8 27.4 30.6 22.8 33.2 26.1 26.1 26.1 28.3 28.6 25.1 30.0 23.3 24.0 20.5
28.3 26.2 28.4 21.4 32.3 23.7 23.4 26.2 25.8 27.1 22.5 31.3 24.0 MD 1 23.0
30.1 26.1 .29.1 23.5 34.8 24.3 27.3 29.8 26.9 31.1 24.2 MD 2 25.6 28.2 19.4
27.6 26.2 27.7 23.2 31.8 24.3 26.3 29.8 25.0 29.6 19.6 29.2 20.0 26.2 23.1
27.1 22.3 29.7 24.0 31.0 27.1 29.4 25.9 24.8 29.5 27.8 26.5 23.8 28.2 24.0
27.0 26.7 27.2 24.1 32.8 25.4 28.3 25.6 23.1 MD 5 26.8 28.2 23.1 27.6 21.9
28.6 25.2 25.4 21.3 32.8 20.5 26.2 27.2 27.5 27.1 27.2 27.6 20.4 26.3 22.2
28.2 23.7 22.9 22.8 32.6 25.6 27.0 21.6 25.5 26.9 25.0 28.4 21.3 26.8 22.6
28.9 25.9 28.6 21.8 31.1 25.0 22.5 25.3 26.4 27.7 24.6 25.6 22.3 27.2 24.5
23.5 28.9 25.5 22.6 FD 4 25.8 26.2 26.1 26.0 28.7 22.9 26.7 20.7 25.8 22.7
FD 3 23.9 28.8 22.2
23.6 24.8 25.8 27.7 28.8 25.8 27.3 21.4 28.2 22.2
23.3 27.0
23.4 26.1 26.9 23.9 28.1 19.9 27.5 21.9 29.0 21.0
28.0
23.2 23.1 30.4 20.8 21.5 24.9
19.6 FM 2
25.5
22.4 22.2
19.6
FD 5
RAT/ LITTER #
MATERNAL DOSAGE GROUP II
0.3 MG/KG/DAY
POSTPARTUM DAY 15
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
22.4 34.4 27.5 29.6 29.2 25.4 18.8 29.4 29.5 31.8 23.4 26.2 24.5 29.5 26.1
25.9 34.4 29.1 27.0 24.0 27.0 18.6 30.6 28.7 33.9 21.5 27.8
2 4 .8
29.9 24.7
25.7 32.6 27.8 28.1 23.0 28.0 16.8 28.6 29.2 31.9 22.0 27.4 25.5 29.9 24.9
24.5 32.8 23.7 30.5 27.3 27.2 19.2 28.3 29.5
3 3 .8
24.4 26.5 25.1 29.4 27.3
20.9 33.2 28.5 26.6 26.1 27.1 15.6 29.7
2 6 .9
34.0 25.7 24.7 24.5 29.0 26.0
26.3 35.0 29.6 27.1 24.3 26.8 19.5 29.1
2 8 .0
30.9
1 8 .7 2 6 .1
25.0 28.9 22.2
23.6 33.9 30.0 28.8 22.3 25.0 20.2 30.2 25.8 31.9 23.3 28.0 24.6 29.4 22.8
26.5 18.7 21.1 19.0 21.5 26.8 23.0
27.1 28.8 24.0 18.3 17.9
2 7 .8
26.5 33.9
2 4 .8
26.5 MD 3 27.9 24.7
28.2 26.3 23.9 25.6 19.3
2 7 .9
23.3 33.1 24.3 23.7
2 4 .9
26.8 25.0
26.3 23.1 25.8 29.0 19.7
2 7 .5
29.0
21.1
2 7 .5
24.3 27.7 18.1
26.1 28.4 24.9 20.2 15.9 28.3 28.8
2 4 .9
MD 1
2 4 .8 2 8 .6
27.0
29.0 26.4 22.2 27.3 17.8
2 8 .9
29.3
2 2 .7
25.0
2 4 .1
27.5 26.7
25.4 24.9 23.6 23 . 3 19.6
2 9 .3
24.8
2 3 .3
24.4 25.1 28.6 22.7
17.1 24.6 22.9 F M 11 17.5
23.3 23.6
FD 8 27.4
22.6 26.7 21.3 FD 2 15.9
19.3
2 6 .8
23.2
21.8 FD 1 FD15
2 1 .5
25.6
24.6 23.2
FD 5
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
418-028:PAGE C-119
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C44 (PAGE 8) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
PUP # i 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
RAT/
LITTER #
MATERNAL DOSAGE GROUP III
1 MG/KG/DAY
POSTPARTUM DAY 15
19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
24.4 21.2 23.5 24.8 25.5 25.5 31.1 28.7 29.9 29.0 27.3 27.4 NOT :PREGNANT 27.5 25.0 29.2 27.1 28.9 28.4 26.0 27.7 28.8 26.9 27.4 23.1 30.5 30.5 30.8 NOT ]PREGNANT 28.7 30.6 30.8 21.9 24.4 22.8 27.7 31.8 29.9 21.6 25.0 21.1
25.1 25.1 26.9 28.4
23.2 27.9 29.8 26.1 29.8
29.5 24.6 30.3 23.9
23.5 25.3 28.3 28.8
25.9 27.8 26.4 27.0 30.9
27.8 22.2 27.2 26.5
24.8 24.1 29.2 29.4
24.7 25.7 26.3 25.8 29.8
31.3 24.6 29.0 21.9
24.5 21.5 30.5 28.3
27.7 28.2 26.7 26.7 27.6
28.2 24.1 28.5 22.6
18.8 23.4 29.2 27.9
26.7 28.1 25.7 27.4 28.2
29.7 24.3 29.3 20.8
21.2 21.4 27.8 25.0
27.2 26.4 28.9 MM 2 27.8
27.6 23.3 28.7 22.0
19.1 23.6 26.8 24.3
28.2 26.4 27.9 20.1 29.8
27.7 22.8 29.5 21.9
23.3 23.9 29.8 24.1
25.0 28.4 25.2 20.6 29.9
30.1 23.5 25.1 26.4
19.6 21.3 26.9 26.6
20.5 26.4 24.7 20.9 26.9
30.1 24.2 23.5 16.8
21.9 19.6 29.9 28.0
24.9 18.1 26.1 22.4 29.8
27.9 24.3 27.1 17.4
20.3 20.2 26.2 25.8
26.5 24.8 24.9 24.5
FS
28.3 22.9 24.6 21.6
21.3 21.0 FM 2 22.0
24.2
23.8 23.3
21.9
24 .3
23.4 21.1
23.8 22.9 26.7
21.4
22.8 22.1
FD 2 FMI 1
RAT/ LITTER #
MATERNAL DOSAGE GROUP IV
3 MG/KG/DAY
POSTPARTUM DAY 15
19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
34.5 36.4 35.7 MS 33.1 33.6 23.1 26.5 23.4 24.8 22.1 25.2 23.6 23.5 23.2 23.0 22.4 24.1 24.7 19.3 24.0 23.5 23.0 MD 2 26.1 26.1 26.3 27.4 22.4 24.2 23.4 24.9 21.7 25.4 24.5 24.0 NOT PREGNANT NOT PREGNANT; MATING NOT CONFIRMED 39.0 41.2 43.5 40.1 40.8 30.7 26.7 29.1 27.6 24.9 27.1 31.4 31.3 30.4 31.2 31.2 30.0 28.3 31.3 31.6 29.9 29.2 32.0 31.4 31.2 30.0 32.0 30.1 30.0 16.8 21.7 19.4 19.6 18.2 19.9 26.7 27.5 29.3 27.1 28.0 28.1
32.9 24.8 23.3 18.8 23.9 23.0
32.4 23.7 22.5 20.6 22.4 22.7
28.4 31.3 30.0 MD 1 19.5 27.3
28.0 28.9 27.6 30.8 21.8 MM 3
33.7 24.2 21.3 19.4 27.3 26.3
26.5 30.3 29.2 30.2 17.0 25.3
33.0 24.0 22.7 23.6 24.6 25.0
26.3 30.3 31.9 31.9 21.4 26.1
FD 1 24.0 23.1 17.0 22.6 21.9
25.1 23.4 21.8 21.4 24.6
26.2 30.0 30.7 30.9 22.3 26.3
28.0 29.9 26.8 29.5 21.5 25.6
21.1 21.6 22.6 27.5 23.7
29.0 29.0 30.8 32.1 20.9 25.2
24.7 21.9 22.1 25.6 22.0
28.7 FS FS
20.0 25.3
22.5 24 .8 24.4 23.2
28.7
19.8
23.0 20.1
uu
19.9
18.1 FD10
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
418-028:PAGE C-120
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C44 (PAGE 9) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
RAT/ LITTER #
MATERNAL DOSAGE GROUP V
10 MG/KG/DAY
POSTPARTUM DAY 15
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
27.5 23.2 27.0 17.0 30.9 25.6 23.5 28.5 29.1 25.3 25.9 27.4 27.2 26.4 30.1
26.3 26.7 25.9 13.8 27.6 24.5 24.2 22.7 29.3 24.6 26.9 28.2 26.1 24.3 29.4
26.2 26.2 27.1 15.3 30.0 24.4 25.0 27.8 29.7 30.7 26.4 27.1 25.8 28.1 31.0
26.2 25.7 26.2 14.8 29.7 23.7 21.9 25.5 30.9 28.8 23.9 27.0 26.1 25.6 30.4
26.6 25.4 25.8 16.6 28.7 26.2 21.7 25.1 29.3 27.8 26.7 27.1 24.5 23.8 29.7
26.2 MD 2 24.3 15.1 25.7 23.4 23.2 26.3 28.5 26.9 26.2 27.9 26.6 25.5 28.5
26.1 22.5 27.5 17.0 29.3 18.7 22.1 26.6 29.4 29.2 25.3 25.8 20.8 23.3 29.5
28.0 25.2 25.8 15.9 27.5 24.0 21.6 25.8 28.8 MM 2 25.5 25.3 25.2 22.7 30.1
26.4 27.5 24.2 14.9 31.4 23.8 22.2 27.4 24.0 26.4 24.5 25.4 24.0 24.1 30.5
25.8 23.6 25.7 15.8 MD 1 21.4 20.0 25.1 29.7 23.6 26.5 24.8 27.6 25.2 25.1
27.3 24.9 25.1 15.2 25.6 25.3 22.7 24.6 29.0 26.5 24.6 26.6 25.1 22.1 27.3
26.3 24.6 16.2 27.0 26.8 21.4 25.5 28.0 26.2 23.4 24.3 26.1 17.4 29.3
22.1 27.5 15.1 29.2 27.4 24.0
FS 28.0 27.0 23.7 24.7 20.3 22.2 FD13
22.0 25.1
25.1 28.3 23.6 20.8 20.5
25.1 22.9 24.5 24.5 20.4 FD 1
25.1
20.1 24.3
23.2
FM 2 20.0
21.3 22.4
21.2 17.7
FD 1 FS 19.2 19.1
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
418-028-.PAGE C-121
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C44 (PAGE 10) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
RAT/ LITTER #
MATERNAL DOSAGE GROUP I
0 MG/KG/DAY
POSTPARTUM DAY 22
19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
43.0 43.0 39.6 34.5 44.0 37.0 38.7 48.1 37.9 34.8 41.2 47.9 34.0 35.4 34.4
44.2 43.7 41.8 34.4 45.6 31.1 37.4 48.4 37.4 39.9 25.4 46.2 33.7 37.2 38.5
41.1 40.3 36.2 39.4 47.2 34.9 37.5 25.8 37.1 37.9 30.1 48.8 27.0 38.8 35.5
39.4 44.2 39.0 35.8 44.0 29.4 36.4 43.9 35.0 33.8 36.9 50.0 29.9 29.2 37.1
39.0 42.2 39.9 35.0 48.9 32.6 35.0 45.5 34.7 39.2 33.3 45.5 33.7 MD 1 30.8
39.5 37.9 42.5 35.6 46.4 30.4 33.1 43.1 34.5 32.3 30.9 MD 2 33.5 32.9 35.5
40.7 41.6 41.2 38.3 46.9 31.4 34.6 36.4 38.4 35.3 31.5 45.4 32.9 35.1 38.5
33.4 41.1 39.7 36.0 44.6 33.3 37.6 49.3 34.3 34.1 33.6 45.9 28.6 32.5 35.4
42.7 39.0 37.6 33.2 44.2 33.9 35.3 43.6 32.4 MD 5 29.0 45.9 28.0 33.6 40.7
40.0 36.9 35.4 34.1 45.4 33.4 35.7 41.6 37.1 34.7 32.8 46.8 28.9 33.5 36.0
41.6 41.8 38.6 34.9 44.6 35.4 34.4 41.1 38.5 35.2 30.9 42.5 33.0 34.7 34.5
41.6 36.7 39.6 32.1 43.1 37.9 37.2 37.8 34 .3 34.3 31.5 44.2 33.7 35.2 33.8
41.4 42.6 36.3 34.5 FD 4 29.6 35.7 36.6 34.5 38.3 32.4 47.1 30.3 34.7 37.4
FD 3 41.0 37.6 33.4
42.1 35.4
35.7 32.8 40.0 32.6 37.1 35.7 45.0 28.6 33.0 36.0
26.8 36.7
43.1 34.6 31.7 31.7 43.1 28.6 35.1 38.6
45.4
35.8 25.3 40.2 FM 2 37.1 28'. 9 23.9 29.1 34.5
31.8 33.0
26.8
FD 5
RAT/ LITTER #
MATERNAL DOSAGE GROUP II
0.3 MG/KG/DAY
POSTPARTUM DAY 22
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
33.4 57.1 46.5 48.4 32.3 39.7 33.1 46.0 38.9 46.5 38.6 40.7 33.8 41.4 40.7
34.4 55.6 47.4 47.0 32.5 40.9 25.3 46.4 39.1 51.0 38.6 40.1 30.7 39.9 42.3
26.5 51.3 48.5 45.9
39.1 43.1 30.5 47.2 34.4 49.7 31.7 41.3 32.2 40.2 42.1
33.6 51.4 44.5 46.3 30.7 42.9 31.8 46.2 37.1 47. 33.6 40.2 31.1 40.8 40.5
29.0 57.7 44.2 44.8 30.1 42.1 31.6 48.4 39.3 50.5 37.3 39.6 34.4 39.6 44.4
30.4 53.8 44.4 43.4 34.9 38.1 34.6 44.9 39.5 47.0 35.2 38.1 30.2 39.3 34.9
33.2 51.8 45.8 44.6 29.3 29.1 31.0
45.8 39.5 48.0 40.1 42.9 32.7 40.5 40.0
28.5 33.3
47.6 44.0 29.6 35.7 31.9 43.2 41.3 45.8 35.4 38.5 MD 3 39.4 35.3
49.3 45.6 28.7 42.7 30.8 44.6 39.7 45.0 31.1 36.3 35.9 37.5 36.9
26.3
50.3 45.0 30.7 43.2 29.1 43.7 36.9
34.0 40.3 31.5 39.1 41.3
32.4 24.0
41.3 39.2 29.1 39.2 32.9 45.2 40.5
45.4 38.1 31.2 30.5 27.9 42.9 33.0
37.8 MD 1 34.2 37.0 43.3
40.5 38.9 32.7 40.2 42.6
28.9
45.1 41.0 29.3 37.0 31.9 42.6 32.2
36.9 39.4 34.6 37.7 43.1
29.9 26.4
25.8 40.6 27.6 FM11 27.0
43.4
34.6 FD 2 24.9
37.5 29.9 34.5 37.8
FD 8 31.1
29.4
28.6 FD 1 FD15
36.2 35.6
29.1 27.1
FD 5
FM 6 27.5
FD 8
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
418-028:PAGE C-122
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C44 (PAGE 11) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
RAT/ LITTER #
19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
MATERNAL DOSAGE GROUP III
1 MG/KG/DAY
POSTPARTUM DAY 22
35.4 31.5 30.7 34.7 35.5 35.5 43.6 40.5 42.9 45.7 45.8 49.6 NOT PREGNANT 39.1 39.8 41.8 49.7 42.2 45.8 39.0 39.8 39.7 46.5 41.8 44.0 41.4 40.9 41.2 NOT :PREGNANT 39.3 41.4 41.4 34.2 33.7 32.2 47.4 47.0 49.2
3.0 34.7 28.0
26.0 30.4 41.5 42.0
40.0 47.5 38.5 41.8 41.4
39.5 33.7 45.8 36.4
32.3 27.9 40.8 49.1
37.1 48.8 38.2 46.1 40.6
42.6 30.9 48.8 29.4
31.9 36.0 38.6 46.6
33.5 40.5 43.4 47.6 41.9
41.6 32.3 46.4 33.0
24.2 35.0 42.5 50.2
38.6 47.3 37.3 44.3 38.9
44.1 32.1 45.5 29.4
31.3 31.2 37.2 45.5
37.3 48.8 42.8 37.7 40.2
38.5 32.5 42.8 28.2
28,4 29.3 41.3 48.4
38.4 44.4 41.4 MM 2 40.4
41.5 33.0 46.7 28.4
30.2 28.0 38.4 41.8
38.8 45.0 37.1 38.6 40.4
41.2 31.5 42.7 36.9
25.0 31.0 38.4 39.5
36.2 47.1 41.3 32.0 38.7
39.6 34.6 48.8 28.4
28.6 29.0 42.5 42.8
38.1 41.9 35.6 31.7 37.5
41.6 31.1 40.6 30.3
26.6 31.8 39.9 46.1
35.8 30.8 35.6 38.0 37.0
38.0 33.9 39.5 34.2
31.6 30.1 35.5 37.9
30.1 48.3 38.5 37.6
FS
38.1 30.7 38.5 35.6
28.2 33.8 FM 2 45.5
36.4
36.8 34.2
33.9
27.5
26,1 27.4
30.3 29.7 24.0
33.8
30.3 24.6
FD 2 FM11
RAT/ LITTER #
MATERNAL DOSAGE GROUP IV
3 MG/KG/DAY
POSTPARTUM DAY 22
19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
47.2 47.4 49.4 MS 44.4 46.3 31.3 36.4 34.3 31.3 32.7 33.1 32.8 35.2 33.6 33.2 34.6 33.3 36.0 39.4 36.2 34 .0 30.1 MD 2 32.8 30.6 32.9 32.0 33.6 31.6 37.1 41.2 37.1 33.5 39.4 37.1
NOT :PREGNANT NOT ;PREGNANT; MATING NOT CONFIRMED 57.5 59.1 54.8 55.5 57.6 51.3 44.7 41.2 47.9 45.6 47.6 43.0 43.6 41.0 42.9 41.0 40.1 48.7 46.5 46.1 48.6 45.9 49.4 43.5 44.3 43.8 44.3 42.9 45.7 31.7 28.5 28.1 30.5 32.5 29.3 44.5 44.2 44.0 43.8 45.6 46.2
45.3 28.9 32.2 32.8 28.3 38.3
47.5 44.0 48.4 MD 1 33.2 42.0
46.0 32.0 30.6 35.6 26.9 35.8
45.7 42.9 44.0 43.5 33 .4 MM 3
45.4 32.7 33.9 31.7 27.1 36.0
44.1 42.7 42.8 43.5 35.7 39.5
45.0 31.5 30.6 36.8 28.3 37.8
47.5 41.3 50.1 40.9 27.5 38.6
FD 1 29.6 34.7 31.7 31.7 36.4
45.8 40.4 47.2 42.5 33.0 42.7
33.0 29.9 28.5 30.0 30.6
42.7 41.2 39.7 41.4 37.2 41.3
33.2 34 .4 32.7 32.9 36.0
45.3 38.2 46.2 43.2 36.8 42.2
33.4 32.1 33.7 35.5 39.9
39.9 FS FS
32.3 41.2
28.1 27.8 32.1 34.8
39.5
33.8
34 . 5 24.7
TJU
31.4
23 .7 FD10
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
19
20
418-028:PAGE C-123
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770G.1)
TABLE C44 (PAGE 12) : PUP BODY WEIGHTS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
PUP # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
RAT/ LITTER #
MATERNAL DOSAGE GROUP V
10 MG/KG/DAY
POSTPARTUM DAY 22
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
43.5 33.2 37.9 15.1 32.3 31.2 34.8 39.9 39.1 43.4 37.3 45.7 37.8 35.2 48.6
45.6 36.3 38.1 15.8 33.5 30.6 33.3 43.1 38.9 45.6 34.6 40.7 34.6 33.3 51.7
43.0 35.4 33.7 16.0 37.9 29.9 32.3 38.4 40.8 45.0 36.4 43.6 35.3 33.8 54.1
44.3 34.5 35.8 16.2 39.1 30.5 31.8 44.4 43.3 50.8 33.5 45.8 37.1 37.4 47.6
45.4 36.6 38.9 14.4 39.3 27.0 29.3 33.2 40.0 40.4 36.7 45.1 36.1 37.4 49.5
43.3 MD 2 34.9 16.0 35.4 35.9 32.4 39.6 38.4 40.9 37.4 43.8 39.9 33.6 52.1
44.0 31.6 35.5 15.3 35.3 25.0 32.5 40.4 39.8 47.8 35.6 41.2 39.6 35.5 46.9
43.0 32.2 35.6 14.8 37.0 31.7 29.0 40.6 42.0 MM 2 32.4 44.2 33.9 33.7 46.5
42.9 31.7 37.9 14.5 37.2 30.2 31.1 39.5 39.6 44.3 34.5 42.6 39.1 35.0 47.5
44.2 32.0 35.7 18.1 MD 1 34.5 30.6 35.6 32.2 39.5 33.8 39.1 31.2 31.0 46.8
45.6 30.9 35.0 14.9 34.6 30.6 31.1 42.5 38.7 41.2 35.2 41.0 39.9 33.8 43.9
36.9 33.7 15.9 36.3 31.8 31.7 42.4 37.6 39.2 36.1 41.0 36.2 27.5 48.8
34.9 34.9 14.2 35.6 31.5 30.1
FS 37.9 44.0 32.9 40.2 38.6 25.6 FD13
34.8 34.4
32.5 33.3 30.5 24.4 33.0
38.4 34.9 39.0 32.4 32.2 FD 1
40.9
24.4 32.9
28.9 29.9
FM 2 27.6 26.8
34.2 31.0
FD 1 23.8
FS 23 .8
ALL WEIGHTS WERE RECORDED IN GRAMS (G) .
MEAN LITTER WEIGHTS INCLUDE ONLY WEIGHTS OF LIVE PUPS.
FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE
SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED)
NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
418-028:PAGE C-124
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION /DEVELO PMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE C4 5 (PAGE 1) : PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
PUP # i 2 3 4 5 6 7 8 9 10 il 12 13 14 15 16 17 18 19 20 21 22 23
RAT/ LITTER #
MATERNAL DOSAGE GROUP I
0 MG/KG/DAY
19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
M A M A M A M A F A F A F A F A F A F A F A F A F A FD 3 MA MA MA MA MA FA FA FA FA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA MA FA FA FA FA FA M A M A M A M A M A M A M A F A F A F A F A F A FD 4 MA MA MA MA MA MA FA FA FA FA FA FA FA FA FA FA FA FA MA MA MA MA MA MA FA FA FA FA FA FA FA FA FA M A M A M A M A M A M A M A M A F A F A F A F A F A F A F A F A FM 2 MA MA MA MA MA FA FA FA FA FA FA FA FA FA FA M A M A M A M A M A M A M A M A MD 5 F A F A F A F A F A F A F A M A M A M A M A M A M A M A M A M A F A F A F A F A F A F A F A F A F A F A FD 5 M A M A M A M A M A MD 2 F A F A F A F A F A F A F A F A F A MA MA MA MA MA MA MA MA FA FA FA FA FA FA FA FA M A M A M A M A MD 1 F A F A F A F A F A F A F A F A F A F A MA MA MA MA MA MA MA MA MA MA MA FA FA FA FA FA
RAT/ LITTER #
MATERNAL DOSAGE GROUP II
0 .3 MG/KG/DAY
19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
M A M A M A M A M A M A M A M A F A F A F A F A F A F A F A F A F A FM 6 MA MA FA FA FA FA FA MA MA MA MA MA MA MA MA MA MA MA MA FA FA FA MA MA MA MA MA MA MA MA FA FA FA FA FA FA M A M A M A M A M A M A M A M A M A M A F A F A F A F A F A F A F A F A FD 8 M A M A M A M A M A M A F A F A F A F A F A F A F A FM11 FD 2 FD 1 M A M A M A M A M A M A M A M A F A F A F A F A F A F A F A FD15 MA MA M A MA MA MA MA FA FA FA FA FA FA MA M A MA MA MA MA MA FA FA FA FA FA FA
MA MA MA MA MA FA FA FA FA M A M A M A M A M A M A F A F A F A F A F A F A F A F A F A F A FD 5 M A M A M A M A M A M A M A M A M A M A MD 1 F A F A F A F A F A M A M A M A M A M A M A M A MD 3 F A F A F A F A F A M A M A M A M A M A M A F A F A F A F A F A F A F A FD 8 MA MA MA M A M A MA M A M A FA FA FA FA FA FA
FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
418-028:PAGE C-125
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C45 (PAGE 2) : PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
PUP # 1 2
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
RAT/ LITTER #
MATERNAL DOSAGE GROUP III
1 MG/KG/DAY
19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
MA M A MA MA M A MA MA MA FA FA FA FA FA FA FA FA M A M A M A M A M A M A M A F A F A F A F A F A F A F A F A F A F A FD 2 M A M A M A M A M A M A M A F A F A F A F A F A F A F A FM 2 MA MA MA MA MA MA MA MA MA FA FA FA FA FA FA
NOT PREGNANT MA MA MA MA MA MA MA MA MA FA FA FA FA FA FA MA MA MA MA MA MA FA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA MA FA FA FA FA FA FA M A M A M A M A M A M A M A M A MM 2 F A F A F A F A F A F A F A MA M A MA MA MA MA FA FA FA FA FA FA FA FS NOT PREGNANT MA MA MA MA MA MA MA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA MA FA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA FA FA FA FA FA FA M A M A M A M A M A M A M A M A M A F A F A F A F A F A F A F A F A FM11
RAT/ LITTER #
MATERNAL DOSAGE GROUP IV
3 MG/KG/DAY
19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
M A M A M A M S F A F A F A F A F A F A FD 1 MA M A MA MA MA MA FA FA FA FA FA FA FA FA FA FA MA MA MA MA MA MA FA FA FA FA FA FA FA FA M A M A M A M A M A MD 2 F A F A F A F A F A F A F A F A F A MA M A MA MA MA MA MA FA FA FA FA FA FA FA FA FA FA MA M A MA MA MA MA FA FA FA FA FA FA FA FA FA UU
NOT PREGNANT
NOT PREGNANT; MATING NOT CONFIRMED
MA MA MA FA FA MA MA MA MA MA MA MA MA FA FA FA FA FA MA MA MA MA MA MA MA MA MA FA FA FA FA FA FA
MA MA FA FA FA FA FA FA FA FA FA FA FA Fs M A M A M A M A M A F A MD 1 F A F A F A F A F A F A F S
M A M A M A M A M A M A F A F A F A F A F A F A F A F A F A F A FD10 M A M A M A M A M A M A M A MM 3 F A F A F A F A F A F A
FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
418-028:PAGEC-126
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C45 (PAGE 3) : PUP VITAL STATUS AND SEX FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
PUP # 1 2
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
RAT/ LITTER #
MATERNAL DOSAGE GROUP V
10 MG/KG/DAY
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
MA MA MA MA FA FA FA FA FA FA FA M A M A M A M A M A MD 2 F A F A F A F A F A F A F A F A F A F A MA MA MA MA MA MA MA FA FA FA FA FA FA MA MA MA MA MA MA MA MA FA FA FA FA FA M A M A M A M A M A M A M A M A M A MD 1 F A F A F A F A F A FM 2 MA M A MA MA MA MA MA MA MA MA MA MA MA FA FA FA M A M A MA M A FA FA FA FA FA FA FA FA FA FA MA M A MA MA MA FA FA FA FA FA FA FA F S MA M A MA MA M A MA FA FA FA FA FA FA FA M A M A M A M A M A M A M A MM 2 F A F A F A F A F A F A F A MA MA MA MA MA MA MA FA FA FA FA FA FA FA MA MA MA MA MA MA FA FA FA FA FA FA FA FA MA MA MA MA MA MA MA MA MA MA MA FA FA FA FA MA MA MA MA MA MA MA MA MA MA FA FA FA FA FA M A M A M A M A M A M A M A M A F A F A F A F A FD13 FD 1
F A FD 1 F S FA FA F A
FIRST LETTER -- M-MALE, F-FEMALE, U-SEX UNDETERMINABLE SECOND LETTER -- A-ALIVE, S-STILLBORN, U-UNCERTAIN, D-DIED, M-MISSING (PRESUMED CANNIBALIZED) NUMBER FOLLOWING "SECOND LETTER" INDICATES THE DAY POSTPARTUM THE EVENT OCCURRED.
418-028:PAGE C-127
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C46 (PAGE 1) : CLINICAL OBSERVATIONS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)
LITTER NUMBER
DAY POSTPARTUM
OBSERVATIONS a
I
0
19010
1- 2
1/14 PUPS: PALE IN APPEARANCE.
19044
1- 2
1/17 PUPS: BACK, BRUISE (2.5 CM X 2.0 CM).
19050
1 1/15 PUPS : PALE IN APPEARANCE.
19072
18-22
1/16 PUPS: RIGHT EYE, CORNEAL OPACITY.b
II
0.3
19004
8 1/17 PUPS: COLD TO TOUCH; NOT NESTING OR NURSING.
19036
1- 4
1/14 PUPS: BACK, BRUISE (2.0 CM IN DIAMETER).
19037
18 4/15 PUPS: DEHYDRATION.
19071
11 1/14 PUPS: COLD TO TOUCH.
III
1
19003
17 1/16 PUPS: DEHYDRATION.
19064
9 1/18 PUPS: DEHYDRATION.
a. Tabulation restricted to adverse observations; all other pups appeared normal. b. Confirmed at necropsy.
418-028:PAGE C-128
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C46 (PAGE 2) : CLINICAL OBSERVATIONS FROM BIRTH TO DAY 22 POSTPARTUM - INDIVIDUAL DATA - FI GENERATION PUPS
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)
LITTER NUMBER
DAY POSTPARTUM
OBSERVATIONS a
IV
3
19039
9- 16
1/14 PUPS: LEFT EYE, PERIORBITAL DISCOLORATION, PURPLE.
19054 19058
1 2- 7
20-22
1/15 PUPS: RIGHT HINDLIMB, LACERATION. 1/ 5 PUPS: RIGHT HINDLIMB, SCAB (0.1 CM X 1.0 CM).
1/13 PUPS: RIGHT EYE, ENLARGED.b
V
10
19006
11 1/17 PUPS: COLD TO TOUCH.
19020
22 13/13 PUPS: NOT NURSING; DEHYDRATION b; EMACIATION b.
19049
2- 4
2/15 PUPS: WHOLE BODY, EXCLUDING HEAD, DISCOLORATION, PURPLE.
19070
8- 10
1/13 PUPS: HEAD, SCAB (DID NOT EXCEED 0.1 CM X 0.5 CM) .
a. Tabulation restricted to adverse observations; all other pups appeared normal. b. Confirmed at necropsy.
418-028-.PAGEC-129
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C47 (PAGE 1) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FI GENERATION PUPS
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)
LITTER NUMBER
DAY POSTPARTUM
OBSERVATIONS a
19010
3 1 PUP: FOUND DEAD. NO MILK IN STOMACH.
ALL OTHER TISSUES APPEARED NORMAL.
22 13 PUPS: APPEARED NORMAL.
19012 22 16 PUPS: APPEARED NORMAL. 19019 22 15 PUPS: APPEARED NORMAL. 19021 22 14 PUPS: APPEARED NORMAL.
19023 4 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL 22 12 PUPS: APPEARED NORMAL.
19041 22 18 PUPS: APPEARED NORMAL. 19042 22 15 PUPS: APPEARED NORMAL. 19044 22 16 PUPS: APPEARED NORMAL. 19050 22 15 PUPS: APPEARED NORMAL.
19053
5 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL.
22 15 PUPS: APPEARED NORMAL.
19065 5 1 PUP: FOUND DEAD. NO MILK IN STOMACH.
ALL OTHER TISSUES APPEARED NORMAL. 22 19 PUPS: APPEARED NORMAL.
19068 2 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL 22 14 PUPS: APPEARED NORMAL.
19072 22 16 PUPS: APPEARED NORMAL.
19074
1 1 PUP: FOUND DEAD. ALL TISSUES APPEARED NORMAL 22 14 PUPS: APPEARED NORMAL.
19075 22 16 PUPS: APPEARED NORMAL.
a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the individual pup clinical observations table (Table C44) for external clinical observations confirmed at necropsy.
418-028(PAGE C-130
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE C4 7 (PAGE 2) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FI GENERATION PUPS
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)
LITTER NUMBER
DAY POSTPARTUM
OBSERVATIONS a
II
0.3 19004 22 17 PUPS APPEARED NORMAL.
19009
22
7 PUPS APPEARED NORMAL.
19016 22 15 PUPS APPEARED NORMAL.
19018 22 14 PUPS APPEARED NORMAL.
19026 8 1 PUP FOUND DEAD. NO MILK IN STOMACH. ALL OTHER TISSUES APPEARED NORMAL.
22 18 PUPS APPEARED NORMAL.
19036 1 1 PUP FOUND DEAD. NO MILK IN STOMACH. ALL OTHER TISSUES APPEARED NORMAL.
2 1 PUP FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION.
22 13 PUPS APPEARED NORMAL.
19037
15
1 PUP FOUND DEAD. NO MILK IN STOMACH.
AUTOLYSIS PRECLUDED FURTHER EVALUATION.
22 1 PUP KIDNEYS: RIGHT, PELVIS, MODERATE DILATION.
ALL OTHER TISSUES APPEARED NORMAL.
14 PUPS APPEARED NORMAL.
19043 22 13 PUPS APPEARED NORMAL.
19047 22 13 PUPS APPEARED NORMAL.
19048
22
9 PUPS APPEARED NORMAL.
19052 5 1 PUP FOUND DEAD. NO MILK IN STOMACH. ALL OTHER TISSUES APPEARED NORMAL.
22 16 PUPS APPEARED NORMAL.
a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the individual pup clinical observations table (Table C44) for external clinical observations confirmed at necropsy.
418-028:PA
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C47 (PAGE 3) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FI GENERATION PUPS
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)
LITTER NUMBER
DAY POSTPARTUM
OBSERVATIONS a
II 0.3 cont.
19055
1 1 PUP: FOUND DEAD. NO MILK IN STOMACH.
ALL OTHER TISSUES APPEARED NORMAL.
22 15 PUPS: APPEARED NORMAL.
19061 3 i PUP: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION.
22 12 PUPS: APPEARED NORMAL.
19067 8 1 PUP: FOUND DEAD. NO MILK IN STOMACH. ALL OTHER TISSUES APPEARED NORMAL.
22 13 PUPS: APPEARED NORMAL.
19071 22 14 PUPS: APPEARED NORMAL.
a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the individual pup clinical observations table (Table C44) for external clinical observations confirmed at necropsy.
418-028:PAGE C-132
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C47 (PAGE 4) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FI GENERATION PUPS
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)
LITTER NUMBER
DAY POSTPARTUM
OBSERVATIONS a
III
19003
22 16 PUPS APPEARED NORMAL.
19007
2 1 PUP FOUND DEAD. ALL TISSUES APPEARED NORMAL 22 17 PUPS APPEARED N O R M A L .
19008 19013 19015 19017 19024 19029
22 14 PUPS APPEARED NORMAL. 22 15 PUPS APPEARED NORMAL. 22 15 PUPS APPEARED NORMAL. 22 14 PUPS APPEARED NORMAL. 22 15 PUPS APPEARED NORMAL. 22 15 PUPS APPEARED NORMAL.
19034
1 1 PUP STILLBORN. ALL TISSUES APPEARED NORMAL. 22 13 PUPS APPEARED NORMAL.
19056 19057 19060 19064
22 14 PUPS APPEARED N O R M A L . 22 17 PUPS APPEARED N O R M A L . 22 14 PUPS APPEARED NORMAL. 22 17 PUPS APPEARED N O R M A L .
a Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the individual pup clinical observations table (Table C44) for external clinical observations confirmed at necropsy.
418-028:PAGE C-133
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C47 (PAGE 5) : NECROPSY OBSERVATIONS - INDIVIDUAL D ATA - FI GENERATION PUPS
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)
LITTER NUMBER
DAY POSTPARTUM
OBSERVATIONS a
19002
1 1 PUP: FOUND DEAD. A L L TISSUES APPEARED NOR M A L 1 PUP: STILLBORN. AUTOLYSIS PRECLUDED FURTHER EVALUATION.
22 9 PUPS: APPEARED NORMAL.
19005 19035
22 16 PUPS: APPEARED NORMAL. 22 14 PUPS: APPEARED NORMAL.
19039
2 1 PUP: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION.
22 14 PUPS: APPEARED NORMAL.
19040 19045 19054 19058 19062
22 17 PUPS: APPEARED NORMAL. 22 15 PUPS: APPEARED NORMAL. 22 5 PUPS: APPEARED NORMAL. 22 13 PUPS : APPEARED NORMAL. 22 15 PUPS: APPEARED N O R M A L .
19063
1 1 PUP: STILLBORN. AL L TISSUES A PPEARED NORMAL. 22 13 PUPS: APPEARED NORMAL.
19066
1 1 PUP: FOUND DEAD. NO M ILK IN STOMACH. ALL OTHER TISSUES APPEARED NORMAL.
1 PUP: STILLBORN. AL L TISSUES APP E A R E D NORMAL. 22 12 PUPS: APPEARED NORMAL.
19069
10 1 PUP: FOUND DEAD. NO M ILK IN STOMACH. AUTOLYSIS PRECLUDED FURTHER EVALUATION.
22 16 PUPS : APPEARED NORMAL.
19073
22 13 PUPS: APPEARED NORMAL.
Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the individual pup clinical observations table (Table C44) for external clinical observations confirmed at necropsy.
418-028-.PAGE C-134
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVE LOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-770S.1)
TABLE C47 (PAGE 6) : NECROPSY OBSERVATIONS - INDIVIDUAL DATA - FI GENERATION PUPS
MATERNAL DOSAGE GROUP MATERNAL DOSAGE (MG/KG/DAY)
LITTER NUMBER
DAY POSTPARTUM
OBSERVATIONS a
19001
22 11 PUPS: APPEARED NORMAL.
19006
1 1 PUP: FOUND DEAD. ALL TISSUES APP E A R E D NORMAL 1 PUP: STILLBORN. ALL TISSUES APPEARED NORMAL.
2 1 PUP: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION.
22 17 PUPS: APPEARED NORMAL.
19011 19020
22 13 PUPS: APPEARED NORMAL. 22 13 PUPS: APPEARED NORMAL.
19022
1 1 PUP: FOUND DEAD. AUTOLYSTS PRECLUDED FURTHER EVALUATION.
22 14 PUPS: APPEARED NORMAL.
19025 19027
22 20 PUPS: APPEARED NORMAL. 22 14 PUPS: APPEARED NORMAL.
19028
1 1 PUP: STILLBORN. ALL TISSUES APPEARED NORMAL. 22 12 PUPS: APPEARED NORMAL.
19030 19031 19032 19033 19049 19059
22 13 PUPS: APPEARED NORMAL. 22 14 PUPS: APPEARED NORMAL. 22 14 PUPS: APPEARED NORMAL. 22 14 PUPS: APPEARED NORMAL. 22 15 PUPS: APPEARED NORMAL. 22 15 PUPS: APPEARED NORMAL.
19070
1 1 PUP: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION.
13 1 PUP: FOUND DEAD. AUTOLYSIS PRECLUDED FURTHER EVALUATION.
22 12 PUPS: APPEARED N O R M A L .
a. Complete necropsies were not performed on pups in which autolysis or cannibalization precluded evaluation. Refer to the individual pup clinical observations table (Table C44) for external clinical observations confirmed at necropsy.
418-028TAGE C-135
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C48 (PAGE 1 ) : PUP LIVER WEIGHTS - INDIVIDUAL DATA - FI GENERATION PUPS
RAT/
LITTER
LIVER
NUMBER
M
F
T
DOSAGE GROUP I
0 MG/KG/DAY
19012
1.864
2.008
1.936
19019
1.436
1.636
1.536
19021
1.360
1.558
1.459
19023
1.814
1.878
1.846
19041
1.114
1.232
1.173
19042
1.390
1.552
1.471
19044
1.798
1.736
1.767
19050
1.336
1.406
1.371
19053
1.438
1.562
1.500
19065
1.266
1.354
1.310
DOSAGE GROUP II
0.3 MG/KG/DAY
19004
1.138
1.246
1.192
19009
2.350
2.356
2.354
19016
1.874
1.633
1.784
19018
1.768
1.752
1.760
19026
1.062
1.214
1.138
19036
1.596
1.596
1.596
19037
1.170
1.182
1.176
19043
2.098
2.074
2.086
19047
1.510
1.462
1.486
19048
1.826
1.985
1.897
DOSAGE GROUP III
1 MG/KG/DAY
19003
1.268
0.998
1.133
19007
1.324
1.278
1.301
19008
1.516
1.732
1.624
19013
1.976
1.736
1.856
19015
1.416
1.510
1.463
19017
2.102
2.188
2.145
19024
1.504
1.550
1.524
19029
2.076
1.456
1.766
19034
1.550
1.670
1.610
19056
1.500
1.646
1.573
19005
1.296
1.312
1.304
M = MALE
F = FEMALE
T = TOTAL
ALL WEIGHTS WERE RECORDED IN GRAMS (G).
TERMINAL BODY WEIGHT MFT
42.68 39.70 34.74 46.02 33.00 36.12 44.30 36.42 35.60 33.08
42.24 37.50 33.80 44.38 31.02 36.16 39.82 34.86 35.92 31.00
42.46 38.60 34.27 45.20 32.01 36.14 42.06 35.64 35.76 32.04
30.78 56.35 45.32 45.50 32.30 40.74 30.66 46.34 38.78 48.96
30.12 53.20 38.10 41.70 30.04 34.30 29.16 43.80 36.62 46.45
30.45 54.10 42.61 43.60 31.17 37.52 29.91 45.07 37.70 47.84
30.78 35.34 41.82 46.36 38.06 44.96 40.04 43.22 41.24 40.88 33.56
27.58 29.70 40.10 42.36 35.84 43.88 37.62 33.24 38.76 39.48 30.84
29.18 32.52 40.96 44.36 36.95 44.42 38.83 38.23 40.00 40.18 32.20
418-028-.PAGE C-136
PROTOCOL 418-028: ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST (SPONSOR'S STUDY NUMBER: T-7706.1)
TABLE C48 (PAGE 2): PUP LIVER WEIGHTS - INDIVIDUAL DATA - FI GENERATION PUPS
RAT/
LITTER
NUMBER
M
DOSAGE GROUP IV
19035
1.192
19039
1.540
19040
1.226
19045
1.624
19054
2.137
19058
2.364
19062
1.470
19063
2.040
19066
1.582
g! PJij
GROUP V
19001
1.855
19006
1.358
19011
1.290
19020
0.454
19022
1.336
19025
1.098
19027
1.283
19028
1.550
19030
1.594
19031
1.842
LIVER F
1.316 1.380 1.582 1.730 2.495 2.110 1.702 2.132 1.702
1.902 1.512 1.434 0.540 1.286 1.160 1.286 1.742 1.632 1.870
T 3 MG/KG/DAY
1.254 1.460 1.404 1.677 2.280 2.237 1.586 2.106 1.642
10 MG/KG/DAY 1.881 1.435 1.362 0.497 1.311 1.129 1.284 1.64 6 1.613 1.856
TERMINAL BODY WEIGHT M FT
33.82 35.14 31.48 37.66 57.13 47.80 42.50 47.60 43.76
32.04 31.46 30.28 37.18 56.55 45.08 39.86 46.10 42.82
32.93 33.30 30.88 37.42 56.90 46.44 41.18 46.53 43.29
44.10 35.20 36.28 15.30 36.60 30.00 33.05 39.80 39.94 43.06
44.24 32.84 35.44 15.52 34.46 26.70 31.46 40.10 39.16 40.80
44.18 34.02 35.86 15.41 35.53 28.35 32.17 39.95 39.55 41.93
418-028-.PAGE C-137
APPENDIX D PROTOCOL AND AMENDMENTS
418-028:PAGE D-l
905 Shechy Drive, BMg. A Horsham, PA 19044 Telephone: (215)443-3710 Telefax: (215) 4434587
ARGUS RESEARCH
Charles River Laboratories
Discovery and Development Services
PROTOCOL 418-028
SPONSOR'S STUDY NUMBER: T-7706.1
STUDY TITLE: Oral (Gavage) Combined Repeated Dose Toxicity Study of T-7706 with the Reproduction/Developmental Toxicity Screening Test
PURPOSE:
The purpose of this study is to provide information on the possible health hazards that may result from repeated exposure of Crl:CD(SD)IGS BR VAF/Plus male and female rats to a test substance beginning before cohabitation, through mating and continuing for at least 42 days (male rats) or through parturition until day 21 of lactation (female rats). This repeated dose study incorporates a reproduction/developmental toxicity screening test that can be used to provide initial information on possible effects on male and female reproductive performance (e.g., gonadal function, mating behavior, conception, development ofthe conceptus and parturition). The study also places emphasis on neurological effects as a specific endpoint and should identify the neurotoxic potential of a test substance, which may warrant further in-depth investigation.
TESTING FACILITY:
Because of the selectivity of the endpoints and the short duration of the study, the screening test will not provide evidence for definitive claims of no reproduction/developmental effects. Inparticular, it offers only limited means of detecting postnatal manifestations of prenatal exposure or effects that may be induced during postnatal exposure.
Argus Research 905 Sheehy Drive, Building A Horsham, Pennsylvania 19044-1297 Telephone: (215) 443-8710 Telefax: (215)443-8587
STUDY DIRECTOR:
Raymond G. York, PhD., DABT
Associate Director of Research
Email:
raymond.york@criver.com
Address as cited above for Testing Facility
SPONSOR:
3M Corporate Toxicology 3M Center, Building 220-2E-02 St. Paul, Minnesota 55144-1000
418-028:PAGE D-2
STUDY MONITOR:
John Butenhoff, Ph.D., DABT, CIH
3M Corporate Toxicology
3M Medical Department
Telephone: (651)733-1962
Telefax: (651) 733-1773
Email:
jlbutenhoff@mmm.com
Protocol 418-028 Page 2
REGULATORY CITATIONS:
Organisation for Economic Co-operation and Development (1996). OECD Guidelinefo r Testing o f Chemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996.
Organisation for Economic Co-operation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final].
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 Standardf o r Safety Studies on Drugs, MHW Ordinance Number 21, March 26,1997.
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 Testing Facility's Quality Assurance Unit (QAU) will audit the protocol, the raw data and the report, and will inspect critical phases of those portions of the study conducted at the Testing Facility in accordance with the Standard Operating Procedures of the Testing Facility.
The final report will include a compliance 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.
Should any portion o f the study be conducted by a subcontractor or by the Sponsor, the Study Director will ensure that a qualified Principal Investigator is identified by the facility conducting thatportion of the study. The QAU forthis facility will conduct critical phase inspections and audit respective results and reports for that study portion according to the SOPs of that facility. Such critical phase inspection reports and report audits will be submitted by the facility to the Principal Investigator and the Study Director. The dates of the inspections and report submissions will be incorporated into a QAU Statement generated by that facility and provided
418-028 :PAGE D-
Protocol 418-028 Page 3
to the Testing Facility for inclusion in the final report. In addition, this facility will provide a statement of GLP compliance, as described above, signed by the Principal Investigator for inclusion in the final report.
SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE:
See ATTACHMENT 1 to the protocol.
TEST SUBSTANCE AND VEHICLE:
Identification:
Test Substance:
T-7706 [Perfluorohexane Sulfonate Potassium Salt (PFHS)] Lot identification will be documented in the raw data.
The Sponsor will provide to the Testing Facility documentation or certification of the identity, composition, method of synthesis, strength and activity/purity ofthe test substance. This documentation will be included in the final report.
Vehicle:
Aqueous 0.5% carboxymethlycellulose (CMC) (medium viscosity) prepared using reverse
osmosis membrane processed deionized water (R.O. deionized water). Lot identification and Supplier will be documented in the raw data.
Neither the Sponsor nor the Study Director is aware of any potential contaminants likely to be present in the vehicle that would interfere with the results of this study. Therefore, no analyses other than those mentioned in this protocol will be conducted.
Safety Precautions:
Gloves, dust-mist/HEPA-filtered mask, appropriate eye protection and uniform/lab coat to be worn during formulation preparation and dosage. The Material Safety Data Sheet (MSDS) is attached to the protocol (ATTACHMENT 2).
Storage:
Bulk Test Substance: Bulk Vehicle Components: Prepared Test Substance and Vehicle Formulations:
Room temperature. Room temperature.
Refrigerated (2C to 8C).
All test substance shipments should be addressed to the attention of Julian Gulbinski, Manager of Formulation Laboratory, at the previously cited Testing Facility address and telephone number.
418-028 :PAGE D-4
Protocol 418-028 Page 4
Shipments should include information concerning storage conditions and shipping cartons should be labeled appropriately. The recipient should be notified in advance of shipment.
FORMULATION:
Frequency of Preparation:
Formulations (suspensions) will be prepared weekly at the Testing Facility.
Detailed preparation procedures will be attached to this protocol (ATTACHMENT 3).
Adjustment for Purity:
The test substance will be considered 100% pure for the purpose of dosage calculations.
Testing Facility Reserve Samples:
The Testing Facility will reserve a sample of each lot of bulk test substance (approximately 1 g) andbulk vehicle components (approximately 1 g or 5 mL) used during the course of the study. Samples will be stored under the previously cited conditions.
ANALYSES:
Results ofrequired analyses will be provided to the Testing Facility for inclusion in the study report.
Samples additional to those described below may be taken if deemed necessary during the course of die study. Additional analyses, if required, will be documented by protocol amendment.
Bulk Test Substance Sampling:
A sample of approximately 1 g of the test substance will be taken on the last day of treatment and sent (ambient conditions) to:
Principal Investigator: Lisa Clemen
3M Environmental Technology and Safety Services
Building 2-3E-09
St Paul, Minnesota 55133-3331
Telephone: (651) 778-5568
Telefax:
(651) 778-6176
Email:
laclemen@mmm.com
The recipient will be notified in advance of sample shipment.
418-028:PAGE D-5
Analyses of Prepared Formulations:
Protocol 418-028 Page 5
Concentration and Homogeneity:
Concentration and homogeneity of the prepared formulations will be verified during the course ofthis study. Quadruplicate samples (2 mL each) will be taken from the top, middle and bottom of each concentration on the first day of preparation. Two samples from each quadruplicate set will be shipped for analysis; the remaining samples will be retained at the Testing Facility as backup samples. Quadruplicate samples will be taken from each concentration on the last day of preparation. Two samples from each quadruplicate set will be shipped for analysis; the remaining samples will be retained as backup samples. Backup samples will be stored under the previously cited conditions and discarded at the Testing Facility upon the request of the Sponsor.
Stability:
Stability of the prepared formulations will be documented during this study. Two sets of duplicate samples (2 mL each) from each concentration will be taken on the first day of preparation. One sample of each duplicate set will be shipped on the day of preparation. These samples will be analyzed at the following time points: as soon after preparation as possible and ten days after the first 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 the request of the Sponsor.
Shipping Instructions:
Samples to be analyzed will be shipped (refrigerated) to:
Principal Investigator; Lisa Clemen
3M Environmental Technology and Safety Services
Building 2-3E-09
St. Paul, Minnesota 55133-3331
Telephone; (651) 778-5568
Telefax: (651) 778-6176
Email:
laclemen@mmm.com
The recipient will be notified in advance of sample shipment.
DISPOSITION:
Prepared formulations will be discarded at the Testing Facility. All remaining bulk test substance will be returned to:
Dan Hakes 3M EHSR - Auto & Chem Grp 3M Center, Building 236-1B-10 St. Paul, Minnesota 55144-1000 Telephone: (651) 733-2392
418-028;PAGE D-6
TEST SYSTEM:
Protocol 418-028 Page 6
Species/Strain and Reason for Selection:
The Crl:CD(SD)IGS BR VAF/Plus rat was selected as the Test System because: 1) it is one mammalian species accepted for use in toxicity studies and it has been widely used throughout industry; 2) this strain of rat has been demonstrated to be sensitive to reproductive and developmental toxins; and 3) historical data and experience exist at the Testing Facility0'35
Number:
Initial population acclimated:
100 male and 100 virgin female rats.
Population selected for main study:
75 male and 75 virgin female rats (15 per sex per
dosage group).
Population selected for toxicokinetic study: 15 male and 15 female rats (three per sex per
dosage group).
Body Weight and Age:
Male rats will be ordered to weigh from 275 g to 300 g each at receipt, at which time they will be expected to be at least 60 days of age. Female rats will be ordered to weigh from 200 g to 225 g each at receipt, at which time they will be expected to be at least 56 days of age. Actual body weights will be recorded the day after receipt and will be documented in the raw data. The weight ranges will be included in the final report. At study initiation, the weight variation of the rats will not exceed 20% of the mean weight of each sex.
Sex:
Both male and female rats will be evaluated.
Source:
Charles River Laboratories, Inc.
The rats will be shipped in filtered cartons by air freight and/or track from Charles River Laboratories, Inc., to the Testing Facility.
Identification:
Rats are permanently identified using Monel self-piercing ear tags (Gey Band and Tag Co., Inc., No. MSPT 20101). Male and female rats are assigned temporarynumbers at receipt and given unique permanent identification numbers when assigned to the study before administration of the first dosage. Pups will not be individually identified during lactation; all parameters will be evaluated in terms of the litter.
418-028 :PAGE D-7
ANIMAL HUSBANDRY:
Protocol 418-028 Page 7
All cage sizes and housing conditions are in compliance with the Guide fo r the Care and Use o f Laboratory A n im a ls^. Argus Research is an AAALAC-accredited facility.
Housing:
Fo generation rats will be individually housed in stainless steel wire-bottomed cages except during the cohabitation and postpartum periods. During cohabitation, each pair of rats will be housed in the male rat's cage. Beginning no later than day 20 ofpresumed gestation, Fo generation female rats will be individually housed in nesting boxes. Each dam and delivered litter will be housed in a common nesting box during the postpartum period.
Nesting Material:
Nesting material (bed-o'cobs) will be provided.
Bedding will be changed as often as necessary to keep the animals dry and clean. Analyses for possible contamination are conducted semi-annually and documented in the raw data.
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 64F to 79F (18C to 26C) and monitored constantly. Room humidity will also be monitored constantly and maintained at 30% to 70%.
An automatically controlled 12-hour light:12-hour dark fluorescent light cycle will be maintained. Each dark period will begin at 1900 hours EST. The light cycle may be adjusted by the Study Director or designee if deemed necessary to accommodate scheduled laboratory activities. Any such adjustment will be documented in the raw data.
Diet:
Rats will be given Certified Rodent Diet #5002 (PMI Nutrition International) available ad libitum from individual feeders. Feed will be removed the evening prior to the scheduled sacrifice.
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.
418-028 :PAGE D-8
Protocol 418-028 PageS
Contaminants:
Neither the Sponsor nor the Study Director is aware of any potential contaminants likely to be present in the certified diet, in the drinking water or in the nesting materials 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.
DAY NUMBERING SYSTEM:
Gestation day 0 is defined as the day spermatozoa are observed in a smear of the vaginal contents and/or a copulatory plug observed in situ.
The day o f birth is designated lactation day 0 (postpartum day 0) in the Health Effects Test Guidelines - Reproduction and Fertility Effects (Office of Prevention, Pesticides and Toxic Substances 870.3800, August, 1998) and in the OECD Guideline for the Testing o f Chemicals Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (Section 4, No. 422,22 March 1966). This same day is designated day 1 postpartum (day 1 of lactation) in the Standard Operating Procedures of the Testing Facility. Throughout this protocol, the day ofbirth will be designated day 1 postpartum (day 1 of lactation) and all subsequent ages of the FI generation rats and days of the lactation period will be determined and cited accordingly.
RANDOMIZATION AND COHABITATION:
Upon arrival, rats will be assigned to individual housing on the basis of computer-generated random units. During an acclimation period of at least five days, male and female rats will be selected for study on the basis ofphysical appearance and body weights recorded during acclimation. The rats will be assigned to dosage groups based on computer-generated (weightordered) randomization procedures.
Within each dosage group, consecutive order will be used to assign rats to cohabitation, one male rat per female rat. The cohabitationperiod will consist of a maximum of 14 days. Female rats with spermatozoa observed in a smear ofthe vaginal contents and/or a copulatory plug observed in situ will be considered to be at day 0 of presumed gestation and assigned to individual housing. Female rats not mated within the first seven days ofcohabitation will be assigned alternate male rats that have mated (same dosage group) andwill remain in cohabitation for a maximum of seven additional days.
Day 1 of lactation (postpartum) is defined as the day of birth and is also the first day on which all pups in a litter are individually weighed (pup body weights will be recorded after all pups in a litter are delivered and groomed by the dam).
Litters will not be culled during the lactation period, because random selection of pups for culling could result in potential biases in pup viabilities and body weight gains over this period.
418-028 :PAGE D-9
Protocol 418-028 Page 9
Within each dosage group, consecutive order will be used to assign the first 10 male and the first 10 female rats to a functional observational battery (FOB) and motor activity assessment, blood sample collection for clinical chemistry and hematology (CC&H), and histological evaluations.
On day 22 postpartum, a table of random units will be used to select five male and five female pups per litter for blood sample and liver collection; these pups will only be selected from the ten dams selected for FOB, motor activity, CC&H and histological evaluation.
ADMINISTRATION.
Route and Reason for Choice:
The oral (gavage) route was selected for use because: 1) in comparison with the dietary route, the exact dosage can be accurately administered; and 2) it is one of the possible routes for environmental exposure.
Method and Frequency:
Dosages will be adjusted daily for body weight changes and given at approximately the same time each day. The first day of dosage is designated as day 1 o f study.
Male rats will be given the test substance once daily beginning 14 days before a cohabitation period that consists of a maximum 14 days. Dosage will continue through the day before sacrifice, after completion of the cohabitation period, after a minimum of 42 days of administration.
Female rats will be given the test substance once daily beginning 14 days before a cohabitation period that consists of a maximum of 14 days. Dosage will continue through the day before scheduled sacrifice (day 21 of lactation).
Rationale for Dosage Selection:
'
Dosages were selected by the Sponsor based on previous studies conducted with the test substance, taking into account possible differences in sensitivity between pregnant and nonpregnant rats. The highest dosage will be expected to cause toxic effects but not mortality or obvious suffering. The descending sequence of the lower dosage levels will be selected for the purpose of demonstrating any dosage-related response, with no adverse effects expected at the lowest level.
418-028:PAGE D-10
Dosage Levels. Concentrations and Volumes:
Protocol 4 1S-028 Page 10
D osage G roup
'
N um ber o f R ats Per Sex
D osage (m g /k g /d ay )
C o n cen tratio n ' (m g /m U
D osage V o lu m e (m L /k g )
A rg u s B atch N u m b er
i 15 + 3*
0
0
10 B -4 1 8 -0 2 8 -A (D a y .M o n th .Y e a r)
a 15 + 3*
0 .3
0 .03
10 B -4 18 -0 2 8 -B (D a y .M o n th .Y e a r)
u i 15 + 3*
1
0.1
10 B -4 1 8 -0 2 8 -C (D a y .M o n th .Y e a r)
IV 15 + 3*
3
0 .3
10 B -4 1 8 -0 2 8 -D (D a y .M o n th . Y ear)
V 15 + 3*
10
1
10 B -4 1 8 -0 2 8 -E (D ay .M o n tr.. Y ear)
a. T h e te st su b stan ce w ill b e c o n sid e re d 100% p u re fo r th e p u rp o se o f dosage calcu latio n s b . T h re e a d d itio n a l ra ts p e r s e x p e r d o sa g e g ro u p w ill b e assig n e d to to x ico k in etic sa m p le co llectio n .
TESTS. ANALYSES AND MEASUREMENTS - Fo GENERATION:
Viability - Male and Female Rats:
All Periods:
At least twice daily.
Clinical Observations and/or General Appearance - Male and Female Rats:
Acclimation Period:
Weekly.
Dosage Period:
Daily before dosage. On the first day of dosage, postdosage observations will be recorded at approximately hourly intervals forthe first fourhours and at the end of the normal working day. Subsequent postdosage observations will be recorded at intervals deemed appropriate by the Study Director or designee after determination of peak toxicologic effects.
Maternal Behavior:
Days 1, 5, 8, IS and 22 postpartum. Observed abnormal behavior recorded daily.
Clinical observations may be recorded more frequently than cited above, if deemed appropriate by the Study Director and/or Study Monitor.
Data collected for rats assigned to toxicokinetic sample collection will not be summarized or analyzed statistically.
Detailed Clinical Observations - Male and Female Rats:
Once before the first dosage and at least once weekly thereafter, detailed clinical observations will be conducted for all male and female rats. These observations will be made outside the cage in a standard arena at the same time each day of conduct Effort will be made to ensure that variations in the test conditions are minimal and that observations are conducted by observers unaware of treatment groups. Signs noted should include, but not be limited to: changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g., lacrimation, piloerection, pupil size, unusual respiratorypattern). Changes in gait, posture
418-028 :PAGE D -ll
Proiocol 418-028 Page 11
and response to handling as well as the presence of clonic or tonic movements, sterotypic behavior (e.g., excessive grooming, repetitive circling), difficult or prolonged parturition or bizarre behavior (e.g., self-mutilation, walking backwards) should also be recorded.
Body Weights - Male and Female Rats:
Acclimation Period:
Weekly.
Dosage Period:
Daily.
Sacrifice:
Terminal weight.
Feed Consumption Values - Male Rats (recorded and tabulated):
Dosage Period:
Weekly.
Feed Consumption Values - Female Rats (recorded and tabulated):
Dosage Period:
Weekly to cohabitation.
Gestation Period:
Days 0,7,10,12,15, 18,20 and 25 (if necessary).
Postpartum Period:
Days 1,5,8 and 15.
Feed consumption not tabulated after day 15 postpartum, when it is expected that pups will begin to consume maternal feed.
Feed Consumption Values - Male and Female Rats:
Feed consumption values may be recorded more frequently than cited above if it is necessary to replenish the feed. During cohabitation, when two rats occupy the same cage with one feedjar, replenishment of the feedjars will be documented. Individual values will not be recorded or tabulated.
Toxicokinetic Sample Collection:
On day 14 and 42 of study, blood samples (approximately 1 mL each) will be collected from each male rat assigned to the toxicokinetic sample collection portion of the study (3 pei group).
Onday 14 of study and day 21 of presumed gestation, blood samples (approximately 1mL each) will be collected from each female rat assigned to the toxicokinetic sample collection portion of the study (3 per group). Samples will be collected prior to dosage on day 14 of study. The time of eachblood collection will be recorded in the raw data.
418-028:PAGE D-12
Protocol 418-028 Page 12
Blood will be collected from the orbital sinus. If necessary, blood may be collected from an alternate site; if so, the alternate site will be documented in the raw data.) The samples will be transferred into EDTA-coated (purple top) tubes and spun in a centrifuge. The resulting serum will be transferred into polypropylene tubes labeled with the protocol number, Sponsor study number, animal number, sex, group number, dosage level, day of study, collection interval, date of collection, species, generation and storage conditions. All samples will be immediately frozen on dry ice and maintained frozen (S-70C) until shipment for analysis.
After the last blood sample collection, rats will be sacrificed and samples of the liver will be collected for analysis.
Shipping Instructions:
Samples to be analyzed will be shipped on dry ice to:
Principal Investigator: Lisa Clemen
3M Environmental Technology and Safety Services
Building 2-3E-09
St. Paul, Minnesota 55133-3331
Telephone:
(651) 778-5568
Telefax:
(651) 778-6176
Email:
laclemen@mmm.com
The recipient will be notified in advance of sample shipment
Estrons Cycling and Mating:
Estrous cycling will be evaluated by examination of vaginal cytology beginning with the day after the first administration and then until spermatozoa are observed in a smear of the vaginal contents and/or a copulatory plug is observed in situ during the cohabitation period.
Caesarean-Sectioning - Toxicokinetic Stndv:
On day 21 of presumed gestation, blood and liver samples will be collected from all female rats designated for toxicokinetic sample collection.
Blood samples will be collected from the rats as previously described. After sacrifice, the liver of each rat will be excised and the liver weight will be recorded. The median liver lobe will be frozen and stored (<-20C) until shipment for possible analysis.
The fetuses will be removed from the uterus and blood samples will be collected from each fetus via decapitation. Blood will be placed into tubes, pooled per litter, allowed to clot and spun in a centrifuge; the resulting serum will be transferred into labeled polypropylene tubes. All samples will be immediately frozen on dry ice and maintained frozen (<-70C) until shipment for analysis.
CO
418-028 :PAGE D -l
Protocol 418-028
Page 13
The liver from each fetus will be collected, pooled per litter and placed into labeled tubes. The samples will be frozen and stored (<-20C) until shipment for analysis.
Samples will be shipped on dry ice to Lisa Clemen at the previously cited address.
Natural Delivery:
Female rats will be evaluated for:
Adverse Clinical Signs Observed During Parturition.
Duration of Gestation (day 0 of presumed gestation to the time the first pup is observed).
Litter Size (defined as all pups delivered).
Pup Viability at Birth.
Functional Observational Battery:
On one occasion during the course of the study, a functional observational battery (FOB)(S'S)will be conducted on 10 male and 10 female rats per group. For male rats, this assessment will be conducted shortly before scheduled sacrifice, but prior to blood sample collection for hematology and clinical chemistry evaluations. Female rats should be tested during the lactation period, shortly before scheduled sacrifice.
The FOB, to be conducted by an observer unaware of the group assignment of the rat, will assess the following parameters:
1. Lacrimation, salivation, palpebral closure, prominence of the eye, pupillary reaction to light, piloerection, respiration, and urination and defecation (autonomic functions).
2. Sensorimotor responses to visual, auditory, tactile and painful stimuli (reactivity and sensitivity).
3. Reactions to handling and behavior in the open field (excitability).
4. Gait pattern in the open field, severity of gait abnormalities, air righting reaction, and landing foot splay (gait and sensorimotor coordination).
5. Forelimb and hindlimb grip strength.
6. Abnormal clinical signs including but not limited to convulsions, tremors and other unusual behavior, hypotonia or hypertonia, emaciation, dehydration, unkempt appearance and deposits around the eyes, nose or mouth.
418-028-.PAGE D-14
Protocol 418-028 Page 14
Evidence of the ability of this battery to detect the effects of positive control substances will be provided (Testing Facility Positive Control Data). Data will also be provided to document interobserver reliability if more than one observer is involved in the testing.
Motor Activity Test:
Motor activity will be evaluated on 10 male and 10 female rats per group once during the course of the study. This assessment will be conducted shortly before scheduled sacrifice, but prior to blood sample collection.
The movements of each rat will be monitored by a passive infrared sensor mounted outside a stainless-steel wire-bottomed cage (40.6 x 25.4 x 17.8 cm). Each test session will be 1.5 hours in duration with the number of movements and time spent in movement tabulated at each fiveminute interval. The apparatus will monitor a rack of up to 32 cages and sensors during each session, with each rat tested in the same location on the rack across test sessions. Groups will be counterbalanced across testing sessions and cages.
Data will be provided to demonstrate that the test system is capable of detecting increases in activity produced by positive control substances (Testing Facility Positive Control Data).
HEMATOLOGY AND CLINICAL CHEMISTRY:
At scheduled sacrifice, the rats (fasted) assigned to hematology and clinical chemistry (H&CC) sample collection will be exsanguinated from the inferior vena cava following sacrifice by carbon dioxide asphyxiation. Approximately 5 mL of blood will be collected and processed as described below. Determinations additional to those described below may be conducted if the known properties of the test substance may, or are suspected to, affect related metabolic profiles (e.g., calcium, phosphate, fasting triglycerides and fasting glucose, specific hormones, and cholinesterase).
Hematology:
Approximately 1 mL of blood will be collected into EDTA-coated tubes and maintained on wet ice orrefrigerated until shipment for analysis of the following hematologic parameters:
Erythrocyte Count (RBC) Hematocrit (HCT)
Hemoglobin (HGB) Mean CorpuscularHemoglobin (MCH) Mean CorpuscularHemoglobin Concentration (MCHC)
Mean Corpuscular Volume (MCV) Leukocyte Count, Total (WBC)
Leukocyteij^lHB} Differential Platelet Count (PLAT) Mean Platelet Volume (MPV) Cell Morphology
Two blood smear slides will be prepared at the Testing Facility for each sample for measurements of differential leukocyte count. All samples (on wet ice) and slides (ambient conditions) will be shipped to Redfield Laboratories at the following address.
Approximately 1.8 mL of blood will be added to a tube containing 0.2 mL of sodium citrate (0.129 M). The contents will be mixed and maintained on wet ice until the tubes are centrifuged
418-028:PAGE D-15
Protocol 418-028 Page 15
(within 30 minutes of the collection time). The resulting plasma will be transferred 2.0 mL polypropylene tubes labeled with study number, Sponsor's study number, rat number, dosage level, day of study, collection interval, date of collection, species, generation and storage. All samples will be frozen on dry ice and maintained frozen (<-70C) until shipment on dry ice by overnight courier for measurement o f prothrombin time (PT) and activated partial thromboplastin time (APTT).
Clinical Chemistry:
Approximately 2 mL of blood will be collected into serum separator tubes and centrifuged. The resulting sera samples will be immediately frozen on dry ice and maintained frozen (<-70C) until shipment for analysis of the following parameters:
Total Protein (TP) Triglycerides (TRI) Albumin (A) Globulin (G) Albumin/Globulin Ratio (A/G) Glucose (GLU) Cholesterol (CHOL) Total Bilirubin (TBILI) Urea Nitrogen (BUN) Creatinine (CREAT)
Creatinine Kinase (CK) Alanine Aminotransferase (ALT) Aspartate Aminotransferase (AST) Alkaline Phosphatase (ALK) Calcium (CA) Phosphorus (PHOS) Sodium (NA) Potassium (K) Chloride (CL)
Samples will be shipped (on dry ice) to Redfield Laboratories at the following address. Shipping Instructions:
Samples will be shipped to arrive on Monday through Friday according to the conditions described above to:
Principal Investigator. Ms. Phyllis Powell Redfield Laboratories A Division of CRL-DDS 100 East Boone Street P.O. Box 308 Redfield, Arkansas 72132 Telephone: (501) 397-2540 Telefax: (501) 397-2002
The recipient will be notified in advance of sample shipment
URINALYSIS:
Urinalysis will not be conducted unless indicated based on expected or observed toxicity of the test substance.
418-028:P AGE D-16
METHOD OF SACRIFICE:
Protocol 418-028 Page 16
Fo generation rats will be sacrificed by carbon dioxide asphyxiation.
GROSS NECROPSY AND HISTOPATHOLOGY - Fo GENERATION RATS:
Scheduled Sacrifice - Toxicokinetic Study:
Scheduled sacrifice of male rats will be conducted on day 42 of study. Scheduled sacrifice of female rats will be conducted on day 21 of presumed gestation.
Blood samples will be collected from the rats as previously described. After sacrifice, the liver of each rat will be excised and the liver weight will be recorded. The median liver lobe will be frozen and stored (<-20C) until shipment for analysis. Fetal samples will be collected as previously described.
Carcasses will be discarded without further evaluation.
Samples will be shipped on dry ice to Lisa Clemen at the previously cited address.
Scheduled Sacrifice - Main Study:
Scheduled sacrifice o f male rats will be conducted on the day following the last dosage administration, after a minimum of 42 days of dosage. Scheduled sacrifice of female rats will be conducted on day 22 o f lactation.
Gross necropsy of all male and female rats will include aninitial physical examination of external surfaces and all orifices, as well as the cranial, thoracic and abdominal cavities and their
contents. Special attention will be paid to the organs of the reproductive system. The number of implantation sites and corpora lutea will be recorded.
Male and female rats will be examined for gross lesions. Gross lesions will be retained in neutral buffered 10%formalin and examined histologically. Tissue trimming and histopathology will be performed under the supervision of or by a Board-Certified VeterinaryPathologist.
The ovaries and the uterus with cervix of each female rat will be weighed, and ovaries, uterus, vagina and a mammary gland will be retained in neutral buffered 10% formalin. Uteri of apparently nonpregnant rats will be examined afterbeing pressed between glass plates to confirm the absence of implantation sites, and retained in neutral buffered 10% formalin.
418-028:PAGE D-17
SpermEvaluations of Male Rats:
Protocol 418-028 Page 17
To assess the potential toxicity of the test article on the male reproductive system, the endpoints listed below will be evaluated from the first 10 male rats in each dosage group.
Organ Weights: The following organs will be individually weighed: right testis, left testis, left epididymis (whole and cauda), right epididymis, seminal vesicles (with and without fluid) and prostate.
Sperm Evaluations: Sperm concentration and motility will be evaluated using computerassisted sperm analysis (CASA). Motility will be evaluated by the Hamilton Thome IVOS by collection of a sample from the left vas deferens. A homogenate will be prepared from the left cauda epididymis for evaluation by the Hamilton Thome IVOS to determine sperm concentration (sperm per gram of tissue weight). The remaining portion of the left cauda epididymis will be used to manually evaluate sperm morphology. Sperm morphology evaluations will include the following: 1) determination of the percentage of normal sperm in a sample of at least 200; and 2) qualitative evaluation of abnormal sperm, including such categories as abnormal head, abnormal tail, and abnormal head and tail.
See ATTACHMENT 4 for additional tissues to be weighed and retained from the ten rats per sex per group assigned to histological sample collection and evaluation.
All other tissues will be discarded.
Scheduled Sacrifice of Female Rats that Do Not Deliver Litters:
Rats that do not deliver a litter will be sacrificed on day 25 ofpresumed gestation. Gross necropsy, examination and tissue retention will be conducted as described previously for rats at scheduled sacrifice.
Dams with No Surviving Puds:
Dams with no surviving pups will be sacrificed after the last pup is found dead, missing or presumed cannibalized. Gross necropsy, examination and tissue retention will be conducted as described above for rats at scheduled sacrifice.
418-028-.PAGE D-18
Rats Found Dead or Moribnnd:
Protocol 418-028 Page 18
Rats that die or are sacrificed because of moribund condition, abortion or premature delivery will be examined for the cause of death or moribund condition on the day the observation is made. The rats will be examined for gross lesions. Testes and epididymides of male rats will be excised and paired organ weights will be recorded. The epididymides will be retained in neutral buffered 10% formalin. The testes will be fixed in Bouin's solution for 48 to 96 hours and then retained in neutral buffered 10% formalin. Pregnancy status and uterine contents of female rats will be recorded. Aborted fetuses and/or delivered pups will be examined to the extent possible. Uteri of apparently nonpregnant rats will be examined after being pressed between glass plates to confirm the absence of implantation sites. Ovaries and uteri will be retained in neutral buffered 10% formalin.
TESTS. ANALYSES AND MEASUREMENTS - FI GENERATION.
Viability:
Preweaning Period:
Litters will be observed for dead pups at least twice daily. The pups in each litter will be counted once daily.
Clinical Observations and/or General Appearance:
Preweaning Period:
Once daily.
Pups will be observed if they are warm and clean, for evidence of a nest and if pups are grouped together and nursing or have milk in stomach. Each pup will be examined for general shape of the head, trunk, limbs, tail andpresence of anus.
Clinical observations may be recorded more frequently than cited above, if deemed appropriate by the Study Director and/or the Study Monitor.
Body Weights:
Preweaning Period:
Days 1 (birth), 8,15 and 22 postpartum.
Sacrifice:
Terminal weight.
Feed Consumption Values (recorded and tabulated):
Preweaning Period:
Not recorded.
METHOD OF SACRIFICE - FI GENERATION PUPS:
FI generation pups will be sacrificed by carbon dioxide asphyxiation.
418-028:PAGE D-19
Protocol 418-028 Page 19
NECROPSY - FI GENERATION:
Gross lesions will be retained in neutral buffered 10% formalin for possible future evaluation. Unless specifically cited below, all other tissues will be discarded.
Pups Found Dead on Day 1 Postpartum:
Pups that die before examination of the litter for pup viability will be evaluated for vital status at birth. The lungs will be removed and immersed in water. Pups with lungs that sink will be identified as stillborn; pups with lungs that float will be identified as livebom, and to have died shortly after birth. Pups with gross lesions will be preserved in Bouin's solution for possible future evaluation.
Pups Found Dead or Moribund on Days 2 to 4 Postpartum:
Pups found dead or sacrificed because of moribundity will be examined for gross lesions and for the cause of death or the moribund condition. Pups with gross lesions will be preserved in Bouin's solution for possible future evaluation.
Scheduled Sacrifice:
On day 22 postpartum, pups will be will be sacrificed and examined for gross lesions; gross lesions will be preserved in neutral buffered 10%formalin. Necropsy will include a single cross section of the head at the level of the frontal-parietal suture and examination of the crosssectioned brain for apparent hydrocephaly.
Blood samples will be collected from each selected pup (S per sex per litter from the 10 females per group selected for FOB and motor activity assessment, blood sample collection for H&CC, and histological evaluations) from the vena cava. The blood will be placed into tubes, pooled per litter, allowed to clot and spun in a centrifuge; the resulting serum will be transferred into labeled polypropylene tubes. All samples will be immediately frozen on dry ice and maintained frozen (<-70C) until shipment for analysis. The liver from each selected pup will be collected excised and the organ weight recorded. The median lobe will be frozen and stored (<-20C) until shipment for possible analysis. Frozen samples will be shipped to Lisa Clemen at the previously cited address. The remaining portion of each liver will be retained in neutral buffered 10% formalin for possible histological evaluation. The livers will be processed and evaluated histologically as described for the Fo generation rats in Histological Evaluation in ATTACHMENT 4.
418-028-.PAGED-20
PROPOSED STATISTICAL TESTS(916): The following schematic represents statistical analyses of the data.
Protocol 418-028 Page 20
I. Parametric
A. Bartlett's T e s tc
Type of Test3 II. Nonparametric11
A. KruskaMAfaflis Test (5 78% *ea at any concent attun)
1 S ignificant a t p 0 .0 0 1
I I
N o n p aram etric
--------------------------- 1 N o t S ig n ifican t
I I
A n aly sis o f V a ria n c e
I----------------------------S ig n ifican t a t p < 0 .0 5
I I
D u n n 's T e s t
I N o t S ig n ifican t
I;
S ig n ifican t a t p < 0 .0 5
I
N ot S ignificant
B. F isheT a E x act T e st on
P ro p o rtio n o f T ie s (>79% M ast arty concartlratfon)
DunnetfsTest
B . A n a ly sis o f V a ria n c e w ith R e p e a te d M e a s u re s
r
S ig n ifican t a t p 0 .0 5
N ot S ignificant
I
(D o sag e) D u n n e tfs T e st
I
(D o s a g e x B lock In teractio n ) O n e-w ay A N O V A fo r e a c h block
r
S ig n ific a n t a t p < 0 .0 5
1
N o t S ig n ifican t
D u n n e tfs T est
III. Test for Proportion Data
Variance Test for Homogeneity of the Binomial Distribution
Statistically significant probabilities are reported as eitherp < 0.05 o xp < 0.01. Proportion data are not included in this category, c. Test for homogeneity of variance.
er p
418-028:PAGE D-21
Protocol 418-028 Page 21
Test items in the FOB using interval scales, such as the grip-strength tests and the landing foot splay test, as well as body weight data and feed consumption values will be analyzed as described under the Parametric heading of the schematic. Bartlett's Test of Homogeneity of Variances(9)will be used to estimate the probability that the groups had different variances. A nonsignificant result (p>0.001) will indicate that an assumption of homogeneity of variance is not inappropriate, and the data will be compared using the Analysis of Variance Test*10*. If that test is significant (p<0.05), the groups exposed to the test article/substance will be compared with the control group using Dunnett's Test(U). IfBartlett's Test is significant (p<0.001), the Analysis of Variance Test is not appropriate, and the data will be analyzed as described under the Nnnnarametric heading of the schematic. When 75% or fewer of the scores in all the groups are tied, the Kruskal-Wallis Test*12*will be used to analyze the data, and in the event of a significant result (p<0.05), Dunn's Test*13*will be used to compare the groups exposed to the test article/substance with the control group. When more than 75% of the scores in any group are tied, Fisher's Exact Test*14*will be used to compare the proportion of ties in the groups.
Data from the motor activity test, with repeated measurements within a session, will be analyzed using an Analysis of Variance with Repeated Measures*15*, as described under that heading in the schematic. A significant effect (p<0.05) in that test can appear as effect of Concentration (a difference between groups in the total across all measurements in a session) or as an interaction between Concentration and Block (a difference between groups at specific measurement periods). If the Concentration effect is significant, the totals for the control group and the groups given the test article/substance will be compared using Dunnett's Test. If the Concentration x Block interaction is significant, an Analysis of Variance Test will be used to evaluate the data at each measurement period, and a significant result (p<0.05) will be followed by a comparison of the groups using Dunnett's Test.
Test items in the FOB having graded or count scores will be analyzed using the procedures described under the Nonparametric heading of the schematic.
Clinical observation incidence data, as well as the descriptive and quantal data from the FOB, will be analyzed as contingency tables using the Variance Test for Homogeneity of the Binomial Distribution*16*.
Alternate or additional statistical evaluations may be performed if deemed necessary or appropriate.
418-028 :PAGE D-22
Protocol 418-028 Page 22
DATA ACQUISITION. VERIFICATION AND STORAGE:
Data generated during the course of this study will be recorded either by hand or using the Argus Autom ated D ata Collection and M anagement System, the Vivarium Temperature and Relative Humidity M onitoring System, the Coulboum Instruments Passive Infrared M otor Activity System, the C oulboum Instruments Auditory Startle System, the Coulboum Instruments Spatial Delayed Alternation System, and/or the passive avoidance software. All data will be tabulated, summarized and/or statistically analyzed using the Argus Autom ated Data Collection and M anagement System, the Vivarium Temperature and Relative Hum idity M onitoring System, M icrosoft Excel [part ofMicrosoft Office 97 (version SR-2)] and/or The SA S System (version 6.12).
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.
KEY PERSONNEL:
Executive Director o f 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 o f Operations and Compliance: Barbara J. Patterson, B.A. Director of Laboratory Operations: John F. Barnett, B.S. Director of Study Management: Valerie A. Sharper, M.S. Manager o f Animal Operations: Dena C. Lebo, V.M.D. Chairperson, Institutional Animal Care and Use Committee: Douglas B. Learn, Ph.D. Consultant, Veterinary Pathology: W. Ray Brown, D.V.M., Ph.D., ACVP
418-028 :PAGE D-23
RECORDS TO BE MAINTAINED:
Protocol 418-028 Page 23
Protocol and Amendments. Test Substance, Vehicle and/or Reagent Receipt, Preparation and Use. Animal Acquisition. Randomization Schedules. Mating History. Treatment (if prescribed by StaffVeterinarian). General Comments. Clinical Observations and/or General Appearance. Body Weights. Feed Consumption Values. Natural Delivery Observations. FOB and Motor Activity Observations. Blood Sample Collection, Processing and Shipment. Gross Necropsy Observations. Organ Weights. Photographs (if required). Study Maintenance (room and environmental records). Feed and Water Analyses. Packing and/or Shipment Lists.
FINAL REPORT:
The Study Directorwill provide periodic updates of study progress to the Sponsor. Draft summary tables of unaudited computer-recorded data may accompany these updates. Statistical analyses will not be performed on these interim data.
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
The Sponsor will receive one copy of the draft report and two copies of the final report. 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 datawill 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.
418-028 :PAGE D-24
Protocol 418-028 Page 24
INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE STATEMENT:
The procedures described in this protocol have been reviewed by the Testing Facility's Institutional Animal Care and Use Committee. All procedures described in this protocol that involve study animals will be conducted in a manner to avoid or minimize discomfort, distress or pain to the animals.
The Sponsor's signature below documents the fact that information concerning the necessity for conducting this study and the fact that this is not an unnecessarily duplicative study may be obtained from the Sponsor. No alternative (in vitro) procedures were available for meeting the stated purposes of the study.
REFERENCES:
1. Christian, M.S. and Voytek, P.E. (1982). In Vivo R eproductive and M utagenicity Tests. Environmental Protection Agency, Washington, D.C. National Technical Information Service, U.S. Department of Commerce, Springfield, VA 22161.
2. Christian, M.S. (1984). Reproductive toxicity and teratology evaluations of naltrexone (Proceedings of Naltrexone Symposium, New York Academy of Sciences, November 7, 1983), J. Clin. Psychiat. 45(9):7-10.
3. Lang, P.L. (1988). Em bryo and F etal D evelopm ental Toxicity (Terotology) C ontrol D ata in the C harles R iver Crl:CDBR R at. Charles River Laboratories, Inc., Wilmington, MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.)
4. Institute of Laboratory Animal Resources (1996). Guidefo r the Care and Use o f Laboratory A nim als. National Academy Press, Washington, D.C.
5. Haggerty, G.C. (1989). Development of Tier I neurobehavioral testing capabilities for incorporation into pivotal rodent safety assessment studies. J. Amer. Col. Toxicol. 8:53 70.
6. Irwin, S. (1968). Comprehensive observational assessment: la. A systemic quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia (Berlin) 13:222-257.
7. Moser, V.C. (1989). Screening approaches to neurotoxicity: A functional observational battery. J. Amer. Col. Toxicol. 8:85-94.
8. GDonoghue, J.L. (1989). Screening for neurotoxicity using a neurologically based examination and neuropathology. J. Amer. Col. Toxicol. 8:97-116.
9. SokaL R.R. and Rohlf, F.J. (1969). Bartlett's test ofhomogeneity of variances. Biom etry, W.H. Freeman and Co., San Francisco, pp. 370-371.
418-028 :PAGE D-25
Protocol 418-028 Page 25
10. Snedecor, G.W. and Cochran, W.G. (1967). Analysis of Variance. Statistical M ethods, 6ih 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. 50:1096-1121.
12. Sokal, R.R. and Rohlf, F.J. (1969). Kruskal-Wallis Test. Biom etry, W.H. Freeman and Co., San Francisco, pp. 388-389.
13. Dunn, O.J. (1964). Multiple comparisons using rank sums. Technometrics 6(3):241-252.
14. Siegel, S. (1956). Nonparam etric Statisticsfo r the B ehavioral Sciences, McGraw-Hill, New York, pp. 96-104.
15. SAS Institute, Inc. (1988). Repeated measures analysis of variance. SAS/STATTM User's Guide, Release 6.03 Edition, Cary, NC, pp. 602-609.
16. Snedecor, G.W. and Cochran, W.G. (1967). Variance test for homogeneity of the binomial distribution. Statistical M ethods, 6th Edition, Iowa State University Press, Ames, pp. 240-241.
PROTOCOL APPROVAL:
FOR THE TESTING FACILITY
Qh- U
-----
Alan M. Hoberman, Ph.D., DABT Director of Research
Bufe. r^.
L fi Thetsa H. Woodard, D.1 V Member, Institutional Animal Care and
Use Committee
FOR THE SPONSOR
JohnButenhoff, Ph.D., DABT, CIH StudyMonitor and Sponsor's Representative
418-028 :PAGE D-26
Protocol 418-028 Page 26
Date
Z-(p tf/HL 2-00 ZDate
JL M t* Date
a
Date
418-028:PAGE D-27
ATTACHMENT 1 SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE
418-028-.PAGED-28
ATTACHMENT 1
STUDY SCHEMATIC
Protocol 418-028 Page 1 o f3
COMBINED REPEAT DOSE AND REPRODUCTIVE/DEVELOPMENTAL TOXICITY SCREEN*
First Day of Test Substance Dosage
Male Rats
Last Day of Test Substance Dosage*
Last Day of Test Substance Dosage*
Female Rats
Motor Activity/FOBb
2 Weeks
2 Weeks
Natural Delivery
Presumed Gestation
Postpartum Period
3 Weeks
Day 21 Day 22*
Motor Activity/FOBd
Dosage Period
a. For additional details see "Tests, Analyses and Measurements" section of the protocol. b. FOB and motor activity evaluations conducted on ten males per group. c. Male rats sacrificed after completion of at least 42 days of dosage; necropsy and retention
of male reproductive organs. Hematology, clinical biochemistry and histological samples collected from ten male rats per group. d. Ten female rats per group assigned to FOB evaluation and motor activity evaluatioa e. Ten female rats per group and their litters sacrificed on day 22 postpartum; necropsy and retention of female reproductive organs Hematology, clinical biochemistry and histological samples collected. Remaining female rats sacrificed on day 22 postpartum and discarded.
418-028:PAGE D-29
ATTACHMENT 1
Protocol 418-028
Page 2 of3
SCHEDULE*
26 MAR 02 01 APR 02
01 APR 0 2 - 12 JUN 02
14 APR 02 PM - 21 APR 02 AM 21 APR 02 PM - 28 APR 02 AM
14 APR 02 15 APR 02 28 APR 02 06 MAY 02
19 MAY 02
06 MAY 02 - 07 MAY 02
Animal Receipt - Acclimation Begins.
Start o f Dosage Period - Male Rats (14 days before cohabitation and through a 14-day cohabitation period until the day before sacrifice after at least 42 days o f dosage).
Dosage Period - Female Rats (14 days before cohabitation through Day 22 of lactation).
Cohabitation Period (Maximum of 14 days). Male 1 (7 days) Male 2 (7 days)
Day 14 Toxicokinetic Sample Collection
First Possible Day 0 of Presumed Gestation. Last Possible Day 0 ofPresumed Gestation.
First Possible Day 21 ofPresumed Gestation Toxicokinetic Sample Collection and Sacrifice Toxicokinetic Study Female Rats Last Possible Day 21 ofPresumed Gestation Toxicokinetic Sample Collection and Sacrifice Toxicokinetic Study Female Rats
FOB and Motor Activity Evaluation -10 Male Rats per Group
a. The start date o f the study is the day the Study Director signs the protocol. b. Throughout this schedule, the day ofbirth is designated day 1postpartum (day 1 of
lactation) and all subsequent ages ofthe FI generation rats and days of the lactation period will be determined and cited accordingly, as described above the protocol section, "Day Numbering System."
418-028'.PAGE D-30
ATTACHMENT 1
06 MAY 02 23 MAY 02 10 MAY 02 23 MAY 02 12 MAY 02
13 MAY 02
23 MAY 02 - 09 JUN 02 27 MAY 02 - 13 JUN 02
24 SEP 02
Protocol 418-028 Page 3 o f 3
First Possible Delivery (Day 21 of presumed gestation). Last Possible Delivery (Day 25 of presumed gestation).
First Possible Day 25 of Presumed Gestation Female Sacrifice. Last Possible Day 25 of Presumed Gestation Female Sacrifice.
Day 42 Toxicokinetic Sample Collection and Scheduled Sacrifice Toxicokinetic Study Male Rats
Scheduled Sacrifice - Main Study Male Rats (Earliest possible date). Hematology, Clinical Biochemistry and Histological Sample Collection of Selected Male Rats.
FOB and Motor Activity Evaluation -1 0 Female Rats per Group.
Day 22 Postpartum - Sacrifice Female Rats and Pups. Hematology, Clinical Chemistry and Histological Sample Collection of Selected Female Rats and Pups.
Draft Final Report
418-028:PAGED-31
ATTACHMENT 2 MATERIAL SAFETY DATA SHEET
418-028:PAGE D-32
MATERIAL SAFETY DATA SHEET (Experimental)
3M 3M Center St. Paul, Minnesota 55144-1000
1-800-364-3577 or (651) 737-6501 (24 hours)
Copyright, 1999, Minnesota Mining and Manufacturing Company. All rights reserved. Copying and/or downloading of this information for the purpose of properly utilizing 3M products is allowed provided that: 1) the information is copied in full with no changes unless
prior agreement is obtained from 3M, and 2) neither the copy nor the original is resold or otherwise
distributed with the intention of earning a profit thereon.
DIVISION: 3M SPECIALTY MATERIALS
MATERIAL: L-9051 DEVELOPMENTAL PRODUCT
ISSUED: December 07, 1999 SUPERSEDES: May 17, 1999 DOCUMENT: 04-5470-2
1. INGREDIENT
C.A.S. NO.
PERCENT
POTASSIUM PERFLUOROHEXANE SULFONATE.... RESIDUAL ORGANIC FLUOROCHEMICALS.......
3871-99-6 Mixture
100.0 Unknown
This material is not listed on the TSCA inventory and should be used
for research and development purposes only under the direct
supervision of a technically qualified individual.
2. PHYSICAL DATA
BOILING POINT:..... VAPOR PRESSURE:.... VAPOR DENSITY:..... EVAPORATION RATE:... SOLUBILITY IN MATER: SPECIFIC GRAVITY:...
PERCENT VOLATILE:... P H : ................. VISCOSITY:......... MELTING POINT:.....
N/A Negligible N/A Negligible slight ca. 1.0 Water*1
(Bulk) Negligible N/A N/D N/D
APPEARANCE AND ODOR: Off-white crystalline solid, sharp odor.
Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately
418-028 :PAGE D-33
H5DS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999
PAGE 2
3. FIRE AND EXPLOSION HAZARD DATA
flash p u i n i :................. 212 t setaflash Setaflash Closed Cup
FLAMMABLE LIMITS - LEL:.......N/A FLAMMABLE LIMITS UEL:.......N/A AUTOIGNITION TEMPERATURE:..... N/D
EXTINGUISHING MEDIA: Mater, Carbon dioxide, Dry chemical, Foam
SPECIAL FIRE FIGHTING PROCEDURES:
Wear full protective clothing, including helmet, self-contained,
positive pressure or pressure demand breathing apparatus, bunker coat
and pants, bands around arms, waist and legs, face mask, and
protective covering for exposed areas of the head.
-
UNUSUAL FIRE AND EXPLOSION HAZARDS: See Hazardous Decomposition section for products of combustion.
4. REACTIVITY DATA
STABILITY: Stable
INCOMPATIBILITY - MATERIALS/CONDITIONS TO AVOID: None known.
HAZARDOUS POLYMERIZATION: Hazardous polymerization will not occur.
HAZARDOUS DECOMPOSITION PRODUCTS: Hay produce fluorocarbon gases if exposed to very high temperatures (over 300 C ) .
5. ENVIRONMENTAL INFORMATION
SPILL RESPONSE: Observe precautions from other sections. Collect spilled material. Use wet sweeping compound or water to avoid dusting. Clean up residue. Place in a closed container.
RECOMMENDED DISPOSAL: 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 accept chemical waste.
Abbreviations: N/D - Not Determined N/A - Not Applicable CA Approximately
418-028:PAGE D-34
MSDS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999
PAGE 3
5. ENVIRONMENTAL INFORMATION
(continued)
ENVIRONMENTAL DATA: Not determined.
REGULATORY INFORMATION: Volatile Organic Compounds: N/D. VOC Less H20 & Exempt Solvents: N/D.
Since regulations vary, consult applicable regulations or authorities before disposal. U.S. EPA Hazardous Haste Number = None (Not U.S. EPA Hazardous).
OTHER ENVIRONMENTAL INFORMATION: This product may contain one or more organic fluorochemicals that have the potential to resist degradation and persist in the environment.
EPCRA HAZARD CLASS: FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: No
6. SUGGESTED FIRST AID
EYE CONTACT: Immediately flush eyes with large amounts of water. Get immediate medical attention.
SKIN CONTACT: Flush skin with large amounts of water. If irritation persists, get medical attention.
INHALATION: If signs/symptoms occur, remove person to fresh air. If signs/symptoms continue, call a physician.
IF SWALLOWED: If swallowed, call a physician immediately. Only induce vomiting at the instruction of a physician. Never give anything by mouth to an unconscious person.
7. PRECAUTIONARY INFORMATION
EYE PROTECTION:
Avoid eye contact. Avoid eye contact with vapor, spray, or mist. The following should be worn alone or in combination, as appropriate, to prevent eye contact: Wear vented goggles.
Abbreviations: N/D Not Determined N/A - Not Applicable CA - Approximately
418-028-.PAGED-35
MSOS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999
PAGE 4
7. PRECAUTIONARY INFORMATION
(continued)
SKIN PROTECTION;
Avoid skin contact. Near appropriate gloves when handling this material. A pair of gloves made from the following material(s) are recommended: butyl rubber, polyethylene/polyvinylidene chloride (Saranex). 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. Provide appropriate local exhaust ventilation at transfer points. Use in a well-
ventilated area. Provide sufficient ventilation to maintain emissions below recommended exposure limits. If exhaust ventilation is not adequate, use appropriate respiratory protection. Provide ventilation adequate to control vapor concentrations below recommended exposure limits and/or control spray or mist.
Local exhaust ventilation is recommended where the Res airborne.
material beco
RESPIRATORY PROTECTION:
Avoid breathing of airborne material. Select one of the following NIOSH approved respirators based on airborne concentration of contaminants and in accordance with OSHA regulations: half-mask supplied air respirator, full-face supplied air respirator.
PREVENTION OF ACCIDENTAL INGESTION: Do not eat, drink or smoke when using this product. Wash exposed areas thoroughly with soap and water. Wash hands after handling and before eating.
RECOMMENDED STORAGE:
Store at room temperature. Keep container dry. Keep container closed when not in use.
FIRE AND EXPLOSION AVOIDANCE: Not determined.
EXPOSURE LIMITS
INGREDIENT
VALUE UNIT
TYPE AUTH SKIN*
POTASSIUM PERFLUOROHEXANE
SULFONATE.......................... . RESIDUAL ORGANIC FLUOROCHEMICALS.... .
0.1 0.1
MG/M3 MG/M3
TWA 3M TWA 3M
Y Y
* SKIN NOTATION: Listed substances indicated with *Y' under SKIN refer to
Abbreviations: N/D Not Determined N/A - Not Applicable CA Approximately
418-028'.PAGE D-36
MSDS: L-9051 DEVELOPMENTAL PRODUCT December 07, 1999
PAGE 5
EXPOSURE LIMITS
(continued)
INGREDIENT
VALUE UNIT
TYPE AUTH SKIN*
the potential contribution to the overall exposure by the cutaneous route including mucous membrane and eye, either by airborne or, more particularly, by direct contact with the substance. Vehicles can alter skin absorption.
SOURCE OF EXPOSURE LIMIT DATA: - 3M: 3M Recommended Exposure Guidelines
.
8. HEALTH HAZARD DATA
EYE CONTACT: No information was found regarding effects from eye contact.
Single exposure may cause:
Mild Eye Irritation: signs/symptoms can include redness, swelling, pain, and tearing.
SKIN CONTACT: No information was found regarding effects from skin contact.
May be absorbed through the skin and persist in the body for an extended time.
Single exposure may cause:
Moderate Skin Irritation: signs/symptoms can include redness, swelling, itching, and dryness.
INHALATION: No information was found regarding effects from inhalation exposure.
May be absorbed by inhalation and persist in the body for an extended time.
Single overexposure, above recommended guidelines, say 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.
No information was found regarding effects from swallowing.
Animal studies conducted on organic fluorochemicals which may be present in this product indicate effects including liver disturbances, weight loss, loss of appetite, lethargy, and neurological, pancreatic, adrenal and hematologic effects. There are no known human health
Abbreviations: N/D - Not Determined N/A Not Applicable CA - Approximately
418-028'.PAGE D-37
MSDS: L-9051 DEVELOPMENTAL PRODUCT DecsnDer 07, 1999
PAGE 6
8. HEALTH HAZARD DATA
(continued)
effects fro anticipated exposure to tnese organic fiuorochemicals when used as intended and instructed.
OTHER HEALTH HAZARD INFORMATION: This product may contain one or ore organic fiuorochemicals that have the potential to be absorbed and reaain in the body for long periods of time, either as the parent Molecule or as metabolites, and may accumulate with repeated exposures. There are no known human health effects fro anticipated exposure to these organic fiuorochemicals when used as intended and instructed.
The presence of organic fiuorochemicals in the blood of the general population and subpopulations, such as workers, has been published dating back to the 1970's. 3M's epidemiological study of its own workers indicates no adverse effects.
SECTION CHANGE DATES
PRECAUTIONARY INFO. SECTION CHANGED SINCE May 17, 1999
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. SM MAKES NO WARRANTIES, EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR COURSE OF PERFORMANCE OR USAGE OF TRADE. User is responsible for determining whether the 3M product is fit for a particular purpose and suitable for user's method of use or application. Given the variety of factors that can affect the use and application of a 3M product, some of which are uniquely within the user's knowledge and control, it is essential that the user evaluate the 3M product to determine whether it is fit for a particular purpose and suitable for user's method of use or application.
3M provides information in electronic form as a service to its customers. Due to the remote possibility that electronic transfer may have resulted in errors, omissions or alterations in this information, 3M makes no representations as to its completeness or accuracy. In addition, information obtained from a database may not be as current as the information in the MSDS available directly from 3M.
418-028:PAGE D-38
ATTACHMENT 3 TEST SUBSTANCE PREPARATION PROCEDURE
418-028-.PAGE D-39
ATTACHMENTS
Protocol 418-028 Version: 418-028M 9M A R 021
Page 1 of 2
T E S T SUBSTANCE PREPARATION PRO CEDURE
Test Substance: T-7706
Vehicle:
Aqueous 0.5% CMC (medium viscosity)
A. Purpose:
The purpose of this procedure is to provide a method fo r the preparation of dosage suspensions of T-7706 for oral (gavage) administration to rats on Argus Research Study number 418-028.
B. General Information:
1. All suspension containers will be labeled and color-coded. Each label will specify the protocol number, test substance identification, Argus batch number, concentration, dosage level, preparation date, expiration date and storage conditions.
2. Suspensions will be prepared:
__ Daily
X_ W eekly
_For_ days of use
_ Approximately every ten days
By Sponsor
3. Suspensions will be administered at a final dosage volume of J O . mL/kg.
4. Safety: X Gloves, uniform/lab coat, goggles or safety glasses with side shields X Dust-mist/HEPA-filtered Mask ___ Half-Face Respirator if not used in a chemical fum e hood ___ Full-Face Respirator/Positive Pressure Hood ___ Tyvek Suit or tyvek apron and sleeves
5. Dosage suspensions adjusted for % Activity/Purity or Correction Factor.
__ Yes
_X_ No (Calculations based on 100% )
__ % Activity
__ % Purity __ Correction Factor
6. Sampling requirements: Cited in protocol
7. Storage: Cited in protocol
418-028 :PAGE D-40
ATTACHMENT 3
Protocol 418-028 Version: 418-028/19 MAR 091
Page 2 of 2 T E S T SUBSTANCE PREPARATIO N PRO CEDURE
NOTE:
Prior to test substance preparation accurately measure the required am ount of the appropriate vehicle (R .O . deionized w ater should be used for calibration purposes) in a graduated cylinder, pour the required am ount o f vehicle into a beaker. Carefully mark each beaker at ihe meniscus. This mark will be used during the preparation to bring the test substance slurry up to volume.
C. Dosage Suspension Preparation:
1. W eigh the required amount of test substance on a piece of weigh paper or into an appropriately sized mortar (see PREPARATION CALCULATIO NS).
2. If weigh paper is used, transfer the test substance to an appropriately sized mortar. If necessary, grind the test substance into a fine powder. Slowly add a small amount of vehicle and grind. Continue to add vehicle slowly and grind the vehicle and the test substance together to form a fine slurry. Transfer the vehicle/test substance slurry to a marked beaker.
3. Rinse the m ortar and pestle with additional vehicle to remove any remaining test substance. Transfer rinse to beaker.
4. Add additional vehicle to the beaker to bring volume up to the mark. Place on m agnetic stir plate and agitate prior to and during sampling, aliquotting and/or administration.
5. R epeat steps (1 ) through (4) for each concentration.
Written By;
jj.fy g *
Approved by
Date:
Clarification: v\s/ Nn o
Yes [see attached clarification form]
Initial/Date : C .fL . 7 3 ^ 0 3
418-028:PAGE D-41
ATTACHMENT 4 TISSUES TO BE WEIGHED, RETAINED AND EXAMINED HISTOLOGICALLY
418-028:PAGE D-42
ATTACHMENT 4
Protocol 418-028 Page 1 o f2
TISSUES TO WEIGHED AND RETAINED FOR POSSIBLE EXAMINATION FROM TEN RATS PER SEX PER GROUP
The ten rats per sex per group assigned to functional observational battery and motor activity tests will be assigned to hematology, clinical biochemistry and histological evaluations.
Tissues to be Weighed:
The following organs will be excised, trimmed and individually weighed as soon as possible after excision to avoid drying.
liver spleen
kidneys
brain
adrenals
heart
thymus
ovaries
testes
uterus (with cervix)
right epididymis
prostate
left epididymis (whole and cauda)
seminal vesicles (with and without fluid)
Tissues to be Retained:
The following tissues or representative samples will be retained in neutral buffered 10% formalin.
brain (representative regions including cerebrum, cerebellum, pons)
small and large intestines (including Peyer*s patches)
lungs (perfused with neutral buffered 10%formalin)
lymph nodes (submandiblar and mediastinal)
peripheral nerve (sciatic or tibial)
gross lesions
spinal cord (cervical, thoracic and lumbar)
stomach
liver
kidneys
adrenals
spleen
heart
thymus
thyroid/parathyroid
trachea
uterus
urinarybladder
bone marrow (sternum)
testes*
ovaries
prostate
uterus
seminal vesicles (with coagulating gland) vagina
mammary gland (female rats only)
Testes will be fixed in Bouin's solution for 48 to 96 hours before being retained in neutral buffered 10%formalin.
Additionally, the remainingportion of the left epididymis (corpus and caput), as well as the right epididymis will be fixed in neutral buffered 10%formalin.
418-028 :PAGE D-43
ATTACHMENT 4
Protocol 418-028 Page 2 o f 2
Histological Examination:
Histological examination of retained tissues, including reproductive organs, will be conducted for the assigned ten rats per sex from the control and high dosage groups and from the FI generation pups (livers) from the control and high dosage groups. If lesions attributed to the test substance are observed in the rats exposed to the high test substance concentration, the same tissues will be examined from the assigned ten rats per sex exposed to the lower test substance concentrations. Should results warrant examination of the lower dosage groups and conduct of quantitative evaluation, scheduled report date and prices will be adjusted accordingly.
Thepostlactional ovary should contain primordial and growing follicles as well as the large coipora lutea of lactation. Histopathological examination may detect qualitative depletion of the primordial follicle population. A quantitative evaluation of primordial follicles will be conducted for Fo generation female rats; the number of rats, ovarian section selection and section sample size will be statistically appropriate for the evaluation procedure used. Examination will include enumeration of the number of primordial follicles, which can be combined with small growing follicles, for comparison of ovaries of rats assigned to treated and control groups.
Shipping Instructions:
Tissues to be examined histologically will be shipped (ambient conditions) to:
Principal Investigator: W. Ray Brown, D.V.M., Ph.D., ACVP
Veterinary Pathologist
Research Pathology Services, Inc.
438 E. Butler Avenue
New Britain, Pennsylvania 18901
Telephone: (215)345-7070
Telefax: (215) 345-4326
Email:
WRBRPS@concentric.net
The recipient will be notified in advance of sample shipment.
418-028-.PAGE D-44
905 Sheehy D trn, BUg. A Horsham, PA 19044
Telephone: (2f5)443-87<0
Tckfiuc (215) 443-8587
ARGUS RESEARCH
C h a rle s R iver Laboratories Discovery and Development Services
PROTOCOL 418-028
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
SPONSOR'S STUDY NUMBER: T-7706.1
Amendment 1-17 April 2002
1. Detailed Clinical Observations - Male and Female Rats (page 10 of the protocol):
[Effective Date: 1 April 2002] Detailed clinical observations will not be recorded for male and female rats assigned to toxicokinetic sampling.
Reason for Change:
This change was made because sufficient data for evaluation o f detailed clinical observations will be available from the rats assigned to the main study.
2. Feed Consumption Values - Male Rats and Female Rats (page 11 of the protocol):
[Effective Date: 1 April 2002] Feed consumption values will not be recorded or tabulated for male and female rats assigned to toxicokinetic sampling.
Reason for Change:
This change was made because sufficient data for evaluation o f feed consumption will be available from the rats assigned to the main study.
Any revisions made to this finalized amendment must be made by subsequent amendment
418-028:PAGED-45
3. Estrous Cycling and Mating (page 12 of the protocol):
Protocol 418-028 Amendment 1 Page 2
[Effective Date: 1 April 2002] For the rats assigned to toxicokinetic sampling, estrous cycling will be evaluated during the cohabitation period until spermatozoa are observed in a smear ofthe vaginal contents and/or a copulatory plug is observed in situ, but not during the dosage period, prior to cohabitation.
Reason for Change:
This change was made because sufficient data for evaluation of estrous cycling will be available from the rats assigned to the main study.
4. Scheduled Sacrifice - Toxicokinatic Study (page 16 o f the protocol):
[Effective Date: 5 April 2002] The number of implantation sites and corpora lutea will be recorded. Carcasses will be discarded without further evaluation.
Reason of Change:
This change was made in order to provide more information about possible toxicity o f the test substance in pregnant rats.
5. Scheduled Sacrifice - Main Study (page 16 o f the protocol):
[Effective Date: 27 March 2002] The number of implantation sites will be recorded, rather than the number of implantation sites and corpora lutea will be recorded.
Reason of Change:
The number of corporalutea will not be recorded because corpora lutea regress at a rapid rate and are not counted on studies at weaning.
6. Scheduled Sacrifice (page 19 ofthe protocol):
[Effective Date: 4 April 2002] The liver from each selected pup will be excised and the organ weight recorded, rather than the liver from each selected pup will be collected excised and the organ weight recorded.
Any revisions made to this finalized amendment mast be made by subsequent amendment
418-028:PAGE D-46
Reason for Change:
Protocol 418-028 Amendment 1 Page 3
This change clarifies the protocol by removing an extraneous word.
'-/-/I -O
Alan M. Hoberman, Ph.D., DABT Director o f Research
Date Raym Associate Director Study Director
Theresa H. Woodard, D.V.M. Member, Institutional Animal Care and Use Committee
y-Zg-tPZ.
Date John Butenhoff; Ph.D., DABT, CIH Date Study Monitor and Sponsor's Representative
Any revisions made to this finalized amendment mast be made by subsequent amendment
418-028-.PAGE D-47
90S Sheehy Drive, Bldg. A Horzham, PA 19044
Telephone: (215) 443-87/0
Telefax: (215) 4 4 3 -8 5 8 7
ARGUS RESEARCH
C h a rle s R iver Laboratories Discovery and Development Services
PROTOCOL 418-028
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
SPONSOR'S STUDY NUMBER: T-7706.1
Amendment 2 - 1 5 July 2002
1. Safety Precautions (page 3 o f the protocol and Attachment 3 page 1 of the protocol):
[Effective Date: 29 April 2002] A half face respirator will be worn in addition to gloves, appropriate eye protection and a uniform/lab coat during formulation preparation o f the bulk test substance.
Reason for Change:
This change was made to match the bulk test substance text with the text located within the Material Safety Data Sheet.
2. Study Schedule (Attachment 1 page 2 of the protocol):
[Effective Date: 29 April 2002] The dates for FOB and motor activity evaluations have been extended to four days (06 MAY 02 - 09 MAY 02) rather than two days (06 MAY 02 - 07 MAY 02).
Any revisions to this finalized amendment must be made by subsequent amendment
418-028:PAGE D-48
Protocol 418-028 Amendment 2 Page 2
Reason for Change:
This change was made because more time is needed to evaluate animals assigned to FOB and motor activity evaluations.
flan Moberman, Ph.D., DABT Director o f Research
24
Raymond G. Yorl P h .d , DABT Associate Director' Research Study Director
Date
1 _____ It jcvly 26C..I
t1-T here H. Woodard, DiY.M. Member, Institutional Animal Care and Use Committee
Date John Butenhoff, Ph.D., DABT, CIH Date Study Monitor and
Sponsor's Representative
Any revisions to this finalized amendment must be made by subsequent amendment
418-028:PAGE D-49
90S Sheehy Drive. Bldg. A
Horshom, PA 19044
Telephone: (215) 443-6710
Telefax: (215) 443-8587
ARGUS RESEARCH
Ch arles R iver Lab o rato ries Discovery and Development Services
PROTOCOL 418-028
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
SPONSOR'S STUDY NUMBER: T-7706.1
Amendment 3 - 1 7 July 2002
1. Bulk Test Substance Sampling. Shinning Instructions. Shipping Instructions. Caesarean-Sectioning - Toxicokinetic Study. Scheduled Sacrifice - Toxicokinetic Study, and Scheduled Sacrifice, (pages 4 , 5 , 1 2 , 1 3 , 1 6 and 19, respectively o f the protocol)
[Effective Date: 29 M ay 2002] Samples for perfluorohexanesulfonate (PFHS) analysis shipped to Lisa Clemen at 3M Environmental Technology and Safety Services will be reshipped and remaining samples, that were to be shipped to Lisa Clemen and have not yet been shipped, will be shipped to:
John Flaherty, Ph.D. (Principal Investigator)
Exygen Research
3058 Research Drive
State College, Pennsylvania 16801
Telephone: (814)272-1039, ext. 122
Telefax:
(814)231-1580
Email: john.flaherty@exygen.com
Any revisions to this finalized amendment must be made by subsequent amendment
418-028:PAGE D-50
Protocol 418-028 Amendment 3 Page 2
These samples include: Bulk test substance sampling (page 4 o f the protocol) Concentration and homogeneity (page 5 o f the protocol) Stability (page 5 o f the protocol) Plasma toxicokinetic samples (page 11 to 12 and page 16 o f the protocol) Plasma samples, rather than serum samples, were retained. Liver toxicokinetic samples (pages 12 and 16 o f the protocol) Pooled fetal serum toxicokinetic samples (pages 12 and 16 o f the protocol) Pooled fetal liver toxicokinetic samples (pages 13 and 16 o f the protocol) Pooled pup serum toxicokinetic samples (page 19 o f the protocol) Pup liver toxicokinetic samples (page 19 o f the protocol)
The analyses w ill be subcontracted to Exygen by the Sponsor and the Quality Assurance Unit for Exygen Research will conduct critical phase inspections and audit the respective results and reports according to the Standard Operating procedures o f that facility. Such critical phase inspection reports and audit reports will be submitted by that facility to the Study Director, Raymond G. York. The date o f the inspections and report submissions w ill be incorporated into a QAU statement generated by Exygen Research for inclusion in the final report for Protocol 418-028.
Reason for Change:
This change was made at the request o f the Sponsor because 3M is not able to complete die formulation analysis with their current staffing.
Director o f Research
Study Director
ficJfL a d -fliJU 1, ___
Theresa H. Woodard, D.V.M. Member, Institutional Animal Care and Use Committee
(p eri!**.
W
Date John Butenhoff, Ph.D., DABT, CIH Date Study Monitor and Sponsor's Representative
Any revisions tothis finalized amendment must be made by subsequent amendment
418-028.-PAGE D-51
905 Sheehf Drive. Bldg. A Horsham, BA 19044 Telephone: (215) 443-8710 Tekfiae (215) 4434587
ARGUS RESEARCH Chartes River Laboratories
Discovery and Development Services
PROTOCOL 418-028
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
SPONSOR'S STUDY NUMBER: T-7706.1
Amendment 4 - 2 0 March 2003
1. Bulk Test Substance Sampling. Shipping Instructions. Shipping Instructions. Caesarean-Sectioning - Toxicokinetic Study. Scheduled Sacrifice - Toxicokinetic Study, and Scheduled Sacrifice, (pages 4 ,5 ,1 2 ,1 3 ,1 6 and 19, respectively of the protocol) and Amendment 3. Item 1: Bulk Test Substance Sampling. Shipping Instructions. Shipping Instructions. Caesarean-Sectioning - Toxicokinetic StudyScheduled Sacrifice - Toxicokinetic Study, and Scheduled Sacrifice (page 1 o f Amendment 3)
[Effective Date: 27 February 2003] The analyses performed by Exygen Research will be done according to Exygen Method ExM-023-071 Revision 1, entitled "Method of Analysis for the Determination of Perfluorohexanesulfonate (PFHS), Perfluorooctanesulfonate (PFOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat Liver, Serum and Urine Revision 1".
Any revisions to this finalized amendment must be made by subsequent am endm ent
418-028:PAGE D-52
Protocol 418-028 Amendment 4 Page 2
Reason for Change:
This change was made at the request of the Exygen Research in order to clarify the method of analysis.
/Ct 7
-tA-'T&'i J
Alan M. oberman, Ph.D., DABT Director i Research
Date
iond G. Yc Pfy.D., DABT Associate DirectX Research Study Director
Date
D&glaf^. Learn, Ph.D. Chair, Institutional Animal Care and Use Committee
John Butenhoff, Ph.D., DABT, CIH Date Study Monitor and Sponsor's Representative
Any revisions to this finalized amendment must be made by subsequent amendment
APPENDIX E
DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY
418-028: PAGE E-1
DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY
1. The following rats were not fasted overnight prior to necropsy.
Dosage Group
I
Dosage (mg/kg/day)
0
n 0.3
m1 rv 3 V 10
Date of Necropsy 28 MAY 02 29 MAY 02
28 MAY 02
29 MAY 02 28 MAY 02 29 MAY 02 28 MAY 02 29 MAY 02
28 MAY 02
Sex Female Female
Female
Female Female Female Female Female
Female
Rat Numbers 19044
19012, 19021. 19068 19009, 19016, 19036, 19043, 19047, 19052, 19055, 19061, 19071
19018, 19037 19017
19013, 19029, 19060 19045, 19058, 19073 19039,19063, 19069 19001, 19028,19031,19033, 19049,19059, 19070
This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter and there were no indications of toxicity in clinical chemistry parameters for the female rats.
2. Postdosage observations were performed out o f the range of 60 10 minutes on the following dates.
Dosage Dosage Group (mg/kg/day)
I0
IV 3
Date 09 APR 02 03 JUN02 03 JUN 02
Number of Rats Male Rats Female Rats
4-1 -1
Range of Time Deviated (minutes) +1 to +2 +8 +7
These deviations did not adversely affect the outcome or interpretation of the study because the extent of the deviation was less than 10 minutes.
3. On day 39 of study (DS 39) (9 May 2002), a postdosage clinical observation was not
recorded for one male rat in the 0.3 mg/kg/day dosage group (19153). This deviation
did not adversely affect the outcome or interpretation of the study because sufficient
data were available to evaluate this parameter.
4. On DS 44 (14 May 2002), dosage volume was not recorded for one male rat in the 3 mg/kg/day dosage group (19156). This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter.
418-028: PAGE E-2
5. On DS 46 (16 May 2002), postdosage clinical observations and dosage volumes were not recorded for two male rats in the 0 mg/kg/day dosage group (19161 and 19167). These deviations did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter.
6. Detailed clinical observations were not recorded weekly for the following rats.
Dosage Group
I II III IV V
Dosage (mg/kg/day)
0 0.3
1 3 10
Date 09 MAY 02 09 MAY 02 09 MAY 02 09 MAY 02 09 MAY 02
Sex Female Female Female Female Female
Rat Numbers 19023, 19041.19050
19004 19008 19054,19062 19020,19030
These deviations did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter.
7. On DS 13 (13 April 2002), feed left values were not recorded for all rats before they were placed into cohabitation. This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter.
8. On days 1 and 2 of lactation (DLs 1 and 2) (10 May 2002 and 11 May 2002, respectively), one pup in the 0 mg/g/day dosage group (litter 19050) was recorded as having an adverse clinical observation without the sex being recorded. This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter.
9. On DL 3 (12 May 2002), one litter in the 10 mg/kg/day dosage group (19022) was not recorded as having been observed. All pups appeared normal on DL 4. This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter.
10. On DL 5 (12 May 2002), maternal observation was not recorded for one rat in the 0.3 mg/kg/day dosage group (19018). Maternal behavior on DL 8 was normal for this rat. This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter.
11. On 19 May 2002, the frozen liver sample for one female rat with a non-confirmed date of mating in the 0 mg/kg/day dosage group (19077) was lost before sample shipment. This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter.
418-028: PAGE E-3
On DL 22 (31 May 2002) the liver weight of one pup in the 1 mg/kg/day dosage group (pup 9 in litter 19024) was not recorded. This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. All deviations are documented in the raw data.
Associate Director d Study Director
Date
APPENDIX F CERTIFICATE OF ANALYSIS
418-028'.PAGE F-l
Certificate of Analysis
Nominal Product: Potassium perfluorohexanesulfonate: C6Fi3S03h K(+) Product Code: PFHS; 127498-80 April 15, 2002 Tom Kestner and Joel Miller
The sample of 127498-80 PFHS was analyzed using LCMS, 19F-NMR and `H-NMR analysis techniques.
The overall qualitative and quantitative compositional results that were derived from these combined
analyses are summarized below in TABLE-1.
TABLE-1
Sample: 127498-80: PFHS
Overall Quantitative Compositional Results by LCMS, 19F-NMR, and `H-NMR Analyses
Component Identities *
Relative Wt.% Concentrations
(single trial measurements, excluding any water)
CF3CF2CF2CF2CF2CF2S03H Kl+)
88.93% (NMR)
(CF3)2-CF-(CF2)3-S03() Kt+>
6.83% (NMR)
CF3CFrCF(CF3)-CF2CF2-S03H K(+)
2.75% (NMR)
CF3CF2CF2CF2-CF(CF3)-S03(`) k(+)
0.83% (NMR)
CF3CF2CF2CF(CF3)-CF2-S03(') k(+)
0.56% (NMR)
(CF3)3-C-CF2-CF2S03(-)k (+)
0.078% (NMR)
C6Fi2HS03h Kl+)
0.009% (LCMS)
C7F,5S 03h Kh
0.006% (LCMS)
C4F9S 03wK(+)
0.004% (LCMS)
Probable C,,H2n+2 hydrocarbons
0.0034% (NMR)
Other components
Sum of C6F,,S03() Isomers Sum of Known Impurities
* Trace amounts of other unassigned components were also detected.
<0.001% (LCMS)
99.98% 0.021%
Page 1 of 1
File Reference: CofA PFHS 127498-80.doc
418-028:PAGEF-2
3M SPECIALTY MATERIALS MANUFACTURING DIVISION ANALYTICAL LABORATORY
Request No. GID:32537 To: Dan Hakes - (3-2392) - EHSR - Auto & Chem Group - 236-1B-10
From:
Tom Kestner - (3-5633) - SMMD Analytical Lab - 236-2B-11
Subject:
Chemical Characterization of PFHS (127498-80) by 'H-NMR & ,9F-NMR Spectroscopy
Date:
April 15,2002
SAMPLE DESCRIPTION: 127498-80: PFHS made by George Moore and to be used for toxicological testing.
Nominal product =C6Fi3-S0 3HK(+) (white powder).
OBJECTIVE;
This sample was subjected to 'H-NMR and 19F-NMR spectral analyses to determine the purity of the nominal product and to characterize as many impurity components as possible. Joel Miller also performed an LC/MS analysis and his results were reported to you previously.
EXPERIMENTAL:
A portion of the sample (-400 mg) was totally dissolved in deuterated dimethylsulfoxide (DMSO-de) and then the solution was spiked with a small amount of l,4-bis(trifluoromethyl)benzene (p-HFX) for NMR analysis. A 400 MHz H-NMR spectrum (# h32537.GID.401) and a 376 MHz l9F-NMR spectrum (# f32537.GID.401) were acquired at room temperature using a Varian UNTTYplus 400 FT-NMR spectrometer. The p-HFX was used as a *H/I9F-NMR cross integration standard to permit the cross correlation of the relative 'H and 19F signal intensities for evaluation of the overall sample composition.
RESULTS:
The combined NMR spectral data indicated the sample of 127498-80 consisted of a high purity form of the nominal isomeric product mixture, CnF^+i-SC^ M*+), where `n' was mainly 6 and where the metal cation [`M ^'] was assumed to be K<+). Trace-levels of probable aliphatic hydrocarbon impurity components were also observed and quantified.
The qualitative and quantitative compositional results that were derived from the single trial 'H/'^-NMR cross integration analysis are summarized in TABLE-1 on the following page. Any water that may have been present in the sample was ignored for calculation purposes. The relative weight percent concentrations shown in TABLE-1 should be very close to their respective absolute weight percent values. Trace amounts of other unidentified impurity components were also detected in the NMR spectra, but additional work would be needed in an effort to assign or quantify the unassigned impurities.
Copies of the NMR spectra are attached with the paper copy of this report for your reference. If you have any questions about these results, or if any further work is needed, please let me know.
Tom Kestner
c: Joel Miller George Moore Rick Payfer
F ile R eferen ce: d h 3 2 5 3 7 .G ID .d o c/9 3
Page I of2
418-028:PAGE F-3
April 15,2002
3M SMMD Analytical Lab Request # GID:32537
TABLE-1
Sample: 127498-80: PFHS made by George Moore and to be used for toxicological testing.
Overall Quantitative Compositional Results by 'H/'V-NMR Cross Integration Analysis
Identified Components *
19F/'H-NMR Relative Wt.% Concentrations
(single trial measurement)
C F C W F^F^
88.94%
(CF3)rCF-(CF2)3-S03WKW
6.83%
CF3CF2-CF(CF3)-CF2CF2-S03(-) k(+)
2.75%
CF3CF2CF2CF2-CF(CF3)-S03(') k (+) CF3CF2CF2CF(CF3)-CF2-S03WK(+)
0.83% 0.56%
(CF3)3-C-CF2-CF2S03(') Kl+>
0.078%
Probable CnH2n+2 hydrocarbons
0.0034%
* Trace amounts of other tmassigned components were also detected in the NMR spectra.
Study No. FACT-TCR008
Page 2 o f2
APPENDIX G ANALYTICAL AND BIOANALYTICAL REPORT
418-028:PAGE G-l
ANALYTICAL PHASE
STUDY TITLE Oral (Gavage) Combined Repeated Dose Toxicity Study of T-7706 with the
Reproduction/Developmental Toxicity Screening Test
DATA REQUIREMENTS OECD Principles on Good Laboratory Practice. ENV/MC/CHEM(98)17,
U.S. Food and Drug Administration 21 CFR Part 58, MHW Good Laboratory Practice Standard for Safety Studies on Drugs Ordinance
Number 21, March 26,1997
STUDY DIRECTOR Raymond G. York
ANALYTICAL REPORT COMPLETION DATE July 21, 2003
PERFORMING LABORATORY Exygen Research
3058 Research Drive State College, PA 16801
Phone: 814-272-1039
TESTING FACILITY Argus Research
905 Sheehy Drive, Building A Horsham, PA 19044-1297 Phone:215-443-8710
STUDY SPONSOR 3M Corporate Toxicology
Building 220-2E-02 St. Paul, MN 55144-1000
PROJECT Protocol Number: 418-028 Sponsor's Study Number: T-7706.1 Exygen Study Number: 023-072
Total Pages: 153
418-028.PAGE G-2 Exygen Study No.: 023-072
GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT
Exgyen Study Number 023-072, entitled "Oral (Gavage) Combined Repeated Dose Toxicity Study o f T-7706 with the Reproduction/Developmental Toxicity Screening Test," conducted for 3M Corporate Toxicology, was performed in compliance with U.S. Food and Drug Administration Good Laboratory Practice Regulations 21 CFR Part 58, OECD Principles on Good Laboratory Practice. ENV/MC/CHEM(98)17 and MHW Good Laboratory Practice Standards for Safety Studies on Drugs Ordinance Number 21 by Exygen Research.
/'"John Flaherty Principal Investigator Exygen Research
John Butenhoff Study Monitor 3M Corporate Toxicology
Exygen Research
Date
Date
ZOO3
z f jy i-
Date
Page 2 of 153
418-028 :PAGE G-3 Exygen Study No.: 023-072
QUALITY ASSURANCE STATEMENT
Exygen Research's Quality Assurance Unit reviewed Exygen Study Number 023-072, entitled, "Oral (Gavage) Combined Repeated Dose Toxicity Study o f T-7706 with the Reproduction/Developmental Toxicity Screening Test". All reviewed phases were inspected for conduct according to Exygen Research's Standard Operating Procedures, the Study Protocol, and all applicable Good Laboratory Practice Standards. All findings were reported to the Exygen Principal Investigator and Management and to the Study Director.
Phase
Date Inspected
Date Reported to Date Reported to
Principal
Exygen
Date Reported to
Investigator Management Studv Director
1. Protocol Review
09/24/02
11/20/02
11/22/02
01/20/03
2. Extraction, Fortification
09/24/02
11/21/02
12/18/02
01/20/03
3. Raw Data Review
02/03-07/03
and Draft Analytical and 02/10-11/03
Report Review
02/24/03
02/28/03
03/07/03
4. Final Analytical Report Review
07/21/03
07/21/03
07/21/03
07/21/03
Date
Exygen Research
Page 3 of 153
418-028:PAGE G-4 Exygen Study No.: 023-072
CERTIFICATION OF AUTHENTICITY
This report, for Exygen Study Number 023-072, is a true and complete representation of the raw data for the study.
Submitted by:
Exygen Research 3058 Research Drive State College, PA 16801 (814)272-1039
Principal Investigator, Exygen:
ohn Flaherty Vice President Exygen Research
Exygen Research Facility Management:
Date
Date
Study Monitor, 3M:
%
John Butenhoff 3M Corporate Toxicology
f ) fr
Exygen Research
y J 'u l Rj Date
28 Date
2- fi ff J
Page 4 of 153
418-028:PAGE G-5 Exygen Study No.: 023-072
STUDY IDENTIFICATION
Oral (Gavage) Combined Repeated Dose Toxicity Study o f T-7706 with the Reproduction/Developmental Toxicity Screening Test
PROTOCOL NUMBER:
418-028
SPONSOR'S STUDY NUMBER: T-7706.1
EXYGEN STUDY NUMBER: 023-072
TYPE OF STUDY:
Residue
SAMPLE MATRIX:
Rat Liver, Serum, and Plasma
TEST SUBSTANCE:
Perfluorohexanesulfonate (PFHS)
SPONSOR:
3M Corporate Toxicology Building 220-2E-02 St. Paul, MN 55144-1000
STUDY DIRECTOR:
Raymond G. York Argus Research 905 Sheehy Drive, Building A Horsham, PA 19044-1297
TESTING FACILITY:
Argus Research 905 Sheehy Drive, Building A Horsham, PA 19044-1297
STUDY MONITOR:
John Butenhoff 3M Corporate Toxicology Building 220-2E-02 St. Paul, MN 55144-1000
PERFORMING LABORATORY: Exygen Research 3058 Research Drive State College, PA 16801
ANALYTICAL PHASE TIMETABLE:
Study Initiation Date:
03/26/02
Analytical Start Date:
09/16/02
Analytical Termination Date:
11/13/02
Analytical Report Completion Date: 07/21/03
Exygen Research
Page 5 of 153
418-028: PAGE G-6 Exygen Study No.: 023-072
PROJECT PERSONNEL
The Study Director for this project was Raymond G. York at Argus Research. The following personnel from Exygen Research were associated with various phases o f the study:
Name John Flaherty Karen Risha Paul Connolly Xiaoming Zhu Lawrence Ord Rickey Kelley Amy Sheehan Emily Decker
Mark Neeley
Title Vice President
Scientist Technical Lead-LC/MS
Technician Sample Custodian Sample Custodian
Technician Scientist Scientist
Exygen Research
Page 6 of 153
418-028:PAGE G-7
Exygen Study No.: 023-072
TABLE OF CONTENTS
Page TITLE PAGE............................................................................................................................. 1 GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT............................... 2 QUALITY ASSURANCE STATEMENT............................................................................. 3 CERTIFICATION OF AUTHENTICITY.............................................................................. 4 STUDY IDENTIFICATION................................................................................................... 5 PROJECT PERSONNEL........................................................................................................ 6 TABLE OF CONTENTS..........................................................................................................7 LIST OF TABLES.................................................................................................................... 8 LIST OF FIGURES..................................................................................................................9 LIST OF APPENDICES.........................................................................................................10 1.0 SUMMARY..................................................................................................................... 11 2.0 OBJECTIVE.................................................................................................................... 11 3.0 INTRODUCTION...........................................................................................................11 4.0 ANALYTICAL TEST SAMPLES.................................................................................12 5.0 REFERENCE MATERIAL............................................................................................ 13 6.0 DESCRIPTION OF ANALYTICAL METHOD...........................................................13
6.1. Extraction Procedure................................................................................................. 13 6.2 Preparation o f Standards and Fortification Solutions................................................. 14 6.3 Chromatography............................................................................................................14 6.4 Instrument Sensitivity................................................................................................... 14 6.5 Description of LC/MS/MS Instrument and Operating Conditions............................ 15 6.6 Quantitation and Example Calculation........................................................................ 15 7.0 EXPERIMENTAL DESIGN..........................................................................................17 8.0 RESULTS........................................................................................................................ 18 9.0 CONCLUSIONS..............................................................................................................18 10.0 RETENTION OF DATA AND SAMPLES................................................................19
Exygen Research
Page 7 of 153
418-028:PAGE G-8 Exygen Study No.: 023-072
LIST OF TABLES
Page Table I. Summary o f PFHS in Control Rat Plasma Samples......................................... 21 Table II. Summary o f PFHS in Control Rat Serum Samples.......................................... 21 Table III. Summary o f PFHS in Control Rat Liver Samples........................................... 21 Table IV. Summary o f PFHS Fortification Recoveries in Rat Plasma.............................22 Table V. Summary o f PFHS Fortification Recoveries in Rat Serum..............................22 Table VI. Summary of PFHS Fortification Recoveries in Rat Liver................................23 Table VII. Summary of PFHS Residues in Rat Plasma Samples......................................24 Table VIII. Summary of PFHS Residues in Rat Serum Samples....................................... 26 Table IX. Summary of PFHS Residues in Rat Liver Samples.........................................28 Table X. Summary of PFHS Residues in Dosing Solutions...........................................40 Table XI. Summary of PFHS Residues in Stability Samples..........................................41 Table XII. Summary o f PFHS Residues in Homogeneity Samples................................. 42
Exygen Research
Page 8 o f 153
418-028:PAGE G-9 Exygen Study No.: 023-072
Figure 1.
LIST OF FIGURES
Page Typical Calibration Curve for PFH S................................................................44
Figure 2. Chromatogram Representing a 0.1 ng/mL standard for PFHS....................... 45
Figure 3. Chromatogram Representing a Control Rat Plasma Sample for PFHS (Exygen ID 0202913 Control, Data Set: 091602B).........................................46
Figure 4. Chromatogram Representing a Control Rat Serum Sample for PFHS (Exygen ID: 0202987 Control, Data Set: 091902B).......................................47
Figure 5. Chromatogram Representing a Control Rat Liver Sample for PFHS, (Exygen ID: 0202877 Control, Data Set: 100202A)......................................48
Figure 6. Chromatogram Representing Control Rat Plasma Sample Fortified with 10 ppb o f PFHS (Exygen ID : 0202913 Spk A, Data Set: 091602B) 49
Figure 7. Chromatogram Representing Control Rat Serum Sample Fortified with 10 ppb o f PFHS (Exygen ID: 0202987 Spk A, Data Set: 091902B)..... 50
Figure 8. Chromatogram Representing Control Rat Liver Sample Fortified with 10 ppb o f PFHS (Exygen ID: 0202877 Spk A, Data Set: 100202A).... 51
Figure 9. Chromatogram Representing Rat Plasma Sample Analyzed for PFHS (Exygen ED: 0201816, Sponsor ID: 19176 GROUP I, Data Set: 091602B) ..52
Figure 10. Chromatogram Representing Rat Serum Sample Analyzed for PFHS, DF=10 (Exygen ID: 0201863, Sponsor ID: 19079 GROUP II, Data Set: 091902BR)........................................................................................ 53
Figure 11. Chromatogram Representing Rat Liver Sample Analyzed for PFHS (Exygen ID: 0202050, Sponsor ID: 19018 GROUP II Male 1, Data Set: 100202A)....................................................................................................54
Exygen Research
Page 9 of 153
418-028-.PAGEG-10 Exygen Study No.: 023-072
LIST OF APPENDICES
Page
Appendix A Study Protocol 418-028 (Exygen Study No. 023-072) and Amendments, Deviation and Note to File....................................................55
Appendix B
Analytical Method: Method of Analysis for the Determination of Perfluorohexanesulfonate (PFHS), Perfluorooctanesulfonate (PFOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat Liver, Serum and Urine Revision 1 (Exygen Method No. ExM-023-071 Revision 1) .................110
Exygen Research
Page 10 of 153
418-028:PAGE G -ll Exygen Study No.: 023-072
1.0 SU M M AR Y
Exygen Resarch extracted and analyzed rat liver, serum, and plasma samples for the determination o f perfluorohexanesulfonate (PFHS) according to Exygen Method ExM023-071 Revision 1 (Appendix B).
The limit o f quantitation for PFHS in rat liver was 10 ng/g and 10 ng/mL in rat serum and plasma. The LOQ for each matrix was determined in a method validation study performed at Exygen (Exygen Study No: 023-073).
PFHS in the rat plasma samples ranged from non-detected levels to 237,000 ng/mL. PFHS in the rat serum samples ranged from non-detected levels to 189,000 ng/mL. PFHS in the rat liver samples ranged from non-detected levels to 675,000 ng/g.
The average percent recoveries standard deviations for PFHS in rat plasma, serum, and liver samples were 84% 7%, 95% 12%, and 86% 13% , respectively.
PFHS residues in the dosing solutions, stability samples and homogeneity samples were all within 70% to 125% of their known concentrations.
2.0 O BJE CTIVE
The objective o f the analytical part of this study was to determine levels o f perfluorohexanesulfonate (PFHS) in specimens o f rat liver, serum and plasma samples, bulk test substance, concentration and homogeneity formulations, and stability solutions according to Protocol 418-028 (Appendix A).
3.0 INTRODUCTION
This report details the results o f the analysis for the determination of PFHS in rat liver, serum and plasma samples, bulk test substance, concentration and homogeneity formulations, and stability solutions using the analytical method entitled, "Method of Analysis for the Determination o f Perfluorohexanesulfonate (PFHS), Perfluorooctanesulfonate (PFOS) and Pentadecafluorooctanoic Acid (PFOA) in Rat Liver, Serum and Urine Revision 1."
The study was initiated on March 26, 2002, when the study director signed protocol number 418-028. The analytical start date was September 16, 2002, and the analytical termination date was November 13,2002.
Exygen Research
Page 11 of 153
418-028:PAGE G-12 Exygen Study No.: 023-072
4.0 A N A L Y T IC A L TEST SAM PLES
The control rat liver (Exygen ID 0202877) used for the matrix blanks and matrix fortifications was received frozen on dry ice on August 7, 2002 from Pel-Freez Biologicals, Rogers, Arkansas. The control rat plasma (Exygen ID 0202912 and 0202913) used for the matrix blanks and matrix fortifications was received frozen on dry ice on August 8, 2002 from Pel-Freez Biologicals, Rogers, Arkansas. The control rat serum (Exygen ID 0202987) used for the matrix blanks and matrix fortifications was received frozen on dry ice on August 15, 2002 from Pel-Freez Biologicals, Rogers, Arkansas.
Dosage solution/suspension samples (Exygen ID 0201753-0201755) were received refrigerated at Exygen from Argus Research on May 29, 2002. Dosage solution/suspension samples (Exygen ID 0201757-0201758) were received refrigerated at Exygen from Argus Research on June 11, 2002. These samples were logged in by Exygen personnel and placed in refrigerated storage.
Bulk TA/S sample (Exygen ID 0201756) was received ambient at Exygen from Argus Research on June 11, 2002. This sample was logged in by Exygen personnel and placed in refrigerated storage.
Median liver lobe (Exygen ID 0201759-0201787), pooled fetal liver (Exygen ID 0201788-0201800), plasma (Exygen ID 0201801-0201860), pooled fetal serum (Exygen ID 0201861-0201874), pooled pup serum (Exygen ID 0201875-0201924), and pup livers (Exygen ID 0201925-0202408) were received frozen on dry ice at Exygen from Argus Research on June 18, 2002. These samples were logged in by Exygen personnel and placed in frozen storage.
Median liver lobe (Exygen ID 0203650) and pooled fetal liver (Exygen ID 0203651) were received frozen on dry ice at Exygen from Argus Research on September 11, 2002 and logged in by Exygen personnel and placed in frozen storage.
Prepared formulations (Exygen ID 0203923-0203962) were received frozen from 3M on September 19,2002 and logged in by Exygen personnel and placed in frozen storage.
Sample log-in and chain of custody information can be found in the raw data package associated with this study. Storage records will be kept at Exygen Research.
Exygen Research
Page 12 of 153
418-028:PAGE G-13 Exygen Study No.: 023-072
5.0 R E FE R E N CE M A T E R IA L
The analytical standard PFHS was received at Exygen on January 26, 2000 from 3M Environmental Technology and Services.
The available information for the reference material is listed below. The reference material was stored frozen.
Compound Exygen Inventory No..
PFHS
SP244
TCR No. SE036
Purity (%) Expiration Date
99.99
01/01/10
The molecular structures o f test substance is given below:
Name: PFHS Chemical Name: Perfluorohexanesulfonate Molecular Weight: 399
6.0 D E SCR IPTIO N O F A N A L Y T IC A L M ETH O D
The analytical method ExM-023-071 Revision 1 was used for this study.
6.1. Extraction Procedure
A 1 mL aliquot o f the serum and plasma and 1 g o f liver were used for the extraction procedure for the laboratory controls and fortifications. Due to insufficient sample size, a 100 pL aliquot of the serum and plasma and 0.1 g of the liver were used for the extraction procedure for the study samples. After fortification o f appropriate samples, the serum samples were brought up to 20 mL with Type I Water and the liver samples were brought up to 10 mL with Type I Water. The serum samples were vortexed for ~ 1 minute and the liver samples were homogenized with a tissuemizer for ~ 1 minute. An aliquot of one milliliter was transferred from each sample and 5 mL o f acetonitrile was added and the samples were shaken for ~ 20 minutes. The samples were centrifuged and the supernatant was decanted onto a conditioned SPE column. Then the samples were eluted with 2 mL o f methanol. Each sample was analyzed by LC/MS/MS electrospray.
An extraction procedure was not necessary for the bulk test substance, concentration and homogeneity formulations, and the stability solutions. 10 mg o f the bulk test substance was weighed and brought to volume with methanol in a 100-mL volumetric flask. The
Exygen Research
Page 13 of 153
418-028: PAGE G-14 Exygen Study No.: 023-072
sample was then diluted 100000 times with methanol to fit in the range of the analytical curve and analyzed by LC/MS/MS electrospray. The concentration and homogeneity formulations and the stability solutions were all diluted appropriately with methanol and analyzed by LC/MS/MS electrospray.
6.2 Preparation of Standards and Fortification Solutions
A stock standard solution of PFHS was prepared on August 20, 2002 as specified in Exygen method ExM-023-071 Revision 1. The stock standard solution was prepared at a concentration of 100 pg/mL by dissolving 10 mg of each standard (corrected for purity only) in methanol. From this solution, a 1.0 pg/mL fortification standard solution was prepared by taking 1 mL of the stock and bringing the volume up to 100 mL with methanol.
A 0.1 pg/mL fortification standard was prepared by taking 10 mL o f the 1.0 pg/mL fortification standard and bringing the volume up to 100 mL with methanol.
A set of standards containing PFHS was prepared via dilution of the 0.1 pg/mL and various calibration solutions in the following manner:
Initial Cone. (pg/mL)1 0.1 0.1 0.1 0.005 0.002 0.001
1of PFHS
Volume (mL) 5 2 1 10 10 10
Diluted to (mL) 100 100 100 100 100 100
Final Cone. (pg/mL) 0.005 0.002 0.001 0.0005 0.0002 0.0001
The stock standard solution and all fortification and calibration standard solutions were stored in a refrigerator (4 2C) when not in use. Documentation of standard preparation can be found in the raw data associated with this report.
63 Chromatography
Quantification o f PFHS was accomplished by LC/MS/MS electrospray. The retention time o f PFHS was ~ 8.3 min. Peaks above the LOQ were not detected in any of the control samples corresponding to the analyte retention time.
6.4 Instrument Sensitivity
The smallest standard amount injected during the chromatographic run had a concentration o f 0.0001 pg/mL o f PFHS.
Exygen Research
Page 14 o f 153
418-028 :PAGE G -15 Exygen Study No.: 023-072
6.5 Description of LC/MS/MS Instrument and Operating Conditions Instrument: Micromass Quattro Ultima (Micromass)
Interface: Electrospray (Micromass)
Computer: COMPAQ Professional Workstation AP200
Software: Windows NT, Masslynx 3.3
HPLC:
Hewlett Packard (HP) Series 1100 HP Quat Pump HP Vacuum Degasser HP Autosampler HP Column Oven
HPLC Column:Genesis Cg(Jones Chromatography), 2.1 mm x 50 mm, 4p
Column Temp.: 35 C Injection Voi.: 15 pL Mobile Phase (A): 2 mM Ammonium Acetate in type I water Mobile Phase (B): Methanol
Time 0.0 2.0 5.0 9.0 9.5 14.0 14.5 20.0
%A 90 90 10 10 0 0 90 90
% B Flow Rate fmL/minl 10 0.3 10 0.3 90 0.3 90 0.3 100 0.3 100 0.3 10 0.3 10 0.3
Ions monitored:
Analvte PFHS
Mode Negative
Transition Monitored 399 -> 80
Approximate Retention Time ('mini
~8.3 min.
6.6 Quantitation and Example Calculation
Fifteen microliters of sample or calibration standard were injected into the LC/MS/MS. The peak area was measured and the standard curve was generated (using 1/x fit weighted linear regression) by Masslynx software using six concentrations of standards. The concentration was determined from the equations below.
Equation 1 calculated the amount o f analyte found (in ng/mL, based on peak area) using the standard curve (linear regression parameters) generated by the Masslynx software
Exygen Research
Page 15 of 153
418-028:PAGE G-16 Exygen Study No.: 023-072
program. Then Equation 2 calculated the amount of analyte found in ng/g for liver and ng/mL for serum and plasma.
Equation 1: Analyte found (ng/mL) = (Peak area - intercept) x DF x AF slope
Where: AF = Aliquot Factor DF = Dilution Factor
Equation 2: Analyte found (ppb, ng/g for liver and ng/mL for serum and plasma) =
analvte found (ng/mL) x FV (m P sample volume (mL) or sample weight (g) Where: FV = Final Volume
For samples fortified with known amounts o f PFHS prior to extraction, Equation 3 calculated the percent recovery.
Equation 3: Recovery (%) =
//analvte found (ppb) - analvte in control (ppb)) xl00% amount added (ppb)
To find the total analyte found corrected for the salt content Equation 4 was used.
Equation 4:
Total Analyte Found Corrected (ppb) = analyte found (ppb) x salt correction factor
Where the salt correction factor = 0.91.
An example of a calculation using an actual sample follows:
Rat liver sample Exygen ID 0202877 Spk A (Set: 100202A), fortified at 10 ng/g
where:
peak area
2125
intercept
41.0365
slope
4728.12
dilution factor
1
ppb added (fort level)
10
avg. amt in controls
0 (Not Detected)
final volume
2 mL
aliquot factor
10
sample weight
1.0 g
Exygen Research
Page 16 of 153
418-028: PA G E G - 17 Exygen Study No.: 023-072
From equation 1: Analyte found (ng/mL)
From equation 2: Analyte found (ppb)
From equation 3: % Recovery
From equation 4: Analyte Found Corrected (ppb)
f2 1 2 5 - 41,03651 x 1 x 10 4728.12
4.41 ng/mL
(4.41 ng/mL x 2 mL) (1.0 g)
8.82 ppb
((8.82 ppb - 0 ppb) x 100% 10 ppb
88%
8.82 ppb x 0.91
8.03 ppb
7.0 EXPER IM EN TAL DESIGN
Each set o f samples (liver, serum or plasma) consisted o f one matrix blank, two matrix blanks fortified at known concentrations, and ~ 20 samples. Each sample was extracted using the method and then analyzed in duplicate.
Exygen Research
Page 17 of 153
418-028:PAGE G-18 Exygen Study No.: 023-072
8.0 RESU LTS
The PFHS found in the control rat plasma, serum, and liver samples are listed in Tables
I-m. Peaks were not detected in any o f the control plasma or serum samples
corresponding to the analyte retention time. Some peaks were detected in the control liver samples corresponding to the analyte retention time; however, the peaks detected were all below the LOQ o f 10 ppb.
Fortification recoveries for PFHS in the rat plasma, serum, and liver samples are detailed in Tables IY-VI. The average percent recoveries standard deviations for PFHS in rat plasma, serum, and liver samples were 84% 7%, 95% 12%, and 86% 13%, respectively.
PFHS in the rat plasma samples ranged from non-detected levels to 237,000 ng/mL. Individual results are listed in Table VII. PFHS in the rat serum samples ranged from non-detected levels to 189,000 ng/mL. Individual results are listed in Table V III. PFHS in the rat liver samples ranged from non-detected levels to 675,000 ng/g. Individual results are listed in Table IX.
PFHS residues in the dosing solutions ranged from 88% to 125% o f their known concentrations. The results are listed in Table X.
PFHS residues found in the stability samples ranged from 91% to 122% of their known concentrations. The results are listed in Table XI.
PFHS residues found in the homogeneity samples ranged from 70% to 116% o f their known concentrations. The results are listed in Table XII.
9.0 CO N CLU SIO N S
The rat liver, serum, and plasma samples were successfully extracted and analyzed for PFHS according to analytical method ExM-023-071 Revision 1. The bulk test substance, concentration and homogeneity formulations, and stability solutions were also successfully analyzed for PFHS according to analytical method ExM-023-071 Revision 1.
Exygen Research
Page 18 of 153
418-028:PAGE G-19 Exygen Study No.: 023-072
10.0 RETEN TION OF D A TA AND SAM PLE S
When the final analytical report is complete, all original paper data generated by Exygen Research will be shipped to the sponsor. This does not include facility-specific raw data such as instrument or temperature logs. Exact copies o f all raw data, as well as a signed copy of the final analytical report and all original facility-specific raw data, will be retained in the Exygen Research archives for the period o f time specified in 21 CFR Part 58, OECD ENV/MC/CHEM(98)17, and MHW Ordinance Number 21. Retained samples of reference substances are archived by the sponsor.
Exygen Research
Page 19 of 153
418-028:PAGE G-20 Exygen Study No.: 023-072
TABLES
Exygen Research
Page 20 of 1S3
418-028:PAGE G-21 Exygen Study No.: 023-072
Table I. Summary of PFHS in Control Rat Plasma Samples
Sponsor ID
LOT 17824 LOT 17824 LOT 05024 LOT 17824
Exygen ID
0202913 Control 0202913 Control 0202912 Control 0202913 Control
Set Number
091602AR 091602B 091802A 091902A
PFHS Found (ppb)
ND ND ND ND
Table II. Summary of PFHS in Control Rat Serum Samples
Sponsor ID
36119-3 36119-3 36119-3 36119-3 36119-3
Exygen ID
0202987 Control 0202987 Control 0202987 Control 0202987 Control 0202987 Control
Set Number
091902B 092002A 092002B 092302A 101102A
PFHS Found(ppb)
ND ND ND ND ND
Table HI. Summary of PFHS in Control R at Liver Samples
Sponsor ED
LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT 21824 LOT21824 LOT21824 LOT21824 LOT 21824 LOT 21824 LOT21824
Exygen ID
0202877 Control 0202877 Control A 0202877 Control A 0202877 Control
0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control 0202877 Control
Set Number
092802A 092602A 092602B 092702A 092702B 100202A 100102A 100302A 100402A 100402BR 100902AR 100902BR 101002A 101002B 101102AR 101402A
PFHS Found(ppb)
ND ND 2.32 (NQ) 3.84 (NQ) 3.85 (NQ) ND ND ND ND 2.09 (NQ) 3.95 (NQ) 2.01 (NQ) 1.85 (NQ) 3.95 (NQ) 4.73 (NQ) 3.37 (NQ)
ND = Not Detected (Area less than the lowest concentration of the calibration standards (0.1 ng/mL)) NQ = Not Quantifiable (Area is greater than 0.1 ng/mL but less than LOQ (10 ng/mL))
Exygen Research
Page 21 of 153
418-028:PAGE G-22 Exygen Study No.: 023-072
Table IV. Summary of PFHS Fortification Recoveries in Rat Plasma
Sponsor m
LOT 17824 LOT 17824 19176 GROUP 1 LOT 17824 LOT 17824 19176 GROUP I LOT 05024 LOT 05024 19076 GROUP I LOT 17824 LOT 17824 19076 GROUP I
Exygen m
0202913 Spk A 0202913 SpkB 0201801 Spk C 0202913 SpkA 0202913 Spk B 0201816 Spk C 0202912 Spk A 0202912 SpkB 0201846 Spk C 0202913 Spk A 0202913 SpkB 0201831 SpkC
Set Number
Amount Added (ppb)
091602A 091602A
10 50
091602A 091602B 091602B 091602B 091802A 091802A 091802A 091902A 091902A 091902A
5000 10 50
5000 10 50
5000 10 50
5000
Average: Standard Deviation: Relative Standard Deviation:
% Recovery
91 84 77 86 84 78 88 86 89 71 96 82
84 7 8
Table V . Summary o f PFHS Fortification Recoveries in Rat Serum
Sponsor m
36119-3 36119-3 19076 GROUP I 36119-3 36119-3 19012 GROUP I 36119-3 36119-3 19036 GROUP II 36119-3 36119-3 19005 GROUP IV 36119-3 36119-3
Exygen m
0202987 Spk A 0202987 SpkB 0201861 SpkC 0202987 Spk A 0202987 Spk B 0201875 SpkC 0202987 SpkA 0202987 Spk B 0201890 SpkC 0202987 SpkA 0202987 SpkB 0201905 SpkC 0202987 SpkA 0202987 Spk B
Set Amount
Number Added(ppb)
091902B
10
091902B
50
091902B 092002A
5000 10
092002A
50
092002A 092002B
5000 10
092002B
50
092002BR
5000
092302A
10
092302A
50
101102A
200000
101102A
10
101102A
50
Average:
Standard Deviation:
Relative Standard Deviation:
% Recovery
92 96 94 106 105 90 97 97 120 90 101 88 78 72
95 12 12
Exygen Research
Page 22 of 153
418-028-.PAGE G-23 Exygen Study No.: 023-072
Table VI. Summary of PFHS Fortification Recoveries in Rat Liver
Sponsor ID
LOT 21824 LOT 21824
19176 GROUP I LOT 21824 LOT 21824
19076 GROUP I LOT 21824 LOT 21824
19076 GROUP I LOT 21824 LOT 21824
19012 GROUP I, Male 1 LOT 21824 LOT 21824
19021 GROUP LMale 1 LOT 21824 LOT 21824
19018 GROUP n,Male 1 LOT21824 LOT 21824
19041 GROUP I, Male 1 LOT 21824 LOT 21824
19036 GROUP n,Male 1 LOT21824 LOT21824
19003 GROUP m, Male 1 LOT 21824 LOT21824
19008 GROUP m, Male 1 LOT 21824 LOT 21824
19015 GROUP m. Male 1 LOT 21824 LOT 21824
19035 GROUP IV, Male 1 LOT21824 LOT 21824
19040 GROUP IV, Male 2 LOT21824 LOT 21824
19006 GROUP V, Male 1 LOT 21824 LOT 21824
19020 GROUP V, Male 2 LOT 21824 LOT 21824
19025 GROUP V, Male 1
Exygen ID
0202877 Spk A 0202877 SpkB 0201759 Spk C 0202877 Spk A 0202877 SpkB 0201774 Spk C 0202877 SpkA 0202877 SpkB 0201788 Spk C 0202877 Spk A 0202877 SpkB 0201925 Spk C 0202877 SpkA 0202877 SpkB 0201945 SpkC 0202877 SpkA 0202877 SpkB 0202050 SpkC 0202877 SpkA 0202877 SpkB 0201965 SpkC 0202877 SpkA 0202877 SpkB 0202070 SpkC 0202877 SpkA 0202877 SpkB 0202119 SpkC 0202877 SpkA 0202877 SpkB 0202139 SpkC 0202877 SpkA 0202877 SpkB 0202159 SpkC 0202877 Spk A 0202877 SpkB 0202229 Spk C 0202877 SpkA 0202877 SpkB 0202249 SpkC 0202877 SpkA 0202877 SpkB 0202320 SpkC 0202877 SpkA 0202877 SpkB 0202340 SpkC 0202877 SpkA 0202877 SpkB 0202360 Spk C
Exygen Research
Set Number
Amount Added (ppb)
092802A
10
092802A
50
092802A 092602A 092602A
5000 10 50
092602A 092602B 092602B 092602B 092702A 092702A 092702A 092702B 092702B
5000 10 50
5000 10 50
5000 10 50
092702B 100202A
5000 10
100202A 100202A 100102A 100102A 100102A
50 5000
10 50 5000
100302A 100302A 100302A 100402A
10 50 5000 10
100402A 100402A
50 5000
100402BR
10
100402BR
50
100402BR 100902AR
5000 10
100902AR
50
100902AR 100902BR
5000 10
100902BR 100902BR 101002A
50 5000
10
101002A
50
101002AR
5000
101002B
10
101002B
50
101002BR
5000
101102AR
10
I01102AR
50
101102AR
25000
101402A 101402A
10 50
101402ARR
5000
Average: Standard Deviation:
Relative Standard Deviation:
% Recovery
83 87 96 125 110 100 104 87 111 75 93 94 83 100 109 88 71 76 74 77 76 98 81 77 81 79 62 70 78 86 72 81 79 72 70 72 96 93 84 97 72 90 88
75 83 95 77 110
86 13 16
' Page 23 of 153
418-028:PAGE G-24 Exygen Study No.: 023-072
Table VII. Summary of PFHS Residues in Rat Plasma Samples
S p o n so r
n>
19176 GROUP I 19176 G R O U P I* 19177 G R OU P I 19177 G R O U P I* 19178 GROUP I 19178 G R O U P I* 19179 G R OU P H 19179 G R O U P II* 19180 GROUP n 19180 G R O U P II* 19181 G R O U P n 19181 G R O U P n * 19182 G R OU P m 19182 GROU P m * 19183 GROUP HI 19183 G R O U P HI* 19184 GROUP m 19184 G R O U P HI* 19185 G R O U P IV 19185 GR O U P IV* 19186 G R O U P IV 19186 G R O U P IV* 19187 G R O U P IV 19187 G R O U P IV* 19188 GROUP V 19188 G R O U P V* 19189 GR OU P V 19189 GR O U P V* 19190 G R OU P V 19190 G R OU P V* 19176 GR O U P I 19176 G R O U P 1* 19177 GROU P I 19177 G R O U P I* 19178 GROUP I 19178 G R O U P I* 19179 GR OU P H 19179 G R O U P n * 19180 GR O U P n 19180 G R O U P H* 19181 G R O U P H 19181 G R O U P n * 19182 GR O U P m 19182 GROUP m * 19183 G R O U P m 19183 GR O U P m * 19184 G R O U P ID 19184 GROU P ffl* 19ISS G R O U P r v 19185 GROU P IV * 191S6 G R O U P IV 19186 GROU P IV * 19187 G R O U P IV 19187 GR O U P IV * 19188 GR OU P V 19188 GROUP V* 19189 GROUP V 19189 GROUP V* 19190 C R O U P V 19190 GROUP V*
Exygen ID
0201801 0201801 Dup b j.
0201802 0201802 Dup b j.
0201803 0201803 D up Inj.
0201804 0201804 Dup b j.
0201805 0201805 D up Inj.
0201806 0201806 D up Inj.
0201807 0201807 Dup Inj.
0201808 0201808 D up Inj.
0201809 0201809 D up Iqj.
0201810 0201810 D up Inj.
0201811 0201811 D up Inj.
0201812 0201812 D up Inj.
0201813 0201813 D up Inj.
0201814 0201814 D up Inj.
0201815 0201815 D u p Inj
0201816 0201816 D u p Inj
0201817 0201817 D u p Iqj
0201818 0201818 D u p Inj
0201819 0201819 D up lq
0201820 020I820D upIqj
0201821 0201821 D up b j
0201822 0201822 D up b j
0201823 0201823 D up b j
0201824 0201824 D u p Iqj
0201825 0 2 0 1 8 2 5 D u p fay
0201826 0201826 D up b j
0201827 020IS27 D u p Inj
0201828 0201828 D u p Inj
0201829 0201829 D up b j
0201830 0201830 D up b j
M atrix
PD 14 PLASM A PD 14 PLASM A PD 14 PLASM A P D 14 PLASM A PD 14 PLASMA PD 14 PLASM A PD 14 PLASM A PD 14 PLASM A PD 14 PLASM A PD 14 PLA SM A PD 14 PLA SM A PD 14 PLA SM A PD 14 PLASM A PD 14 PLASM A PD 14 PLASMA P D 14 PLASM A PD 14 PLASM A PD 14 PLASM A PD 14 PLASM A PD 14 PLASM A PD 14 PLASM A PD 14 PLASM A PD 14 PLASM A P D 14 PLA SM A PD 14 PLASMA PD 14 PLASM A PD 14 PLASM A PD 14 PLASM A PD 14 PLASM A PD 14 PLASM A PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA PD 42 PLASMA
C ollection D ate
4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14*02 4/14/02 4/14/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 S/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5/12/02 5A2/Q2 5/12/02 5/12/02 5/12/02 V I2/02 5/12/02 V 12/02 5/12/02 5/12/02 V I2/02 5/12/02 5/12/02 V I 2/02 5/12/02 V I2/02 5/12/02
Set N um ber
091602A 091602A 091602A 091602A 091602A 091602A 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602AR 091602B 091602B 091602B 091602B 09162B 091602B 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 0 9 I6 0 2 B R 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 09162BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR 091602BR
PFHS F o und (ttf/m L )
182 172 103 108 46.5** 43.3TM 18300 19400 15700 15300 20000 20400 58000 58000 68300 69500 117000 115000 70400 71900 126000 125000 237000 228000 197000 182000 187000 183000 177000 170000 245 256 382 376 74.7TM 65.4TM 57400 60200 35700 36400 37100 38500 91000 85900 90300 87500 90700 89300 119000 119000 137000 142000 128000 127000 188000 188000 224000 225000 191000 193000
^Although the method used allows for alternate sample volumes or weights and all the peak area responses are within the calibration curve limits, the precision for the 0.1 mL or 0.1 g samples below 100 ppb has not been validated. * Duplicate Injection
Exygen Research
Page 24 o f 153
418-028:PAGE G-25 Exygen Study No.: 023-072
Table VII (cont'd). Summary of PFHS Residues in Rat Plasma Samples
Sponsor ID
19076 GROU P I 19076 G R O U P I* 19077 GROUP I 19077 G R O U P I* 19078 GROU P I 19078 G R O U P I* 1 9 0 7 9 G R O U P 11 19079 G R O U P H* 19080 GROUP D 19080 G R O U P II* 19081 GR OU P n 19081 GR OU P n* 19082 GROUP in 19082 GROUP m * 19083 GROU P HI 19083 G R O U P HI* 19084 G R O U P IH 19084 G R O U P HI* 19085 G R O U P IV 19085 G R O U P IV* 19086 G R O U P IV 19086 GROU P rv* 19087 G R O U P IV 19087 G R O U P IV* 19088 GROU P V 19088 GROUP V* 19089 GROUP V 19089 GROUP V* 19090 GROUP V 19090 GROU P V* 19076 GROUP I 19076 G R O U P I* 19077 GROUP I 19077 G R O U P I* 19078 GROUP 1 19078 G R O U P I* 19079 GROUP n 19079 G R O U P II* 19080 GROUP U 19080 GROUP n* 19081 G R O U P n 19081 G R O U P 11* 19082 G R O U P III 19082 G R O U P HI* 19083 G R O U P lU 19083 G R O U P III* 19084 GROUP HI 1 9 0 8 4 G R O U P 111* 19085 G R O U P rV 19085 G R O U P IV* 19086 G R O U P IV 19086 G R O U P IV* 19087 GROU P IV 19087 G R O U P IV* 19088 GROU P V 19088 GROUP V* 19089 GROUP V 19089 GROUP V* 19090 GROUP V 19090 GROUP V*
* Duplicate Injection
Exygen n>
0201846 0201846 D u p Inj
0201847 0201847 D up Inj
0201848 0201848 Dup by
0201849 0201849 Dup by
0201850 0201850 Dup b j
0201851 0201851 D up by
0201852 0201852 D up Inj
0201853 0201853 Dup by
0201854 0 2 0 1 8 5 4 D u p fay
0201855 0201855 Dup b j
02Q1856 0201856 D u p Inj
0201857 0201857 D up Inj
0201858 0201858 D up Inj
0201859 0201859 D up Inj
0201860 0201860 D u p Inj
0201831 0 2 0 1 8 3 1 D u p fay
0201832 0201832 D up Inj
0201833 0201833 Dup b j
0201834 0 2 0 1 8 3 4 D u p fay
0201835 0201835 D up Inj
0201836 0201836 D up Inj
0201837 0201837 Dup b j
0201838 0201838 D up Inj
0201839 0 2 0 1 8 3 9 D u p fay
0201840 0201840 Dup by
0201841 0 2 0 1 8 4 1 D a p fay
0201842 0201842 D up Inj
0201843 0201843 D up Inj
0201844 0 2 0 1 8 4 4 D u p fay
0201845 0201845 Dup b j
M atrix
GD 21 PLASM A G D 21 PLA SM A G D 21 PLASMA GD 21 PLASM A G D 21 PLASMA GD 21 PLASM A G D 21 PLASMA G D 21 PLA SM A G D 21 PLASMA G D 21 PLASM A GD 21 PLASM A G D 21 PLASMA GD 21 PLASM A GD 21 PLASM A GD 21 PLASM A G D 21 PLASMA GD 21 PLA SM A G D 21 PLASMA GD 21 PLASM A GD 21 PLASM A GD 21 PLASM A GD 21 PLASM A GD 21 PLASM A GD 21 PLASM A GD 21 PLASM A GD 21 PLASM A GD 21 PLASM A GD 21 PLASM A GD 21 PLASM A GD 21 PLASM A P D 14 PLA SM A P D 14 PLA SM A P D 14 PLA SM A PD 14 PLA SM A PD 14 PLASM A PD 14 PLA SM A PD 14 PLA SM A P D 14 PLA SM A PD 14 PLA SM A P D 14 PLA SM A P D 14 PLA SM A PD 14 PLA SM A P D 14 PLA SM A PD 14 PLA SM A PD 14 PLA SM A P D 14 P L A S M A PD 14 PLA SM A PD 14 PLASM A PD 14 PLA SM A PD 14 PLA SM A P D 14 PLA SM A P D 14 PLA SM A PD 14 PLA SM A PD 14 PLA SM A P D 14 PLA SM A PD 14 PLA SM A P D 14 PLA SM A PD 14 PLA SM A PD 14 PLASM A PD 14 PLASM A
CoLlectlan Date
5/9/02 5/9/02 5/19/02 5/19/02 5/7/02 5/7/02 5/9/02 5/9/02 5/9/02 5/9/02 5/10/02 5/10/02 5/9/02 5/9/02 5/7/02 5/7/02 5/9/02 5/9/02 5/6/02 5/6/02 5/6/02 5/6/02 5/6/02 5/6/02 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02 4/14/02
Set Number
091802A 091802A 091802A 091802A 091802A 091802A 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 0918Q2AR 091802AR 091S02AR 091802AR 091802AR 091802AR 091802AR 0918Q2AR 091802AR 091B02AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091802AR 091902A 091902A 091902A 091902A 091902A 091902A 091902AR 091902A R 091902AR D91902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR 09I902A R 091902AR 091902AR 091902AR 091902AR 091902AR 091902AR
PFHS Feund (ng/mL)
ND ND ND ND ND ND 4150 4000 3240 3230 2640 2670 7150 7280 18000 18100 6490 6900 24800 25400 40700 40800 32500 32300 72600 73600 53200 54400 52200 52800 ND ND 386 398 ND ND 3800 3530 2600 2630 2040 2090 10400 10100 13100 14000 5540 5980 16900 17900 24800 25200 19200 20000 43900 43000 47100 48200 34000 35900
ND = Not Detected (Area less than lowest calibration standard of 0.1 ng/mL)
Exygen Research
Page 25 of 153
418-028:PAGE G-26 Exygen Study No.: 023-072
Table VIII. Summary of PFHS Residues in Rat Serum Samples
S ponsor ID
19076 GR OU P I 19076 G R O U P I* 19078 GROUP I 19078 G R O U P I* 19079 G R O U P n 19079 G R O U P D* 19080 GROU P U 19080 G R O U P II* 19081 G R O U P H 19081 G R O U P II* 19082 GROUP m 19082 GR O U P m * 19083 GROUP m 19083 GROU P m * 1 9 084 G R O U P HI 19084 GROUP m * 19085 GRO U P IV 19085 GR OU P IV* 19086 GRO U P IV 19086 G R O U P IV* 19087 G R O U P IV 19087 G R O U P IV* 19088 GROU P V 19088 GROUP V* 19089 GROUP V 19089 GROUP V* 19090 GROUP V 19090 GROUP V* 19012 GROUP 1 19012 G R O U P I* 19019 GROU P I 19019 G R O U P I* 19021 G R O U P I 19021 G R O U P I* 19023 GROU P I 19023 G R O U P I* 19041 G R O U P I 19041 G R O U P 1* 19042 GROUP I 19042 G R O U P I* 19044 GROUP I 19044 G R O U P I* 19050 GROUP I 19050 G R O U P I* 19053 GROU P I 19053 G R O U P I* 19065 GROUP I 19065 G R O U P I* 19004 GR OU P H 19004 GROUP n* 19009 G R O U P 0 19009 GROUP n * 19016 GR OU P D 19016 GROUP 0* 19018 GR O U P n 19018 G R O U P D* 19026 GR OU P U 19026 GROUP n* 19036 G R O U P 0 19036 GROU P n*
E xygea ID
0201861 0201861 D uplnj
0201862 0201862 D up Inj
0201863 0201863 D up Inj
0201864 0201864 D up Inj
0201865 0201865 D up Inj
0201866 0201866 D up Inj
0201867 0201867 D up Inj
0201868 0201868 Diq) by
0201869 0201869 Dup Inj
0201870 0201870 D up Inj
0201871 0201871 D uplnj
0201872 0201872 Dup Inj
0201873 0201873 D up Inj
0201874 0201874 Dup Inj
0201875 0201875 D uplnj
0201876 0201876 Dup by
0201877 0201877 D up Inj
0201878 0201878 D up Inj
0201879 0201879 Dup Inj
0201880 0201880 D up Inj
0201881 0201881 D u plnj
0201882 0201882 D uplnj
0201883 0201883 D uplnj
0201884 0201884 D up Inj
0201885 0201885 Dup by
0201886 0201886 D up Inj
0201887 0201887 D i? Inj
0201888 0201888 D up Inj
0201889 0201889 Dup by
0201890 0201890 Dup Ini
M atrix
Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal S m irn Pooled Fetal Scrum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal S c n n Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal S o u m Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Serum Pooled Fetal Scrum Pooled Fetal Serum Pooled Fetal Serum Pooled P up Seram Pooled P u p S e n m Pooled P u p Serum Pooled P u p S ense Pooled P u p Serum Pooled Pup Serum Pooled P u p Scram Pooled P up Scram Pooled P up Scram Pooled P up Scram Pooled P up Serum Pooled P up Scrum Pooled Pup Serum Pooled P up Serum Pooled P up Serum P ooled? 19 Seram Pooled P up Serum Pooled P u p Serum Pooled P up Seram Pooled P u p Seram Pooled Pup Scram Pooled P up Seram Pooled P up Scram Pooled P u p Serum Pooled Pup Serum Pooled Pup Scrum Pooled P up Scram Pooled P u p Serum Pooled P u p Serum Pooled P u p Serum Pooled P u p Seram Pooled P up Serum
C o llectio n D ite
5/9/02 5/9/02 5 / 7 A) 2 5/7/02 5/9/02 5/9/02 5/9/02 5/9/02 5/10/02 5/10/02 5/9/02 5/9/02 5/7/02 5/7/02 5/9/02 5/9/02 5/6/02 5/6/02 5/6/02 5/6/02 5/6/02 5/6/02 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 5/9/02 5/29/02 5/29/02 5/30/02 5/30/02 5/29/02 5/29/02 5/31/02 5/31/02 5/31/02 5/31/02 5/30/02 5/30/02 5/28/02 5/28/02 5/31/02 5/31/02 5/30/02 5/30/02 5/30/02 5/30/02 5/31/02 5/31/02 5/28/02 5/28/02 5/28/02 5/28/02 5/29/02 5/29/02 5/31/02 5/31/02 5/28/02 5/28/02
Set N um ber
091902B 091902B 091902B 091902B 091902BR 091902BR 0919G2BR 091902BR 091902BR Q91902BR 09I902BR 09I902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 091902BR 0919Q2BR 092002A 092002A D92002A 092002A 092002A 092002A 092002A D92002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002A 092002AR. 092002AR 092002AR 092002AR 092002AR 092002AR 092002AR 092002AR 092002AR 0920Q2AR 092002BR bbbb 0 9 2 0 0 2 B ^ ^ ^
PFH S Fm m d (n s/m L )
ND ND ND ND 6460 6800 3940 4040 5280 5370 12600 13500 15700 15700 11700 11600 38600 40200 33000 34700 36900 39200 35700 38400 44900 47900 47900 51200 ND ND 65.3** 68.9** 81.1** 86.0** 45.6** 42.7** ND ND ND ND ND ND ND ND ND ND ND ND 9650 9560 7940 7940 8490 8200 8630 8720 5490 5420 6300 6370
**Although the method used allows for alternate sample volumes or weights and all the peak area
responses are within the calibration curve limits, the precision for the 0.1 mL or 0.1 g samples below 100 ppb has not been validated.
* Duplicate Injection
ND = Not Detected (Area less than lowest calibration standard of 0.1 ng/mL)
Exygen Research
Page 26 o f 153
418-028: PAGE G-27 Exygen Study No.: 023-072
Table VIII (cont'd). Summary of PFHS Residues in Rat Serum Samples
Sponsor ID
19037 GROUP D 19037 GROUP 0 1?043 GROUP II 19043 GROUP H* 19047 GROUP n 19047 GROUP D 19048 GROUP 0 19048 GROUP II* 19003 GROUP HI 19003 G R O U P 111* 19007 GR OU P HI 19007 GROU P HI* 19008 G R OU P m 19008 GROUP m * 19013 GR OU P m 19013 GROU P m * 19015 GR O U P DI 19015 G R OU P m * 19017 GROU P m 19017 GROUP HI* 19024 GROUP m 19024 GROUP m * 19029 GR O U P 01 19029 GROUP UI* 19034 G R OU P 01 19034 GROUP HI* 19056 GR OU P m 19056 GROUP m * 19005 GROUP IV 19005 GROUP IV* 19035 GROUP IV 19035 GROU P IV* 19039 GROUP IV 19039 GRO U P IV* 19040 GROUP IV 19040 GROUP IV* 19045 GROUP IV 19045 G R OU P IV* 19054 GROUP IV 19054 GROUP IV* 19058 GROU P IV 19058 GROUP IV* 19062 GROUP IV 19062 GROUP IV* 19063 GROUP IV 19063 G R OU P IV* 19066 GROUP IV 19066 GROUP IV* 19001 GROUP V 19001 G R O U P V* 19006 GROUP V 19006 GROU P V* 19011 GROUP V 19011 G R O U P V* 19020 GROUP V 19020 GROUP V* 19022 GROUP V 19022 GROUP V* 19025 GROUP V 19025 G R O U P V* 19027 GROUP V 19027 GROUP V* 19028 GROUP V 19028 GROUP V* 19030 GROUT V 19030 GR OU P V* 19031 GROUP V 19031 G R O U P V*
* Duplicate Injection
Exygen ID
0201891 0201891 Dup Iq
0201892 0201892 Dap Iq
0201893 0201893 D up Inj
0201894 0201894 D up Inj
0201895 0201895 D up Inj
0201896 0201896 D up Inj
0201897 0201897 Dup Iq
0201898 0201898 Dup Inj
0201899 0201899 D ap Iq
0201900 0201900 D up Inj
0201901 0201901 D up I q
0201902 0201902 Dup Iq
0201903 0201903 Dup Iq
0201904 0201904 D up Inj
0201905 0201905 Dup Iq
0201906 0201906 Dap Iq
0201907 0201907 Dup Iq
0201908 0201908 Dup Iq
0201909 0201909 Dup Iq
0201910 0201910 Dup Iq
0201911 0201911 D ap Iq
0201912 0201912 Dup Inj
0201913 0201913 Dup Iq
0201914 0201914 Dup Iq
0201915 0201915 Dup Iq
0201916 0201916 Dup Iq
0201917 0201917 Dup Iq
0201918 0201918 D up Inj
0201919 0201919 Dup Iq
0201920 0201920 Dap Iq
0201921 0201921 Dup Iq
0201922 0201922 D up Inj
0201923 0201923 Dup Iq
0201924 0201924 Don b i
M a tril
Pooled Pup Serum Poded Pup Sarco Pooled Pop Senas Pooled Pup Serum P o d ed Pup Serum P o d ed Pop Serum Pooled Pup Serum Pooled Pup S eu m Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum P o d ed Pup Serum P o d ed Pup Serum P o d e d Pup Serum P o d ed Pup Serum Pooled Pup Serum Pooled Pup Serum Poded Pup Seum P o d ed Pup Serum P o d e d Pup Serum Pooled Pup S eu m Pooled Pup Serum P o d ed Pop Serum P oded Pup Seum P o d ed Pup Serum P o d ed Pup Serum P o d ed Pup Serum P o d ed Pop Serum P o d ed Pup Serum P o d ed Pup Serum P o d e d Pup Serum P o d e d Pup Serum Pooled Pup Senun P o d ed Pup Serum P o d ed Pup Serum P o d ed Pup Serum P o d ed Pup Serum Pooled Pup Serum P o d ed Pup Serum P o d ed Pup Serum P o d ed Pop Serum P o d e d Pup Serum Pooled Pup Serum Pooled Pup Serum P o d ed Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pop S eu m Pooled Pup Serum Pooled Pup S eu m Pooled Pup Serum P o d ed Pup Serum P o d e d Pup Serum P o d ed Pup Serum Poded Pup Seum P o d e d Pup Serum Pooled Pup Serum Pooled Pup Serum Pooled Pup Serum Poded Pop Seum P o d ed Pup Serum Pooled Pup Serum P o d ed Pup Serum Pooled Pup S eum P o d ed Pup Serum Pooled Pup Serum Pooled Pup S eu m
C ollection D ate
5/29/02 5/29/02 5/28/02 5/28/02 5/28/02 5/28/02 5/31/02 5/31/02 5/30/02 5/30/02 5/30/02 5/30/02 5/31/02 5/31/02 5/29/02 S/29/02 5/31/02 5/31/02 5/28/02 5/28/02 5/31/02 5/31/02 5/29/02 5/29/02 5/30/02 5/3&Q2 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/31/02 5/29/02 5/29/02 5/30/02 5/30/02 5/28/02 5/28/02 5/31/02 5/31/02 5/28/02 5/28/02 5/31/02 5/31/02 5/29/02 5/29/02 5/31/02 5/31/02 5/13/02 5/13/02 5/13/02 5/13/02 V I 3/02 5/13/02 5/14/02 V 14/02 5/31/02 5/31/02 5/30/02 5/30/02 5/31/02 5/31/02 5/28/02 5/28/02 5/31/02 5/31/02 5/28/02 5/28/02
Set Num ber
092002BR 092002BR 092002 BR 092002BR 092002 BR 092002 BR 092002 BR 092002BR 092002BR 092002BR 092002BR 092002 BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 092002BR 0920Q2BR 092002BR 092002BR 092002BR 092002BR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AK 0923O2AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302A R 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302A R 092302AR 092302AR 092302AR 092302AR 09232AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR 092302AR
PFHS
F o u n d Ine/tnL )
12800 13000 5750 5970 8990 8810 11700 11700 37300 37400 47300 46300 44000 45400 24300 24600 36900 37000 20800
21200
42900 45000 24900 22600 45000 43700 19700 20500 30900 30800 34600 33500 22600 22800 40700 38400 27800 29300 42900 43800 25800 25800 41200 41100 19800 19100 36800 39300 29000 32700 47900 52400 162000 164000 72800 76200 84100 89400 50200 53900 57200 53700 162000 163000 184000 189000 71200 76200
Exygen Research
Page 27 of 153
418-028:PAGE G-28 Exygen Study No.: 023-072
Table IX. Summary of PFHS Residues in Rat Liver Samples
S ponsor ID
19176 G RO U P I 19176 G R O U P I* 19177 G RO U P I 1 9 1 7 7 G R O U P I* 19178 G R O U P I 1 9178 G R O U P I* 1 9179 G R O U P II 19179 G R O U P U* 1 9 1 8 0 G R O U P II 19180 G R O U P n * 19181 G R O U P n 19181 G R O U P H* 19182 G R O U P m
19182 g r o u p n r
1 9 1 8 3 G R O U P III
19183 GROUP in*
19184 G R O U P m
19184 G R O U P n r
19185 G R O U P IV 19185 G R O U P IV * 1 9186 G R O U P IV 1 9 1 8 6 G R O U P IV * 1 9187 G R O U P IV 1 9187 G R O U P IV *
19188 G R O U P V 19188 G R O U P V * 19189 G R O U P V 19189 G R O U P V* 19190 G R O U P V 19190 G R O U P V*
19076 G R O U P I 1 9 0 7 6 G R O U P I* 19077 G RO U P I 1 9 0 7 7 G R O U P 1* 19078 G R O U P I 1 9 0 7 8 G R O U P l* 19081 G R O U P H F e m a le 1
n1 9 0 8 1 G R O U P F e m a l e 1 *
19079 G R O U P U 19079 G R O U P H* 19080 G R O U P II 19080 G R O U P H* 19082 G RO U P m
19082 G R O U P n r
19083 G R O U P m
19083 GROUP n r
19084 G RO U P m
19084 GROUP n r
1 9085 G R O U P IV 1908S G R O U P IV * 19086 G R O U P IV 1 9086 G R O U P IV *
E xygen ID
0201759 0 2 0 1 7 5 9 D u p Inj
0201760 0 2 01760 D u p Inj
0201761 0201761 D u p Inj
0201762 0 2 0 1 7 6 2 D u p Inj
0201763 0 2 0 1 7 6 3 D u p Inj
0201764 02 0 1 7 6 4 D u p Inj
0201765 0 2 0 1 7 6 5 D u p Inj
0201766 0 2 0 1 7 6 6 D u p Inj
0201767 0 2 0 1 7 6 7 D u p Iqj
0201768 0 2 01768 D u p Inj
0201769 02 0 1 7 6 9 D u p Inj
0201770 0 2 0 1 7 7 0 D u p Inj
0201771 0201771 D u p Inj
0201772 0 2 0 1 7 7 2 D u p Inj
0201773 0 2 0 1 7 7 3 D u p Inj
0201774 0 2 0 1 7 7 4 D u p Inj
0201775 0 2 0 1 7 7 5 D u p Inj
0201776 0 2 0 1 7 7 6 D u p Inj
0203650 0 2 0 3 6 5 0 D u p Inj
0201777 0 2 0 1 7 7 7 D u p Inj
0201778 0 2 0 1 7 7 8 D u p Inj
0201779 0 2 0 1 7 7 9 D u p Inj
0201780 0 2 0 1 7 8 0 D u p Inj
0201781 0201781 D u p Inj
0201782 0 2 0 1 7 8 2 D u p Inj
0201783 0 2 01783 D u p Inj
M a trix
M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M ed ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M ed ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv er L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M ed ian L iv e r L o b e M ed ian L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M ed ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n liv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M ed ia n L aver L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M ed ian L iv er L obe M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M ed ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv er L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M ed ian L iv e r L o b e M ed ian L iv e r L o b e M ed ian L iv e r L o b e M e d ia n L iv er L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M ed ian L iv er L obe M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M ed ia n L iv e r L o b e M e d ia n L iv e r L o b e
C o lle c tio n D a te
5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5/1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2 5 /1 2 /0 2
5 /9 /0 2 5 /9 /0 2 5/1 9 /0 2 5 /1 9 /0 2 5 /7 /0 2 5 /7 /0 2 5 /1 0 /0 2 5 /1 0 /0 2 5 /9 /0 2 5 /9 /0 2 5 /9 /0 2 5 /9 /0 2 5 /9 /0 2 5 /9 /0 2 5 /7 /0 2 5 /7 /0 2 5 /9 /0 2 5 /9 /0 2 5 /6 /0 2 5 /6 /0 2 5 /6 /0 2 5 /6 /0 2
S et N um ber
092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092802A 092602A 092602A 092602A 092602A 092602A 092602A 092602A 092602A 092602A R 092602A R 092602A R 092602A R 092602A R 092602A R 092602AR 092602A R 092602A R 092602A R 092602A R 092602A R 092602A R 092602A R
PFH S F o u n d (n g /m L )
606 576 138 141 326 335 40100 42300 36800 37900 52900 52800 149000 154000 124000 121000 172000 177000 194000 187000 408000 407000 416000 420000 501000 511000 659000 675000 612000 603000 ND ND 8 2 .2 " 8 2 .4 " ND ND 628 633 1040 974 762 725 1960 2080 3070 3090 2700 2750 6360 6640 9740 9370
^Although the method used allows for alternate sample volumes or weights and all the peak area
responses are within the calibration curve limits, the precision for the 0.1 mL or 0.1 g samples below 100
ppb has not been validated.
* Duplicate Injection
ND = Not Detected (Area less than lowest calibration standard of 0.1 ng/mL)
Exygen Research
Page 28 of 153
418-028:PAGE G-29 Exygen Study No.: 023-072
Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples
S ponsor ID
E xygen ID
19087 G R O U P IV 1 9087 G R O U P IV
19088 G R O U P V 19088 G R O U P V * 19089 G R O U P V 19089 G RO U P V 19090 G R O U P V 19090 G R O U P V *
19076 G R O U P I 19076 G R O U P I* 19078 G R O U P I 1 9 0 7 8 G R O U P I* 19081 G R O U P D F em ale 2 19081 G R O U P n F e m a le 2* 19079 G R O U P H 19079 G R O U P H* 19080 G R O U P II 19080 G R O U P H* 19082 G R O U P m 19082 G R O U P m * 19083 G R O U P m 19083 G R O U P m 19084 G R O U P m 1 9 0 8 4 G R O U P H I* 190B 5 G R O U P IV 1 9085 G R O U P IV * 19086 G R O U P IV 1 9086 G R O U P IV * 19087 G R O U P IV 1 9087 G R O U P IV * 19088 G R O U P V 19088 G R O U P V * 19089 G R O U P V 19089 G R O U P V* 19090 G R O U P V 19090 G R O U P V * 19012 G R O U P I, M a le 1 1 9 0 1 2 G R O U P 1, M a le 1* 19012 G R O U P I, M a le 2 19012 G R O U P I, M ale 2* 19012 G R O U P I, M a le 3 19012 G R O U P I, M a le 3 * 19012 G R O U P I, M a le 4 19012 G R O U P I, M ale 4 * 19012 G R O U P I, M a le 5 1 9012 G R O U P I, M ale 5 * 19012 G R O U P I, F e m a le 7 1 9012 G R O U P I, F e m a le 7* 19012 G R O U P I, F e m a le 8 19012 G R O U P I, F e m a le 8* 1 9 012 G R O U P 1, F e m a le 14 19012 G R O U P I. F e m a le 14*
0201784 0 2 0 1 7 8 4 D u p Inj
0201785 0 2 0 1 7 8 5 D u p Inj
0201786 0 2 0 1 7 8 6 D u p Inj
0201787 0 2 0 1 7 8 7 D u p Inj
0201788 0 2 0 1 7 8 8 D u p Inj
0201789 0 2 0 1 7 8 9 D u p Inj
0203651 0203 6 5 1 D u p Inj
0201790 0 2 0 1 7 9 0 D u p Inj
0201791 0 2 0 1 7 9 1 D u p Inj
0201792 0 2 0 1 7 9 2 D u p Inj
0201793 0 2 0 1 7 9 3 D u p Inj
0201794 0 2 0 1 7 9 4 D u p Inj
0201795 0 2 0 1 7 9 5 D u p Inj
0201796 0 2 0 1 7 9 6 D u p Inj
0201797 0 2 0 1 7 9 7 D u p Inj
0201798 0 2 0 1 7 9 8 D u p Inj
0201799 02C 1799 D u p Inj
0201800 0 2 0 1 8 0 0 D u p Inj
0201925 0 2 0 1 9 2 5 D u p Inj . 0201926 0 2 0 1 9 2 6 D u p Inj
0201927 0 2 0 1 9 2 7 D u p Inj
0201928 0 2 0 1 9 2 8 D u p Inj
0201929 0 2 0 1 9 2 9 D u p Inj
0201930 0 2 0 1 9 3 0 D u p Inj
0201931 0 2 0 1 9 3 1 D u p Inj
0201932 0 2 0 1 9 3 2 D u p Inj
M a trix
M e d ia n L iv er L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e M e d ia n L iv er L o b e M e d ia n L iv e r L o b e M ed ian L iv er L o b e M e d ia n L iv e r L o b e M e d ia n L iv e r L o b e P o o le d F etal L iv e r P o o le d F e ta l L iv e r P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F e ta l L iv e r P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F etal liv e r P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F etal L iv er P o o le d F etal L iv e r P o o le d F etal L iv er P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F etal L iv e r P o o le d F etal L iv e r
P u p L iv ers P u p L iv e rs P u p L iv ers P u p L iv ers P up L iv e n P u p L iv ers P u p L iv ers P up L iv e n P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv ers P u p L iv ers
C o lle c tio n D a te
5 /6 /0 2 5 /6 /0 2 5 /9 /0 2 5 /9 /0 2 5 /9 /0 2 5 /9 /0 2 5 /9 /0 2 5 /9 /0 2 5 /9 /0 2 5 /9 /0 2 5 /7 /0 2 5 /7 /0 2 5 /1 0 /0 2 5 /1 0 /0 2 5 /9 /0 2 5 /9 /0 2 5/9 /0 2 5 /9 /0 2 5 /9 /0 2 5 /9 /0 2 5 /7 /0 2 5 /7 /0 2 5 /9 /0 2 5 /9 /0 2 5 /6 /0 2 5 /6 /0 2 5 /6 /0 2 5 /6 /0 2 5 /6 /0 2 5 /6 /0 2 5 /9 /0 2 5 /9 /0 2 5 /9 /0 2 5 /9 /0 2 5 /9 /0 2 5/9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2
S et N um ber
092602A R 092602A R 092602A R 092602A R 092602A R 092602A R 092602A R 092602A R 092602B
092602B 092602B 092602B 092602B 092602B 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092602B R 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A
PFH S F o u n d (n g /m L )
7500 7210 19000 20000 15100 15300 14700 15100 2 7 .7 ^ 2 5 .7 ~ ND ND 789 821 1460 1480 1810 1880 2180 2290 4560 4550 3020 3150 7320 7170 8510 8590 5630 5920 22200 22800 20100 19800 14700 13600 ND ND ND ND
ND ND ND ND ND ND ND ND ND ND ND ND
AAAlthough the method used allows for alternate sample volumes or weights and all the peak area
responses are within the calibration curve limits, the precision for the 0.1 mL or 0.1 g samples below 100
ppb has not been validated.
* Duplicate Injection
ND = Not Detected (Area less than lowest calibration standard of 0.1 ng/mL)
Exygen Research
Page 29 of 153
418-028:PAGE G-30 Exygen Study No.: 023-072
Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples
Sponsor ID
Exygen ID
1 9 0 1 2 G R O U P I, F e m a le IS 1 9 0 1 2 G R O U P I, F em ale IS * 1 9 0 1 2 G R O U P I, F em ale 16 1 9 0 1 2 G R O U P I, F e m a le 16*
1 9 0 1 9 G R O U P I, M ale 1 1 9 0 1 9 G R O U P I, M ale 1* 19019 G R O U P I, M ale 2 1 9 0 1 9 G R O U P I, M ale 2* 19019 G R O U P I, M ale 3 1 9 0 1 9 G R O U P I, M ale 3* 19019 G R O U P I, M ale 7 1 9019 G R O U P I, M ale 7* 1 9 0 1 9 G R O U P 1. M a le 8 1 9 0 1 9 G R O U P I, M ale 8* 1 9 0 1 9 G R O U P I, F e m a le 11 1 9 0 1 9 G R O U P I, F em ale 11* 1 9019 G R O U P I, F em ale 12 1 9019 G R O U P I, F e m a le 12* 1 9 0 1 9 G R O U P I, F e m a le 13 1 9019 G R O U P I, F em ale 13* 1 9 0 1 9 G R O U P I, F e m a le 14 1 9 0 1 9 G R O U P I, F e m a le 14* 1 9 0 1 9 G R O U P I, F em ale IS 1 9 0 1 9 G R O U P 1, F e m a le IS *
19021 G R O U P I, M a le 1 19021 G R O U P I, M ale 1* 19021 G R O U P I, M ale 2 1 9021 G R O U P I, M ale 2 * 19021 G R O U P I, M a le 6 19021 G R O U P I, M ale 6* 19021 G R O U P I, M ale 8 1 9 0 2 1 G R O U P 1, M a le 8 * 19021 G R O U P I, M a le 9 19021 G R O U P I, M ale 9* 1 9 0 2 1 G R O U P I, F e m a le 11 1 9 0 2 1 G R O U P 1, F e m a le 1 1* 19021 G R O U P I, F em ale 12 19021 G R O U P I, F em ale 12* 1 9021 G R O U P I, F e m a le 13 19021 G R O U P I, F em ale 13* 19021 G R O U P I, F em ale 14 19021 G R O U P I, F e m a le 14* 1 9 0 2 3 G R O U P 1, M a le 1 1 9023 G R O U P I, M a le 1* 19023 G R O U P 1, M ale 2 1 9 0 2 3 G R O U P I, M a le 2 * 19023 G R O U P I, M ale 3 1 9 0 2 3 G R O U P I, M a le 3 * 19023 G R O U P I, M ale 6 1 9023 G R O U P I, M a le 6* 19023 G R O U P I, M ale 7 19023 G R O U P L M a le 7*
0201933 0 2 0 1 9 3 3 D a p Inj
0201934 0 2 0 1 9 3 4 D a p Inj
0201935 0 2 0 1 9 3 5 D u p Inj
0201936 0 2 0 1 9 3 6 D u p Inj
0201937 0 2 0 1 9 3 7 D u p Inj
0201938 0 2 0 1 9 3 8 D u p Inj
0201939 0 2 0 1 9 3 9 D u p Inj
0201940 0 2 0 1 9 4 0 D u p Inj
0201941 0 2 0 1 9 4 1 D u p Inj
0201942 0 2 0 1 9 4 2 D u p Inj
0201943 0 2 0 1 9 4 3 D u p Inj
0201944 0 2 0 1 9 4 4 D u p Inj
0201945 02 0 1 9 4 S D u p Inj
0201946 0 2 0 1 9 4 6 D u p Inj
0201947 0 2 0 1 9 4 7 D u p Inj
0201948 0 2 0 1 9 4 8 D u p Inj
0201949 0 2 0 1 9 4 9 D u p Inj
0201951 0201 9 5 1 D u p Inj
0201952 0 2 0 1 9 5 2 D u p Inj
0201953 0 2 0 1 9 5 3 D u p Inj
0201954 0 2 0 1 9 5 4 D u p Inj
0201955 0 2 0 1 9 5 5 D u p Inj
0201956 0 2 0 1 9 5 6 D u p Inj
0201957 0 2 0 1 9 5 7 D u p Inj
0201958 0 2 0 1 9 5 8 D u p Inj
0201959 0 2 0 1 9 5 9 D u p Ini
Matrix
P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv ers P up L iv e n P u p L iv ers P u p L iv e n P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv e n P up L iv e n P up L iv e n P up L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P up L iv e n
Collectioa Date
5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2
Set Number
092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 092702A 0927O 2A 092702A 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B
PFHS Found (ng/mL)
ND ND ND ND ND ND ND ND 2 1 .7 * * 1 8 .3 * * 2 0 .5 * * 1 8 .9 * * ND ND ND ND ND ND 3 4 .0 * * 3 0 .6 * * ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND 5 0 .6 * * 5 3 .5 * * 3 4 .0 * * 3 7 .0 * * 1 9 .6 * * 2 4 .1 * * ND ND 3 0 .8 * * 3 4 .0 * *
^Although the method used allows for alternate sample volumes or weights and all the peak area
responses are within the calibration curve limits, the precision for the 0.1 mL or 0.1 g samples below 100
ppb has not been validated.
* Duplicate Injection
ND = Not Detected (Area less than lowest calibration standard o f 0.1 ng/mL)
Exygen Research
Page 30 of 153
418-028:PAGE G-31 Exygen Study No.: 023-072
Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples
S ponsor ID
9 19023 G R O U P I, F e m a le 8 19023 G R O U P I, F e m a le 9 19023 G R O U P I, F e m a le 9* 19023 G R O U P I, F e m a le 10 19023 G R O U P I, F e m a le 10* 1 9023 G R O U P I, F e m a le 11 1 9 0 2 3 G R O U P I, F e m a le 11 * 1 9 0 2 3 G R O U P 1, F e m a le 12 19023 G R O U P I, F e m a le 12* 19021 G R O U P l F em ale 10 19021 G R O U P I, F em ale 10*
19041 G R O U P I. M ale 1 19041 G R O U P I, M a le 1* 19041 G R O U P I, M a le 2 19041 G R O U P I. M a le 2* 1 9 0 4 1 G R O U P 1, M a le 3 19041 G R O U P I. M ale 3* 19041 G R O U P I, M a le 4 19041 G R O U P I, M ale 4 * 19041 G R O U P I, M a le 5 19041 G R O U P I, M ale 5* 19041 G R O U P I, F e m a le 8 1 9 0 4 1 G R O U P 1, F e m a le 8* 19041 G R O U P I, F e m a le 9 19041 G R O U P I, F e m a le 9* 19041 G R O U P I, F e m a le 15 19041 G R O U P I, F e m a le 15* 19041 G R O U P I, F em ale 16 19041 G R O U P I, F e m a le 16* 19041 G R O U P I, F e m a le 17 1 9 0 4 1 G R O U P 1, F e m a le 1 7 * 19004 G R O U P n , M ale 2 19004 G R O U P H , M a le 2* 19004 G R O U P H , M a le 3 19004 G R O U P II. M a le 3* 1 9004 G R O U P H M a le 4 19004 G R O U P H , M a le 4* 19004 G R O U P U , M ale 5 19004 G R O U P H , M a le 5* 19004 G R O U P H , M ale 6 19004 G R O U P D , M ale 6* 1 9004 G R O U P H F em ale 9 19004 G R O U P II, F em ale 9* 1 9 0 0 4 G R O U P H , F e m a le 11 1 9004 G R O U P n . F e m a le 11* 19004 G R O U P n , F e m a le 15 1 9 0 0 4 G R O U P 11, F e m a le 1 5 * 1 9 0 0 4 G R O U P 11, F e m a le 1 6 19004 G R O U P II, F em ale 16* 19004 G R O U P n . F em ale 17 1 9004 G R O U P H , F em ale 17*
E xygen ID
0201960 0 2 0 1 9 6 0 D a p Inj
0201961 0 2 0 1 9 6 1 D u p Inj
0201962 0 2 0 1 9 6 2 D u p Inj
0201963 0 2 0 1 9 6 3 D u p Inj
0201964 0 2 0 1 9 6 4 D u p Inj
0201950 0 2 0 1 9 5 0 D u p Inj
0201965 0 2 0 1 9 6 5 D u p Inj
0201966 0 2 0 1 9 6 6 D u p Inj
0201967 0 2 0 1 9 6 7 D u p Inj
0201968 0 2 0 1 9 6 8 D u p Inj
0201969 0 2 0 1 9 6 9 D u p Inj
0201970 0 2 0 1 9 7 0 D u p Inj
0201971 0 2 0 1 9 7 1 D u p Inj
0201972 0 2 0 1 9 7 2 D u p In j
0201973 0 2 0 1 9 7 3 D u p Inj
0201974 0 2 0 1 9 7 4 D u p Inj
0202025 0 2 0 2 0 2 5 D u p Inj
0202026 0 2 0 2 0 2 6 D u p Inj
0202027 0 2 0 2 0 2 7 D u p In j
0202028 0 2 0 2 0 2 8 D u p Inj
0202029 0 2 0 2 0 2 9 D u p Inj
0202030 0 2 0 2 0 3 0 D u p Inj
0202031 0202031 D u p lq j
0202032 0 2 0 2 0 3 2 D u p In j
0202033 0 2 0 2 0 3 3 D u p Inj
0202034 0 2 0 2 0 3 4 D u p In j
M a trix
P u p L iv e rs P u p L iv ers P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv ers P u p L iv e rs P u p L iv e rs P u p L iv ers P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv ers P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv ers P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs
C o lle c tio n D a te
5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 A 1 2
S et N um ber
092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B 092702B R 092702B R 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R 100102A R
PFH S F o u n d (n g /m L )
ND ND ND ND ND ND ND ND ND ND ND ND ND ND 2 4 .4 ~ 2 6 .6 ~ 2 6 .0 * * 2 4 .7 * A ND ND ND ND ND ND 3 0 .6 ^ 3 0 . 8 AA ND ND ND ND ND ND 1220 1160 1160 1120 2380 2480 1670 1670 2070 2000 1870 1880 1740 1710 1070 1060 1450 1530 946 983
^Although the method used allows for alternate sample volumes or weights and all the peak area
responses are within the calibration curve limits, the precision for the 0.1 mL or 0.1 g samples below 100
ppb has not been validated.
* Duplicate Injection
ND = Not Detected (Area less than lowest calibration standard o f 0.1 ng/mL)
Exygen Research
Page 31 of 153
418-028:PAGE G-32 Exygen Study No.: 023-072
Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples
S ponsor ID
E xygen ID
1 9018 G R O U P H M ale 1
1 9 0 1 8 G R O U P II, M a le 1*
1 9018 G R O U P H , M ale 4 19018 G R O U P U , M ale 4 *
1 9018 G R O U P I t M ale 5 19018 G R O U P H , M ale 5*
1 9018 G R O U P H M ale 6 19018 G R O U P H M ale 6*
1 9018 G R O U P H M ale 7 19018 G R O U P H , M a le 7*
1 9 0 1 8 G R O U P II, F e m a le 9
19018 G R O U P n . F em ale 9*
n,1 9 0 1 8 G R O U P F e m a l e 1 0
19018 G R O U P H F em ale 10*
1 9 0 1 8 G R O U P D , F e m a le 11
1 9 0 1 8 G R O U P n . F e m a le 11 *
1 9018 G R O U P II, F em ale 12
1 9018 G R O U P H F em ale 12*
1 9018 G R O U P II, F em ale 14
1 9018 G R O U P D , F em ale 14*
19026 G R O U P D, M a le s 1 9 0 2 6 G R O U P H M a le 5*
1 9026 G R O U P H M ale 1
n,1 9 0 2 6 G R O U P
M ale 1*
1 9 0 2 6 G R O U P It, M a le 3
1 9026 G R O U P n , M ale 3*
19026 G R O U P II, M ale 4
n,1 9 0 2 6 G R O U P M a l e 4 *
1 9 0 2 6 G R O U P II, M ale 7
1 9026 G R O U P B , M a le 7*
n.1 9 0 2 6 G R O U P
F em ale 12
n,1 9 0 2 6 G R O U P F e m a l e 1 2 *
1 9 0 2 6 G R O U P I t F e m a le 13
n,1 9 0 2 6 G R O U P F e m a l e 1 3 *
1 9026 G R O U P I t F em ale 14
1 9026 G R O U P H F em ale 14*
n.1 9 0 2 6 G R O U P
F e m a le IS
1 9 0 2 6 G R O U P B , F e m a le IS *
1 9 0 2 6 G R O U P I t F e m a le 18
1 9 0 2 6 G R O U P B , F em ale 18*
19036 G R O U P I t M ale 1
1 9 0 3 6 G R O U P I t M a le 1* 19036 G R O U P I t M ale 2
19036 G R O U P I t M ale 2*
19036 G R O U P H , M ale 4
n.1 9 0 3 6 G R O U P M a l e 4 *
1 9 0 3 6 G R O U P I t M ale S
19036 G R O U P H , M a le S *
1 9 0 3 6 G R O U P I t M ale 6 19036 G R O U P D , M a le 6*
1 9 0 3 6 G R O U P B , F em ale 7
1 9 0 3 6 G R O U P I t F e m a le 7*
0202050 0 2 0 2 0 S 0 D u p Inj
0202051 0 2 0 2 0 5 1 D u p ln j
0202052 0 2 0 2 0 5 2 D u p ln j
0202053 0 2 0 2 0 5 3 D u p ln j
0202054 0 2 0 2 0 5 4 D u p ln j
0202055 0 2 0 2 0 5 5 D u p Inj
0202056 0 2 0 2 0 5 6 D u p ln j
0202057 0 2 0 2 0 5 7 D u p ln j
0202058 0 2 0 2 0 5 8 D u p ln j
0202059 0 2 0 2 0 5 9 D u p ln j
0202063 0 2 0 2 0 6 3 D u p Inj
0202060 0 2 0 2 0 6 0 D u p Inj
0202061 0 2 0 2 0 6 1 D u p ln j
0202062 0 2 0 2 0 6 2 D u p Inj
0202064 0 2 0 2 0 6 4 D u p ln j
0202065 0 2 0 2 0 6 5 D u p Inj
0202066 0 2 0 2 0 6 6 D u p Inj
0202067 0 2 0 2 0 6 7 D u p Inj
0202068 0 2 0 2 0 6 8 D u p Inj
0202069 0 2 0 2 0 6 9 D u p ln j
0202070 0 2 0 2 0 7 0 D u p Inj
0202071 0 2 0 2 0 7 1 D u p Inj
0202072 0 2 0 2 0 7 2 D u p Inj
0202073 0 2 0 2 0 7 3 D u p Inj
0202074 0 2 0 2 0 7 4 D u p Inj
0202075 0 2 0 2 0 7 5 D u p Inj
M a trix
P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv e rs P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv e rs P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv ers P up L iv e n P u p L iv e n P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv e rs P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv ers P u p L iv ers
C o lle c tio n D a te
5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2
S et N um ber
100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A 100202A R 100202A R 100202A R 100202A R 100202A R 100202A R 100202A R 100202A R 100202A R 100202A R 100202A R 100202A R 100202A R 100202A R 100202A R 100202A R 100202A R 100202A R 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A
PFH S F o u n d (n g /m L )
839 816 788 818 886 872 868 888 523 514 556 596 804 785 649 664 743 751 788 815 937 928 1130 1130 1170 1150 1140 1130 1050 1010 946 956 928 919 1040 1140 1780 1830 1270 1310 746 748 169 174 707 693 965 946 667 649 622 620
* Duplicate Injection
ND = N ot D etected (Area less than low est calibration standard o f 0.1 ng/mL)
Exygen Research
Page 32 of 153
418-028:PAGE G-33 Exygen Study No.: 023-072
Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples
S ponsor
ID
E xygen
ID
1 9 0 3 6 G R O U P a F e m a le 8
0202076
1 9036 G R O U P U . F em ale 8* 0 2 0 2 0 7 6 D u p ln j
1 9 0 3 6 G R O U P n , F e m a le 11
0202077
1 9 0 3 6 G R O U P D , F em ale 11 * 0 2 0 2 0 7 7 D u p ln j
1 9036 G R O U P H , F em ale 12
0202078
1 9 0 3 6 G R O U P II, F em ale 12 0 2 0 2 0 7 8 D u p Inj
1 9 0 3 6 G R O U P n , F e m a le 13
0202079
1 9 0 3 6 G R O U P H F e m a le 13 0 2 0 2 0 7 9 D u p Inj
1 9037 G R O U P U , M a le 6
0202082
19037 G R O U P U . M ale 6
0 2 0 2 0 8 2 D u p Inj
1 9 0 3 7 G R O U P II, F e m a le 15
0202089
1 9 0 3 7 G R O U P 11, F e m a le 1 5 * 0 2 0 2 0 8 9 D u p In j
19037 G R O U P H M ale 2
0202080
19037 G R O U P n , M a le 2*
0 2 0 2 0 8 0 D u p Inj
1 9037 G R O U P II, M ale 3
0202081
1 9037 G R O U P U , M a le 3
19037 G R O U P n, M ale 7
0202081 D u p ln j 20831983
1 9037 G R O U P II, M a le 7*
19037 G R O U P n, M ale 8
0 2 0 2 0 8 3 D u p Inj 0202084
19037 G R O U P D , M a le 8*
0 2 0 2 0 8 4 D u p Inj
1 9037 G R O U P II, F em ale 10
0202085
1 9 0 3 7 G R O U P II, F e m a le 10* 0 2 0 2 0 8 5 D u p Inj
1 9 0 3 7 G R O U P a F e m a le 11
0202086
1 9 0 3 7 G R O U P H , F e m a le 11 * 0 2 0 2 0 8 6 D u p In j
1 9 0 3 7 G R O U P II, F e m a le 13
0202087
1 9 0 3 7 G R O U P a F e m a le 13* 0 2 0 2 0 8 7 D u p Inj
1 9 0 3 7 G R O U P a F e m a le 14
0202088
1 9 0 3 7 G R O U P a F em ale 14*
19003 G R O U P m , M ale 1 1 9003 G R O U P m , M a le 1* 19003 G R O U P m , M ale 3
0 2 0 2 0 8 8 D u p Inj 0202119
0 2 0 2 1 1 9 D u p Inj 0202120
19003 G R O U P H I, M ale 3*
19003 GROUP m , M a l e 5 19003 G R O U P m , M ale 5*
0 2 0 2 1 2 0 D u p Inj 0202121
0202121 D u p ln j
19003 G R O U P H I, M a le 7
0202122
19003 G R O U P i a M ale 7*
19003 GROUP m , M a l e 8
0 2 0 2 1 2 2 D u p Inj 0202123
19003 G R O U P i a M ale 8* 19003 G R O U P U I, F em ale 9
0 2 0 2 1 2 3 D u p Inj 0202124
1 9 0 0 3 G R O U P i a F e m a le 9* 0 2 0 2 1 2 4 D u p Inj
1 9003 G R O U P m . F e m a le 10
0202125
19003 G R O U P III, F em ale 10* 0 2 0 2 1 2 5 D u p Inj
1 9 0 0 3 G R O U P m . F e m a le 11
0202126
1 9 0 0 3 G R O U P H I, F e m a le 11 * 0 2 0 2 1 2 6 D u p Inj
1 9003 G R O U P i a F em ale 15
0202127
19003 G R O U P H I, F e m a le 15* 0 2 0 2 1 2 7 D u p Inj
1 9 0 0 3 G R O U P m . F e m a le 16
0202128
19003 G R O U P H I, F em ale 16* 0 2 0 2 1 2 8 D u p Inj
1 9007 G R O U P m , M ale 1
0202129
1 9 0 0 7 G R O U P i a M a le 1*
0 2 0 2 1 2 9 D u p Inj
1 9007 G R O U P i a M ale 2
0202130
1 9 0 0 7 G R O U P m , M a le 2*
0202130 D u p ln j
M a trix
P up L iv e n P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv e rs P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv ers P u p L iv e rs P u p L iv e rs P u p L iv ers P u p L iv e rs P u p L iv ers P u p L iv e n P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv ers P u p L iv e rs P u p L iv e rs P u p L iv ers P u p L iv e n P up L iv e n P u p L iv e rs P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv e n P u p L iv e n P up L iv e n P u p L iv e n P u p L iv e n P up L iv e n P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n
C o lle c tio n D a te
5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2
Set N um ber
PFH S F o u n d (n g /m L )
100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A 100302A R 100302A R 100302A R 100302A R 100302A R 100302A R 100302A R 100302A R 100302A R 100302A R 100302A R 100302A R 100302A R 100302A R 100302A R 100302A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 10Q 402A R ' 100402A R 100402A R 100402A R 100402A R
668 650 554 543 676 642 494 490 906 900 956 965 1670 1670 1430 1380 1280 1270 1760 1770 1150 1160 1300 1320 1680 1670 1330 1350 4640 4730 6250 6320 4490 4650 4540 4440 5820 5840 4100 4170 4400 4340 3270 3240 4810 4920 5430 5630 3030 3090 4310 4400
* D uplicate Injection
ND = N ot D etected (A rea less than low est calibration standard o f 0.1 ng/m L)
Exygen Research
Page 33 of 153
418-028:PAGE G-34 Exygen Study No.: 023-072
Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples
S ponsor ID
E xygen
n>
19007 G R O U P m , M ale 3
0202131
19007 G R O U P III, M a le 3*
0202131 D u p ln j
19007 G R O U P m M ale 6
0202132
19007 G R O U P m , M ale 6*
0 2 0 2 1 3 2 D u p Inj
1 9 0 0 7 G R O U P m , M ale 7
0202133
1 9007 G R O U P H I, M ale 7* 1 9 0 0 7 G R O U P 111, F e m a l e 9
0 2 0 2 1 3 3 D u p Inj 0202134
19007 G R O U P m . F em ale 9* 0 2 0 2 1 3 4 D u p Inj
1 9 0 0 7 G R O U P H I, F e m a le 11 19007 G R O U P m , F e m a le 11*
0202135 0 2 0 2 1 3 5 D u p Inj
1 9007 G R O U P m . F em ale 12
0202136
1 9 007 G R O U P m F e m a le 12*
1 9 0 0 7 G R O U P in , F e m a le 13
0202136 D u p ln j 0202137
1 9007 G R O U P III, F e m a le 13* 0 2 0 2 1 3 7 D u p Inj
1 9 0 0 7 G R O U P H I, F e m a le 16
0202138
1 9007 G R O U P m , F em ale 16* 0 2 0 2 1 3 8 D u p Iqj
1 9008 G R O U P H I, M ale 1
0202139
1 9 0 0 8 G R O U P 1C , M a le 1*
0 2 0 2 1 3 9 D u p Inj
19008 G R O U P m , M ale 3
0202140
19008 G R O U P m , M a le 3*
19008 G R O U P m , M ale 4
0 2 0 2 1 4 0 D u p Inj 0202141
19008 G R O U P m , M ale 4*
0 2 0 2 1 4 1 D u p Inj
19008 G R O U P H I, M ale 6
19008 G R O U P in , M a le 6*
19008 G R O U P H I. M ale 7
19008 GROUP i n , M a l e 7*
19008 G R O U P m . F em ale 9
0202142 0202142 D u p ln j
0202143 0 2 0 2 1 4 3 D u p Inj
0202144
1 9 008 G R O U P m , F e m a le 9 * 0 2 0 2 1 4 4 D u p Inj
19008 G R O U P m , F em ale 10
0202145
19008 G R O U P H I, F em ale 10*
1 9 0 0 8 G R O U P m . F e m a le 11
0 2 0 2 1 4 5 D u p Inj 0202146
19008 G R O U P U I, F em ale 11* 0 2 0 2 1 4 6 D u p Inj
1 9008 G R O U P m , F em ale 12
0202147
19008 G R O U P m . F em ale 12* 0 2 0 2 1 4 7 D u p Inj
19008 G R O U P m . F em ale 13
19008 G R O U P m . F em ale 13*
0202148 0 2 0 2 1 4 8 D u p Ipj
19013 G R O U P U I, M ale 1
0202149
1 9013 G R O U P III, M a le 1*
0 2 0 2 1 4 9 D u p Inj
19013 G R O U P m , M ale 4
0202150
19013 G R O U P m , M ale 4*
0 2 0 2 1 5 0 D u p Inj
1 9 0 1 3 GROUP m , M a le 3
0202151
19013 G R O U P m , M ale 5*
0 2 02151 D u p Inj
19013 G R O U P m , M ale 6
19013 GROUP in , M a l e 6*
0202152 0202152 D u p ln j
1 9013 G R O U P m , M ale 9
19013 GROUP m , M a l e 9*
1 9 0 1 3 G R O U P U I, F e m a le 11
0202153 0 2 0 2 1 5 3 D u p Inj
0202154
19013 G R O U P m , F e m a le 11*
1 9 0 1 3 G R O U P ni. F e m a le 12
0 2 0 2 1 5 4 D u p Inj 0202155
19013 G R O U P H I, F em ale 12* 0 2 0 2 1 5 5 D u p Inj
19013 G R O U P H I, F em ale 13
0202156
19013 G R O U P m , F em ale 13 0 2 0 2 1 5 6 D u p Inj
M a trix
P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv e rs P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv e n P u p L iv e rs P u p L iv e rs P u p L iv e n P u p L iv e rs P u p L iv ers P u p L iv ers P up liv e rs P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv ers P u p L iv e rs P u p L iv ers P u p L iv e rs P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv e rs P u p L iv e rs P u p L iv ers P u p L iv ers
C o lle c tio n D a te
5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5/3 1 /0 2 5 /3 1 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5/2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5/2 9 /0 2 5/2 9 /0 2 5/2 9 /0 2 5/2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2
S et N um ber
100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402A R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R 100402B R
PFH S F o u n d (n g /m L )
4450 4370 4430 4600 5630 5720 6340 6330 3850 3820 5230 5130 6630 6870 5720 5690 3920 3810 5080 5070 4090 4070 4810 4750 4690 4380 5190 5050 3070 2770 4120 3760 2790 2480 2440 2340 1590 1790 1950 2050 2030 2090 2420 2480 2180 2280 2130 2150 2000 2010 1680 1780
* Duplicate Injection
ND = N ot D etected (Area less than low est calibration standard o f 0.1 ng/mL)
Exygen Research
Page 34 of 153
418-028:PAGE G-35 Exygen Study No.: 023-072
Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples
Sponsor ID
Exygen ID
19013 G R O U P m , F e m a le 14
0202157
19013 G R O U P H I, F e m a le 14* 0 2 0 2 1 5 7 D u p ln j
19013 G R O U P m . F e m a le 15
0202158
19013 G R O U P H I, F e m a le 15* 0 2 0 2 1 5 8 D u p Inj
19015 G R O U P III, M ale 1
0202159
1 9015 G R O U P m , M a le 1*
0 2 0 2 1 5 9 D u p Inj
19015 G R O U P m , M ale 3
1 9 0 1 5 G R O U P in, M a le 3 *
0202160 0 2 0 2 1 6 0 D u p Inj
19015 G R O U P m , M ale 6
0202161
19015 G R O U P ID . M a le 6*
02 0 2 1 6 1 D u p Inj
19015 G R O U P H I, M ale 7 19015 G R O U P in , M a le 7*
0202162 0 2 0 2 1 6 2 D u p Inj
19015 G R O U P m , M a le 8
0202163
19015 G R O U P m , M a le 8* 1 9015 G R O U P m , F e m a le 10
0 2 0 2 1 6 3 D u p Inj 0202164
19015 G R O U P m , F e m a le 10* 19015 G R O U P H I, F e m a le 12 19015 G R O U P m , F e m a le 12* 19015 G R O U P m . F e m a le 13 19015 G R O U P m , F e m a le 13*
0 2 0 2 1 6 4 D u p Inj 0202165
0 2 0 2 1 6 5 D u p Inj 0202166
0 2 0 2 1 6 6 D u p Inj
1 9015 G R O U P m , F e m a le 14
0202167
1 9015 G R O U P m , F e m a le 14* 0 2 0 2 1 6 7 D u p Inj
19015 G R O U P m . F e m a le 15
0202168
19015 G R O U P m . F e m a le 15* 0 2 0 2 1 6 8 D u p Inj
1 9005 G R O U P IV , M a le 1
0202219
19005 G R O U P IV , M ale 1*
0 2 0 2 2 1 9 D u p Inj
19005 G R O U P IV , M a le 2
0202220
1 9005 G R O U P IV , M ale 2*
0 2 0 2 2 2 0 D u p Inj
19005 G R O U P IV , M a le 3 19005 G R O U P IV , M ale 3*
0202221 0202221 D u p ln j
19005 G R O U P IV , M a le 5
0202222
19005 G R O U P IV , M ale 5* 19005 G R O U P IV , M a le 6
0 2 0 2 2 2 2 D u p Inj 0202223
19005 G R O U P IV , M a le 6*
0 2 0 2 2 2 3 D u p Inj
1 9005 G R O U P IV , F e m a le 8 19005 G R O U P IV , F e m a le 8*
0202224 0 2 0 2 2 2 4 D u p Inj
19005 G R O U P IV , F e m a le 10
0202225
1 9005 G R O U P IV , F e m a le 10* 1 9 0 0 5 G R O U P IV , F e m a le 11
0 2 0 2 2 2 5 D u p Inj 0202226
19005 G R O U P IV , F em ale 11 0 2 0 2 2 2 6 D u p Inj
19005 G R O U P IV , F e m a le 12
0202227
19005 G R O U P IV , F e m a le 12* 0 2 0 2 2 2 7 D u p Inj
1 9005 G R O U P IV , F e m a le 15
0202228
19005 G R O U P IV , F em ale 15* 0 2 0 2 2 2 8 D u p Inj
19035 G R O U P IV , M a le 1
0202229
19035 G R O U P IV , M ale 1*
0 2 0 2 2 2 9 D u p Inj
1 9035 G R O U P IV , M a le 2
0202230
19035 G R O U P IV , M ale 2 *
0 2 0 2 2 3 0 D u p Inj
19035 G R O U P IV , M a le 4
0202231
1 9035 G R O U P IV , M ale 4*
0 2 0 2 2 3 1 D u p Inj
19035 G R O U P IV , M ale 5
0202232
19035 G R O U P IV , M ale 5
0202 2 3 2 D u p ln j
Matrix
P u p L iv ers P up L iv e n P up L iv e n P up L iv e n P up L iv e n P u p L iv ers P u p L iv e n P up L iv e n P up L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P up L iv e n P up L iv e n P u p L iv e n P u p L iv ers P up L iv e n P up L iv e n P up L iv e n P up L iv e n P up L iv e n P o p L iv ers P up L iv e n P up L iv e n P up L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P up L iv e n P up L iv e n P u p L iv ers P u p L iv e n P u p L iv ers P u p L iv e n P up L iv e n P up L iv e n P u p L iv ers P u p L iv e n P u p L iv ers P up L iv e n P up L iv e n P up L iv e n P up L iv e n P u p L iv e n P up L iv e n P up L iv e n P u p L iv e n P up L iv e n P up L iv e n P u p L iv e n P up L iv e n P up L iv e n
Collection Date
5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2
Set Number
100402B R 100402B R 100402B R I00402B R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 10 0 9 0 2 A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R I00 9 0 2 A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902A R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R
PFHS Fonad(ne/mLl
2290 2300 2000 2070 2950 2840 2780 2840 2860 2940 3150 3220 4680 4710 3800 3800 4280 4180 4000 3950 3800 3890 5330 5420 8860 8800 9280 9370 10500 11100 8340 9100 11200 10900 11400 11500 12300 12800 12600 12800 9010 9100 11800 12000 11500 12000 14500 14500 13700 13600 11300 10800
* Duplicate Injection
N D --N ot D etected (Area less than low est calibration standard o f 0.1 ng/mL)
Exygen Research
Page 35 o f 153
418-028:PAGE G-36 Exygen Study No.: 023-072
Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples
S ponsor ID
E xygen ID
19035 G R O U P IV , M a le 6
0202233
19035 G R O U P IV , M a le 6*
0 2 0 2 2 3 3 D u p Inj
19035 G R O U P IV , F e m a le 8
0202234
19035 G R O U P IV , F e m a le 8* 0 2 0 2 2 3 4 D u p Inj
19035 G R O U P IV , F e m a le 10
0202235
19035 G R O U P IV , F e m a le 10* 0 2 0 2 2 3 5 D u p Inj
1 9 0 3 5 G R O U P I V , F e m a le 11 19035 G R O U P IV , F e m a le 11*
0202236 0 2 0 2 2 3 6 D u p Inj
19035 G R O U P IV , F e m a le 12
0202237
19035 G R O U P IV , F e m a le 12* 0 2 0 2 2 3 7 D u p Inj
19035 G R O U P IV , F e m a le 13
0202238
19035 G R O U P IV , F e m a le 13* 0 2 0 2 2 3 8 D u p Inj
19039 G R O U P IV , M a le 1
0202239
19039 G R O U P IV , M a le 1*
0 2 0 2 2 3 9 D u p Iqj
19039 G R O U P IV , M a le 2
0202240
19039 G R O U P r v , M a le 2 *
0 2 0 2 2 4 0 D u p Inj
19039 G R O U P IV , M a le 3
0202241
19039 G R O U P IV , M a le 3 *
0 2 0 2 2 4 1 D u p Inj
19039 G R O U P IV , M a le 4
0202242
1 9039 G R O U P IV , M ale 4 *
0 2 0 2 2 4 2 D u p Inj
19039 G R O U P IV , M a le 5
0202243
1 9039 G R O U P IV , M a le 5*
0 2 0 2 2 4 3 D u p Inj
1 9039 G R O U P IV , F e m a le 8
0202244
19039 G R O U P IV , F e m a le 8*
1 9 0 3 9 G R O U P rv, F e m a le 11
0 2 0 2 2 4 4 D u p Inj 0202245
19039 G R O U P IV , F e m a le 11* 0 2 0 2 2 4 5 D u p Inj
19039 G R O U P IV , F e m a le 12
0202246
19039 G R O U P IV , F e m a le 12* 0 2 0 2 2 4 6 D u p Inj
1 9039 G R O U P IV , F e m a le 14
0202247
1 9039 G R O U P IV , F e m a le 14* 0 2 0 2 2 4 7 D u p Inj
1 9 0 39 G R O U P IV , F e m a le 15
0202248
19039 G R O U P IV , F e m a le 15* 0 2 0 2 2 4 8 D u p Inj
19040 G R O U P IV , M a le 2
19040 GROUP rv , M a l e 2*
0202249 0 2 0 2 2 4 9 D u p Inj
19040 G R O U P IV , M a le 3
0202250
19040 G R O U P IV , M a le 3 *
0 2 0 2 2 5 0 D u p Inj
1 9040 G R O U P IV , M a le 4
0202251
1 9040 G R O U P IV , M a le 4*
0 2 0 2 2 5 1 D u p Inj
19040 G R O U P IV , M ale 5 1 9040 G R O U P fV , M a le 5*
0202252 0 2 0 2 2 5 2 D u p Inj
1 9040 G R O U P IV , M a le 7
0202253
1 9040 G R O U P IV , M a le 7*
0 2 0 2 2 5 3 D u p Inj
1 9 0 4 0 G R O U P IV , F e m a le 11
0202254
19040 G R O U P IV , F e m a le 11* 0 2 0 2 2 5 4 D u p Inj
1 9040 G R O U P IV , F e m a le 12
0202255
19040 G R O U P IV , F em ale 12* 0 2 0 2 2 5 5 D u p Inj
1 9 040 G R O U P IV , F e m a le 13
0202256
19040 G R O U P IV , F em ale 13* 0 2 0 2 2 5 6 D u p Inj
19040 G R O U P IV , F e m a le 15
0202257
1 9040 G R O U P IV , F e m a le 15* 0 2 0 2 2 5 7 D u p Inj
19040 G R O U P IV , F e m a le 16
0202258
1 9040 G R O U P IV , F e m a le 16* 0 2 0 2 2 5 8 D u p Inj
M a trix
P up L iv e n P up L iv e n P u p L iv e n P u p L iv en P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv e n P up L iv e n P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P up L iv e n P u p L iv e n P up L iv e n P u p L iv e n P up L iv e n P u p L iv ers P up L iv e n P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv ers P u p L iv e n P up L iv en P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv en P u p L iv e n P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv en P u p L iv e n P u p L iv e n P u p L iv e n P up L iv e n P u p L iv e n
C o lle c tio n D a te
5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 S /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /2 9 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2
Set N um ber
100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R I00902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R 100902B R I0 0 9 0 2 B R 100902B R 100902B R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 1 0 I0 0 2 A R 101002A R 1 0 I0 0 2 A R 101002A R 101002A R 101002A R 101002A R
PFH S F o u n d (n g /m L )
10600 10500 12000 13300 10000 10400 18500 18400 12600 12000 17300 17300 5320 5200 6160 6310 5300 5150 5870 6130 6500 6430 4910 5010 3510 3710 4550 4620 4310 4180 5110 4920 6480
7690
11500 11200 7540 7750 13000 12200 11100 11100 12100 11200 10600 10700 14100 14000 12400 12300 14900 15700
* Duplicate Injection
ND = N ot D etected (Area less than low est calibration standard o f 0.1 ng/mL)
Exygen Research
Page 36 of 153
418-028: PAGE G-37 Exygen Study No.: 023-072
Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples
S ponsor ID
E xygen ID
19045 G R O U P IV , M a le !
0202259
1 9045 G R O U P IV , M ale 1*
0 2 0 2 2 5 9 D u p Inj
1 9045 G R O U P IV , M a le 2 1 9045 G R O U P IV , M ale 2* 19045 G R O U P IV , M ale 4
0202260 0 2 0 2 2 6 0 D u p Inj
0202261
19045 G R O U P IV , M ale 4*
0 2 0 2 2 6 1 D u p Inj
1 9045 G R O U P IV , M ale 5
0202262
19045 G R O U P IV , M ale 5*
0 2 0 2 2 6 2 D u p Inj
1 9045 G R O U P IV , M a le 6
0202263
1 9 0 4 5 G R O U P IV , M ale 6* 19045 G R O U P IV , F e m a le 8
0 2 0 2 2 6 3 D u p Inj 0202264
19045 G R O U P IV , F e m a le 8* 0 2 0 2 2 6 4 D u p Inj
1 9 0 4 5 G R O U P IV , F e m a le 9 19045 G R O U P IV . F e m a le 9*
0202265 0 2 0 2 2 6 5 D u p Inj
19045 G R O U P IV , F e m a le 10
0202266
19045 G R O U P IV , F e m a le 10* 0 2 0 2 2 6 6 D u p Inj
1 9 0 45 G R O U P IV , F e m a le 11
0202267
19045 G R O U P IV , F e m a le 11* 19045 G R O U P IV , F e m a le 14
0 2 0 2 2 6 7 D u p Inj 0202268
19045 G R O U P IV , F e m a le 14 0 2 0 2 2 6 8 D u p Inj
1 9 0 0 6 G R O U P V , M ale 1
0202320
1 9 0 0 6 G R O U P V , M a le 1*
0 2 0 2 3 2 0 D u p Inj
1 9006 G R O U P V , M a le 2
0202321
1 9 0 0 6 G R O U P V , M ale 2*
02 0 2 3 2 1 D u p Inj
1 9006 G R O U P V , M ale 3
0202322
1 9 0 0 6 G R O U P V , M ale 3*
0 2 0 2 3 2 2 D u p In]
1 9006 G R O U P V , M ale 4 19006 G R O U P V , M ale 4 *
0202323 0 2 0 2 3 2 3 D u p Inj
1 9 0 0 6 G R O U P V , M ale 5
0202324
1 9 0 0 6 G R O U P V . M ale 5*
0 2 0 2 3 2 4 D u p Inj
1 9 0 0 6 G R O U P V , F e m a le 8
0202325
1 9006 G R O U P V , F e m a le 8* 0 2 0 2 3 2 5 D u p Inj
1 9006 G R O U P V , F e m a le 10
0202326
1 9 0 06 G R O U P V , F e m a le 10* 0 2 0 2 3 2 6 D u p Inj
1 9 0 0 6 G R O U P V , F e m a le 11
0202327
19006 G R O U P V , F em ale 11* 0 2 0 2 3 2 7 D u p Inj
1 9006 G R O U P V , F e m a le 13
0202328
1 9006 G R O U P V , F e m a le 13* 0 2 0 2 3 2 8 D u p Inj
1 9006 G R O U P V , F em ale 18
0202329
1 9006 G R O U P V , F e m a le 18* 0 2 0 2 3 2 9 D u p Inj
19011 G R O U P V , M ale 2
0202330
19011 G R O U P V , M a le 2*
0 2 0 2 3 3 0 D u p Inj
19011 G R O U P V , M ale 3
0202331
19011 G R O U P V , M ale 3*
02 0 2 3 3 1 D u p Inj
19011 G R O U P V , M ale 4
0202332
19011 G R O U P V , M ale 4*
0 2 0 2 3 3 2 D u p Inj
19011 G R O U P V , M ale 5
0202333
19011 G R O U P V , M a le 5*
0 2 0 2 3 3 3 D u p Inj
19011 G R O U P V , M ale 6
0202334
19011 G R O U P V , M ale 6
0 2 0 2 3 3 4 D u p Inj
19011 G R O U P V , F e m a le 9
0202335
19011 G R O U P V , F em ale 9* 0 2 0 2 3 3 5 D u p Inj
M a trix
P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv e n P u p leiv e rs P u p L iv ers P u p L iv e n P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv ers P up L iv e n P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv e n P u p L iv ers P u p liv e rs P u p L iv e n P u p L iv e n P u p L iv ers P u p L iv e n P u p L iv e n P u p L iv e n P u p L iv e n
C o lle c tio n D a te
5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5/2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /2 8 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5/3 0 /0 2 5 /3 0 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2
S et N um ber
1 0I002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002A R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 1010Q 2BR 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R 101002B R
PFH S F o u n d (n g /m L )
6200 6210 4830 4900 7820 7510 5700 5750 4840 4970 7350 7350 6510 6740 8350 8010 6520 6380 6030 5870 13500 13700 16500 16700 25800 26100 30100 29400 30200 29800 23300 22500 17700 16400 25000 25000 16700 16500 20700 20200 19200 20000 18700 19900 19300 19000 18600 19300 14000 14100 20800 21100
* D uplicate Injection
ND = N ot D etected (Area less than low est calibration standard o f 0.1 ng/mL)
Exygen Research
Page 37 of 153
418-028:PAGE G-38 Exygen Study No.: 023-072
Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples
Sponsor ID
Exygen ID
19011 G R O U P V , F e m a le 10
0202336
19011 G R O U P V , F e m a le 10 0 2 0 2 3 3 6 D u p Inj
19011 G R O U P V , F e m a le 11
0202337
19011 G R O U P V , F e m a le 11* 0 2 0 2 3 3 7 D u p Inj
19011 G R O U P V , F em ale 12
0202338
19011 G R O U P V , F e m a le 12* 0 2 0 2 3 3 8 D u p Inj
19011 G R O U P V , F e m a le 13
0202339
19011 G R O U P V , F em ale 13* 0 2 0 2 3 3 9 D u p Inj
19020 G R O U P V , M a le 2
0202340
19020 G R O U P V . M ale 2*
0 2 0 2 3 4 0 D u p Inj
19020 G R O U P V , M a le 4
0202341
19020 G R O U P V , M ale 4 *
0 2 0 2 3 4 1 D u p Inj
19020 G R O U P V , M a le 5
0202342
19020 G R O U P V , M ale 5*
0 2 0 2 3 4 2 D u p Inj
19020 G R O U P V , M ale 7
0202343
19020 G R O U P V , M ale 7*
0 2 0 2 3 4 3 D u p Inj
19020 G R O U P V , M ale 8
0202344
19020 G R O U P V , M ale 8*
0 2 0 2 3 4 4 D u p Inj
19020 G R O U P V , F e m a le 9
02021345
19020 G R O U P V , F em ale 9 * 0 2 0 2 3 4 5 D u p Inj
19020 G R O U P V , F e m a le 10
0202346
19020 G R O U P V , F e m a le 10* 0 2 0 2 3 4 6 D u p Inj
1 9 0 2 0 G R O U P V , F e m a le 11
0202347
19020 G R O U P V , F em ale 11* 0 2 0 2 3 4 7 D u p Inj
1 9020 G R O U P V , F e m a le 12
0202348
19020 G R O U P V , F e m a le 12* 0 2 0 2 3 4 8 D u p In j
1 9020 G R O U P V , F e m a le 13
0202349
19020 G R O U P V , F e m a le 13* 0 2 0 2 3 4 9 D u p Inj
19022 G R O U P V . M a le 1
0202350
1 9 0 2 2 G R O U P V , M a le 1*
0 2 0 2 3 5 0 D u p Inj
19022 G R O U P V , M ale 4
0202351
19022 G R O U P V , M ale 4*
0 2 0 2 3 5 1 D u p Inj
19022 G R O U P V , M a le 5
0202352
19022 G R O U P V , M ale 5*
0 2 0 2 3 5 2 D u p Inj
19022 G R O U P V , M a le 7
0202353
1 9022 G R O U P V , M ale 7*
0 2 0 2 3 5 3 D u p Inj
19022 G R O U P V , M ale 8
0202354
19022 G R O U P V , M ale 8*
0 2 0 2 3 5 4 D u p Inj
1 9 0 2 2 G R O U P V , F e m a le 11
0202355
19022 G R O U P V , F e m a le 11* 0 2 0 2 3 5 5 D u p Inj
19022 G R O U P V . F e m a le 12
0202356
19022 G R O U P V , F e m a le 12* 0 2 0 2 3 5 6 D u p Inj
19022 G R O U P V , F em ale 13
0202357
19022 G R O U P V , F em ale 13* 0 2 0 2 3 5 7 D u p In j
19022 G R O U P V , F e m a le 14
0202358
19022 G R O U P V , F e m a le 14* 0 2 0 2 3 5 8 D u p In j
19022 G R O U P V , F e m a le IS
0202359
19022 G R O U P V , F e m a le 15* 0 2 0 2 3 5 9 D u p In j
19025 G R O U P V , M ale 2
0202361
19025 G R O U P V , M ale 2*
0 2 0 2 3 6 1 D u p Inj
19025 G R O U P V , M ale 7
0202362
1 9025 G R O U P V , M ale 7*
0 2 0 2 3 6 2 D u p Inj
Matrix
P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P up L iv e n P u p L iv ers P u p L iv e n P u p L iv ers P u p L iv e rs P u p L iv ers P u p L iv e rs P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv e rs P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv ers
Collection Date
5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 1 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2
Set Number
101002B R R 101002B R R 10 I0 0 2 B R R 101002B R R 101002B R R 101002B R R 101002B R R 101002B R R 101102A R
10U 02A R 101102A R 101102A R 101102A R 101102A R 10M 02A R 101102A R 101102A R 101102A R 101102A R 101102A R 101102A R 101102A R 101102A R 101102A R 101102A R 101102A R 101102A R 101102A R 101102A R 101102A R 10 1 1 0 2 .A R 101102A R 101102A R 101I02A K 101102A R 101102A R 101102A R 101102A R 101102A R 1D 1102A R 101102A R 1011Q 2A R 101102A K 101102A R 101102A R 101102A R 101102A R 101I02A R 101402A R 101402A R 101402A R 101402A R
PFHS Found (ng/mL)
18700 20000 23500 22400 21900 22500 21000 21400 11800 11300 9460 9190 8130 8510 9280 9050 8750 8750 14800 14300 12200 12600 14400 14300 15600 15300 20900 21300 11100 11000 12700 12400 12500 12800 11800 11600 14400 14300 13700 14100 17400 17500 12200 11600 15700 15300 ' 14100 14200 21700 21900 18600 18600
* Duplicate Injection
N D = N ot D etected (Area less than low est calibration standard o f 0.1 ng/m L)
Exygen Research
Page 38 of 153
418-028:PAGE G-39
E xygen Study N o .: 0 2 3 -0 7 2
Table IX. (cont'd). Summary of PFHS Residues in Rat Liver Samples
S ponsor
ID
E xygen
ID
19025 G R O U P V . M ate 8 19025 G R O U P V , M a le 8* 1 9 0 2 5 G R O U P V , M a le 13 1 9025 G R O U P V , M ale 13* 1 9025 G R O U P V . F em ale 14 19025 G R O U P V , F e m a le 14* 1 9025 G R O U P V , F em ale 15 19025 G R O U P V , F em ale 15* 1 9025 G R O U P V , F e m a le 18 19025 G R O U P V , F em ale 18* 1 9 0 2 5 G R O U P V , F e m a le 19 1 9025 G R O U P V , F em ale 19* 1 9025 G R O U P V , F em ale 20 1 9 0 2 5 G R O U P V , F e m a le 2 0 *
19025 G R O U P V , M a le 1 1 9 0 2 5 G R O U P V , M a le 1*
0202363 0 2 0 2 3 6 3 D u p Inj
0202364 0 2 0 2 3 6 4 D u p Inj
02021365 0 2 0 2 3 6 5 D u p Inj
0202366 02C 2366 D u p Inj
0202367 0202367 D u p lp j
0202368 0 2 0 2 3 6 8 D u p Inj
0202369 0 2 0 2 3 6 9 D u p Inj
0202360 0 2 0 2360 D u p Inj
M a trix
P u p L iv e n P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv ers P u p L iv e rs P u p L iv e rs
C o lle c tio n
Date
5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2 5 /3 0 /0 2
Set
Number
101402A R 1014Q 2A R 101402A R 101402A R 101402A R 1014O 2A R 101402A R 101402A R 101402A R 101402A R 101402A R 101402A R 101402A R 101402A R 101402A K R 101402A RR
PFHS Found (ng/mL)
21400 21800 18300 19400 14700 15300 26400 26500 19800 19500 18900 18800 16800 17600 13300 14400
* Duplicate Injection
ND = Not Detected (Area less than lowest calibration standard of 0.1 ng/mL)
Exygen R esearch
Page 39 of 153
418-028: PAGE G-40 Exygen Study No.: 023-072
Table X. Summary of PFHS Residues in Dosing Solutions
Sample Description
B -4 1 8 -0 2 8 -A (0 7 J u n .0 2 ) 0 m g /m L 1 o f 4 B -4 1 8 -0 2 8 -A (0 7 J u n .0 2 ) 0 m g /m L 1 o f 4 B -4 18 -0 2 8 -B (2 4 .M a y .0 2 ) 0 .0 3 m g /m L 1 o f 4 B -4 1 8 -0 2 8 -B (2 4 .M a y .0 2 ) 0 .0 3 m g /m L 1 o f 4 B -4 1 8 -0 2 8 -C (2 4 .M a y .0 2 ) 0 .1 m g /m L 1 o f 4 B -4 1 8 - 0 2 8 0 (2 4 .M a y .0 2 ) 0 .1 m g /m L 1 o f 4 B -4 1 8 -0 2 8 -D (0 7 J u n .0 2 ) 0 .3 m g /m L 1 o f 4 B -4 1 8 -0 2 8 -D (0 7 J u n .0 2 ) 0 .3 m g /m L 1 o f 4 B -4 1 8 -0 2 8 -E (2 4 .M a y .0 2 ) 1 m g /m L l o f 4 B -4 1 8 -0 2 8 -E (2 4 .M a y .0 2 ) 1 m g /m L 1 o f 4
B u lk T A /S S a m p le (0 9 J u n .0 2 )
BulkTA/S Sample ( 0 9 J u n . 0 2 )
Set Number
110702C 110702C 110702C 110702C 110702C 110702C 110702C 110702C 110702C R 110702C R 110702C 110702C
PFHS
PFHS
PFHS
Known Concentration(ng/mL) Found(ng/mL) Recovery(%)
0
ND
.
0 ND
30000 30000 100000 100000 300000 300000 1000000 1000000 100000 100000
26500 27300 88900 91000 268000 278000 1010000 1000000 125000 122000
88 91 89 91 89 93 101 100 125 122
ND = Not Detected (Area less than lowest calibration standard of 0.1 ng/mL)
Exygen Research
Page 40 o f 153
418-028: PAGE G-41 Exygen Study No.: 023-072
Table XI. Summary of PFHS Residues in Stability Samples
3M ID
E 02-0514-38611 E 0 2 -0 5 1 4 -3 8 6 1 1 * E 02-0514-38412 E D 2-0514-38612* E 02-0514-38613 E02-0514-38613* E 02-0514-38614 E 02-0514-38614* E 02-0514-38615 E 02-0514-38615* E 02-0514-38616 E02-0514-38616* E 0 2 -0 5 1 4 -3 8 6 1 7 E02-0514-38617* E 0 2 -0 5 1 4-38618 E02-0514-38618* E 02-0514-38619 E 02-0514-38619* E 0 2 -05 1 4 -3 8 6 2 0 E 02-0514-38620*
E x rg ea ID
0203923 0203923 D up Inj
0203924 0203924 D ap Inj
0203925 0203925 D ap Inj
0203926 0203926 D ap Inj
0203927 0203927 D u p Inj
0203928 0203928 D up Inj
0203929 0203929 D up Inj
0203930 0203930 Dup h j
0203931 0203931 D ap hij
0203932 0203932 D u s Ini
S a m p le D o c iU n
B-418-028 A (29 M ar 02) 0 m g/m L 1 o f4 B-418-028 A (29 M ar 0 2 )0 m g/m L 1 o f 4 B -418-028 A (29 M ar 02) 0 m g/m L 2 o f 4 B -418-028 A (29 M ar 02) 0 m g/m L 2 o f 4 B-418-028 B (29 M ar 02) 0.03 m g/m L 1 o f 4 B -418-028 B (29 M ar 02) 0.03 m g/m L 1 o f 4 B -418-028 B (29 M ar 02) 0.03 m g/m L 2 o f 4 B-418-028 B (29 M ar 02) 0.03 m g/m L 2 o f 4 B -418-028 C (29 M ar 02) 0.1 m g/m L 1 o f 4 B-418-028 C (29 M ar 02) 0.1 m g/m L 1 o f 4 B -418-028 C (29 M ar 02) 0.1 m g/m L 2 o f 4 B -418-028 C (29 M a r 02) 0.1 m g/m L 2 o f 4 B -418-028 D (29 M ar 02) 0J m g/m L 1 o f 4 B-418-028 D (29 M ar 02) 0 3 m g/m L 1 o f 4 B -418-028 D (29 M ar 02) 0.3 m g/m L 2 o f 4 B-418-028 D (29 M ar 02) 0 J m g/m L 2 o f 4 B -418-028 E (29 M m 02) 1 m g/m L 1 o f4 B -418-028 E (29 M ar 02) 1 m g/m L 1 o f 4 B -418-028 E (29 M ar 02) 1 m g/m L 2 o f 4 B-418-028 E (29 M ar 02) 1 m g/m L 2 o f 4
Set N um ber
110502A 110502A 1I0502A 110502A 110502A 110502A 110502A 110502A 110502A 110502A 110502A 110502A 110502A 1105O2A 110502A 110502A 110702AR U0702AR 110702AR 110702AR
PFH S
K now C one.
lu /n L )
0 0 0 0
30000
30000
30000
30000
100000 100000 100000 100000
300000
300000
300000
300000
1000000 1000000 1000000 1000000
PFH S Found
(aefm L )
ND ND ND ND
29700 29600 29700
29500
122000
117000
100000 100000
308000
316000 326000
324000 910000 919000 1030000
1010000
PFH S R ecovery
<% )
-
.
99 99 99 98
122
117
100 100
103 105 109 108 91 92 103
101
* Duplicate Injection
ND = Not Detected (Area less than lowest calibration standard of 0.1 ng/mL)
Exygen Research
Page 41 of 153
418-028:PAGE G-42 Exygen Study No.: 023-072
Table XII. Summary of PFHS Residues in Homogeneity Samples
3M ID
E 02-0514-38621 E 02-0S14-38621* E 02-0514-38622 E 02-0514-38622* E 0 2 -0514-38623 E 0 2 -0 5 14-38623 * E 02-0514-38624 E 02 -0 5 14-38624* E 02-0514-38625 E 2-0 5 1 4 -3 8 6 2 5 * E 02-0514-38626 E O 2-0514-38626* E 02-0514-38627 E 02-0514-38627* E 0 2-0514-38628 E 02-0514-38628* E 02-0514-38629 E 0 2 -0514-38629* E 02-0514-38630 H 02-0514-38630* E 0 2 -0 5 14-38631 E 02-0514-38631*
E 02-0514-38632 E 02-0514-38632* E 02-0514-3B 633 E 02-0514-38633* E 02-0514-38634 E 02-0514-38634* E 02-0514-38635 E 0 2 -0514-38635* 0 2 -0 5 1 4 -3 8 6 3 6 E 02-0514-38636* E 0 2 -0 5 14-38637 E 0 2 -0 5 14-38637* E 02-0514-38638 E 02-0514-38638* E 02-0514-38639 E 02-0514-38639* E 0 2 -0 5 14-38640 E 02-0514-38640* E 02-0514-38641 E 02-0514-38641* 0 2 -0 5 1 4 -3 8 6 4 2 E 02-0514-38642* 0 2 -0 5 1 4 -3 8 6 4 3 E 0 2 -0514-38643* E 0 2 -0 5 14-38644 E 02-0514-38644* E 02-0514-38645 E 02-0514-38645* E 02-0514-38646 0 2 -0 5 1 4 -3 8 6 4 6 * E 0 2 -0 5 14-38647 0 2 -0 3 1 4 -3 8 6 4 7 * E 02-0514-38648 E 02 -0514-38648* E 0 2-0514-38649 E 02-0514-38649* E 0 2 -0 5 14-38650 E 02-0514-38650*
E xygen ID
S am p le D e sc rip tio n
Set N um ber
0203933
B -4 1 8 -0 2 8 -A (2 9 M a r0 2 ) 0 m g /m L 1 o f 12 T
110702A
0203933 D up Inj
B -4 1 8 -0 2 8 -A (2 9 M a r0 2 ) 0 m g /m L 1 o f 1 2 T
110702A
0203934
B -4 1 8 -0 2 8 -A (2 9 M a r0 2 ) 0 m g /m L 2 o f 1 2 T
110702A
0 2 0 3 9 3 4 D u p Inj
B -4 18 -0 2 8 -A (2 9 M a i0 2 ) 0 m g /m L 2 o f 1 2 T
110702A
0203935
B -4 1 8 -0 2 8 -A (2 9 M a i0 2 ) 0 m g /m L S o f 12M
110702A
0 2 0 3 9 3 5 D u p Inj B -4 1 8 -0 2 8 -A (2 9 M a i0 2 ) 0 m g /m L 5 o f 1 2 M
110702A
0203936
B -4 1 8 -0 2 8 -A (2 9 M a r0 2 ) 0 m g /m L 6 o f 12 M
110702A
0 2 0 3 9 3 6 D u p Inj B - 4 1 8 -0 2 8 -A (2 9 M a i0 2 ) 0 m g /m L 6 o f 12 M
110702A
0203937
B -4 1 8 -0 2 8 -A (2 9 M a r0 2 ) 0 m g /m L 9 o f 12B
110702A
02 0 3 9 3 7 D up Inj
B -4 1 8 -0 2 8 -A (2 9 M a r0 2 ) 0 m g /m L 9 o f 12B
110702A
0203938
B - 4 18 -0 2 8 -A (2 9 M a i0 2 ) 0 m g /m L 10 o f 12 B
1 I0 7 0 2 A
0203938 D up Inj B -4 1 8 -0 2 8 -A (2 9 M a r0 2 ) 0 m g /m L 10 o f 12B
1 10702A
0203939
B -4 1 8 -0 2 8 -B (2 9 M a i0 2 ) 0 .0 3 m g /m L 1 o f 1 2 T 1 1 0 7 0 2 A
02 0 3 9 3 9 D up Inj B -4 1 8 -0 2 8 -B (2 9 M m 0 2 ) 0 .0 3 m g /m L 1 o f 1 2 T 1 1 0 7 0 2 A
0203940
B -4 1 8 -0 2 8 -B (2 9 M a r0 2 ) 0 .0 3 m g /m L 2 o f 12 T 1 1 0 7 0 2 A
0203 9 4 0 D up Inj B -4 18 -0 2 8 -B (2 9 M a i0 2 ) 0 .0 3 m g /m L 2 o f 1 2 T 1 1 0 7 0 2 A
0203941
B -4 1 8 -0 2 8 -B (2 9 M a i0 2 ) 0 .0 3 m g /m L 5 o f 1 2 M
ini0 2 0 3 9 4 1 D u p
B -4 1 8 -0 2 8 -B (2 9 M ax 0 2 ) 0 .0 3 m g /m L 5 o f 1 2 M
110702A 110702A
0203942
B -4 1 8 -0 2 8 -B (2 9 M a i0 2 ) 0 .0 3 m g /m L 6 o f 1 2 M 1 1 0 7 0 2 A
0203942 D u p Inj B -4 1 8 -0 2 8 -B (2 9 M a i0 2 ) 0 .0 3 m g /m L 6 o f 1 2 M
0203943
B -4 18 -0 2 8 -B (2 9 M a i0 2 ) 0 .0 3 m g /m L 9 o f 1 2B
110702A 110702A
0203943 D up Inj B -4 18 -0 2 8 -B (2 9 M a i0 2 ) 0 .0 3 m g /m L 9 o f 1 2B 1 1 0 7 0 2 A
0203944
B -4 1 8 -0 2 8 -B (2 9 M a r0 2 ) 0 .0 3 m g /m L 10 o f 12B 1 1 0 7 0 2 A
0 2 0 3 9 4 4 D u p Inj B -4 1 8 -0 2 8 -B (2 9 M a i0 2 ) 0 .0 3 m g /m L 1 0 o f 12B 1 1 0 7 0 2 A
0203945
B -4 1 8 -Q 2 8 -C (2 9 M a i0 2 ) 0 .1 m g /m L 1 o f 1 2 T 1 1 0 7 0 2 A
0 2 0 3 9 4 5 D u p Inj B -4 1 8 -0 2 8 -C (2 9 M a i0 2 ) 0 .1 m g /m L 1 o f 1 2 T
1 I0 7 0 2 A
0203946
B -4 1 8 -0 2 8 -C (2 9 M a i0 2 ) 0 .1 m g /m L 2 o f 1 2 T 1 1 0 7 0 2 A
0 2 0 3 9 4 6 D u p In j B - 4 1 8 -0 2 8 -C (2 9 M a i0 2 ) 0 .1 m g /m L 2 o f 1 2 T
110702A
0203947
B - 4 1 8 -0 2 8 -C (2 9 M a i0 2 ) 0 .1 m g /m L 5 o f 1 2 M 1 1 0 7 0 2 A R
0 2 0 3 9 4 7 D u p Inj B - 4 18 -0 2 8 -C (2 9 M a i0 2 ) 0 .1 m g /m L 5 o f 12 M 1 1 0 7 0 2 A R
0203948
B -4 1 8 -0 2 8 -C (2 9 M a r0 2 ) 0 .1 m g /m L 6 o f 1 2 M 1 1 0 7 0 2 A
0 2 0 3 9 4 8 D u p In j B -4 1 8 -0 2 8 -C (2 9 M a r0 2 ) 0 .1 m g /m L 6 o f 1 2 M 1 1 0 7 0 2 A
0203949
B -4 1 8 -0 2 8 -C (2 9 M a r0 2 ) 0 .1 m g /m L 9 o f 12B 1 1 0 7 0 2 A
0 2 0 3 9 4 9 D up Inj B - 4 18 -0 2 8 -C (2 9 M a i0 2 ) 0 .1 m g /m L 9 o f 12 B
110702A
0203950
B - 4 18 -0 2 8 -C (2 9 M a r0 2 ) 0 .1 m g /m L 1 0 o f l 2 B 1 1 0 7 0 2 A R
0 2 0 3 9 5 0 D u p Inj B -4 1 8 -0 2 8 -C (2 9 M a r0 2 ) 0 .1 m g /m L 1 0 o f l 2 B 1 1 0 7 0 2 A R
0203951
B -4 18 -0 2 8 -D (2 9 M a r0 2 ) 0 .3 m g /m L 1 o f 12 T 1 1 0 7 0 2 A
0203951 D u p Inj B -4 18 -0 2 8 -D (2 9 M a r0 2 ) 0 .3 m g /m L 1 o f l 2 T
110702A
0203952
B -4 1 8 -0 2 8 -D (2 9 M a> 0 2 ) 0 .3 m g /m L 2 o f 12T 1 1 0 7 0 2 A
0203952 D up Inj B -4 1 8 -0 2 8 -D (2 9 M a i0 2 ) 0 .3 m g /m L 2 o f 1 2 T 1 1 0 7 0 2 A
0203953
B -4 1 8 -0 2 8 -D (2 9 M a i0 2 ) 0 .3 m g /m L 5 o f 1 2 M 1 1 0 7 0 2 B
0203953 D up Inj B -4 1 8 -0 2 8 -D (2 9 M a r0 2 ) 0 .3 m g /m L 5 o f 1 2 M 1 1 0 7 0 2 B
0203954
B -4 1 8 -0 2 8 -D (2 9 M a r0 2 ) 0 .3 m g /m L 6 o f 1 2 M 1 1 0 7 0 2 B
0203954 D up Inj B -4 1 8 -0 2 8 -D (2 9 M a i0 2 ) 0 .3 m g /m L 6 o f 1 2M 1 1 0 7 0 2 B
0203955
B -4 1 8 -0 2 8 -D (2 9 M a i0 2 ) 0 .3 m g /m L 9 o f 1 2 B 1 1 0 7 0 2 B
020 3 9 5 5 D up Inj B -4 1 8 -0 2 8 -D (2 9 M a r0 2 ) 0 .3 m g /m L 9 o f 12B 1 1 0 7 0 2 B
0203956
B -4 1 8 -0 2 8 -D (2 9 M a r0 2 ) 0 .3 m g /m L 10 o f 12B 1 1 0 7 0 2 B
0 2 0 3 9 5 6 D u p Inj B -4 1 8 -0 2 8 -D (2 9 M a i0 2 ) 0 .3 m g /m L 10 o f 1 2 B 1 1 0 7 0 2 B
0203957
B -4 1 8 -0 2 8 -B (2 9 M m 0 2 ) 1 m g /m L 1 o f 1 2 T
110702B
0203957 D up Inj
B -4 1 8 -0 2 8 -E (2 9 M a i0 2 ) 1 m g /m L 1 o f 12T
110702B
0203958
B -4 1 8 -0 2 8 -E (2 9 M a i0 2 ) 1 m g /m L 2 o f 12T
110702B
0203958 D up Inj
B -4 1 8 -0 2 8 -E (2 9 M ai0 2 ) 1 m g /m L 2 o f 1 2T
1 10702B
0203959
B -4 1 8 -0 2 8 -E (2 9 M a r0 2 ) 1 m g /m L 5 o f 12 M
110702B
0203959 Dup by
B -4 1 8 -0 2 8 -E (2 9 M a r0 2 ) 1 m g /m L 5 o f 12M
110702B
0203960 0 2 0 3 9 6 0 D up Inj
B -4 1 8 -0 2 8 -E (2 9 M a i0 2 ) 1 m g /m L 6 o f 12 M B -4 1 8 -0 2 8 -E (2 9 M a i0 2 ) 1 m g /m L 6 o f 12M
110702B 110702B
0203961 0203961 D up Inj
0203962 0 2 0 3 9 6 2 D up Inj
B -4 1 8 -0 2 8 -E (2 9 M az0 2 ) 1 m g /m L 9 o f 12B B -4 1 8 -0 2 8 -E (2 9 M a r0 2 ) 1 m g /m L 9 o f l2 B B -4 1 8 -0 2 8 -E (2 9 M a i0 2 ) 1 m g /m L 10 o f 12B B -4 1 8 -0 2 8 -E (2 9 M a i0 2 ) 1 m g /m L 10 o f 12B
110702B 110702B 110702B 110702B
PFH S K now n C one.
(n g /m L )
0 0 0 0 0 0 0 0 0 0 0 0 30000 30000 30000 30000 30000 30000 30000 30000 30000 30000 30000 30000 100000 100000 100000 100000 100000 100000 100000 100000 100000 100000 100000 100000 300000 300000 300000 300000 300000 300000 300000 300000 300000 300000 300000 300000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 1000000 1000000
PFH S Found (n g /m L )
ND ND ND ND ND ND ND ND ND ND ND ND 24400 23700 26900 25800 25500 26100 25800 25800 24200 24400 24800 24500 75400 73800 76300 74700 93300 95100 69800 72300 84400 83700 95700 92800 270000 268000 270000 279000 254000 266000 241000 239000 255000 250000 280000 293000 1020000 1090000 987000 980000 1160000 1170000 1040000 994000 1090000 UOOOOO 1110000 1070000
PFH S R eco v ery
(% )
,
. . .
. _ . . 81 79 90 86 85 87 86 86 81 81 83 82 75 74 76 75 93 95 70 72 84 84 96 93 90 89 90 93 85 89 80 80 85 83 93 98 102 109 99 98 116 117 104 99 109 110 111 107
* D uplicate Injection
ND = Not D etected (Area less than low est calibration standard o f 0.1 ng/mL)
Exygen Research
Page 42 of 153
418-028:PAGE G-43 Exygen Study No.: 023-072
FIGURES
E xygen R esearch
Page 43 of 153
418-028: PAGE G-44 Exygen Study No.: 023-072
Figure 1. Typical Calibration Curve for PFHS
Compound 1 name: PFHS Coefficient of Determination: 0.999484 Calibration curve: 2633.68 *x +44.4695 Response type: External Std, Area Curve type: Linear, Origin: Exclude. Weighting: 1/x, Axis trans: None
Exygen Research
Page 44 of 153
418-028:PAGE G-45 Exygen Study No.: 023-072
Figure 2. Chrom atogram Representing a 0.1 ng/mL standard for PFHS
C 0820024.0.1 ng/m L Standard
091902B -2012 S m (Mn. 2x3) 100-1
I.M
299
2 1 -S e p -2 0 0 2 10:34:30 LC/M S/M S#?
MRM of 1 C hannel E S399 >80 4 .2 1 e 3 Are
%-
0 if ).. If fif ^ i
A | r aA^'i
.iiAq I I I p! I
*!
-rime
1.00 2.00
3.00
4.00
5.00
6.00
7.00
8.00
9.00
10.00
11.00
12.00
E xygen R esearch
Page 45 of 153
418-028:PAGE G-46 Exygen Study No.: 023-072
Figure 3. Chromatogram Representing a Control Rat Plasma Sample for PFHS (Exygen ID 0202913 Control, Data Set: 091602B)
0202913 Control
17-SCP-3002 22:52:59 LC/M S/M S*7
Exygen Research
Page 46 of 153
418-028:PAGE G-47 Exygen Study No.: 023-072
Figure 4.
Chromatogram Representing a Control Rat Serum Sample for PFHS (Exygen ID: 0202987 Control, Data Set: 091902B)
Exygen Research
Page 47 of 153
418-028: PAGE G-48 Exygen Study No.: 023-072
Figure 5.
Chromatogram Representing a Control Rat Liver Sample for PFHS, (Exygen ID: 0202877 C o n tro l, Data Set: 100202A)
0202877 C ontrol
03-0ct-2002 00:12:19 LC/MS/MS #7
Exygen Research
Page 48 o f 153
418-028:PAGE G-49 Exygen Study No.: 023-072
Figure 6. Chromatogram Representing Control Rat Plasma Sample Fortified with 10 ppb of PFHS (Exygen ID: 0202913 Spk A, Data Set: 091602B)
0202913 Spk A, 10 ppb 091602B-208Sm(Mn, 2x3)
17-S*p-2002 23:14:44
LCM SM SS7 MRM o fi Channel E
Exygen Research
Page 49 of 153
418-028:PAGE G-50 Exygen Study No.: 023-072
Figure 7. Chromatogram Representing Control Rat Serum Sample Fortified with 10 ppb of PFHS (Exygen ID: 0202987 Spk A, Data Set: 091902B)
0202987 Spk A, 10 ppb
091902B -2009 S m (Mn. 2x3)
21-Sep-2002 09:29:14 LC/MS/MS97
MRM of 1 C hannel E S -
Exygen Research
Page 50 of 153
418-028:PAGE G-51 Exygen Study No.: 023-072
Figure 8. Chromatogram Representing Control Rat Liver Sample Fortified with 10 ppb of PFHS (Exygen ID: 0202877 Spk A, Data Set: 100202A)
0202877 Spk A, 10 ppb
03-0ct-2002 08:33:57 LC M S/M S87
MRM o1 1 Channel ES-
Exygen Research
Page 51 of 153
418-028:PAGE G-52 Exygen Study No.: 023-072
Figure 9. Chromatogram Representing Rat Plasma Sample Analyzed for PFHS (Exygen ID: 0201816, Sponsor ID: 19176 GROUP I, Data Set: 091602B)
0201816
-,0916029-212 Sm (Mn. 2x3)
100
16-Sep-2002 00:41:24
LCAISM S#7
9.07 2772
MftM o1 1 C hannel E S 399 >00
2.16e4
Area
%-
0/\.V*
I--
1.00 2.00 3.00 4,00 5030 6.00
8.00 .00 10.00 11.00 124)0
Exygen Research
Page 52 of 153
418-028:PAGE G-53 Exygen Study No.: 023-072
Figure 10. Chromatogram Representing Rat Serum Sample Analyzed for PFHS, DF=10 (Exygen ID: 0201863, Sponsor ID: 19079 GROUP n , Data Set: 091902BR)
0201863, DF-10
0919Q2BR-308 Sm (Mn. 2x3)
10CK
24-Sep-2002 02:50:15
LC/MS/MS #7
8.80 2488
MRM of 1 Gharrnd ES399 > BO
3 .9 1 8 4
Area
%-
HS0-
aw
aw
Bin
7.00
"i" i aW
9.QQ
10...0..0.... .. 11.00 1"2.i0T0ima
Exygen Research
Page 53 of 153
418-028:PAGE G-54 Exygen Study No.: 023-072
Figure 11. Chromatogram Representing Rat Liver Sample Analyzed for PFHS (Exygen ID: 0202050, Sponsor ID: 19018 GROUP II Male 1, Data Set: 100202A)
0202050
100202A-213 Sm (Mn. 2x3) ^Q01
621
21848
03-0ct200210.-00:52 LCMS/M S 07
M RM of 1 C hannel E S -
399 >00 1.19*5
A rsa
%-
2.00 3.00
00 ' 6.00 ' 7.00
8.00
-*--i T im e
11.00 12.00
Exygen Research
Page 54 of 153
418-028: PAGE G-55 Exygen Study No.: 023-072
APPENDIX A
Study Protocol 418-028
(Exygen Study No. 023-072) and
Amendments, Deviation and
Note to File
Exygen Research
Page 55 of 153
418-028:PAGE G-56 Exygen Study No.: 023-072
905 Drtw, iWj. A
noanam m m w h Telephone (21S) 443-0710 T rita r (II S ) 443SSS7
ARGUS RESEARCH
Chartes River Laboratories Discovery and Developm ent Services
PROTOCOL 418-028
SPONSOR'S STUDY NUMBER: T-7706.1
STUDY TITLE: Oral(Gavage)CombinedRepeatedDoseToxicityStudyofT-7706with theReproduction/DevelopmentalToxicityScreeningTest
rORPQSq:
Thepurposeofthisstudyistoprovideinformationanthepossiblehealth hazardsthatmay resultfromrepratedexposureofCrl:CD(SD)IGS BR VAF/Plusmaleandfemaleratstoatestsubstancebeginningbefore cohabitation,throughmatingandcontinuingforatleast42days(male rats)orthroughparturitionuntilday21oflactation(femaletats). This repeateddosestudyincorporatesareproduction/developmentaltoxicity screeningtestthatcanbeusedtoprovideinitialinformationonpossible effectsonmaleandfemalereproductiveperformance(e.g.,gonadal function,matingbehavior,conception,developmentoftheconceptusand parturition). Thestudyalsoplacesemphasisonneurologicaleffectsasa specificendpointandshouldidentifydieneurotoxicpotentialofatest substance,whichmay warrantfurtherin-depthinvestigation.
TESTING FACILITY:
Becauseoftheselectivityoffoemidpointsandfoeshortdurationofthe study,thescreeningtestwillnotprovideevidencefordefinitiveclaimsof noreproduction/developmentaleffects. Inparticular,itoffersonlylimited meansofdetectingpostnatalmanifestationsofprenatalexposureoreffects thatmaybeinducedduringpostnatalexposure.
ArgusResearch 905 SheefayDrive,BuildingA Horsham,Pennsylvania 19044-1297 Telephone: (215)443-8710 Telefax: (215)443-8587
STUDY DIRECTOR:
Raymond G. York,Ph.D, DABT
AssociateDirectorofResearch
Email:
iaymond.yoric@criver.com
AddressascitedaboveforTestingFacility
SPONSOR:
3M CorporateToxicology 3M Center,Building220-2E-Q2 StPaul,Minnesota 55144-1000
Exygen Research
Page 56 of 153
418-028:PAGE G-57 Exygen Study No.: 023-072
STUDY MONITOR:
JohnButenhoS,Ph.D.,DABT, CIH
3M CorporateToxicology
'
3M MedicalDepartment
Telephone: (651)733-1962
Telefax: (651)733-1773
Email: jlbutenhoff@mnun.com
P ro to co l 418 -0 2 8 P ig c 2
REGULATORY CITATIONS:
OrganisationforEconomicCo-operationandDevelopment(1996). OECD Guidelinefo r Testing o fChemicals. Section4,No.422: CombinedRepeatedDoseToxicityStudywiththe Reproduction/DevelopmentalToxicityScreeningTest,adopted22March 1996.
OrganisationforEconomicCo-operationandDevelopment(1998). TheRevisedOECD PrinciplesofGood LaboratoryPractices[C(97)186/Final].
U.S.FoodandDrugAdministration. GoodLaboratoryPracticeRegulations;FinalRule. 21 CFRPartS8.
JapaneseMinistryofHealthandWelfare(1997). GoodLaboratoryPractice Standardfa r Safety Studies on Drugs, M H W OrdinanceNumber21,March26,1997.
REGULATORY COMPLIANCE:
ThisstudywillbeconductedincompliancewiththeGoodLaboratoryPractice(GLP) regulationscitedabove.
Allchangesorrevisionsofthisprotocolshallbedocumented,signedbytheStudyDirectorand theSponsor,datedandmaintainedwiththeprotocol.
TheTestingFacility'sQualityAssuranceUnit(QAU)willaudittileprotocol,therawdataand filereport,andwillinspectcriticalphasesofthoseportionsofthestudyconductedattheTesting FacilityinaccordancewiththeStandardOperatingProceduresoftheTestingFacility.
ThefinalreportwillincludeacompliancestatementsignedbytheStudyDirectorthatthereport accuratelyreflectstherawdataobtaineddotingtheperformanceofthestudyandthatall applicableGLP regulationswerefollowedintheconductofthestudy. Shouldsignificant
deviationsbota GLP regulationsoccur,eachwillbedesciibedindetail,togetherwithhowthe deviationmightaffectthequalityorintegrityofthestudy.
ShouldanyportionofthestudybeconductedbyasubcontractororbytheSponsor,theStudy DirectorwillensuretintaqualifiedPrincipalInvestigatorisidentifiedbytilefacilityconducting thatportionofthestudy. TheQAU forthisfacilitywillconductcriticalphaseinspectionsend auditrespectiveresultsandreportsforthatstudyportionaccordingtotheSOPsofthatfacility. Suchcriticalphaseinspectionreportsandreportauditawillbesubmittedbythefacilitytothe
PrincipalInvestigatorandtheStudyDirector. Thedatesoftheinspectionsandreport submissionswillbeincorporatedintoaQAU Statementgeneratedbythatfacilityandprovided
Exygen Research
Page 57 o f 153
418-028-.PAGE G-58 Exygen Study No.: 023-072
P ro to co l 4 1 8 -0 2 8 Pge3
totheTestingFacilityforinclusioninthefinalreport Inaddition,thisfacilitywillprovidea statementofGLP compliance,asdescribedabove,signedbythePrincipalInvestigatorfor inclusioninthefinalreport
SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE.
SeeATTACHMENT 1totheprotocol.
TEST SUBSTANCE AND VEHICLE:
Identification:
TestSubstance:
T-7706 [PerfluorohexaneSulfonatePotassiumSalt(PFHS)] Lotidentificationwillbe documentedintherawdata.
TheSponsorwillprovidetotheTestingFacilitydocumentationorcertificationofdieidentity, composition,methodofsynthesis,strengthandactivity/purityofthetestsubstance This documentationwillbeincludedindiefinalreport
Vehicle:
Aqueous0.5%carboxymethlycellulose(CMC) (mediumviscosity)preparedusingreverse osmosismembraneprocesseddeionizedwater(R.O.deionizedwater). Lotidentificationand Supplierwillbedocumentedindierawdata.
NeithertheSponsornordieStudyDirectorisawareofanypotentialcontaminantslikelytobe presentindievehiclethatwouldinterferewithdieresultsofthisstudy. Therefore,noanalyses otherthanthosementionedinthisprotocolwillbeconducted.
SsfetvPrecautions:
Gloves,dust-mist/HEPA-filteredmask,appropriateeyeprotectionanduniform/labcoattobe wornduringformulationpreparationanddosage. TheMaterialSafetyDataSheet(MSDS)is attachedtotheprotocol(ATTACHMENT 2).
Storage:
BulkTestSubstance: BulkVehicleComponents; PreparedTestSubstance andVehicleFormulations:
Room temperature. Room temperature.
Refrigerated(2C to 8C).
AlltestsubstanceshipmentsshouldbeaddressedtodieattentionofJulianGulbinslri,Managerof FormulationLaboratory,atthepreviouslycitedTestingFacilityaddressandtelephonenumber.
Exygen Research
Page 58 of 153
418-028: PAGE G-59 Exygen Study No.: 023-072
P ro to co l 4 18-028 Pgc4
ShipmentsshouldincludeinfonnatiooconcerningStongeconditionsandshippingcartonsshould belabeledappropriately. Therecipientshouldbenotifiedinadvanceofshipment.
FORMULATION:
FrequencyofPreparation:
Formulations(suspensions)willbepreparedweeklyattheTestingFacility.
Detailedpreparationprocedureswillbeattachedtothisprotocol(ATTACHMENT 3).
AdjustmentforPurity:
Thetestsubstancewillbeconsidered100%pureforthepurposeofdosagecalculations.
Testing Facility Reserve Samples:
TheTestingFacilitywillreserveasampleofeachlotofbulktestsubstance(approximately1g) andbulkvehiclecomponents(approximately1gor5mL) usedduringthecourseofthestudy. Sampleswillbestoredunderthepreviouslycitedconditions.
ANALYSES:
ResultsofrequiredanalyseswillbeprovidedtotheTestingFacilityforinclusioninthestudy report.
Samplesadditionaltothosedescribedbelowmaybetakenifdeemednecessaryduringdiecourse ofthestudy. Additionalanalyses,ifrequired,willbedocumentedbyprotocolamendment
BulkTestShdiw SamnHuw
A sampleofapproximately1gofthetestsubstancewillbetakenonthelastdayoftreatment andsent(ambientconditions)to:
PrincipalInvestigator, lisaClemen 3M EnvironmentalTechnologyandSafetyServices Building2-3E-09 StPaul,Minnesota55133-3331 Telephone: (6S1)778-5568 Telefax: (651)778-6176 Email: laelemen@mmtn.com
Therecipientwillbenotifiedinadvanceofsampleshipment
Exygen Research
Page 59 of 153
418-028.PAGE G-60 Exygen Study No.: 023-072
Analyses of Prepared Formulations:
P ro to co l 41 8 -0 2 8 P ig e 5
ConcentrationandHomogeneity:
Concentrationandhomogeneityofthepreparedformulationswillbeverifiedduringthecourse ofthisstudy. Quadruplicatesamples(2mL each)willbetakenfromthetop,middleandbottom ofeachconcentrationonthefirstdayofpreparation. Two samplesfromeachquadruplicateset willbeshippedforanalysis;theremainingsampleswillberetainedattheTestingFacilityas backupsamples. Quadruplicatesampleswillbetakenfromeachconcentrationonthelastdayof preparation. Two samplesfromeachquadruplicatesetwillbeshippedforanalysis;the remainingsampleswillberetainedasbackupsamples. Backupsampleswillbestoredunderthe previouslycitedconditionsanddiscardedatdieTestingFacilityupontherequestoffileSponsor.
Stability.
Stabilityofthepreparedformulationswillbedocumentedduringthisstudy. Two setsof duplicatesamples(2mL each)fromeachconcentrationwillbetakenonthefirstdayof preparation. Onesampleofeachduplicatesetwillbeshippedonthedayofpreparation. These sampleswillbeanalyzedatthefollowingtrinepoints: assoonafterpreparationaspossibleand tendaysafterthefirstanalysis. TheremainingsampleswillberetainedatfireTestingFacilityas backupsamples. Backupsampleswillbestoredunderthepreviouslycitedconditionsand discardedattheTestingFacilityupontherequestoftheSponsor.
ShippingInstructions:
Samplestobeanalyzedmilbeshipped(refrigerated)to;
PrincipalInvestigator LisaClemen 3M EnvironmentalTechnologyandSafetyServices Building2-3E-09
StPaul,Minnesota55133-3331 Telephone: (651)778-5568 Telefax: (651)778-6176 Email: laclemen@mmm.com
Therecipientwillbenotifiedinadvanceofsampleshipment
DISPOSITION:
PreparedformulationswillbediscardedattheTestingFacility. Allremainingbulktest substancewillbereturnedto:
DanHakes 3M EHSR -Auto& Chem Grp
3M Crater,Building236-1B-10 StPaul,Minnesota55144-1000 Telephone: (651)733-2392
Exygen Research
Page 60 o f 153
418-028:PAGE G-61 Exygen Study No.: 023-072
P ro to co l 4 1 & 4 2 8 Page 6
TEST SYSTEM:
Sneriea/Strain and Reason for Selection:
TheCrL`CD(SD)IGSBR VAF/PlusratwasselectedastheTestSystembecause: 1)itisone mammalian speciesacceptedforuseintoxicitystudiesandithasbeenwidelyusedthroughout industry,2)thisstrainofrathasbeendemonstratedtobesensitivetoreproductiveand developmentaltoxins;and3)historicaldataandexperienceexistatdieTestingFacility0'31'
Initialpopulationacclimated:
100maleand 100virginfemalerats.
Population selected for main study:
75 m ale and 75 virgin female rats (15 per sex per
dosagegroup).
Populationselectedfortoxicoldneticstudy; 15maleandISfemalerats(threepersexper
dosagegroup).
Body Weightand Age:
Maleratswillbeorderedtoweighfrom275gto300geachatreceipt,atwhichtimetheywillbe expectedtobeatleast60daysofage. Femaleratswillbeorderedtoweighfrom200gto225g eachatreceipt,atwhichtimetheywillbeexpectedtobeatleast56daysofage. Actualbody weightswillberecordedthedayafterreceiptandwillbedocumentedintherawdata. The weightrangeswillbeincludedindiefinalreport. Atstudyinitiation,theweightvariationofthe ratswillnotexceed20% ofdiemeanweightofeachsex.
Bothmaleandfemaleratswillbeevaluated.
CharlesRiverLaboratories,Inc.
Theratswillbeshippedinfilteredcartonsbyairfreightand/ortruckfromCharlesRiver Laboratories,Inc.,totheTestingFacility.
Identification:
RatsarepermanentlyidentifiedusingMonel self-piercingeartags(GeyBandandTagCo., Inc.,No.MSPT 20101). Maleandfemaleratsareassignedtemporarynumbersatreceiptand givenuniquepermanentidentificationnumberswhenassignedtothestudybeforeadministration ofthefirstdosage. Pupswillnotbeindividuallyidentifiedduringlactation;allparameterswill beevaluatedintermsofthelitter.
Exygen Research
Page 61 o f 153
418-028:PAGE G-62 Exygen Study No.: 023-072
ANIMAL HUSBANDRY:
P ro to co l 4 1 8 -0 2 8 P*ge7
AllcagesizesandhousingconditionsareincompliancewiththeGuidefa r the Care and Vie o f Laboratory Animals^. AlgosResearchisanAAALAC-accreditedfacility.
Homing:
Fogenerationratswinbeindividuallyhousedinstainlesssteelwire-bottomedcagesexcept duringdiecohabitationandpostpartumperiods. Duringcohabitation,eachpairofratswillbe housedinthemalerafscage. Beginningnolaterthanday20ofpresumedgestation,Fo generationfemaleratswillbeindividuallyhousedinnestingboxes. Eachdam anddelivered litterwillbehousedinacommon nestingboxduringthepostpartumperiod.
Nesting M aterial
Nestingmaterial(bed-o'cobs)willbeprovided.
Beddingwillbechangedasoftenasnecessarytokeeptheanimalsdryandclean. Analysesfor possiblecontaminationarcconductedsemi-annuallyanddocumentedintherawdata.
Room Air. Tem perature and Hnm ldltv
Theanimalroomisindependentlysuppliedwithatleastteachangesperhourof100% freshair thathasbeenpassedthrough99.97%HEPA filters. Roomtemperaturewillbemaintainedat 64Fto79F(18Cto26C)andmonitoredconstantly. Room humiditywillalsobemonitored constantlyandmaintainedat30% to70%.
Light
An automaticallycontrolled12-hourlight:12-hourdarkfluorescentlightcyclewillbe maintained. Eachdarkperiodwillbeginat1900hoursEST. Thelightcyclemaybeadjustedby dieStudyDirect-ordesigneeifdeemednecessarytoaccommodatescheduledlaboratory activities. Anysuchadjustmentwillbedocumentedintherawdata.
P ie t:
RatswillbegivenCertifiedRodentDiet#5002(PM1NutritionInternational)availablead libitum fromindividualfeeders. Feedwillberemovedtheeveningpriortothescheduled sacrifice:
W ater:
Waterwillbeavailablead libitum fromindividualbottlesattachedtothecagesorfroman
automaticwateringaccesssystem. Allwaterwillbefromalocalsourceandpassedthrougha
reverseosmosismembranebeforeuse. Chlorinewillbeaddedtotheprocessedwaterasa
bacteriostat;processedwaterisexpectedtocontainnomorethan1.2ppm chlorineatthetimeof
analysis. Waterisanalyzedmonthlyforpossiblebacterialcontaminationandtwiceannuallyfor
possiblechemicalcontamination.
.
Exygen Research
Page 62 of 153
418-028: PAGE G-63 Exygen Study No.: 023-072
P ro to co l 4 1 8 -0 2 8 Page 8
C ontam inant:
NeithertheSponsornortheStudyDirectorisawareofanypotentialcontaminantslikelytobe presentinthecertifieddiet,inthedrinkingwaterorindienestingmaterialsatlevelsthatwould interferewiththeresultsofthisstudy. Therefore,noanalysesotherthanthoseroutinely performedbyfoefeedsupplierorthosementionedinthisprotocolwillbeconducted.
DAY NUMBERING SYSTEM:
Gestationday0isdefinedasfoedayspermatozoaareobservedinasmearoffoevaginal contentsand/oracopulatoryplugobservedin situ.
Thedayofbirthisdesignatedlactationday0(postpartumday0)infoeHealthEffectsTest Guidelines-ReproductionandFertilityEffects(OfficeofPrevention,PesticidesandToxic Substances870.3800,August,1998)midinfoeOECD GuidelineforfoeTestingofChemicalsCombinedRepeatedDose ToxicityStudywiththeReproducton/DevelopmentalToxicity ScreeningTest(Section4,No.422,22March 1966). Thissamedayisdesignatedday 1 postpartum(day1oflactation)intileStandardOperatingProceduresoftheTestingFacility. Throughoutthisprotocol,thedayofbirthwillbedesignatedday lpostpartum(day1of lactation)andallsubsequentagesoftheFI generationratsanddaysofthelactationperiodwill bedeterminedandcitedaccordingly.
RANDOMIZATION AND COHABITATION:
Uponarrival,ratswillbeassignedtoindividualhousingonthebasisofcomputer-generated randomunits. Duringanacclimationperiodofatleastfivedays,maleandfemaleratewillbe selectedforstudyonfoebasisofphysicalappearanceandbodyweightsrecordedduring acclimation. Theratswillbeassignedtodosagegroupsbasedancomputer-generated(weightordered)randomizationprocedures.
Withineachdosagegroup,consecutiveorderwillbeusedtoassignratstocohabitation,onemale ratperfemalerat Thecohabitationperiodwillconsistofamaximumof14days. Femalerats withspermatozoaobservedinasmearoffoevaginalcontenteand/oracopulatoryplugobserved insitu willbeconsideredtobeatdayOofpresumedgestationandassignedtoindividual bousing. Femaleratenotmatedwithinthefirstsevendaysofcohabitationwillbeassigned alternatemaleratsthathavemated(samedosagegroup)andwillremainincohabitationfora maximum ofsevenadditionaldays.
Day 1oflactation(postpartum)isdefinedasfoedayofbirthandisalsothefirstdayonwhichall pups inalitterareindividuallyweighed(pupbodyweightswillberecordedafterallpupsina litteraredeliveredandgroomedbyfoedam).
litterswillnotbeculledduringthelactationperiod,becauserandomselectionofpupsfor cullingcouldresultinpotentialbiasesinpupviabilitiesandbodyweightgainsoverthisperiod.
Exygen Research
Page 63 o f 153
418-028:PAGE G-64 Exygen Study No.: 023-072.
P ro to co l 4 1S -02S
Page9
Withineachdosagegroup,consecutiveorderwillbeusedtoassignthefirst10malearidthefirst 10femaleratstoafunctionalobservationalbattery(FOB)andmotoractivitynnnt blood samplecollectionforclinicalchemistryandhematology(CC&H), andhistologicalevaluations.
On day22postpartum,atableofrandomunitswillbeusedtoselectfivemaleandfivefemale pupsperlitterforbloodsampleandlivercollection;thesepupswillonlybeselectedfromtheten damsselectedforFOB,motoractivity,CC&H andhistologicalevaluation.
ADMINISTRATION:
RouteandReason forChoice:
Theoral(gavage)routewasselectedforusebecause: 1)incomparisonwifethedietaryroute, theexactdosagecanbeaccuratelyadministered;and2)itisoneoffeepossiblerouteafor environmentalexposure.
Methodand Frequency:
Dosageswillbeadjusteddailyforbodyweightchangeandgivenatapproximatelythesame timeeachday. Thefirstdayof dosageisdesignatedasday1ofstudy.
Maleratswillbegiventhetestsubstanceoncedailybeginning14daysbeforeacohabitation periodfeatconsistsofamaximum 14days. Dosagewillcontinuethroughthedaybefore sacrifice,aftercompletionoffeecohabitationperiod,afteraminimumof42daysof administration.
Femaleratswillbe giventhetestsubstanceoncedailybeginning 14daysbeforeacohabitation periodthatconsistsofamaximumof14days. Dosagewillcontimiethroughthedaybefore scheduledsacrifice(day21oflactation).
RationaleforDosageSelection:
DosageswereselectedbytheSponsorbasedonpreviousstudiesconductedwiththetest substance;talcingintoaccountpossibledifferencesinsensitivitybetweenpregnantand nonpregnantrats. Thehighestdosagewillbeexpectedtocausetoxiceffectsbutnotmortalityor obvioussuffering. Thedescendingsequenceofthelowerdosagelevelswillbeselectedfigfee purposeofdemonstratinganydosage-relatedresponse,withnoadverseeffectsexpectedatthe lowestlevel.
Exygen Research
Page 64 of 153
418-028: PAGE G-65 Exygen Study No.: 023-072
DosageLevel*.Concentration!aadVolumes:
P ro to co l 4 1 8 -0 2 8 P m g elO
Do--go Q rw
I
a zn IV V
Nuotar ofb o hrSa 15+3*
15+3*
15+ 3*
15+3*
13+3*
Do--ge < i w w
0
0J l 3
10
Co-- o ta d a *
( m i/ tn U
0 0.03 0.1 0J
1
Do--fp Votane
10 10 10 10 10
Art-- B a b N u m b e r
B*41M2I-A(Dqr.MoMh.Ynr)
B-41M2-B(Doy.Monlh.Yr)
B-*lS-Q2K^jfJHc*A.Ycrl B-418-02S-D(Diy.MoQ&.Ytr}
B-dlS^|-E<Dy.Monfc.Yeur)
"flu-- ftddtooodranp c p < t donggroup wfllbuMrig--diotaricctanfei*opk ralltction.
TESTS. ANALYSES AND MEASUREMENTS -FoGENERATION:
Viability-MaleadFemaleRati:
AllPeriods:
Atleasttwicedaily.
Clinical Observations and/or General Appearance - Male m l Female Rats:
AcclimationPeriod:
Weekly.
DosagePeriod:
Dailybeforedosage. On thefirstdayofdosage, postdosageobservationswillberecordedatapproximately hourlyintervalsfordiefirstfourhoursandatfileendofthe normalworkingday. Subsequentpostdosageobservations willberecordedatintervalsdeemedappropriatebythe
StudyDirectorordesigneeafterdeterminationofpeak toxicologiceffects.
MaternalBehavior
Days 1,5 ,8,ISand22postpartum. Observedabnormal behaviorrecordeddaily.
Clinicalobservationsmayberecordedmorefrequentlythancitedabove,ifdeemedappropriate byfileStudyDirectorand/orStudyMonitor.
Datacollectedforntsassignedtotoxicokineticsamplecollectionwillnotbesummarizedor analyzedstatistically.
DetailedClinicalObservations-Male and FemaleRats:
Oncebeforethefirstdosageandatleastonceweeklythereafter,detailedclinicalobservations willbeconductedforallmaleandfemalerats. Theseobservationswillbemadeoutsidethecage inastandardarenaatthesametimeeachdayofconduct Effortwillbemadetoensurethat variationsinthetestconditionsareminimalandthatobservationsam conductedbyobservers
unawareoftreatmentgroups. Signsnotedshouldinclude,butnotbelimitedto: changesinskin, for,eyes,mucousmembranes,occurrenceofsecretionsandexcretionsandautonomicactivity (e.g.,lacrimarion,piloerection,pupilsize,unusualrespiratorypattern). Changesingait,posture
Exygen Research
Page 65 of 153
418-028:PAGE G-66 Exygen Study No.: 023-072
P ro to co l 4 1 M 2 8
Page 11
andresponsetohandlingaswellasfeepresenceofclonicortonicmovements,sterotypic behavior(e.g,excessivegrooming,repetitivecircling),difficultorprolongedparturitionor bizarrebehavior(e.g,self-mutilation,walkingbackwards)shouldalsoberecorded.
BodyWeights-MaleandFemaleRata:
AcclimationPeriod:
Weekly.
D osage Period:
D aily.
Sacrifice:
Terminalweight.
FeedConsnmnUnn Values-MaleRats(recordedandtabulated):
DosagePeriod:
Weekly.
Feed Consnmotion Valnea-FemaleBeta(recordedandtabulated):
DosagePeriod:
Weeklytocohabitation.
GestationPeriod:
Days0,7,10,12,15,18,20and25(ifnecessary).
PostpartumPeriod:
Days 1,5,8and15.
Feedconsumptionnottabulatedafterday 15postpartum,when itisexpectedthatpupswin begin toconsumematernalfeed.
FeedConsnmntianValues-Male FemaleHeim:
Feedconsumptionvaluesmayberecordedmorefrequentlythancitedaboveifitisnecessaryto replenishthefeed. Duringcohabitation,whentworatsoccupythesamecagewithonefeedjar, replenishmentofthefeedjarswillbedocumented. Individualvalueswillnotberecordedor tabulated.
ToxfeoldnetteSamnleCollection:
On day14and42ofstudy,bloodsamples(approximately1mL each)willbecollectedfrom eachmaleratassignedtothetaxiedrineticsamplecollectionportionofthestudy(3pergroup).
On day14ofstudyandday21ofpresumedgestation,bloodsamples(approximately1mL each) willbecollectedfromeachfemaleratassignedtothetoxicokineticsamplecollectionportionof thestudy(3pargroup). Sampleswillbecollectedpriortodosageonday14ofstudy. Thetime ofeachbloodcollectionwillberecordedintherawdata.
Exygen Research
Page 66 of 153
418-028 :PAGE G-67 Exygen Study No.: 023-072
P ro to c o l 41S-Q 2S P a g e 12
Bloodwillbecollectedfromtheorbitalsinus. Ifnecessary,bloodmaybecollectedfroman alternatesite;ifso,thealternatesitewillbedocumentedindierawdata.) Thesampleswillbe transferredintoEDTA-coated(purpletop)tubesandspuninacentrifuge. Theresultingserum willbetransferredintopolypropylenetubeslabeledwiththeprotocolnumber,Sponsorstudy number,snimalnumber,sex,groupnumber,dosagelevel,dayofstudy,collectionintervaldate ofcollection,species,generationandstorageconditions. Allsampleswillbeimmediatelyfrozen ondryiceandmaintainedfrozen(-70*0untilshipmentforanalysis.
Afterthelastbloodsamplecollection,tatswillbesacrificedandsamplesoftheliverwillbe collectedforanalysis.
Shinning Instructions:
Samplestobeanalyzedwillbeshippedondryiceto;
PrincipalInvestigator LisaClemen 3M EnvironmentalTechnologyandSafetyServices Building2-3E-09 St.Paul,Minnesota55133-3331 Telephone: (651)773-5568 Telefax: (651)778-6176 Email: laclemen@iimnii.com
Therecipientwillbenotifiedinadvanceofsampleshipment
Batrous Cycling and Mating:
Estrouscyclingwillbeevaluatedbyexaminationofvaginalcytologybeginningwiththeday afterthefirstadministrationandthenuntilspermatozoaarcobservedinasmearofthevaginal contentsand/oracopulatoryplugisobservedinsitu duringthecohabitationperiod.
Caesarean-Sectioning - Toxicoldnetfc Study:
On day21 ofpresumedgestation,bloodandliversampleswillbecollectedfromallfemalerats designatedfortmticokmeticsamplecollection.
Bloodsampleswillbecollectedfromtheratsaspreviouslydescribed. Aftersacrifice,theliver ofeachratwillbeexcisedandtheliverweightwillberecorded. Themedianliverlobewillbe frozenandstored(<-20"C)untilshipmentforpossibleanalysis.
Thefetuseswillberemovedfromtheuterusandbloodsampleswillbecollectedfromeachfetus viadecapitation. Bloodwillbeplacedintotubes,pooledperlitter,allowedtoclotandspunina centrifuge;theresultingserumwillbetransferredintolabeledpolypropylenetubes. Allsamples willbeimmediatelyfrozenondryiceandmaintainedfrozen(<-70*C)untilshipmentfor analysis.
Exygen Research
Page 67 o f 153
418-028:PAGE G-68 Exygen Study No.: 023-072
Pnxocol 41S-028
P lg c l3
Theliverfromeachfetuswillbecollected,pooledperlittertadplacedintolabeledtubes. The sampleswillhefrozenandstored(<-20C)untilshipmentforanalysis.
SampleswillbeshippedondryicetoLisaClemenatthepreviouslycitedaddress.
NaturalDelivery.
Femaleratswillbeevaluatedfor
AdverseClinicalSignsObservedDuringParturition.
DurationofGestation(dayOofpresumedgestationtothetimethefirstpupisobserved),
litterSize(definedasallpopsdelivered).
PupViabilityatBirth.
FunctionalObservationalBattery:
On oneoccasionduringthecourseofthestudy,afunctionalobservationalbattery(FOB)15'"will beconductedon10maleand10femaleratspergroup. Formalerats,thisassessmentwillbe conductedshortlybeforescheduledsacrifice,butpriortobloodsamplecollectionfor hematologyandclinicalchemistryevaluations. Femaleratsshouldbetestedduringthelactation period,shortlybeforescheduledsacrifice.
TheFOB,tobeconductedbyanobserverunawareofthegroupassignmentoftherat,willassess thefollowingparameters:
1. Lacrimation,salivation,palpebralclosure,prominenceoftheeye,pupillary reactiontolight,piloerection,respiration,andurinationanddefecation (autonomicfunctions).
2. Sensorimotorresponsestovisual,auditory,tactileandpainfulstimuli(reactivity andsensitivity).
3. Reactionstohandlingandbehaviorintheopenfield(excitability).
4. Gaitpatterninfeeopenfield,severityofgaitabnormalities,airrightingreaction, andlandingfootsplay(gaitandsensorimotorcoordination).
5. Forelimbandhindlimbgripstrength.
6. Abnormalclinicalsignsincludingbutnotlimitedtoconvulsions,tremorsand otherunusualbehavior,hypotoniaorhypertonia,emaciation,dehydration, unkemptappearanceanddepositsaroundtheeyes,noseormouth.
Exygen Research
Page 68 o f 153
418-028:PAGE G-69 Exygen Study No.: 023-072
P ro to co l 4 1 8 -0 2 8 P age 14
Evidenceofdieabilityofthisbatterytodetectdieeffectsofpositivecontrolsubstanceswillbe provided(TestingFacilityPositiveControlData). Datawillalsobeprovidedtodocument interobserverreliabilityifmorethanoneobserverisinvolvedinthetesting.
MotorActivityTest
Motoractivitywillbeevaluatedon 10maleand10femaleratspergrouponceduringthecourse ofthestudy. Thisassessmentwillbeconductedshortlybeforescheduledsacrifice,butpriorto bloodsamplecollection.
Themovementsofeachntwillbemonitoredbyapassiveinfraredsensormountedoutsidea stainless-steelwire-bottomedcage(40.6x2S.4x 17.8cm). Eachtestsessionwillbe1.5hoursin durationwiththenumberofmovementsandtimespentinmovementtabulatedateachfiveminuteinterval. Theapparatuswillmonitora rackofupto32cagesandsensorsduringeach session,witheachrattestedinthesamelocationcmtherackacrosstestsessions. Groupswillbe counterbalancedacrosstestingsessionsandcages.
Datawillbeprovidedtodemonstratethattheteatsystemiscapableofdetectingincreasesin activityproducedbypositivecontrolsubstances(TestingFacilityPositiveControlData).
HEMATOLOGY AND CLINICAL CHEMISTRY:
Atscheduledsacrifice,therata(fasted)assignedtohematologyandclinicalchemistry(H&CC) samplecollectionwillbeexsanguinatedfromtheinferiorvenacavafollowingsacrificeby carbondioxideasphyxiation. Approximately5mL ofbloodwillbecollectedandprocessedas describedbelow. Determinationsadditionaltothosedescribedbelowmaybeconductedifthe knownpropertiesofthetestsubstancemay,oraresuspectedto,affectrelatedmetabolicprofiles (e.g.,calcium,phosphate,fastingtriglyceridesandfastingglucose,specifichormones,and cholinesterase).
flNwtetwr
Approximately1mL ofbloodwillbecollectedintoEDTA-coatedtubesandmaintainedonwet iceorrefrigerateduntilshipmentforanalysisofthefollowinghematologicparameters:
ErythrocyteCount(RBC) Hematocrit(HCT) Hemoglobin(HGB) Mean CorpuscularHemoglobin(MCH) Mean CorpuscularHemoglobin Concentration(MCHC)
MeanCorpuscularVolume(MCV) LeukocyteCount,Total(WBC) LeukocyteCount,Differential PlateletCount(PLAT) Mean PlateletVolume (MPV) CellMorphology
Two bloodsmearslideswillbepreparedattheTestingFacilityforeachsamplefor measurementsofdifferentialleukocytecount Allsamples(onwetice)andslides(ambient conditions)willbeshippedtoRedfieldLaboratoriesatthefollowingaddress.
Approximately1.8mL ofbloodwillbeaddedtoatubecontaining0.2mL ofsodiumcitrate (0.129M). Thecontentswillbemixedandmaintainedonweticeuntiltiletubesarecentrifuged
Exygen Research
Page 69 of 153
418-028:PAGE G-70 Exygen Study No.: 023-072
Protocol 41&-028 Page 15
(within30minute*ofthecollectiontime). Theresultingplasmawillbetransferred2.0mL polypropylenetubeslabeledwifestudynumber.Sponsor'sstudynumber,ratnumber,dosage level,dayofstudy,collectioninterval,dateofcollection,species,generationandstorage. All sampleswillbefrozenmidryiceandmaintainedfrozen(<-70C)untilshipmentondryiceby overnightcourierformeasurementofprothrombintime(PT)andactivatedpartial thromboplastintime(APTT).
Clinical Cbmitrv
Approximately2mL ofbloodwillbecollectedintoserumseparatortubesandcentrifuged. The
resultingserasampleswillbeimmediatelyfrozenondryiceandmaintainedfrozen(-7QCC) untilshipmentforanalysisoffeefollowingparameters:
TotalProtein(TP) Triglycerides(TRI) Albumin(A) Globulin(G) Albumm/GlobulinRatio(A/G) Glucose(GLU) Cholesterol(CHOL) TotalBilirubin(TBHJ) ' UreaNitrogen(BUN) Creatinine(CREAT)
CreatinineKinase(CK) AlanineAminotransferase(ALT)
AspartateAminotransferase(AST) AlkalinePhosphatase(ALK) Calcium(CA) Phosphorus(PHOS) Sodium(NA)
Potassium(K) Chloride(CL)
Sampleswillbeshipped(ondryice)toRedfieldLaboratoriesatthefollowingaddress.
SMwiIm Instructions:
SampleswillbeshippedtoarriveonMondaythroughFridayaccordingtotheconditions describedaboveto:
PrincipalInvestigator Ms.PhylHsPowell RedfieldLaboratories A DivisionofCRL-DDS 100EastBooneStreet P.O.Box 308 Redfield,Arkansas 72132 Telephone: (501)397-2540 Telefax: (501)397-2002
Therecipientwillbenotifiedinadvanceofsampleshipment.
URINALYSIS:
Urinalysiswillnotbeconductedunlessindicatedbasedonexpectedorobservedtoxicityoffee testsubstance.
Exygen Research
Page 70 of 153
418-028'.PAGE G-71 Exygen Study No.: 023-072
METHOD OP SACRIFICE:
Protocol 41&428 Page 16
Fogenerationratswillbesacrificedbycarbondioxideasphyxiation.
GROSS NECROPSY AND HISTOPATHOLOGY -FoGENERATION RATS:
ScheduledSacrifice-ToxicokiaeticStudy:
Scheduledsacrificeofmaleratswillbeconductedonday42ofstudy. Scheduledsacrificeof femaleratswillbeconductedonday21 ofpresumedgestation.
Bloodsampleswillbecollectedfromtheratsaspreviouslydescribed. Aftersacrifice,theliver ofeachratwillbeexcisedandtheliverweightwillberecorded. Themedianliverlobewillbe frozenandstored(<-20C)untilshipmentforanalysis. Fetalsampleswillbecollectedas
previouslydescribed.
Carcasseswillbediscardedwithoutfurtherevaluation.
SampleswillbeshippedondryicetoLisaClemenatthepreviouslycitedaddress.
ScheduledSacrifice-Mat Shitty-
Scheduledsacrificeofmaleratswillbeconductedonthedayfollowingthelastdosage administration,afteraminimumof42daysofdosage. Scheduledsacrificeoffemaleratswillbe conductedonday22oflactation.
Grossnecropsyofallmaleandfemaleratswillincludeaninitialphysicalexaminationof externalsurfacesandallorifices,aswellasthecranial,thoracicandabdominalcavitiesandtheir contents. Specialattentionwillbepaidtotheorgansofthereproductivesystem. Thenumberof implantationsitesandcorporaluteawillberecorded.
Maleandfemaleratswillbeexaminedforgrosslesions. Grosslesionswillberetainedinneutral buffered10% formalinandexaminedhistologically. Tissuetrimmingandhistopathologywillbe performedunderthesupervisionoforbyaBoard-CertifiedVeterinaryPathologist.
Theovariesandfeeuteruswifecervixofeachfemaleratwillbeweighed,andovaries,uterus, vaginaandanummaryglandwillberetainedinneutralbuffered10% formalin. Uteriof apparentlynonpregnantratswillbeexaminedafterbeingpressedbetweenglassplatestoconfirm theabsenceofimplantationsites,andretainedinneutralbuffered10% formalin.
E xygen R esearch
Page 71 of 153
418-028:PAGE G-72 Exygen Study No.: 023-072
SoennEvaluationofMaleRats:
P ro to co l 41W J2S
Pigc 17
Toassessthepotentialtoxicityofthetestarticleonthemalereproductivesystem,theendpoints listedbelowwillbeevaluatedhornthefirst10maleratsineachdosagegroup.
OrganWeights: Thefollowingorganswillbeindividuallyweighed: righttestis,left testis,leftepididymis(wholeandcauda),rightepididymis,seminalvesicles(withand withoutfluid)andprostate.
SpermEvaluations: Spermconcentrationandmotilitywillbeevaluatedusingcomputerassistedspermanalysis(CASA). MotilitywillbeevaluatedbytheHamiltonThome IVOSby collectionofasamplefromtheleftvasdeferens. A homogenatewillbe preparedfromtheleftcaudaepididymisforevaluationbytheHamiltonThome IVOS to determinespermconcentration(spermpergramoftissueweight). Theremainingportion oftheleftcaudaepididymiswillbeusedtomanuallyevaluatespermmorphology. Spermmorphologyevaluationswillincludethefollowing:1)determinationofthe percentageofnormalspam inasampleofatleast200;and2)qualitativeevaluationof abnormalsperm,includingsuchcategoriesasabnormalhead,abnormaltail,and abnormalheadandtail
SeeATTACHMENT 4 foradditionaltissuestobeweighedandretainedfromthetenratspersex pergroupassignedtohistologicalsamplecollectionandevaluation.
AH othertissueswillbediscarded.
ScheduledSacrificenfKwmleRatsthatDo NotDeliverLitters:
Ratsthatdonotdeliveralitterwillbesacrificedonday2Sofpresumedgestation. Gross necropsy,examinationandtissueretentionwillbeconductedasdescribedpreviouslyforratsat scheduledsacrifice.
nnM withNo SurvivingPubs:
Dams withnosurvivingpupswillbesacrificedafterdielastpupisfounddead,missingor presumedcannibalized. Grossnecropsy,examinationandtissueretentionwillbeconductedas describedaboveforratsatscheduledsacrifice.
E xygen R esearch
Page 72 o f 153
418-028:PAGE G-73 Exygen Study No.: 023-072
found Dead orMoribund:
Protocol 418-028 Page 18
Hatsthatdieoran sacrificedbecauseofmoribundcondition,abortionorprematuredeliverywifi beexaminedforthecauseofdeathormoribundconditiononthedaytheobservationismade. Theratswillbeexaminedforgrosslesions. Testesandepididymidesofmaleratswillbe excisedandpairedorganweightswillberecorded. Theepididymideswillberetainedinneutral buffered10% formalin. ThetesteswifibefixedinBourn'ssolutionfor48to96hoursandthen retainedinneutralbuffered10%formalin. Pregnancystatusanduterinecontentsoffemalerats willberecorded. Abortedfetusesand/ordeliveredpupswillbeexaminedtotheextentpossible. Uteriofapparentlynonpregnantratswillbeexaminedafterbeingpressedbetweenglassplatesto confirmtheabsenceofimplantationsites. Ovariesanduteriwillberetainedinneutralbuffered 10% formalin.
T E ST S. ANALYSES AND MEASUREMENTS -FIGENERATION:
V iability:
PreweaningPeriod:
Litterswillbeobservedfordeadpupsatleasttwicedaily. The pupsineachlitterwillbecountedoncedaily.
Clinical Observations and/or General Appearance.
PreweaningPeriod:
Oncedaily.
PupswillbeobservedifUreyarewarm andclean,forevidenceofanestandifpupsaregrouped togetherandnursingorhavemilkinstomach. Eachpupwillbeexaminedforgeneralshapeof thehead,trunk,limbs,tailandpresenceofanus.
Clinicalobservationsmayberecordedmotefrequentlythancitedabove,ifdeemedappropriate bytheStudyDirectorand/ordieStudyMonitor.
Body Weight:
PreweaningPeriod:
Days 1(birth),8,ISand22postpartum.
Sacrifice:
Terminalweight
FeedC o n m m n rin n Values(recordedandtabulated):
PreweaningPeriod:
Notrecorded.
METHOD OF SACRIFICE -FI GENERATION PUPS:
FI generationpupswillbesacrificedbycarbondioxideasphyxiation.
I
E xygen R esearch
Page 73 of 153
418-028-.PAGE G-74 Exygen Study No.: 023-072
P ro to co l 4 1 8 -0 2 8
P gc19
NECROPSY -FI GENERATION:
Grosslesionswillberetainedinneutralbuffered10% formalinforpossiblefutureevaluation. Unlessspecificallycitedbelow,allothertissueswillbediscarded.
PantFoundDead onDay 1Postpartum.
Pupsthatdiebeforeexaminationofthelitterforpupviabilitywillbeevaluatedforvitalstatusat birth. Thelungswillberemovedandimmersedinwater. Pupswithhtngsthatsinkwillbe identifiedasstillborn;pupswithlungsthatfloatwillbeidentifiedashvebom,andtohavedied shortlyafterbirth. PupswithgrosslesionswillbepreservedinBourn'ssolutionfen-possible futureevaluation.
Pans Found Dead or M oribund on Pays 1 to 4 Postpartum:
PiTOSfounddeadorsacrificedbecauseofmoribunditywillbeexaminedforgrosslesionsandfor thecauseofdeathorthemoribundcondition. Pupswithgrosslesionswillbepreservedin Bonin'ssolutionforpossiblefutureevaluation.
ScheduledSacrifice:
On day22postpartum,piroswillbewillbesacrificedandexaminedforgrosslesions;gross lesionswillbepreservedinneutralbuffered10%fonnalin. Necropsywillincludeasinglecross sectionoftheheadatthelevelofdiefrontal-parietalsutureandnranimationofthecrosssectionedbrainforapparenthydrocephaly.
Bloodsampleswillbecollectedfromeachselectedpiro(5perseatperlitterfromdie10females pergroupselectedforFOB andmotoractivityassessment,bloodsamplecollectionforH&CC, andhistologicalevaluations)fromthevenacava. Thebloodwillbeplacedintotubes,pooledper litter,allowedtoclotandspuninacentrifuge;theresultingserumwillbetransferredintolabeled polypropylenetubes. Allsampleswillbeimmediatelyfrozenon dry iceand maintained frtrrrm (<-70C)untilshipmentforanalysis. Theliverfromeachselectedpupwillbecollectedexcised andtheorganweightrecorded. Themedianlobewillbefrozenandstored(<-20C)until shipmentforpossibleanalysis. FrozensampleswinbeshippedtolisaClemenatthepreviously citedaddress. Theremainingportionofeachliverwillberetainedinneutralbuffered10% formalinforpossiblehistologicalevaluation. Thelivenwillbeprocessedandevaluated histologicallyasdescribedfordieFogenerationratsinHistologicalEvaluationin ATTACHMENT 4.
Exygen Research
Page 74 of 153
418-028:PAGE G-75 Exygen Study No.: 023-072
PROPOSED STATISTICAL TESTS**-1*: Thefollowingschematicrepresentsstatisticalanalysesofthedata.
P ro to co l 4 1 8 -0 2 8 Page 20
I. Parametric
TypeofTest
II. Nonparametric1*
K MtniM
A. KhakaHW W bTM t |tlN N id n r iiir M M |
SgnM cw rt at 0.001
N o tfiip n fta n l
agntfontatftgO.03
I
NotSferttie
M tyafaarvorian eo
fly n H in n a t ftgO-06
NAO-I O Q I M M
B. F ta h rte m c IT a o la 'i Proportion oTTIm
^WlRgavtMMM
SionM eaM M psO O fi
N ot SigrMeBPit
(n w iflo ) D unfW ffaToX
P o o o g o x B lo d i to w e tio n ) O 0*w y AN O VAtoraaohbtac*
W terttp g B jW
I
O unrM tfoToat
MolStonMant
III. T e s t f o r P r o p o r tio n D a ta
Variance T e s t t o r H o m o g e n e i t y
o f th e B inom ial D istribution
a. Statisticallysignificantprobabilitiesan reportedaseitherp <O.OSorp<0.01. b. Proportiondataarenotincludedinthiscategory. c. Testforhomogeneityofvariance.
Exygen Research
Page 75 of 153
418-028:PAGE G-76 Exygen Study No.: 023-072
P ro to co l 4 1 8 -0 2 8 P **e21
TestitemsintheFOB usingintervalscales,suchasthegrip-strengthtestsanddielandingfoot splaytest,aswellasbodyweightdataandfeedconsumptionvalueswillbeanalyzedas describedundertheParametricheadingoftheschematic. Bartlett'sTestofHomogeneityof Variances191willbeusedtoestimatetheprobabilitydratthegraspshaddifferentvariances. A nonsignificantresult(p>0.001)willindicatethatanassumptionofhomogeneityofvarianceis notinappropriate,andthedatawillbecomparedusingtheAnalysisofVarianceTest*101.Ifthat testissignificant(p<0.05),thegroupsexposedtothetestarticle/substancewillbecomparedwith thecontrolgroupusingDurmetfsTest*111.IfBartlett'sTestissignificint(p<0.001),theAnalysis ofVarianceTestisnotappropriate,andthedatawillbeanalyzedasdescribedunderthe Nonnararoetricheadingoftheschematic. When75%orfeweroffirescoresinalldiegroupsare tied,theKruskal-WallisTest*121willbeusedtoanalyzediedata,andintheeventofasignificant result(piO.OS),Dunn'sTest*131willbeusedtocomparethegroupsexposedtothetest article/substancewithdiecontrolgroup. When morethan75% ofthescoresinanygroupare tied,Fisher'sExactTest*1*1willheusedtocomparedieproportionoftiesinthegroups.
Datafromthemotoractivitytest,withrepeatedmeasurementswithinasession,willboanalyzed usinganAnalysisofVariancewithRepeatedMeasures*131,asdescribedunderthatheadinginthe schematic. A significanteffect(p<0.05)inthattestcanappearaseffectofConcentration(a differencebetweengroupsinthetotalacrossallmeasurementsinasession)orasaninteraction betweenConcentrationandBlock(adifferencebetweengroupsatspecificmeasurement periods). IftheConcentrationeffectissignificant,thetotalsforthecontrolgroupandthegroups giventhetestarticle/substancewillbecomparedusingDunnetfsTest IftheConcentrationx Blockinteractionissignificant,anAnalysisofVarianceTestwillbeusedtoevaluatethe<ttat eachmeasurementperiod,andasignificantresult(p<0.05)willbefollowedbyacomparisonof thegroupsusingDunnetfsTest
TestitemsindieFOB havinggradedorcountscoreswillbeanalyzedusingtheprocedures describedundertheNcnmarametricheadingoftheschematic.
Clinicalobservationincidencedata,aswellssthedescriptiveandquanta]datafromtheFOB, willbeanalyzedascontingencytablesusingtheVarianceTestforHomogeneityoftheBinomial Distribution*161.
Alternateoradditionalstatisticalevaluationsmaybeperformedifdeemednecessaryor appropriate.
Exygen Research
Page 76 of 153
418-028:PAGE G-77 Exygen Study No.: 023-072
P ro to co l 4 1 8 -0 2 8 Pge22
DATA ACQUISITION. VERIFICATION AND STORAGE:
DatageneratedduringthecourseofthisstudywillberecordedeitherbyhandorusingdieArgus Automated Data Collection and Management System, theVivarium Temperature and Relative Humidity Monitoring System, theCoulboum Instruments Passive InfraredMotor Activity System, theCoulboum Instruments Auditory Startle System, dieCoulboum Instruments Spatial DelayedAlternation System, and/orthepassiveavoidancesoftware. Alldatawillbetabulated, summarizedand/orstatisticallyanalyzedusingtheArgus AutomatedData Collection and Management System, theVivarium Temperature and Relative HumidityMonitoring System, Microsoft Excel [partofMicrosoftOffice97(versionSR-2)]and/orThe SAS System (version6.12).
RecordswillbereviewedbytheStudyDirectorand/orappropriatemanagementpersonnelwithin 21daysaftergeneration. AlloriginalrecordswillbestoredinthearchivesoftheTesting Facility. Alloriginaldatawillbeboundandindexed. A copyofallrawdatawillbesuppliedto theSponsoruponrequest PreservedtissueswillbestoredattheTestingFacilityatnochargefor oneyearaftermailingofthedraftfinalreport,afterwhichtimetheSponsorwillbecontactedto determinethedispositionofthesematerials.
KEY PERSONNEL:
ExecutiveDirect'ofResearch: MildredS.Christian,PhD.,Fellow,ATS DirectorofResearch: AlanM. Hoberman,PhD.,DABT AssociateDirectorofResearchandStudyDirector RaymondG.York,PhD.,DABT DirectorofOperationsandCompliance: BarbaraJ.Patterson,B.A. DirectorofLaboratoryOperations: JohnF.Barnett,B.S. DirectofStudyManagement: ValerieA.Sharper,M.S. ManagerofAnimalOperations: DenaC.Lebo.Vi4D. Chairperson,InstitutionalAnimalCareandUseCommittee: DouglasB.Leant,PhD. Consultant,VeterinaryPathology: W. RayBrown,D.V.M.,PhD.,ACVP
Exygen Research
Page 77 of 153
418-028:PAGE G-78 Exygen Study No.: 023-072
RECORDS TO BE MAINTAINED:
P ro to co l 418-028 P ig e 2 3
ProtocolandAmendments. TestSubstance,Vehicleand/orReagentReceipt,PreparationandUse. AnimalAcquisition. RandomizationSchedules. MatingHistory. Treatment(ifprescribedbyStaffVeterinarian). GeneralComments. ClinicalObservationsand/orGeneralAppearance. BodyWeights. FeedConsumptionValues. NaturalDeliveryObservations. FOB andMotorActivityObservations. BloodSampleCollection,ProcessingandShipment GrossNecropsyObservations. OrganWeights. Photographs(ifrequired). StudyMaintenance(roomandenvironmentalrecords). FeedandWaterAnalyses. Packingand/orShipmentLists.
FINAL REPORT:
TheStudyDirectorwinprovideperiodicupdatesofstudyprogresstotheSponsor. Draft
summarytablesofunauditedcomputer-recordeddatamayaccompanytheseupdates. Statistical analyseswinnotbeperformedontheseinterimdata.
A comprehensivedraftfinalreportwillbepreparedoncompletionofthestudyandwillbe finalizedfollowingconsultationwiththeSponsor. Thereportwillincludethefollowing:
SummaryandConclusion. ExperimentalDesignandMethod. EvaluationofTestResults. Appendices: Figures,SummaryandIndividualTablesSummarizingtheAboveData, ProtocolandAssociatedAmendmentsandDeviations,StudyDirector'sGLP Compliance Statement,ReportsofSupportingData(ifappropriate)andQAU Statement.
TheSponsorwillreceiveonecopyofthedraftreportandtwocopiesofthefinalreport.
Datawillbehand-and/orcomputer-recorded. RecordswiUbereviewedbytheStudyDirector and/orappropriatemanagementpersonnelwithin21daysaftergeneration. Alloriginalrecords willbestoredinthearchivesoffoeTestingFacility. AlloriginaldatawiUbeboundand indexed. A copyofallrawdatawillbesuppliedtotheSponsoruponrequest Preservedtissues wiUbestoredattheTestingFacilityatnochaigeforoneyearaftermailingofthedraftfinal report,afterwhichtimetheSponsorwillbecontactedtodeterminethedispositionofthese materials.
Exygen Research
Page 78 of 153
418-028:PAGE G-79 Exygen Study No.: 023-072
P ro to co l 41&4T28 Page 24
INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE STATEMENT:
TheproceduresdescribedinthisprotocolhavebeenreviewedbytheTestingFacility's InstitutionalAnimalCareandUseCommittee. Allproceduresdescribedinthisprotocolthat involvestudyanimalswillbeconductedinamannertoavoidorminimizediscomfort,distressor paintothea n im a l .
TheSponsor'ssignaturebelowdocumentsthefactthatinformationconcerningthenecessityfor conductingthisstudyandthefactthatthisisnotanunnecessarilyduplicativestudymaybe obtainedfromfoeSponsor. No alternative(in vitro)procedureswereavailableformeetingthe statedpurposesofthestudy.
REFERENCES:
1. Christian,MS. andVoytek,P.E.(1982). In VivoReproductive <*ndMutagenicity Tests. EnvironmentalProtectionAgency,Washington,D.C.NationalTechnicalInformation Service,U.S.DepartmentofCommerce,Springfield,VA 22161.
2. Christian,MS. (1984). Reproductivetoxicityandteratologyevaluationsof naltrexone(ProceedingsofNaltrexoneSymposium,New YorkAcademyofSciences, November7,1983),I.Clin.PsychiaL45(9):7-10.
3. Lang,P.L.(1988). Embryo and Fetal Developmental Toxicity (Teratology) Control Data . in the Charles River Crl:CDQBR Rat. CharlesRiverLaboratories,Inc.,Wilmington, M A 01887-0630. (DatabaseprovidedbyArgusResearchLaboratories,Inc.)
4. InstituteofLaboratoryAnimalResources(1996). Guidefo r the Care and Use o f LaboratoryAnimals. NationalAcademyPress,Washington,D.C.
3. Haggerty,G.C.(1989). DevelopmentofTierIneurobebavioraltestingcapabilitiesfor incorporationintopivotalrodentsafetyassessmentstudies. I.Amer.Col.ToxicoL8:53 70.
6. Irwin,S.(1968). Comprehensiveobservationalassessment: la. A systemicquantitative procedureforassessingthebehavioralandphysiologicstateofthemouse. Psychopharmacologia(Berlin)13:222-257.
7. Moser,V.C.(1989). Screeningapproachestoneurotoxicity: A functionalobservational battery. J.Amer.Col.ToxicoL8:85-94.
8. O'Donoghue,JX.(1989). Screeningforneurotoxicitynsinganeurologicallybased examinationandneuropathology. J.Amer.CoLToxicol.8:97-116.
9. Solcal,R.R.andRohlfFJ.(1969). Bartlett'stestofhomogeneityofvariances. Biometry, WE. FreemanandCo.,SanFrancisco,pp.370-371.
Exygen Research
Page 79 of 153
418-028:PAGE G-80 Exygen Study No.: 023-072
P ro to co l 4 18-028 Page 25
10. Snedecor,G.W. andCochran,W.G.(1967). AnalysisofVariance.Statistical Methods, 6thEdition,IowaStateUniversityPress,Ames, pp.258-275.
11. Dunnett,C.W.(1955). A multiplecomparisonprocedureforcomparingseveral treatmentswithacontrol J.Aster.StatAssoc.50:1096-1121.
12. SokalRJl andRohlf,FJ.(1969). Kruskal-WallisTest Biometry, W.H.Freemanand Co.,SanFrancisco,pp.388-389.
13. Dans,OJ.(1964). Multiplecomparisonsusingranksums. Technometrics6(3):241-252. 14. SiegelS.(1956). Nonparametric Statisticsfo r theBehavioral Sciences, McGraw-Hill
New York,pp.96-104.
15. SAS Institute,Inc.(1988). Repeatedmeasuresanalysisofvariance. SAS/STAT1* User's Guide, Release6.03Edition,Cary,NC,pp.602-609.
16. Snedecor,G.W. andCochran,W.G.(1967). Variancetestforhomogeneityofthe binomialdistribution. Statistical Methods, 6th Edition,IowaStateUniversityPress, Ames,pp.240-241.
Exygen Research
Page 80 of 153
PROTOCOL APPROVAL: FOR THE TESTING FACILITY
C iv * * u
AlanM. Hoberman,PhD.,DABT DirectorofResearch
Svt&.'X ^ TheresaH.Woodard,D.NOd. -- ,, Member,InstitutionalAnimalCareand
UseCommittee
FOR THE SPONSOR
JohnButcnhofLPhD.,DABT, CIH StudyMontarand Sponsor'sRepresentative
418-028:PAGE G-81 Exygen Study No.: 023-072
P r o to c o l 41W 2 S P*gc 26
Date
2.* fO/HL 2 -0 0 2L
Date ..fib*-.
Date
Date
Exygen Research
Page 81 of 153
418-028:PAGE G-82 Exygen Study No.: 023-072
ATTACHMENT 1 SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE
Exygen Research
Page 82 o f 153
418-028:PAGE G-83 Exygen Study No.: 023-072
ATTACHM ENT!
STUDY SCHEMATIC
P io tc c o l 418-028 P ig e 1 o f 3
COMBINED REPEAT DOSE AND REPRODUCTIVE/DEVELOPMENTAL TOXICITY SCREEN*
F ire! D a y o f T e st S u b sta n c e
P rcn H n g
L ast D ay o f T est S u b sta n c e D osage*
finhh^gtiifn
L ast D ay o f T est S u b sta n c e D osage*
1 2 W eeks | 2 W eeks
*
F e m a le R ats
A ctiv ity /F O B *
i
2Weeks
2Weeks
N atu ral D eliv ery
P resum ed G e sta tio n
3 W eeks
P o stp artu m P erio d
n
D ay 21 D ay 22*
M o to r A ctiv ity /F O B *
er p
DosagePeriod
Foradditionaldetailssee"Testa,AnalysesandMeasurements'1sectionoftheprotocol. FOB andmotoractivityevaluationsconductedontenmalespergroup. c. Maleratssacrificedaftercompletionofatleast42daysofdosage,necropsyandretention ofmalereproductiveorgans. Hematology,clinicalbiochemistryandhistologicalsamples collectedfromteamaleratspergroup. d. TenfemaleratspergroupassignedtoFOB evaluationandmotoractivityevaluation. e. Tenfemaleratspergroupandtheirlitterssacrificedonday22postpartum;necropsyand retentionoffemalereproductiveorgans. Hematology,clinicalbiochemistryand histologicalsamplescollected. Remainingfemaleratssacrificedonday22postpartum anddiscarded.
Exygen Research
Page 83 of 153
418-028:PAGE G-84 Exygen Study No.: 023-072
ATTACHM ENT 1
P ro to co l 4 18-02S Page 2 o f 3
SCHEDULE*
26MAR 02 01APR 02
01APR 02-12JUN 02
14APR 02PM -21APR 02AM 21APR 02PM -28APR 02AM
14APR 02 ISAPR 02 28APR 02 06MAY 02
19MA Y 02
06M A Y 02-07MAY 02
AnimalReceipt-AcclimationBegins.
StartofDosagePeriod-MaleRats(14daysbefore cohabitationandthrougha14-daycohabitation perioduntilthedaybeforesacrificeafteratleast42 daysofdosage).
DosagePeriod-FemaleRats(14daysbefore cohabitationthroughDay22oflactation).
CohabitationPeriod(Maximumof14days). Male 1(7days) Male2(7days)
Day 14ToxicokineticSampleCollection
FirstPossibleDay 0ofPresumedGestation. LastPossibleDay0ofPresumedGestation.
FirstPossibleDay21ofPresumedGestation ToxicokineticSampleCollectionandSacrificeToxicokineticStudyFemaleRata LastPossibleDay21ofPresumedGestation ToxicokineticSampleCollectionandSacrificeToxicokineticStudyFemaleRats
FOB andMotorActivityEvaluation-10MaleRats perGroup
zr f
ThestartdateofthestudyisthedaytheStudyDirectorsignstheprotocol. Throughoutthiischedule,thedayofbirthisdesignatedday1postpartum(day1of lactation)andallsubsequentagesoftheFI generationrateanddaysofthelactation
periodwillbedeterminedandcitedaccordingly,aadescribedabovetheprotocolsection, "DayNumberingSystem."
Exygen Research
Page 84 of 153
418-028:PAGE G-85 Exygen Study No.: 023-072
ATTACHM ENT I
06MAY 02 23MAY 02 10MAY 02 23MAY 02 12MAY 02
13MAY 02
23MAY 02-09JUN 02 -- 27MAY 02-13 JUN 02
24SEP 02
P ro to co l 4 1 * 4 )2 8 P ag e3 o f3
FirstPossibleDelivery(Day21 ofpresumed gestation). LastPossibleDelivery(Day23 ofpresumed gestation).
FirstPossibleDay25 ofPresumedGestation FemaleSacrifice. LastPossibleDay25ofPresumedGestation FemaleSacrifice.
Day42ToxicokineticSampleCollectionand ScheduledSacrifice-ToxicokineticStudyMale Rats
ScheduledSacrifice-MainStudyMaleRats (Earliestpossibledate). Hematology,Clinical BiochemistryandHistologicalSampleCollectionof SelectedMaleRats.
FOB andMotorActivityEvaluation-10Female RatsperGroup.
Day22Postpartum-SacrificeFemaleRatsand Pups. Hematology,ClinicalChemistryand HistologicalSampleCollectionofSelectedFemale RatsandPups.
DraftFinalReport
Exygen Research
Page 85 of 153
418-028:PAGE G-86 Exygen Study No.: 023-072
ATTACHMENT 2 MATERIAL SAFETY DATA SHEET
Exygen Research
Page 86 of 153
418-028:PAGE G-87 Exygen Study No.: 023-072
MATERIAL SAFETY OATA SHEET (Experim ental)
C o p y rig h t, 1989, N in n o io ti M ining and M an u factu rin g Company. A ll r i g h t s ra a a rv a d . Copying a n d /o r dow nloading o f t h i i In f o r m a tio n f o r t h a purpoaa o f p r o p a r ly u t i l i z i n g 3H p ro d u c t* ia allow ed p ro v id ed th a t: 1) th a in fo rm a tio n ia copied in f u l l w ith no change* u nless
p r i o r a g r a a a a n t i s o b ta in e d f r o o 3M, a n d 2) n e ith e r th e copy nor the o rig in a l i s re so ld o r otherw ise
d is trib u te d w ith th e in ten tio n o f earn in g a p ro fit thereon.
DIVISION: 3M SPECIALTY MATERIALS MATERIAL:
L-9051 DEVELOPMENTAL PRODUCT ISSUED: December 0 7 , 1999 SUPERSEDES: May 1 7 , 1999 DOCUMENT: 0 4 -S 4 7 0 -2
1 . INGREDIENT
C .A .S . HO.
PERCENT
POTASSIUM PERFLUOROHEXANE SULFONATE.......... 3 8 7 1 -9 9 -6 RESIDUAL ORGANIC FUNMOCHEMXCALS................ M ix tu re
101.0 Unknown
T h i i n o t a r i a l i a n o t l i s t e d on th a T5CA i n v e n t o r y and sh o u ld ha u s e d
fo r research and devalopm ant purposes only under the d ire c t
supervision of a te c h n ic a lly q u alified in d iv id u al.
-
2 . PHYSICAL DATA
BOILING PO IN T:............ VAPOR PRESSURE:.......... VAPOR DENSITY:............ EVAPORATION RATE:. . . SOLUBILITY IN HATER: SPECIFIC GRAVITY:. . .
PERCENT VOLATILE:. . . P H :...................................... V IS C O S IT Y :...................... MELTING POINT:............
N/A N egligible N/A N egligible slig h t ea. 1.0 W ater-1
(Bulk) N egligible N/A N/0
N/D
APPEARANCE AND ODOR: O ff-w hite orys ta l lin e s o lid , sharp odor.
A b b r e v ia tio n s : N/D - N o t D eterm ined N/A - N ot A p p lic a b le CA A p p ro x im a te ly
Exygen Research
Page 87 of 153
418-028:PAGE G-88 Exygen Study No.: 023-072
MSDS: L-905T DEVELOPMENTAL PRODUCT eceeber 07, 1999
PAGE 2
3 . FIRE AND EXPLOSION HAZARD DATA
FLASH POINT:........................................... * 211 F S e t a f l a s h
S e t a f l a s h C lo s e d Cup FLAMMABLE LIMITS L E L :................ N/A FLAMMABLE LIMITS - UEL:................ N/A AUTDIGMITION TEMPERATURE:............N/D
EXTINGUISHING MEDIA: H ator, Carbon d io x id e , Dry e h ea ie e l, Foes
SPECIAL FIRE FIGHTING PROCEDURES:
Hoar f u l l p ro te c tiv e c lo th in s , including h e la e t, olf-containod,
p o a itlv o p re s s u re o r p rts o u ro dewind b ro a th in g a p p a ra tu s, bunkar c o a t
and p a n ts, bands around araa, w aist and la g s. Taco aask, and
p ro te c tiv e cov erin g fo r expoeed areas of th e head.
-
UNUSUAL FIRE AND EXPLOSION HAZARDS: Sea Hazardous D ecoapoeition sectio n fo r p ro d u cts o f conbustion.
. REACTIVITY DATA
STABILITY: S t a b l e
INCOMPATIBILITY - MATERIALS/CONDITIONS TO AVOID: None known.
HAZARDOUS POLYMERIZATION: H azardous p o l y a s r i z a t i o n w i l l n o t o c c u r.
HAZARDOUS DECOMPOSITION PRODUCTS: May p ro d u c e f l u o r o c a r b o n g a s e s i f exposed t o v e r y h ig h t e a p e r a t u r e s (over 310 C ).
S . ENVIRONMENTAL INFORMATION
SPILL RESPONSE: Observe p re c a u tio n s fro a e th e r se c tio n s. C o lle c t s p ille d a a t e r ia l. Use w et sw eep in g ooapound o r w ater to a v o id d u s tin g . C lean up resid u e. P lace in a eloaad container.
RECOMMENDED DISPOSAL: In c in e ra te in an in d u s tria l o r co aaerclal f a c i l i t y in th e presence of a e o a b u s t i b l e a a t e r i a l . C o ab u stio a p ro d u c ts w i l l in c lu d e MF. D isposal a lte r n a tiv e : D ispose of w atte product in a f a c ility p e m itte d to a c c e p t c h e a ic a l w aste.
A b b r e v ia tio n s : N/D N o t D a te r a in e d N/A N e t A p p lic a b le CA A p p r e x ls a te ly
E xygen R esearch
Page 88 of 153
418-028:PAGE G-89 Exygen Study No.: 023-072
SOS: L-90S1 DEVELOPMENTAL PRODUCT Decaaber 07, 1999
5 . ENVIRONMENTAL INFORMATION
(eontinuad)
ENVIRONMENTAL DATA: Not d e te rm in e d .
REGULATORY INFORMATION: V o l a t i l e O rg a n ic Compound*: N/D. VOC L ea* H20 0 E x a a p t G o lv a n ts : N/D.
Slnea re g u la tio n s v ary , co n su lt ap p licab le re g u la tio n s o r a u th o ritie s b e f o r e d i s p o s a l . U .S . EPA H azardous W aste N uabar - None (Not U .S. EPA H a z a rd o u s ).
OTHER ENVIRONMENTAL INFORMATION: This product say c o n ta in one o r so re organic flu o ro ch aaio ala th a t have th e p o te n tia l to r e s i s t degradation and p e r s is t in th e e n v iro n a e n t.
EPCRA HAZARD CLASS: FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Vas CHRONIC: No
6 . SUGGESTED FIRST AID
EVE CONTACT: Ia a e d ia te ly flu sh eyes w ith larg e aaounta of w ater. Got ia a e d ia te aed ical atten tio n .
SKIN CONTACT: Flush sk in w ith la rg e aaounts of w ater, i f i r r ita tio n p e rs is ts , get aedioal atten tio n .
INHALATION: I f sig n s/sy ap to as o ccu r, reaove person to fresh a i r . I f sig n s/sy ap to as co n tin u e, c a ll a physician.
IF SHALLOWED: I f sw ell owed, c a l l a p h y sic ia n ia a e d ia te ly . Only induce v o a itin g a t th a in s tr u c tio n o f a p h y sic ia n . Never give an y th in g by a o u th to an unconscious person.
7 . PRECAUTIONARY INFORMATION
EYE PROTECTION: Avoid eye c o n ta c t. Avoid eye c o n ta ct w ith vapor, sp ra y , o r a i s t . The fo llo w in g sho u ld be worn alone o r in c o a b ln a tio n , a s a p p ro p ria te , to p re v e n t eye c o n ta e t: H ear vented goggle.
3
A b b re v ia tio n * ', N/D - N o t D e te r a in o d N/A - Not A p p lic a b le CA - A p p r o s la a ta ly
E xygen R esearch
Page 89 of 153
418-028:PAGE G-90 Exygen Study No.: 023-072
HSOS: L-9051 DEVELOPMENTAL PROOUCT D W U M r 07, 1969
PAGE 4
7 . PRECAUTIONARY INFORMATION
(continued)
SKIN PROTECTION: Avoid s k in c o n ta c t. H ear a p p ro p ria te g lo v es wbtn h an d lin g th in a t t r i a l . A p a ir o f g lo v e s Bade f r e e th e fo llo w in g a a t e r l a l ( t ) a re
reooaeended: b u ty l ru b b er, polysthylsne/polyvinylldsne ch lo rid e (S eran ex ). Use one o r e a r s o f th e fo llo w in g p erso n al p ro te c tio n ite a s as n ecessary to p re v en t sk in c o n ta c t: head covering, c o v e ra lls . F ro te o tiv e garm ents (o th e r than gloves) should be aade o f e ith e r or th e follow ing n a te ria ls : polyethylene/polyvinylldene chlo rid e (Seranex).
RECOmEIOEO VENTILATION:
Use w ith a p p ro p ria te l o c a l ex h au st v e n tila tio n . Provide a p p ro p ria te
l o c a l e x h a u s t v e n t i l a t i o n a t t r a n s f e r p o i n t s . Use in a w e'll-
'
v e n tila te d are a. Provide s u ffic ie n t v e n tila tio n to aain tain
M is s io n s below rtc o o aen d ed exposure H a l t s , i f exhaust v e n tila tio n
i s n o t adequate, use ap p ro p rle ta re sp ira to ry p ro tectio n . Provide .
v e n tila tio n ad eq u a ta t o c o n tr o l v apor c o n c e n tra tio n s below
recoaacnded exposure l l a l t e an d /o r c o n tro l spray o r e ls t.
Local ax h o u st v e n tila tio n i s reeoaaended sdiere th e nes airborne.
a a t tr ia l beco
RESPIRATORY PROTECTION: Avoid b re a th in g o f a irp o m e q a t e r i a l . S a la c t one o f th e fo llo w in g NIOSH a p p ro v e d r a s p i r a t o r a b a ae d on a i r b o r n e c o n c e n tr a tio n o f c o n t a a i n a n t i an d i n a c c o rd a n c e w ith OSHA r e g u l a t i o n s : h a lf - e e a k supplied a ir rte p ir a to r , fu ll-fa c e supplied a ir re sp ira to r.
PREVENTION OF ACCIDENTAL INGESTION:
Do n o t e a t , d r i n k or s a o k e whan u s in g t h i s p r o d u c t. Hash ax p o ssd
a r e a s th o ro u g h ly w ith s e e p end w a te r . Wash h a n d s a f t e r h a n d lin g and
before eating.
RECOMNDED STORAGE: S to r e a t r o c s t s e p e r a t u r e . Keep c o n t a i n e r d r y . Keep c o n ta in e r c lo se d whan n o t in u s e .
FIRE AND EXPLOSION AVOIDANCE: Not determ ined.
EXPOSURE LIMITS
INGREDIENT
VALUE UNIT
TYPE AUTM SKIN*
POTASSIUM PEftFUJQROHEXANE
. 0.1 M0/H3 RESIDUAL ORGANIC FLUQROCHENICALS.. . . . . (.1 H6/M3
TUA 3M TWA 3H
Y
r
* SKIN NOTATION: L i s t e d s u b s ta n c e s i n d i c a t e d w ith 'Y ` u n d e r SKIN r e f e r t o
A b b r e v ia tio n s : N/O N o t O e te r s in e d N/A - Not A p p lic a b le CA - A p p r o x la a te ly
E xygen R esearch
Page 90 o f 153
418-028:PAGE G-91 Exygen Study No.: 023-072
HSOS: L-9051 DEVELOPMENTAL PROOUCT Oaceaber 7, 1990
PACE 5
EXPOSURE L IH H S
(continuad) .
INGREDIENT
VALUE UNIT
TYPE AUTH SKIN*
th e p o te n tia l c o n trib u tio n to th e o v e ra ll expoeure by th e cutaneous ro u te in c lu d in g au co u s a eab ran e and eye, e ith e r by a irb o rn e o r, aore p a r tic u la r ly , by d ir e c t c o n ta c t w ith th e substance. V ehicles can a lte r akin ab so rp tio n .
SOURCE OF EXPOSURE LIMIT DATA: - 3M: 3M R ec o a a en d e d E x p o su re G u id e lin e s
.
S . HEALTH HAZARD DATA
EYE CONTACT: No i n f o r a a t i o n w as fo u n d r e g a r d in g e f f e c t s f r o a eye c o n ta c t.
Single exposure any cause:
W ild Eye I r r i t a t i o n : s ig n s/a y a p to a s oan in clu d e red n ess, sw elling, p ain , and tearin g .
SKIN CONTACT:
.
No i n f o r a a t i o n w as fo u n d re g a r d in g o f f s e t s f r o a s k in c o n ta c t.
nay be a b so rb e d th ro u g h th e ak in and p a r a i a t in th e body f o r an extended tia e .
S ingle exposure nay cause:
M oderate S k in I r r i t a t io n : sig n e/sy ap to aa can include redness, sw ellin g , itc h in g , and dryness.
INHALATION: No i n f o r a a t i o n w as fo u n d re g a r d in g e f f e c t s f r o a I n h a l a t i o n e x p o su re .
Hay bo ab so rb ed by in h a la tio n and p a r a ia t in th e body f o r an extended tin e .
S in g le ov erex p o su re, above recoaaended g u id e lin e s, aay cause:
I r r ita tio n (upper re s p ira to ry ): aig n slsy ap to as can Include so re n e ss o f th e nose and th ro a t, coughing and sneezing.
IF SWALLOWED: In g e stio n i s n o t a lik e ly ro u te of exposure to th ia product.
No i n f o r a s t i o n w as fo u n d r e g a rd in g e f f e c t s f r o a sw a llow ing.
A n la a l s tu d ie s co n d u cted on o rg a n ic flu o ro e h e a ie a ls which nay be p resen t in th is product in d icate o ffse ts including liv e r disturbances, w eight Ic e s , lo s s o f ip p a tits , le th a rg y , end n eu ro lo g ical, p a n craa tie , a d r e n a l and h a a a t o l o g l c e f f e c t s . T here a r e no known h u s in h e a lth
A b b r e v ia tio n s : N/D N o t D e ta r a in a d NIA - Not A p p lic a b le CA - A p p ro x ia a te ly
E xygen R esearch
Page 91 of 153
418-028:PAGE G-92 Exygen Study No.: 023-072
USDS: L-9051 DEVELOPMENTAL PRODUCT oeeeaber 07. 1999
page e
8 . HEALTH HAZARD DATA
(continued)
e f f e c t s from a n t i c i p a t e d e x p o su re t o th a a a o r g a n is f lu o r o c h e a lo a la
when uaad aa in ta n d a d and ln a tru e ta d .
OTHER HEALTH HAZARD INFORMATION: T his p ro d u ct aay c o n tain ona o r nora organic flu o ro o h an io als th a t
h a v a t h a p o t e n t i a l t o b a a b s o rb e d and ra n a ln I n th e body Tor lo n g
p erio d s o f tla e , e ith e r aa tha parent aolacula o r aa a a ta b o llta a , and a ay a c c u a u la tt w ith r e p e a te d a x p o su rea . There a re no known huaan h e a lth e ffa e ta fro a a n tic ip a te d exposure to th ese organic T lu o ro c h en lc a la whan used a s Intended and In s tru c te d .
The p re te n c e o f o rg a n ic flu o ro e h e e lc a ls In th e blood o f th e g en eral p o p u latio n and aubpopulatlona, such aa w orkers, has been published d a t i n g b a c k t o t h e 1 9 7 0 's . BM'e a p ld a e l o l o g i e s l s tu d y o f i t s own w orkers in d ic a te s no adverse a ffe c ts.
SECTION CHANQE OATES
PRECAUTIONARY INFO. SECTION CHAN6E0 SINCE May 1 7 , 1999
ISSUE
A b b r e v ia tio n s : N/D - N ot O a ts r e in e d N/A - Not A p p lic a b le CA Approxi a a t s l y
T he l n f o r a a t i o n I n t h i s M a t e r i a l S a f e ty D ata S h e e t (MSOS) i s b e lie v e d t o b e c o r r e c t a s o f t h a d a t a I s s u e d . SH MAKES NO WARRANTIES, EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, ANY IMPLIED WARRANT/ OF MERCHANTABILITY OR FITNESS FDR A PARTICULAR PURPOSE OR COURSE OF PERFORMANCE OR USAGE OF TRADE. U ser l a r e s p o n s ib le f o r d a ta r a in in g w h e th e r t h e SN p r o d u c t l a f i t f o r a p a r t i c u l a r p u rp o s e and s u i t a b l e f o r u e e r 'a e e th o d o f use o r a p p lic a tio n . Given th a v a rie ty o f f a c to r s th a t c a n a f f e c t t h e u s e an d a p p l i c a t i o n o f a 3M p ro d u c t, aoae o f w hich a r e u n iq u e ly w ith in th e u s e r 's knowledge and c o n tro l, i t Is e s s e n tia l th a t t h e u s e r e v a l u a t e t h a 3M p r o d u c t t o d a ta r a in a w h e th e r i t l a f i t f o r a p a rtic u la r purpose and s u ita b le fo r u s e r's eethod of use o r ap p licatio n .
3M p r o v id e s l n f o r a a t i o n i n e l e c t r o n i c f o r a a s a s e r v l e t t o i t s e u s t o s s r s . Due to th a re e o te p o s s ib il ity th a t e le c tro n ic tr a n s f e r aay hays re s u lte d i n e r r o r s , o a i i s i o n i o r a l t e r a t i o n s In t h i s ln f o r a a tio n , 3H a ak ea no re p re s e n ta tio n s as to i t s coaplotenoaa o r accuracy. In ad d itio n , ln f o r a a tio n o b ta in e d f r o a a d a ta b ase aay n o t ba a s c u rre n t a s th a l n f o r a a t i o n I n t h e MSOS a v a i l a b l e d i r e c t l y f r o a 3M.
E xygen R esearch
Page 92 of 153
418-028:PAGE G-93 Exygen Study No.: 023-072
ATTACHMENT 3 TEST SUBSTANCE PREPARATION PROCEDURE
Exygen Research
Page 93 of 153
418-028: PAGE G-94 Exygen Study No.: 023-072
ATTACHMENTS
Protocol 4 1 *0 2 8
Version: 418-028(19 M AR 0 2 ' Paje 1 of 2
TEST SUBSTANCE PREPARATION PROCEDURE
Test Substance: T-770B
Vehicle:
Aqueous 0.5% CMC (medium viscosity)
A. Purpose:
The purpose of the procedure is to provide a method for the preparation of dosage suspensions of T-7706 for oral (gavage) administration to rats on Argus
Research Study number418-028.
B. General Information:
1. All suspension containers wffl be labeled and color-coded. Each label will specify the protocol number, test substance identification, Argus batch
number, concentration, dosage level, preparation date, expiration date
and storage conditions.
2. Suspensions will be prepared:
__ Daily
X Weekly _ For_ days of use
_ Approximately every ten days
__ By Sponsor
3. Suspensions wiBbe administered at a final dosage volume of 10 mUka.
4. Safety: X Gloves, unifbrm/lab coat, goggles or safety glasses with side shields X Dust-mistfHEPA-fittered Mask
__ Half-Pace Respiratorifnot used in a chemical fume hood __ Full-Pace Resphator/Positive Pressure Hood ___ Tyvek Suit or tyvek apron and sleeves
5. Dosage suspensions adjusted for %Adhnty/Purity or Correction Factor
__ Yes
X No (Calculations based on 100%)
__ % Activity
__% Purity__ Correction Factor
6. Sampling requirements: Cited in protocol
7. Storage: Cited in protocol
Exygen Research
Page 94 of 153
418-028:PAGE G-95 Exygen Study No.: 023-072
ATTACHMENT 3
Protocol 418-028 Varaion: 41B-Q2BriB M AR 021
Paga 2 of 2
TEST SUBSTANCE PREPARATION PROCEDURE
NOTE:
Priorto test substance preparation accurately measure the required amount of the appropriate vehicle (R.O. deionized water should be used for calibration purposes) in a graduated cylinder, pourthe required amount of vehicle into a beaker. Carefully mark each beaker at die meniscus. This mark will be usad during the preparation to bring the test substance slurry up to volume.
C. Dosage Suspension Preparation:
1. Weigh the required amount of test substance on a piece of weigh paper or
into an appropriately sized mortar (see PREPARATION CALCULATIONS).
2. If weigh paper is used, transfer the test substance to an appropriately sized mortar. Ifnecessary, grind the test substance into a fine powder. Slowly add a small amount of vehicle and grind. Continue to add vehicle slowly and grind the vehicle and the test substance togetherto form a fine slurry. Transfer the vehide/test substance slurryto a marked beaker.
3. Rinse the mortar and pestle with additional vehicle to remove any remaining test substance. Transfer rinse to beaker.
4. Add additional vehicle to the beaker to bring volume up to the mark. Place on magnetic stir plate and agitate prior to and during sampling, aliquotting and/or administration.
5. Repeat steps (1) through (4) for each concentration.
Written By.
Approved by.
Date: w m -
0 ClarificaUon:___No -- Yes [see attached clarification form)
Jnitlal/Date :
Exygen Research
Page 95 of 153
418-028-.PAGE G-96 Exygen Study No.: 023-072
ATTACHMENT 4 TISSUESTO BE WEIGHED, RETAINED AND EXAMINED HISTOLOGICALLY
Exygen Research
Page 96 of 153
418-028.-PAGE G-97 Exygen Study No.: 023-072
ATTACHM ENT 4
P ro to co l 4 18 -0 2 8 Page 1 o f 2
TISSUES TO WEIGHED AND RETAINED FOR POSSIBLE EXAMINATION FROM TEN RATS PER SEX PER GROUP
Thetenratspersexpergroupassignedtofunctionalobservationalbatteryandmotoractivity testswillbeassignedtohematology,clinicalbiochemistryandhistologicalevaluations.
Tissues to be Weighed:
Thefollowingorganswillbeexcised,trimmedandindividuallyweighedassoonaspossible afterexcisiontoavoiddrying.
liver spleen
kidneys
brain
adrenals
heart
thymus
ovaries
testes
uterus(withcervix)
rightepididymis
prostate
leftepididymis(wholeandcauda)
seminalvesicles(withandwithoutfluid)
Tissuestoh*Retained:
Thefollowingtissuesorrepresentativesampleswillberetainedinneutralbuffered10% formalin.
brain(representativeregionsincludingcerebrum,cerebellum,pons)
smallandlargeintestines(includingPeyerispatches)
lungs(perfusedwithneutralbuffered10% formalin)
lymphnodes(submandiblarandmediastinal)
peripheralnerve(sciaticortibial)
grosslesions
spinalcord(cervical,thoracicandlumbar)
stomach
liver
kidneys
adrenals
spleen
heart
thymus
thyroid/parathyroid
trachea
uterus
urinarybladder
bonemarrow(sternum)
testes*
ovaries
prostate
uterus
seminalvesicles(withcoagulatinggland) v a g in a
mammary gland(femaleratsonly)
TesteswillbefixedinBourn'ssolutionfor48to96hoursbeforebeingretainedinneutral buffered10% formalin.
Additionally,theremainingportionoffireloftepididymis(corpusandcaput),aswellastheright epididymiswillbefixedinneutralbuffered10% formalin.
Exygen R esearch
Page 97 of 153
418-028:PAGE G-98 Exygen Study No.: 023-072
ATTACHM ENT 4
P ro to co l 4 1 8 4 )2 8 Page 2 o f 2
Hictnlmrif!Kramhtarina-
Histologicalexaminationofretainedtissues,includingreproductiveorgans,willbeconducted fortheassignedtenratspersexfromthecontrolandhighdosagegroupsandfirmthe FI generationpups(livers)fromdiecontrolandhighdosagegroups. Iflesionsattributedtothe testsubstanceareobservedintheratsexposedtothehightestsubstanceconcentration,them w tissueswillbeexaminedfromtheassignedtentatspersexexposedtothelowertestsubstance concentrations. Shouldresultswarrantexaminationofthelowerdosagegroupsandconductof quantitativeevaluation,scheduledreportdateandpriceswillbeadjustedaccordingly.
TheposQactionalovaryshouldcontainprimordialandgrowingfolliclesaswellasthelarge corporahiteaoflactation. Histopaihologicalexaminationmaydetectqualitativedepletionofthe primordialfolliclepopulation A quantitativeevaluationofprimordialfollicleswillbe conductedforFo generationfemalerats;thenumberofrats,ovariansectionselectionandsection samplesizewillbestatisticallyappropriatefortheevaluationprocedureused. Examinationwill includeenumerationoffoenumberofprimordialfollicles,whichcanbecombinedwithsmall growingfollicles,forcomparisonofovariesofratsassignedtotreatedandcontrolgroups.
ShippingIwatrncHnns:
Tissuestobeexaminedhistologicallywillbeshipped(ambientconditions)to:
PrincipalInvestigator. W.RayBrown,D.V.M.,PhJX,ACVP VeterinaryPathologist ResearchPathologyServices,Inc. 438E.ButlerAvenue New Britain,Pennsylvania 18901 Telephone: (213)343-7070 Telefax: (215)345-4326 Email: WRBRPS@concentric.net
Therecipientwillbenotifiedinadvanceofsampleshipment
Exygen Research
Page 98 of 153
418-028:PAGE G-99 Exygen Study No.: 023-072
tos a*t*rO'*- *
-H M a * M It044 Tdsptam: (IIS) 4 43 J7 I0 Ttfa; (US) MUST
ARCUS RESEARCH
Chartes K n r Laboratories
DiscoveryantiDevelopment Service*
PROTOCOL 418-028
ORAL (GAVAGE) COMBINED REPEATEDDOSE TOXICITY STUDY OF T-7706-WITHTHE REPRODUCTION/DEVELOPMENTAL TOXICITYSCREENINGTEST
. SPONSOR'S STUDYNUMBER: T-7706.1
Amendment 1-17April2002
1. DetailedClinicalObservations-MaleandPwnaleRatfpapeinnfflwprntncniy
[EffectiveDate: lApril2002] Detailedclinicalobservationswillnotbe recordedformaleandfemaleratsassignedtotoxicolrineticsampling.
ReasonforChange:
Thischangewas madebecausesufficientdam farevaluationofdetailedclinical observationswillbeavailablefromfeeratsassignedtofeemainstudy.
2. FeedConsumptionValues-MaleRatsandFemaleRate(page11offeeprotocol):
[EffectiveDate: 1April2002] Feedconsumptionvalueswillnotberecordedor tabulatedformaleandfemaleratsassignedtotoxieoldneticsampling.
Reason far Change:
Thischangewasmadebecausesufficientdatafix'evaluationoffeedconsumption willbeavailablefromtheratsassignedtothemainstudy.
Any revisions made to this
amendment must be made by subsequent am endm ent
Exygen Research
Page 99 of 153
418-028:PAGE G-100 Exygen Study No.: 023-072
3. EstrousCyclingandMarine(page12oftheprotocol):
P ro to co l < 1 8 -0 2 8 A m endm ent 1 P age}
[EffectiveDate: 1April2002] Fortheratsassignedtotoxkolrineticsampling, estronscyclingwillbeevaluatedduringdiecohabitationperioduntilspermatozoa areobservedinasmearofthevaginalcontentsand/oracqpulatoryplugis observedinsitu, butnotduringthedosageperiod,priortocohabitation.
ReasonforChange:
Thischangewas made becausesufficientdataforevaluationofestrouscycling willbeavailablefromtheratsassignedtothemainstudy.
4. ScheduledSacrifice-ToxicoloneticStudy(page16oftheprotocol):
[EffectiveDate: 5April2002] Thenumberofimplantationsitesandcorpora biteawillberecorded. Carcasseswillbediscardedwithoutfurtherevaluation.
Hepson ofChange:
Thischangewas made inordertoprovidemors informationaboutpossible toxicityofthetestsubstanceinpregnantrats.
5.
[EffectiveDate: 27March2002] Thenumberofimplantationsiteswillbe recorded,ratherthanthenumberofimplantationsitesandcorporaluteawillbe recorded.
ReasonofChange:
The numberofcorporaluteawillnotberecordedbecausecorporalutearegressat arapidrateandatenotcountedonstudiesatweaning.
6. ScheduledSacrificefnaae19oftheprotocol:
'
[EffectiveDate: 4April2002] Theliverfromeachselectedpupwillbeexcised andtheorganweightrecorded,ratherthantheliverfromeachselectedpupwill becollectedexcisedandtheorganweightrecorded.
Any revisions made to this finalized amendment m ast be made by sabseqneat am endment
Exygen Research
Page 100 of 153
418-028-.PAGEG-101 Exygeu Study No.: 023-072
Protocol 418-028
A m endant 1
P*ge3
ReasonforChange: Thischangeclarifiestheprotocolbyremovinganextraneousword.
AlanM. Hobennan,PhJD.,DABT Date RaymondG.York,ph-D.,DABT Date
DirectorofResearch
AssociateDirectoroTlCesearch
StudyDirect
C ^ JiJb^ dtV sU jjun-t*.
TheresaH. Woodard,D.V.M.
Date JohnButenhofKPh-D.,DABT, CIHDate
Member, InstitutionalAnimalCare
StudyMonitorand
andUseCommittee
Sponsor'sRepresentative
Any revisions made to this finalized amendment m ust be made by subsequent am endment
Exygen Research
Page 101 of 153
418-028-.PAGE G -102 Exygen Study No.: 023-072
M i ieri 0*1. S * A H r i m M 19014
Tlkphum (2tS)H347IO
Triefte (115)44*05$ 7
ARGUS RESEARCH
Chartes Rher Laboratories D&eowyand Development Services
PROTOCOL 418-028
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706WITH THE REPRODUCTTON/DEVELOPMENTAL TOXICITY SCREENING TEST
SPONSOR'SSTUDY NUMBER: T-7706.1
Amendment2-15 July2002
1. SafetyPrecautions(pace3oftheprotocolandAttachment3pace1of theprotocol):
[EffectiveDate: 29April2002] A halffecerespiratorwillbeworninadditionto gloves,appropriateeyeprotectionandauniform/labcoatduringformulation preparationofthebulktestsubstance.
ReasonforQ'n,F-
Thischangewasmadetomatchthebulktestsubstancetextwiththetextlocated withintheMaterialSafetyDataSheet.
2. Sturfv.Schedule(Attachment1page2oftheprotocol):
[EffectiveDate: 29April2002] ThedatesforFOB andmotoractivity evaluationshavebeenextendedtofourdays(06MAY 02-09MAY 02)rather thantwodays(06MAY 02-07MAY 02).
Any revisions to this finalised amendment most be made by subsequent amendment.
E xygen R esearch
Page 102 of 153
418-028:PAGE G -103 Exygen Study No.: 023-072
P ro to co l 4 1 8 -0 2 8 A m endm ent 2 Page 2
ReasonforChanceThischangewasmadebecausemore timeisneeded toevaluateanimalsassigned toFOB andmotoractivityevaluations.
ThereH. Woodard,D & M .
Date JohnButcnhoff,Ph.D.,DABT, CIH Date
Member, InstitutionalAnimalCare
StudyMonitorand
andUse Committee
Sponsor'sRepresentative
Any revisionstothisfinalizedamendmentmostbemadebysubsequentamendment
E xygen R esearch
Page 103 of 153
418-028:PAGE G-104 Exygen Study No.: 023-072
K B a * Or**. M at A
tkahm.HH 190*4
Telephone (215) 4 4347(0
Tohftoe (IIS) 44USS7
ARCUS RESEARCH
C harles R iver Laboratories
Discoverynnd Development Sendees
PROTOCOL 418-028
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706WITH THE REPRODUCTTON/DEVELOPMENTAL TOXICITY SCREENING TEST
SPONSOR'S STUDY NUMBER: T-7706.1
Amendment3-17 July2002
1. BulkTestSubitaneeSampling.ShinningInstructions.StowingInstructions. Caesarean-Sectioning-ToxicokincticStudy.ScheduledSacrifice-Toxicolrinetic Study,andScheduledSacrifice,fpages4.S.12,13,16and 19,respectivelyofthe protocol)
[EffectiveDate: 29May 2002] Samplesforperfluorohexanesulfonate(PFHS) analysisshippedtoLisaClemenat3M EnvironmentalTechnologyandSafety Serviceswillbereshippedandremainingsamples,thatweretobeshippedtoLisa Clemenandhavenotyetbeenshipped,willbeshippedto:
JohnFlaherty,PhD. (PrincipalInvestigator) ExygenResearch 3058ResearchDrive StateCollege,Pennsylvania16801 Telephone: (814)272-1039,ext122 Telefax: (814)231-1580 Email:john.flaherty@exygen.com
Any revisions to this finalized amendment most be made by subsequent amendment.
Exygen Research
Page 104 of 153
418-028:PAGE G-105 Exygen Study No.: 023-072
P ro to co l 4 1 IW 2 8 A m endm ent 3 Page 2
Thesesamplesinclude: Bulktestsubstancesampling(page4oftheprotocol) Concentrationandhomogeneity(page5ofdieprotocol) Stability(pageSofdieprotocol) Plasmatoxicoldneticsamples(page11to12andpage16oftheprotocol) Plasmasamples,ratherthanserumsamples,wereretained. Livertoxicoldneticsamples(pages12and 16oftheprotocol) Pooledfetalserumtoxicoldneticsamples(pages12and16oftheprotocol) Pooledfetallivertoxicoldneticsamples(pages 13and 16ofdieprotocol) Pooledpupserumtoxicokinedcsamples(page19oftheprotocol) Puplivertoxicoldneticsamples(page19oftheprotocol)
The analyseswillbe subcontractedtoExygenby theSponsorandtheQuality AssuranceUnitforExygenResearchwillconductcriticalphaseinspectionsand audittherespectiveresultsandreportsaccordingtotheStandardOperating proceduresofthatfacility. Suchcriticalphaseinspectionreportsandauditreports willbesubmittedbythatfacilitytotheStudyDirector,RaymondG.York. The dateoftheinspectionsandreportsubmissionswillbeincorporatedintoaQAU statementgeneratedbyExygenResearchforinclusionindiefinalreportfor ProtocoUl8-028.
ReasonforChange:
ThischangewasmadeattherequestoftheSponsorbecause3M isnotableto completediefoimulationanalysiswiththeircurrentstaffing.
^&ian M. Hfibennan,Ph.D.,DABT DirectorofResearch
2- JlL S cU Q
Date RaymondG.York,PhD., iABT Date Directorof
StudyDirector
Ar.C -P u l l
ir- ThereH.Woodard,.VAL 0 Member,InstitutionalAnimalCare
andUse Committee
Date JohnButenhoff,PhD.,DABT, CIHDate StudyMonitorand Sponsor'sRepresentative
Any revisions to this finalized amendment must be made by subsequent amendment
Exygen Research
Page 105 of 153
418-028:PAGE G-106 Exygen Study No.: 023-072
i
. PROTOCOL 418-028 ORAL (GAVAGB) COMBINED REPEATED DOSE TOXICITY STUDY
OF T-7706WITH THE RHPRODUCTION/DEVELOPMENTAL TOXKTTY SCREENINGTEST
SPONSOR'S STUDYNUMBER: T-7706.1 Amendment4-20 March2003
1. BulkTestSubstanceSampling.ShinningInstructions.ShippingInstructions. <-b.?mnn-Sectiminp-TnxicokineticStudy.ScheduledSacrifice-Toricokmetic Study,a n d Sehedwled Reerifine fpape 4, 5,12,13,16Bud19,respectivelyofthe p m t n m n endAmendment3.Item1:BulkTestSubstanceSamnling.Shinning [nptmcHniw ShinningInStmctjpM.f>eMiwm-Seerinnmy. TmrimHnertrStudy ScheduledSacrifice-Toxicokmcdcstudy,andScheduledSacrifice(page 1of Amendment 3) [EffectiveDate: 27February2003] The analysesperformedbyExygenResearch willbedoneaccordingtoExygenMethodExM-023-071 Revirion1,entitled
"M ertw ri rtf A nalyst* f a r Hie TV term m erin n n f Perflpnm heT anem ntffm ate (P F H S ),
' Perfiuarooctanesulfonale(PFOS)andPentadecafluorooctanokAcid(PFOA) in Ratliver,SerumandUrineRevision1".
j i
A ny t f r h k r * ftfa hm Hwt nmanrimaiit m w t h e m ade h y rahaeqim nt m m iin a it.
I.
Exygen Research
Page 106 of 153
418-028:PAGE G-107 Exygen Study No.: 023-072
Protocol 418-028 Amnnrfmnat4 P*e2
W w am n f n r O lim g a -
Thischangewasmade attherequestoftheExygenResearchinordertoclarify themethoderfanalysis.
C l/, jc jf d h n -
PhD., DABT
Date StedyDirector
. Leant. PhD. Chair,InstitutionalAnimalCare andUse Committee
late JohnButenhoff,Fh-D.,DABT, CIHDate StudyMonitorand Sponsor'sRepresentative
i
Any revisions to this fjnaHrrri amendment nrost be made by subsequent amendment. I
Exygen Research
Page 107 of 153
418-028:PAGE G-108 Exygen Study No.: 023-072
PROTOCOL DEVIATION
Deviation Num ber 1____
Date of Occurrence: 10/14/02
Page _1_ of _1_
Exygen Study Number: 023-072
Protocol Num ber 418-028
.. D ESC RIPT IO N O F DEVIATIO N A recovery erf 62% for PFHS Is being accepted for the 5000 ppb spike (0202119 Spk C) in data set 100402A. '
Deviation Issued.
A CTIO N S TAKEN
tor exam ple - d w a lio n tw u td . S O P reywlon. ete.
Recorded By:i
Date: 07hs/o3
IM PACT ON STU D Y The 10 ppb and 50 ppb control matrix spikes included with the set gave acceptable recoveries.
Date
sm signanire (Sponsor! Study Monitor
a
UAForrmXPROTDCOt^DeVAATTON.doc '
. ..
Date
a rt / t~l J to o -* *
Date
Exygen QAU Review V K ^ 7 / / 5 ~ A y
&2S/22A
Viwt= THIStediWicO IS BEMf K -issu e r WJE TO SJSJPead\LOS&Cf oRJfrlMM. WMlT/c
3 ^ 3 0 5 8 Research Drive .rrmsuteCSlege, RA16801, USA
^ T T:: 800288113219 I f F: 814.2277!2.1019 exygeo.com
Exygen Research
Page 108 o f 153
418-028:PAGE G -109 Exygen Study No.: 023-072
3058 Research Orive S u te College, PA 18801
Phone: 814-272-1039 Fax:814-231-1580
NOTE TO RLE
Date: 01/14/03
ExygenResearchStudy# 023-072 PROTOCOL # 416-028
NOTE The PFHS stock solution was inadvertently not corrected for salt content when prepared. The stock solution was used to make the fortification and calibration standards used for the study. Due to the large amount of d ata associated with this study, th e concentrations of fortification and calibration solutions listed throughout th e raw data w ere left uncorrected for the salt content. The final PFHS values recorded w ere corrected to reflect th e difference in PFHS concentration due to th e salt content. The correction was perform ed by multiplying the final ppb value found by 0.91.
Signature:]
u
.Date:.
Exygen Research
July 31, 2001/0
Page 109 of 153
418-028:PAGE G-110 Exygen Study No.: 023-072
APPENDIX B
Analytical Method:
Method of Analysis for the Determination of Perfluorohexanesulfonate (PFHS), Perfluorooctanesulfonate (PFOS) and
Pentadecafluorooctanoic Acid (PFOA) in Rat Liver, Serum and Urine Revision 1
(Exygen Method No. ExM-023-071 Revision 1)
Exygen Research
Page 110 of 153
418-028:PAGE G - l l l Exygen Study No.: 023-072
TITLE MethodofAnalysisfortheDeterminationofPetfhiarohexanesiilfbnate(PFHS), Periluorooctanesuifonate(PROS)andPentadecafluorooctanoicAcid(PPOA)inRat
liver.SerumandUrineRevision1
AHIBQ8S JohnFlaherty,KarenRistia,andEmilyDecker
PAIE ISSUED November20.2002
3M MedicalDepartmentCorporateToxicology 3M Center,Building220-ZE-02 StPaul,M N 55144-1000
PERFORMING LABORATORY ExygenResearch
3038ResearchDrive StateCollege,PA 16801
L3H.il..iDNUMBER ExM-023-071Revision1
TOTAL NUMBER OF PAGES 43
Exygen Research
Page 111 of 153
418-028: PAGE G-112 Exygen Study No.: 023-072
E x y g e n M ed io d N o : E x M -0 2 3 4 7 1 R ev isio n 1
MANAGEMENTAPPROVAL
Z
loahnIFlaherty ' TLaabhonrpatoryManager
ExygenResearch
D a te
7. f g f f t t
JohnL.Butenhoff
Date
SponsorRepresentative
3M MedicalDepartmentCorporateToxicology
Exygen Research
Exygen Research
Page 2 o f 43
Page 112 o f 153
418-028:PAGE G -l 13 Exygen Study No.: 023-072
E x y g en M eth o d N o ; E xM ^X 23^371 R e v ir 1
TABLE OF CONTENTS
TITLE................... .... ....... MANAGEMENT APPROVAL................. TABLE OF CONTENTS........... -......... LISTOF TABLES............. _........ . LESTOF FIGURES......................... 1. SUMMARY......................... X EXPERIMENTAL COMPOUNDS............. 3. CHEMICALS AND SUPPLIES ............. .
3.1. Chemicals........................ 3.2. Standards........ ..... ........ . 3.3. Equipment and Supplies........ ....... 3.4. Solutions..... ,,....... ... ....... 3.5. Preparation op Standard Solutions ......
3.5.1. Stocksolution.. -.............. 3.5.2. FortificationSolutions................ . 3.5.3. CalibrationStandards... _.......... 4. METHOD.......................... 4.1. Flow Diagram .. ... .... ... ,,... 4.X SamplbProcessing.... ............. 43. Batch Setup...... ...... ......... 4.4. Sample Extraction.. ............... 4.4.1. LiverExtraction............... 4.4.2. ScrumsndUrineExtraction.. ....... 4.4.3. SPEColumnConditionmg... -...... 43. Quantitation............. ........ 4.5.1. LC/MS/MS SystemandOperatingConditions 4.S.X CalibrationCurveProcedures...-..... 43.3. SampleAnalysis...... .... ...... 4.6. Acceptance Criteria................. 4.7. Performance Criteria................
4.8. Time Required f o r An a ly se...... .................. .........
5. CALCULATIONS.. ............ ....... 6. SAFETY........................... .
..1
..2
,,3 4 ,,5 7 ,,8
..9 ..9 ..9 9 10 10
11 11 11 12 12 12 13 13 13 13 14 14 14 15 16 17 17 18 18 19
ExygenResearch
P age 3 of 43
Exygen Research
Page 113 of 153
418-028:PAGE G-114 Exygen Study No.: 023-072
E x y g en M eth o d N o : E x M -023-071 R ev isio n 1
LIST OFTABLES Table1. RecoverySummaryofPFHS inRatLiverandSerum.............. 20 Table2. RecoverySummaryofPFOS inRatLiver,SerumandUrine......... 21 Table3. RecoverySummaryofFFOA inRatLiver,SerumandUrine.......... 22
Exygen Research
Exygen Research
P ig e 4 o f4 3
Page 114 of 153
418-028: PAGE G-115 Exygen Study No.: 023-072
E x y g en M eth o d N o: E x M -0 2 3 ^)7 1 R ev isio n 1
LIST OFFIGURES
Figure1. CalibrationCurveforPFHS......... ...... .... ...... 23
Figure2. CalibrationCurveforPFOS........ .......... ........ 24
Figure3. CalibrationCurveforPFOA... ......... .............. 25
Figure4. RepresentativeChromatogramofa0.1ng/mLStandard ContainingPFHS....... ...................... ... 26
Figure5. RepresentativeChromatogramofa0.1ng/mLStandardContainingPFOS...26
Figure6. RepresentativeChromatogramofa0.1ng/mLStandardContainingPFOA..27
Figure7. RepresentativeChromatogramofa0.Sng/mLStandardContainingPFHS...27
Figure8. RepresentativeChromatogramofa0.5ng/mLStandardContainingPFOS...28
Figure9. RepresentativeChromatogramofa0.Sng/mLStandardContainingPFOA..28
Figure10.RepresentativeChromatogramofaS.Ong/mLStandardContainingPFHS...29
Figure 11. RepresentativeChromatogramofaS.Ong/mL StandardContainingPFOS...29
FigureIX RepresentativeChromatogramofaS.Ong/mLStandardContainingPFOA..30
Figure 13. RepresentativeChromatogramofaReagentBlankSampleAnalyzedfor
PFHS.............
30
Figure14. RepresentativeChromatogramofaReagentBlankSampleAnalyzedfor
PFOS____________________
,,..31
Figure IS. RepresentativeChromatogramofaReagentBlankSampleAnalyzedfor PFOA....................................... 31
Figure 16. RepresentativeChromatogram ofaControlLiverSampleAnalyzed forPFHS..... ................................ 32
Figure17. RepresentativeChromatogramofaControlLiverSampleAnalyzed forPFOS........ ............................ 32
Figure 18. RepresentativeChromatogramofaControlLiverSampleAnalyzed forPFOA..................................... 33
Figure 19. RepresentativeChromatogramofaControlSerum SampleAnalyzed forPFHS..................................... 33
Figure20. RepresentativeChromatogramofaControlSerumSampleAnalyzed forPFOS.................................
34
Figure21. RepresentativeChromatogramofaControlSerumSampleAnalyzed forPFOA.........................
34
Figure2X RepresentativeChromatogramofaControlUrineSampleAnalyzed forPFOS..................................... 35
Figure23. RepresentativeChromatogramofaControlUrineSampleAnalyzed forPFOA... -............................ .......35
Figure24. RepresentativeChromatogramofaControlLiverSampleFortified at10ng/gwithPFHS.............................. 36
Exygen Research
Page 5 of 43
Exygen Research
Page 115 of 153
418-028:PAGE G-116 Exygen Study No.: 023-072
E x y g e n M e th o d No: BxM-023-071 Revisioni
LIST OF FIGURES (continued)
Figure25.RepresentativeChromatogramofaControlLiverSampleFortified at10ng/gwithPFOS... .......... ....... ......... .36
Figure26. RepresentativeChromatogramofaControlLiverSampleFortified at10ng/gwithFFOA... .......... .................. .37
Figure27. RepresentativeChromatogramofaControlLiverSampleFortified at50ng/gwithPFH5... ...... .. ......... .....
.37
Figure28. RepresentativeChromatogramofaControlLiverSampleFortified at50ng/gwithFF05.......... ...............
.38
Figure29. RepresentativeChromatogram ofaControlLiverSampleFortified at50ng/gwithFFOA.. ........ ... .... ... .. .
.38
Figure30. RepresentativeChromatogramofaControlSerumSampleFortified at10ng/mLwithPFHS..... ..... ..... ........
.39
Figure31. RepresentativeChromatogramofaControlSeramSampleFortified at10ng/mLwithPFOS.............. ........... .......
.39
Figure32. RepresentativeChromatogramofaControlSerumSampleFortified at10ng/mLwithPFOA...................... ... .40
Figure33. RepresentativeChromatogram ofaControlSerum SampleFortified at50ng/mLwithPFHS................ ........
.40
Figure34. RepresentativeChromatogramofaControlSerumSampleFortified at50ng/mLwithPFOS-................... .....
.41
Figure35. RepresentativeChromatogramofaControlSerumSampleFortified at50ng/mLwithPFOA.. .................... . .41
Figure36.RepresentativeChromatogramofaControlUrineSampleFortified at10ng/mLwithPFOS.._........................... .42
Figure37. RepresentativeChromatogramofaControlUrineSampleFortified at10ng/mLwithPFOA ----- ------------ --------- .42
Figure38. RepresentativeChromatogramofaControlUrineSampleFortified at50ng/mLwithPFOS............. -..... ........ .43
Figure39. RepresentativeChromatogramofaControlUrineSampleFortified at50ng/mLwithPFOA............._...... _....... .43
Exygen Research
Exygen Research
Paged of 43
Page 116 of 153
418-028:PAGE G-117 Exygen Study No.: 023-072
E x y g en M eth o d N o: E x M -0 2 3 -0 7 1 R ev isio n t
1. SUMMARY
ThisreportdetailsamethodofanalysisforresiduesofPerfluorohexanesulfonaie (FFHS), Perfluorooctanesulfonate (PFOS) and Pentadecafluorooctanoic Acid (PFOA)inRatLiver,SerumandUrine.
Residues of FFHS, PFOS and PFOA are extracted from each matrix with acetonitrile. The acetonitrile extract is added to water and loaded onto a conditioned0 8 solidphase extraction (SFE) cartridge. Analyte residues are elutedwith 2 tnL ofmethanol. Quantification ofPFHS, PFOS and PFOA is accomplishedby liquidchromatographyftandemmass spectrometry(LC/MS/MS) analysisusingmultiplereactionmonitoring(MRM).
The proposedlimitofquantitation(LOQ; thelowestfortificationspecifiedby the method which gives adequate recovery according to EPA guidelines) for this methodis10ng/g(parts-per-billion)eachforPFHS,PFOS andPFOA.
The theoreticallimitofdetection(LOD) willbebasedonthesignaltonoiseratio and will be at least greater than 3 times the level of noise, based on the instrumentation system used. For allanalytes, the lowest analytical standard correspondsto0.1ng/mL.
This method was developed usingratliver,serum and urine. Typical percent recoveries standarddeviations(at10andSOng/g)areshownbelow:
F o rtificatio n L evel (site )
10 30
F F H S R ecovery la R a t L iv er
1 1 5 * 9 .9 % ( 3 ) 9 8 % 3 -S % (n 3 )
F o rtificatio n L e v e l (iu t/m L )
10 SO
P F H S R ecovery in R at S erum
108% 4 .7 % (n = 3 ) 111% 9 .6 % (n= 3)
F o rtificatio n L evel
iagf
10
50
P F O S R ecovery in R xt L iv er
96% 8 5 % (n= 3) S 8 % lJ% (n = 3 )
F o rtificatio n L evel
(n e/m L ) 10 SO
P F O S R eco v ery in R a l S erum
8 8 % 9 .8 % (n = 3 ) 1 2 0 % 2 .1 % (n = 3 )
P F O S R e c o v e ry in R a t U rin e
9 3 % 4 .7 % (o > 3 ) 7 9 % L 2 % (n 3 )
F o rtificatio n L evel
(ng/g)
10
SO
P F O A R ecovery in R a t L ive*
98% 3 .1 % (ix 3 ) 94% U % <w 3)
F o rtificatio n L evel
(n ts 'm U 10 SO
P F O A R e c o v e ry in R at S cram
1 1 7 % lJ% (n -3 ) 111% 4 .0 % (ix 3 )
P F O A R e c o v e ry in R a t U rin e
8 9 % 2 J % (n=>3) 8 7 % 2 .1 % (n 3 )
Representative calibration curves are shown in Figures 1-3. Representative chromatogramsareshowninFigures4to39.
Exygen R esesch
Page 7 o f 43
Exygen Research
Page 117 of 153
418-028:PAGE G-118 Exygen Study No.: 023-072
E x y g e n M eth o d N o : E xM -02W > 71 R e rin o n 1
2. EXPERIMENTAL COMPOUNDS
ThestructuresforPFHS,PFOS andPFOA aregivenbelow.
PFHS ChemicalName = Molecularweight =
Perfluorohexancsulfonate 399,asshown
PFHS issuppliedasthepotassiumsalt(CsFnSOjK*),molecularweight= 438
PFOS ChemicalName = Molecularweight =
Perfluorooctanesulfonate 499,asshows
PFOSissuppliedasthepotassiumsalt(CiFitSQjTC)molecularweight= 538
PFOA ChemicalName =* Molecularweight =
PentadecafluorooctanoicAcid 413,asshown
E x y g en R esearch
Exygen Research
PageS of 43
Page 118 of 153
418-028:PAGE G-119 Exygen Study No.: 023-072
E x y g en M eth o d N o : E x M -0 2 3 -0 7 1 R e m io n 1
3. CHEMICALS AND SUPPLIES
3.1. Chemicals__________________________________________________
Chemical
Grade
Source CatalogNo.
Methanol(MeOH)
HPLC EM Science
AmmoniumAcetateReagent JTBaker
Water
Type1
Exygen
Acetonitrile
HPLC EM Science
MX0475-1 0596-01
NA AX0145-1
Type1water= electricalresistivity,minimumof16.67MQ/cm at25C, fromaLabconcoWaterproTMworkstation.
3.2. STANDARDS
S ta n d a rd
TCR Nnmber
Perfluorohexanesulfonaze SB-036
(PFHS)
Petfluorooctanesulfanate SD-018
(PFOS)
Pentadecafluorooctanoic LotNo:
Acid(PFOA)
08316DO
Purity ( % )
Source
99.99allisomers. 3M
84.36straightchain
86.9 3M
96 Aldrich Chem
3 .3 . EQUIPMENT and SUPPLIES
Equipment
Balance,analytical(diaplayatleast0.0001g) 125-mLLDPE naoowmonthbottles Disposableglassmicropipets(50-100& 100-200pL) Tissumizer Wristactionshaker SorvallRC 5C plusCentrifuge 50mL disposablepolypropylenecentrifugetubes ISmL disposablepolypropylenecentrifugetubes Visiprepvacuummanifold SepPakVac6cc(lg)tC18cartridges(part#WAT 036795 2-raLclearHPLC vialKit(cat#5181-3400) ClassA pipetsandvolumetricflasks Standardlabequipment(graduatedcylinders, disposabletubesetc.) Stand-alonedrop-inguardcartridgeholder(part #844017-400) Hypcrcarbdrop-inguardcolumn(4mm) (part# 844017-400) HPLC Pump(LC-10AD) LC/MS/MS andHPLC systems
Supplier Mettler Nalgene Drummond (VWR) Tekmar BurrellScientific Dupout VWR VWR Supelco Waters
Hewlett-Packard varioussuppliers varioussuppliers
KeystoneScientific
KeystoneScientific
Shimadzu Asdescribedin
section4.5.
E xygen R esearch
Page 9 o f 43
Exygen Research
Page 119 of 153
418-028:PAGE G -120 Exygen Study No.: 023-072
E x y g e n M ethod N o: E x M -0 2 1 -0 7 1 R e v ie w s 1
Notes: 1. Isordertoavoidcontamination,theuseofdisposablelabware(containers, tubes,pipettes,etc.)ishighlyrecommended. 2. TeflonorTeflon-linedcontainersorequipmentshouldnotbeused. 3. Itmay benecessarytocheckthesolvents(acetonitrile,methanol)forthe presenceofcontaminants (especiallyPFOA) by LC/MS/MS beforeuse. Certainlotnumbershavebeenfoundtobeunsuitableforuse. 4. Use disposable micropipettes or pipettes to aliquot standard solutions whenpreparingstandardsandsamplesforextraction. 5. Equivalentmaterialsmaybesubstitutedforthosespecifiedinthismethod.
.3 A Solutions
(1) 2 m M ammonium acetate in water is prepared by weighing 0.1S4gofammoniumacetateanddissolvingin1L ofwater.
(2) Hypercarb filtered type I water is prepared by filtering type I water throughaHypercarbguardcolumnusingaHPLC pump at-2-3 mLfmin. Before use, wash the guard cartridge with -25 noL of HPLC grade acetonitrile, then - 25 mL of type I water, then begin collecting the filteredtypeIwatereluateforuseintheextraction. Repeatthewashafter filtering-2Lofwater.
Note: Theaforementionedexampleisprovidedforguidance,alternativevolumes may be prepared as long as the appropriateratiosofthe solventto soluteare maintained.
3.5. P reparation o f Standard Solutions
Analyticalstandardsareusedforthreepurposes: 1. CalibrationStandards-Thesestandardsarepreparedinmethanolandare usedtocalibratedieresponseofthedetectorusedintheanalysis. 2. Laboratory Control Spikes - These fortifications are prepared at concentrationscorrespondingtotheLOQ andSx LOQ and areused to determineanalyticalrecovery. Laboratorycontrolspikesarepreparedin controlmatrix. 3. MatrixSpikes-Thesefortificationsarepreparedbyspikingintothefield samplesataknownconcentration. Matrixspikesareusedtoevaluatethe effectofthesamplematrixon analyticalrecoveryandarepreparedatthe client'srequest
Theanalystmay varytheabsolutevolumesofthestandardsaslongasthecorrect proportionsofsolutetosolventaremaintained.
R xygen R esearch
P age 10 o f 43
Exygen Research
*
Page 120 of 153
418-028: PAGE G -121 Exygen Study No.: 023-072
E x y g en M eth o d N o: E x M -023-071 R ev isio n 1
3.5.1. Stock solution
Prepare individual stock solutions at 100 (jg/mL for PFH5, PPOS and PFOA by weighingout 10 mg ofeachanalyticalstandard(correctedfor purityandifnecessary,saltcontent)anddiluteto100mL withmethanol inseparate 100-mL volumetric flasks. The stocksolutions(in 125-mL LDPE bottles)aretobe storedin a refrigeratorat2C to6C and are stableforamaximum periodofoneyearfromthedateofpreparation.
3.5.2. Fortification Solutions
a. Prepareamixedfortificationstandardat1.0pg/mL(1000ng/mL)of PFHS,PPOS andPFOA byadding 1.0mL ofeachofthe100pg/mL stocksolutionsintoa 100-mLvolumetricflaskandbringuptovolume withmethanol.
b. Prepare amixed fortificationstandardat0.1pg/mL (100ng/mL) of PFHS,PPOS andPFOA bydiluting10.0mL ofthe1.0pg/mLmixed fortificationsolutionto100mL withmethanolinavolumetricflask.
Example:onehundredmicrolitersofthe0.1pg/mL solutionspikedinto1 gofliveror1mL ofserum/urineisequivalenttoa10ppb(10ng/mL or ag/g) fortification.
Storeallfortificationstandardsolutionsinarefrigerator(in125-mLLDPE bottles)at2Cto6Cforamaximum periodofoneyearfromthedateof preparation. Note alsothatadditionalconcentrationsmay bepreparedif necessary.
3.5.3. Calibration Standards
LC/MS/MS calibrationstandardscontainingPFHS, PPOS andPFOA are preparedat0.1,0.2,0.5,1.0,2.0and5.0ng/mLinmethanolviadilutionof the0.1pg/mLmixedfortificationsolution(section3.5.2.b).
The following is a typical example; additional concentrations may be preparedasneeded.
InitialCone. (ng/mL) 100
100 100 5.0 2.0 1.0
Volume (mL)
5.0 2.0 1.0 10.0 10.0 10.0
Dilutedto
(mL) 100 100 100 100 100 100
FinalCone.
(ng/mL) 5.0 2.0
1.0 0.5 02 0.1
The standardsmay be usedforaperiodofone yearCm 125-mL LDPE bottles)whenstoredrefrigerated(at2Cto6"C).
E xygen R esearch
Page 11 of43
Exygen Research
Page 121 of 153
418-028:PAGE G -122 Exygen Study No.: 023-072
E x y g en M eth o d N o: E x M -023-071 R evisio n 1
4. METHOD
4.1. Flow Diagram
The flow diagram of the method is given below, followed by a detailed descriptionofeachstep.
MethodFlowDiagram
Weighappropriateamountofliverormeasureappropriatevolumeofserumorurine (fortifysamplesdesignatedasmatrixspikesandlaboratorycontrolspikes)
4
AddwatertoliverforaAnalvolumeof10mL, addwatertoserumandurineforafinal volumeof20mL,homogenize
i
Remove 1mL andadd5mL ofACN, shake
i
Centrifuge
4
Decantsupernatantinto35mL ofwater 4
LoadontoconditionedSPE 4-
Elutewith2mL methanol 4
LC/MS/MS Analysis
4.2. Sam ple P rocessing
Forliversamples,placefrozensamplesinafoodprocessorandhomogenizewith dry ice. Then place samples in containers and leave open in frozen storage overnighttoallow forCOj sublimation. Seal and placethesamples infrozen storage below -10C until time of extraction. Alternately, if there is an insufficientamountofsample (-lessthan5 g),thennoprocessingisnecessary andthesample can be used as supplied. No sample processingisneededfor serum and urinesamples. However, frozenserum andurinesamplesmust be allowedtocompletelythawtoroomtemperaturebeforeuse.
Exygen Research
P a g e 12 o f 43
Exygen Research
Page 122 of 153
418-028:PAGE G-123 Exygen Study No.: 023-072
E x y g e n M eth o d N o : E x M -0 2 3 4 7 1 R e v isio n 1
4.3. Batch Set ur
a. A batchofsamplesshouldnotcontainmotethan20fieldsamples.
b. Each batch of samples analyzed must includeatleastone control (method blank using control matrix) and two matrix controls fortified at known concentrations (typically 10 and 50 ng/gfa*liverorng/mL forserum and urine)toverifyproceduralrecoveryforthebatch.
c. Atleastonefieldsampleineachbatchmustalsobeseparatelyfortifiedata known concentration and earned through the procedureto verifyrecovery. Additionalsamplesinthebatchmay alsobefortifiedifdesired.
d. Allsamplesrequireduplicateinjections.
4.4. Sample Extraction
4.4.1. Liver Extraction
a. Weigh 1g ofliversampleintoa 50 mL disposablecentrifugetubeand fortify, if appropriate. Note that alternate weights of liver may be measureddependingonthesamplesizeavailableforuse.
b. Addwatertothesampleforafinalvolumeof10mL. Captightly. c. Homogenizesampleusingatiasuemizerfar-1minute. & Transfer 1 mL of the sample using a disposable pipette into 15 mL
disposable centrifuge tubes. Add 5 mL of ACN and shake far -20 minutesonawristactionshaker. e. Centrifuge tubes at -3000 ipm for - 5 minutes. Carefully decant supernatantintoa 50 mL disposablecentrifugetubeand add 35 mL of water. f. LoadthesampleontoaconditionedSPEcolumn(forconditioningdetails, see section 4.4.3.). Discard the eluste. Any analyte residues will be trappedon theSPE columnatthispoint g. Elutewith2 mL ofmethanol. Collect2 mL ofeluteintoagraduated 15 mL centrifugetube. h. AnalyzesamplesusingelectrosprayLC/MS/MS.
4.4.2. Serum and Urine Extraction
a. Measure 1 mL of serum or urine sample into a 50 mL disposable centrifugetubeandfortify,ifappropriate. Notethatalternatevolumesof serumandurinemay bemeasureddependingonsamplesizeavailablefor
E x y g en R esearch
Page 13 o f 43
Exygen Research
Page 123 of 153
418-028-.PAGE G-124 Exygen Study No.: 023-072
Exygm Method No: ExM-023-071 R evtik I
b. Addwatertosampleforafinalvolumeof20mL. Captightlyandvortex for-1minute. Thencontinuewithstepsd-hinsection4.4.1.
4.4.3. SPE Column Conditioning
Place theunconditionedSPEcolumnsonthevacuummanifold. Conditionthe SPE columns bypassing- 10mL ofmethanolthroughthecolumn followed by - 5 mL ofwater. The wadies may be pulledthrough theSPE column usingvacuumataflowrateof-1 drop/secormay beallowedtopassthrough thecolumnunaided. Discardallwashes. Do notallowdiecolumntodry.
4 5 . Quantitation
4.5.1. LC/MS/MS System and Operating Conditions
MassSpec: MicromassQuattroUltima(Micromass) Interface: Electrospray(Micromass)
Harvardinfusionpump(HarvardInstruments),fortuning Computer COMPAQ ProfessionalWorkstationAP200 Software: WindowsNT,Masslynx35
HPLC: HewlettPackard(HP)Series1100 HP QuatPump HP VacuumDegasser HP Autosampler HP ColumnOven
Note: A 4x 10m m hyperearbdropinguardcartridgeisattachedon-lineafter thepuigevalveandbeforediesampleinjectorparttotrapanyresidue contaminantsthatmaybeinthemobilephaseand/orHPLC system.
HPLC Column: GenesisC*(JonesChromatography),2.1m m x30mm, 4|i
ColumnTemperature:35C InjectionVolume: 13pL MobilePhase(A): 2m M AmmoniumAcetateinTypeIwater MobilePhase(B): Mediano!
Tune 0.0 2.0 5.0 9.0 9.5 14.0 14.5 20.0
SlA 90 90 10 10
0 0 90 90
% B FlowRalefmL/mint 10 05 10 0.3 90 05 90 05 100 05 100 0.3 10 05 10 0.3
Exygen Research
Page 14 of43
Exygen Research
Page 124 of 153
418-028:PAGE G-125 Exygen Study No.: 023-072
E iy g e n M e th o d N o : E x M -0 2 3 rf7 1 R ev isio n 1
Itmay benecessarytoadjusttheHPLC gradientinordertooptimizeinstrument performance. Columnswithdifferentdimensions(e.g.2.1x30)andalsocolumns fromdifferentmanufacturers(KeystoneBetasilCm etc.)couldbeused,provided equivalentchromatographyisobtained.
Ionsmonitored:
Analyte PFHS PFOS PFOA
Mode TransitionMonitored
Negative
399-80
Negative
499--99
Negative 413-->369
Approximate RetentionTime
-8.2min. -8.8min -8.6min
Hie retentiontimesmay vary,on aday todaybasis,dependingon thebatchof
mobilephaseetc. Driftinretentiontimes(upto 4 %) isacceptablewithinan analyticalrun,aslongasthedriftcontinuesthrough theentireanalysisand the standardsareincludedatthebeginningandendoftheanalyticalrun.
Note: An alternativeLC/MS/MS systemmay be used once demonstratedtobe equivalent
The mass spectrometer istuned foreach analyte by infusing a - 1.0 pg/mL standardsolution(at10pL/min,usinganinfusionpump) viaa"I"intoastream ofmobilephasecontaining50% methanol and50% 2mM ammonium acetatein waterat0.2mL/minflowrate. Eachanalyteisinitiallytunedfortheparention andthentunedfortheproduction. Once theinstrumentistuned,theoptimized parameters aresaved asatune file. This tune fileisthen used duringroutine analysis.
4.S.Z Calibration Curve Procedures
a. Injectthesame aliquot(between 10 to50 pL) ofeach calibrationstandard (rangingfromthelowestlevelstandardtothehighestlevelprepared),intothe LC/MS/MS.
b. Useweightedlinearstandardcurvesforquantitation. linearstandardcurves are generated fareach analyteby linearregression using 1/x weighting of peak area versus calibration standard concentration using Masslynx (or equivalent)softwaresystem. Anycalibrationstandardfoundtobeastatistical outlier by using an appropriate outlier test, may be excluded from the calculationofthecalibrationcurve. However,thetotalnumberofcalibration standardsthatmay beexcludedmust notexceed20% ofthetotalnumberof standardsinjected.
c. The correlation coefficient (R) for calibration curves generated must be 50.9925 (R150.985). Ifcalibration results falloutside these limits, then appropriate steps must be taken to adjust instrument operation, and the standardsortherelevantsetofsamplesshouldbereanalyzed
E x y g en R esearch
P ag e 15 o f 43
Exygen Research
Page 125 of 153
418'028:PAGE G -126 Exygen Study No.: 023-072
E x y g en M e th o d K o : E x M -0 2 3 4 )7 1 R ev isio n 1
TypicalcalibrationcurvetforPFHS,PFOS andPFOA canbefoundinFigures1 3.
4.5.3 Sample Analysis
a. Inject the same aliquot (between 10 to SO pL) of each standard, sample, recovery,control,etc.intotheLC/MS/MS system.
b. Standardscorrespondingtoatleastfiveormoreconcentrationlevels(starting withdieLOQ levelorbelow)mustbeincludedinananalyticalset
c. An entiresetofcalibrationstandardsshouldbeinjectedatthebeginningofa setfollowedby calibrationstandardsinterspersedapproximatelyevery5-10 samples (to account for a second set of extracted standards). As an alternative, an entireset of calibration standards may be included at the beginningandattheendofasampleset Ineithercase,calibrationstandards mustbethefirstandlastinjectioninasampleset.
d. Theconcentrationofeachsample/fortification/coffirolisdeterminedformthe standard curve, based on the peak area of each analyte. The standard responsesshouldbracketresponsesoftheresiduefoundineach sampleset. Resultsmay bequantitatedupto10% outsidethecurvebyextrapolation. If necessary,dilutethe samples to give a response within thestandardcurve range.
e. Fortificationrecoveriesfallingwithin70to130% areconsideredacceptable.
f. Samplesmustbestoredrefrigeratedbetween2"Cto6"C untilanalysis.
g. Samplesinwhicheithernopeaks aredetectedorpeakslessthanthelowest concentrationofthecalibrationstandards are detected atthecorresponding analyteretentiontime will be reported as ND (not detected). Samples in which peaks aredetectedatthecorresponding analyteretentiontime thatare lessthantheLOQ andgreaterthanorequaltothelowestconcentrationofthe calibrationstandardswillberepentedasNQ (notquantifiable).
The analysisperformedduringthemethoddevelopmentincludedfortificationsat 10and50ng/gofPFHS inratliver,10and50ng/mLofFFHS inserum, 10and 50ng/gofPFOS andPFOA inratliverand10and50ng/mLofPFOS andPFOA inserumandurine. TypicalchromatogramscanbefoundinFigures4-39.
E x y g en R esearch
P e p 16 of 43
Exygen Research
Page 126 of 153
418-028:PAGE G-127 Exygen Study No.: 023-072
1E x y g e n M e t h o d N o : B x M - 0 2 3 - 7 l R e v i x o a
4.6. Acceptance Criteria
The followingcriteriamust be met toensurethepresenceofPFHS, PFOS and PFOA:
1. Thechromatogrammustshow apeakofadaughterionat80amu froma parentof399 amu forPFHS, adaughterionat99 amu from aparentof 499 amu forPFOS, andadaughterionat369amu fromaparentof413 amuforPFOA.
2. MethodblanksmustnotcontainanalyteatlevelsgreaterthantheLOQ. If a blankcontainstheanalyteatlevelsgreaterthan 10ng/mlthen anew blanksamplemustbeobtainedandtheentiresetmustbere-extracted.
3. Recoveriesofcontrolspiresandmatrixspikes(ifany)mustbebetween 70-130% of theirknown values. Ifa control spike falls outside the acceptablelimits,theentiresetofsamplesshouldbere-extracted. Any matrix spike outside 70-130% should be evaluated by the analyst to determineifre-extractioniswarranted.
4. AnycalibrationstandardfoundtobeastatisticaloutlierbyusingtheHuge Em* Test,may beexcludedfromthecalculationofthecalibrationcurve. However, thetotalnumber ofcalibrationstandardsthatcouldbe excluded mustnotexceed20% ofthetotalnumberofstandardsinjected.
5. The correlationcoefficient(R) forcalibrationcurvesgeneratedmust be 20.9925 (R220.985). ifcalibrationresultsfalloutsidetheselimits,then appropriatestepsmust be taken toadjustinstrumentoperation, and the standardsortherelevantsetofsamplesshouldbereanalyzed.
6. Retentiontimesbetween standardsandsamplesmustnotdriftmore than 4 % withinan analyticalrun. Ifretentiontimedriftexceedsthislimit withinananalyticalrunthenthesetmustbereanalyzed.
4.7. Performance Criteria
The followingtwo criteriamustbe performedonceasasystemsuitabilitytest, beforethecommencementofanalysis,when usinganinstrumentationset-upthat hasnotbeenusedfarthismethod.
Fust Criterion:
Run a standard solution on LC/MS/MS corresponding to the estimated LOQ (10ng/mL)inmatrixandobtainasignaltonoiseratiofortheanalytetransitionof atleast9:1,comparedtoareagentblank. Ifthiscriterioncannotbemet,optimize andchange instrumentoperatingparameters (orincreasetheinjectionvolume, if appropriate).
Exygen Research
Page 17 of 43
Exygen Research
Page 127 of 153
418-028:PAGE G-128 Exygen Study No.: 023-072
E x y g en M eth o d M o: E x M -023-071 R e v iik a 1
SecondCriterion: Run asetofstandardsoffiveormoreconcentrationlevels,fromatorbelowthe LOQ, up to the highest concentration level to be included in the analysis. Generate acalibrationcurvefortheanalyteand obtainalinearregressionwith a coefficient of determination (R2)of atleast0.983 forthe analyte. Once this criterionismet,samplesmay beanalyzedwithstandardsinterspersed.
4 .8 . T im e R e q u ir e d f o r A n a l y s is
Onepersoncantakeasetof20samplesthroughthesamplepreparationprocedure inapproximately4hours. TheLC/MS/MS analysisofdieset(containing20field samples, 1 matrix blank, 2 laboratory control spikes, 1 matrix spike and 12 standardinjections)willtakeapproximately14hours.
5. CALCULATIONS
a. Use Equation 1tocalculatetheamountofanalytefoundfinng/mL,basedon peak area) using the standard curve (1/x weighted linear regression parameters)generatedbytheMasslynxsoftwareprogram.
Equation 1:
Analvtefound(ng/mL)= (peakarea-intercept! xDFx aliquotfactor slope
DF = factorbywhichthefinalvolumewasdiluted,ifnecessary. Aliquotfactors1 0 forliver,20forserumandurine
b. Forsamplesfortifiedwithknown amounts ofanalytepriortoextraction,use Equation2tocalculatethepercentrecovery.
Equation2;
Recovery (%) =
[totalanalytefound(ng/mL) -analytefoundincontrol(ng/mL)]
xlOO
analyteadded(ng/mL)
Note: Subtractanalytefoundincontrol(ng/mL)from analytefound(ng/mL), ifng/mLincontrolisgreaterthanLOQ.
Exygen Rocarch
P a g e IB o f 43
Exygen Research
Page 128 of 153
418-028:PAGE G-129 Exygen Study No.: 023-072
B x y g e a M e th o d N o-. E xM -Q Q 3-071 R e v ia io o 1
c. UseEquation3tocalculatetheamountofanalytefound(inppb) Equation3;
A n a ly te fo u n d (n g i'g o r o g ftn L )
fa m h tle fo u n d tn g /m L ) a F V fm U
ta tn p te e ig h t (g ) o r u m p le v o h u n e (m L )
FV =finalvolume
Forrepottingpurposes,samplesinwhich eitherno peaks aredetectedorpeaks lessthanthelowestconcentrationofthecalibrationstandardsaredetectedatthe corresponding analyte retention time will be reported as ND (not detected). Samplesinwhichpeaks aredetectedatthecorrespondinganalyteretentiontime thatarelessthantheLOQ andgreaterthanorequaltothelowestconcentrationof thecalibrationstandardswillbereportedasNQ (notquantifiable).
6. SAFETY
The analyst should read the material safety data sheets for all standards and reagents before performing this method. Use universal precautions when handlingstandardsandreagents,includingworkinginfume hoodsand wearing laboratorycoats,safetyglasses,andgloves.
Exygen Research
Page 19 of 43
418-028:PAGE G -130 Exygen Study No.: 023-072
E x y g e n M eth o d N or E x M -0 2 3 -0 7 1 R e v jo o 1
Table 1. Recovery Summary of PFHS in Rat Liver and Seram
Recovery Summary o f PFHS In Rat Uver
0201684 Spk A 0201684 S p k B 0201684 Spk C
Sam ple 10 0201684 Spk 0201684 Spk E 0201684 Spk F
10 10 10
Average: Standard Deviation:
108 110 128
"nt3 94
Analyte Addad (nqfa)
SO 50 SO
Average: Standard Deviation:
Pereant Recovery
101 98 94 98
iS
Recovery Summary of PFHS In Rat Serum
Sam ple ID
0201682 Spk A 0201682 Sp k B 0201682 Spk C
Analyte Added (nofmO
10 10 10
Average: Standard Deviation:
Percent Recovery (%)
112 103 110
108 4.7
Sam la ID
0201682 Spk D 0201682 Spk E 0201682 Spk F
Analyte Added (ngftnU
so 50 SO
Average: Standard Deviation:
Percent Recovery {%}
107 104 122
111 9.6
E x y g en R esearch
Exygen Research
P age 2 0 o f 43
Page 130 of 153
418-028 :PAGE G-131 Exygen Study No.: 023-072
E x y g e n M eth o d N o : E x M -0 2 3 -0 7 ] R ev isio n J
Table 2. Recovery Summary of PFOS in Rat Liver, Seram and Urine
Recovery Summary of PFOS In Rat Uver
Sample ID
0201684 Spk A 0201084 Spk B 0201884 8pkC
Analyte Added tn a /o )
10 10 10
Average: Standard Deviation:
Percent Recovery
88 98 105
96 as
Samolo IO
0201884 Spk 0 0201684 Spk E 0201684 Spk F
Analyte Added (nota)
50 60 so
Average: Olandaid Deviation:
Percent Recovery A4)
80 88 87
88 1.6
Recovery Summaryof PFOS In Rat Serum
Semple ID
0201682 Spk A 0201682 Spk B 020168281* C
AnalyteAdded (ngftnU
10 10 10
Average:
Standard Deviation:
Percent Recovery O il
80 85 08
at 06
Semple ID
0201682 Spk O 0201682 Spk E 0201682 Spk F
Analyta Addad (naftnU
60 SO SO
Average: Standard Deviation:
Percent Recovery (%)
118 122 121
128 2.1
Recovery Summaryof PFOS In Rat Urine
Semple ID
0201682 8pk A 0201682 Spk B 0201882 SokC
Analyte Added (no/mU
10 10 10
Average: Standard Deviation:
Percent Recovery (%)
98 69 91
93 4.7
Sample ID
0201682 Spk D 0201882 Spk E 0201682 Spk F
Analyte Added (no/mU
50 60 50
Avenge: Standard Deviation:
Percent Recovery OH
80 7B 7*
78 1.1
Exygen Reward)
P tg e 2 1 o f 43
Exygen Research
Page 131 of 153
418-028:PAGE G-132 Exygen Study No.: 023-072
E x y g e n M eth o d N o : E xM -0234371 R e v itto n 1
Table 3. Recovery Summary of PFOA in Rat Liver, Serum and Urine
Recovery Summary of PFOAIn Rat Liver
Sam gl^D ^^^Jm tl^lcA ddto^ii^g^^JJereen^aeovct^l^
0201664 Spk A
10
96
0201884 Spk B
10
101
0201684 8okC
10
89
Average;
88
Standard Deviation;
3.1
Semole ID
0201684 SpkD 0201884 SpkE 0201684 Sok F
Analyte Added Insta)
SO 50 so
Average: Standard Deviation:
Percent Recovery (%)
97 92 4
94 .S
Recovery Summary of PFOA In Rat Serum
Sample ID
0201682 Spk A 0201682 8pk B 0201882 Spk C
Analyte Added InoAnL)
to 10 to
Average: Standard Deviation:
Percent Recovery (%)
118 117 116
117 1S
Semple ID
0201682 Spk D 0201682 SpkE 0201682 Sok F
Analyte Added fnaAnU
SO 60 SO
Average; Standard Deviation:
Percent Recovery (%1
107 112 116
111 AO
Recovery Summary of PFOAin Rat Urine
Sample ID
0201682 Spk A 0201682 Spk B 0201682 Sok C
Analyte Added IngAnU
10 10 10
Avenge: Standard Deviation:
Percent Reaovery (%)
68 91 89
89 U
Sam te
0201682 Spk 0 0201682 SpkE 0201682 Spk F
Analyte Added Ow/mU
50 SO 50
Average: Standard DavfaUon:
Percent Recovery (%)
89 88 85
67 2.1
Exygen Research
Page 22 of 43
Exygen Research
Page 132 of 153
418-028:PAGE G-133 Exygen Study No.: 023-072
Exygea MediodNo: HxM^n3^]71Reviaa 1
Figure 1. Calibration Corre for PFHS
Compound 1 m m *. PFHS Ootfficiontof Ontnwniration: 0JBBI8 CaAntton c m : IPM L2Bn * f. 14134 ftnaponM type xtomaitct Aim Cunw ^fpe Uiesr, Ort^n; Esdude, WeJphdnp: 1 * A * tw w None
Exygen Research
Exygen Research
Page23 of43
Page 133 of 153
418-028:PAGE G-134 Exygen Study No.: 023-072
E x y g e n M eth o d N o : E x M -0 2 3 4 7 1 R e n d o n 1
Figure 2. Calibration Curve for PFOS
Compound 2 name: PFOS Coefficient of Determination: 0.997009 Castration curve: 3211JO * * + 48.9285 Response type: External Std, Area Curve type: Linear, Origin: Exclude, Weighting: 1/x, A s tranx None
E x y g en R esearch
Exygen Research
Page 24 o f 43
Page 134 of 153
418-028:PAGE G -135 Exygen Study No.: 023-072
E x y g en M eth o d N o ; E x M -0 2 3 4 7 1 R ev isio n l
Figure 3. Calibration Curve for FFOA.
Compound 1 name: PFOA Coefficient of Determination: 0.995945 Calibration curve: 31270.9 *x + 3675.36 Response type: External Std, Area Curve type: Linear, Origin: Bdude, Weighting: 1/x, Aids bans: None
E x y g ee R esearch
Exygen Research
P age 23 o f 43
Page 135 of 153
418-028: PAGE G-136 Exygen Study No.: 023-072
E x y g e n M eth o d N o : E x M 4 2 3 -0 7 1 R e v n to o l
Figure 4. Representative Chromatogram of a 0.1 ng/mL Standard Containing PFHS
cootoM,0.1 m
ORTOSArMIin (Msfed)
1h
MfMiuMmOwtnntmfwBtr-
i m i .,.,*
3M 400
vUfk.
j^TI
tOOO 1UB
Figure 5. Representative Chromatogram of a 0.1 ng/mL Standard Containing PFOS
E x y fen R esearch
Exygen Research
P ace 26 o f 43
Page 136 of 153
418-028: PAGE G-137 Exygen Study No.: 023-072
E x y g e n M eth o d N o : E x M -0 2 3 -0 7 1 R e v isio c 1
Figure 6. Representative Chromatogram of a 0.1 ng/mL Standard Containing FFOA
C O V M O M . i.1 mgtmt. P T O A a M W O *
O n ta M N I ttlT M
UMOMSn
Figure 7. Representative Chromatogram of a 03 ng/mL Standard Containing PFHS
co aioa
*wuMoai:}ii
vumnnn
E x y g en R esearch
Exygen Research
P age 27 o f 43
Page 137 of 153
418-028:PAGE G-138 Exygen Study No.: 023-072
Exygea M e t h o d N o : E x M - 0 2 3 - 0 7 1 R e y i r i o n 1
Figure 8. Representative Chromatogram of a 0.5 ng/mL Standard Containing PFOS
eM3H4,t4n9M.WMtfffCS 07ukba-1US*KM) tWa.
JiMOItCtM1GWMtMl7T IMafteiwnit HS-i 4ttM>MM
lu ibo
4uo.Ufi74i0.1iihna.i^arn'o --te----uno
Figure 9. Representative Chromatogram of a 0.5 ng/mL Standard Containing PFOA
LGMSMS fi
E x y g e a R esearch
Exygen Research
Page 28 o f 43
Page 138 of 153
418-028:PAGE G -139 Exygen Study No.: 023-072
H x y g e n M e t h o d N o : ExM-023-Cni R e v i s i o n 1
Figure 10. Representative Chromatogram of a 5.0 ng/mL Standard Containing PTHS
rmto o n w M . t o i^ m .
U M t a i? : .*
LDUfcMS/T
Figure 11. Representative Chromatogram of a 5.0 ng/mL Standard Containing PFOS
CM M M sfcOiwM .W OAa'rtPPOt
O U u UtOCttMMMrtMfcfO?
ExytenReaearch
Exygen Research
P a te 29 o f 43
Page 139 of 153
418-028: PAGE G-140 Exygen Study No.: 023-072
E x y g e n M etb o d N o: E x M -0 2 3 -0 7 1 R e v isio n 1
Figure 12. Representative Chromatogram of a 5.0 ng/mL Standard Containing PFOA
Figure 13. Representative Chromatogram of a Reagent Blank Sample Analyzed for PFHS
HLOCwMM*m*K>ECSnT-
Exygen Research
Exygen Research
P age 30 o f 43
Page 140 of 153
418-028:PAGE G-141 Exygen Study No.: 023-072
E x y g e n M e th o d N a E xM -Q 23-071 R e v isio n 1
Figure 14. Representative Chromatogram of a Reagent Blank Sample Analyzed for PFOS
Figure IS. Representative Chromatogram of a Reagent Blank Sample Analyzed for PFOA
Exygen Research
E xygen R esearch
P tg e 3 1 o f4 3
Page 141 of 153
418-028: PAGE G -142 Exygen Study No.: 023-072
E x y g e n M eth o d N (x E x M -0 2 3 -0 7 1 R e v isio n 1
Figure 16. Representative Chromatogram of a Control Liver Sample Analyzed for PFHS
emmunrsMix
tUMunnsi
Figure 17. Representative Chromatogram of a Control Liver Sample Analyzed for PFOS
QSOTM UJm rBM A
07U M B A 1tftep*vM )
'"1
L C M M K IT UMttf SCManMtS-
-i **3
E xygen R esearch
lan mss
P age 32 o f 43
Exygen Research
Page 142 of 153
418-028-.PAGE G -143 Exygen Study No.: 023-072
E x y g e n M eth o d N o: E xM -Q 2 3 -0 7 ! R e v ie k n 1
Figure 18. Representative Chromatogram of a Control Liver Sample Analyzed for PFOA
nOMMUwBlMkA
OMuttOBtlSSfr
Figure 19. Representative Chromatogram of a Control Serum Sample Analyzed for PFHS
Exygen Reeearch
Exygen Research
P ig e 3 3 o f 43
Page 143 of 153
418-028:PAGE G-144 Exygen Study No.: 023-072
1E x y g e n M e t h o d N o : E x M - G 2 3 ^ } 7 1 R e v i s i o n Figure 20. Representative Chromatogram of a Control Serum Sample
Analyzed for PFOS
cow Miir
Figure 21. Representative Chromatogram of a Control Serum Sample Analyzed for PFOA
O 0 1 V 8 m BIm* A
e*M 0O I*1*M 0 LQM&M07
E xygen R esearch
Exygen Research
Page 34 o f 43
Page 144 of 153
418-028:PAGE G-145 Exygen Study No.: 023-072
E x y g e n M ethod N o : E x M -0 2 3 4 7 1 K e v U io a 1
Figure 22. Representative Chromatogram of a Control Urine Sample Analyzed for PFOS
ilMwHMkA
MWMMOttta
Figure 23. Representative Chromatogram of a Control Urine Sample Analyzed for PFOA
iawutn
E xygen R esearch
Exygen Research
Page 35 o f 43
Page 145 of 153
418-028-.PAGE G-146 Exygen Study No.: 023-072
E z y te n M eth o d N o: E *M -Q 23-C 7 1 R e v is e . 1
Figure 24. Representative Chromatogram of a Control Liver Sample Fortified at 10 ng/g with PFHS
tntS4umra*A,iOM*
L C M S M tff
Figure 25. Representative Chromatogram of a Control liv er Sample Fortified at 10 ng/g with PFOS
amMUwr9F*4i0ppt
etAMMBLtCWfcaWfctWi
Exyfea Research
Exygen Research
Page 36 of43
Page 146 of 153
418-028:PAGE G -147 Exygen Study No.: 023-072
E x y g e n M e th o d N o : E x M -0 2 3 -0 7 1 R evisio n I
Figure 26. Representative Chromatogram of a Control Liver Sample Fortified at 10 ng/g with PFOA
O tIM U w rtpkM O *)
icimimtr
Figure 27. Representative Chromatogram of a Control Liver Sample Fortified at 50 ng/g with PFHS
eoTiMUwrtokasow* otMu-mnanKM
LDMSMSff WMV10INWII-
ISOUSMOAMMOUirJOSJOMD
10S6 USD
Exygen Research
P age 37 o f 43
Exygen Research
Page 147 of 153
418-028:PAGE G-148 Exygen Study No.: 023-072
E x y g e n M eth o d N o: E x M -0 2 3 -0 7 1 R ev isio n 1
Figure 28. Representative Chromatogram of a Control Liver Sample Fortified at 50 ng/g with PFOS
B tU M U n rS p fc fclD p F fe
01 Jut a O P O t O r t t
Figure 29. Representative Chromatogram of a Control Laver Sample Fortified at 50 ng/g with PFOA
aO tSM U w rapfcllM w ta
livU M O U ththU LOHMM07
E xygea R esearch
Exygen Research
Page 38 o f 43
Page 148 of 153
418-028:PAGE G -149 Exygen Study No.: 023-072
1E x y g e n M a t e d N o : B x M - 0 2 3 0 7 1 R e v i s i o n
Figure 30. Representative Chromatogram of a Control Serum Sample Fortified at 10 ng/mL with PFHS
B ntntxM isvks.itpt*
iM iavnaohune
Figure 31. Representative Chromatogram of a Control Serum Sample Fortified at 10 ng/mL with PFOS
Exygen Research
Exygen Research
Page 39 o f 43
Page 149 of 153
418-028:PAGE G-150 Exygen Study No.: 023-072
E x y g en M eth o d N o ; E x M -0 2 3 -0 7 1 R c v u io o 1
Figure 32. Representative Chromatogram of a Control Serum Sample Fortified at 10 ng/mL with PFOA
L C M M U Wt
Figure 33. Representative Chromatogram of a Control Serum Sample Fortified at 50 ng/mL with PFHS
a8ofcm4MBM:tta0
lG M A tt# r
Exygen Research
Exygen Research
Page 40 of 43
Page 150 of 153
418-028:PAGE G -151 Exygen Study No.: 023-072
E x y g eo M eth o d N o : E x M -0 2 3 -0 7 1 R e v isitn 1
Figure 34. Representative Chromatogram of a Control Serum Sample Fortified at 50 ng/mL with FFOS
Figure 35. Representative Chromatogram of a Control Serum Sample Fortified at 50 ng/mL with PFOA
n ma Manapt.!*
B xygw R uearch
Exygen Research
Page 4 1 o f 43
Page 151 of 153
418-028:PAGE G-152 Exygen Study No.: 023-072
E x y g e n M eth o d N o : E xM *Q 23-071 R ev isio n 1
Figure 36. Representative Chromatogram of a Control Urine Sample Fortified at 10 ng/mL with PFOS
EttinaUmtokMOpft.
MiMBIIM
Figure 37. Representative Chromatogram of a Control Urine Sample Fortified at 10 ng/mL with PFOA
BOMBS Uria**** 10ppb
M liiW W iffM M
LCMIMir
Exygen Reaetrch
Exygen Research
Page 4 2 o f 43
Page 152 of 153
418-028:PAGE G-153 Exygen Study No.: 023-072
E x y g e n M eth o d N o : E x M -0 2 3 -0 7 1 R e ro io n 1
Figure 38. Representative Chromatogram of a Control Urine Sample Fortified at 50 ng/mL with PFOS
eOfM3Ur1nSpha*>r*fc
OW-8KOCOKI
IS M M M fr
Figure 39. Representative Chromatogram of a Control Urine Sample Fortified at 50 ng/mL with PFOA
OaHM) IMn>pk D,Mfb
E xygen R esearch
Exygen Research
Page 43 o f 43
Page 153 of 153
APPENDIX H TEMPERATURE AND RELATIVE HUMIDITY REPORTS
ARGUS
418-028-.PAGE H -1
Temperature and Relative Humidity Report Location: Room 05
Protocol Number: 418-028
Range of Dates: 26-Mar-2002 14:20 to 10-Jun-2002 08:59
Target Range: Species: Rat
Total Number of Days: Total Number of Hours: Total Number of Data Points:
Temperature 64F to 79F
77 1818.25
1817
Relative Humidity 30% to 70%
77 1818.25
1817
Mean ( SD):
Maximum: Median: Minimum:
Number of Points in Range (%): Number of Points High (%); Number of Points Low (%):
69.2
71.0 69.2 66.0
1817 0 0
( 0.7)
(100.0) (0.0) (0.0)
54.6
64.5 55.3 36.4
1817 0 0
( 4.4)
(100.0) (0.0) (0.0)
Report Generated: 10-Jur>-2002 at 13:26
COMMENTS:
REVIEWED BY:
DATE: (3
APPENDIX I POSITIVE CONTROL DATA
418-028:PAGE 1-1
Historical Control Data
This Functional Observation Battery Standard Operating Procedure and Studies conducted to document the training and competency of the technical staff and Motor Activity Negative Control Data and Positive Control Data are available at the Testing Facility.
Page 1
418-028:PAGE 1-2
Summary Information for Functional Observation Battery
Study Number - Title
Iu-Life Start
Test Substance
Dosage Information Number of
rog/kg mIVkg Dosages
012-006- ValidationofFunctional
ObservationalBatteryandMotorActivity
MeasureUsingPositiveTestSubstances
12/89
acrylamide
50
1
7
physostigmine
0.75
1.5
1
DDT
75 1
1
012-014- NeurotoxicityEvaluationof
PositiveControlSubstancesin
Crl:CDBRVAF/PlusRats
9/91 acrylamide 40 1
9
IDPN
200 1
3
carbaryl
75 5
1
DDT
75 5
1
triadimefon 200 5
1
012-015- NeurotoxicityEvaluationof DDT inCrl.CDBRVAF/PhisRats
3/92
DDT
75 1
1
012-017- NeurotoxicityEvaluationof PositiveControlSubstancesin Crl:CDBR VAF/PlusRats
012-022- NeurotoxicityEvaluationof Carbary!inCtiCDBR VAF/PhisRats 012-031- NeurotoxicityEvaluationof PositiveControlSubstancesin Crl:CDBR VAF/PlusRats
5/92 acrylamide
40
IDPN
200
carbaryl
40
DDT 75
d-ampbetamme
4.0
10/92
carbaryl
40,200
7/93 acrylamide 45
IDPN
250
carbaryl
40
DDT 75
d-amphetamine
4
1 1 5 1 1
5
1 1 5 1 1
9 3 1 1 1
1
10 4 1 1 1
Page 2
012-056- NeurotoxicityEvaluationof PositiveControlSubstancesin Crl:CDBRVAF/PlusRats
012-075-NeurotoxicityEvaluationof PositiveControlSubstancesin Crl:CDBRVAF/PlusRats
012-081-NeurotoxicityEvaluationof PositiveControlSubstancesin Crl:CDBRVAF/PlusRats
418-028:PAGE 1-3
11/95
acrylamide IDPN carbaryl DDT
d-amphetamine
45 250 40 75 4.0
1 1 1 1 1
10 5 1 1 1
3/98 acrylamide 30 1
trimethyttin 8 1
MK-801
0J 1
caibaryl
100 4
DDT 100 2
17 1 1 1 1
11/01
acrylamide IDPN
d-amphetamine carbaryl DDT
30 250 40 100 100
1 1 1 4 2
10 1 1 1 5
Page 3
418-028 :PAGE 1-4
Summary Information for Motor Activity
Study - Title
In-Life Start
012-011- TheAssessmentofMotor ActivityinNeonatalandAdultRodents usingPassiveInfraredSensors
5/91
012-014-NeurotoxicityEvaluationof PositiveControlSubstancesin Crl:CDBR VAF/Plus Rats
9/91
012-016- MotorActivityEvaluationin CrfcCDBR VAF/Plus Rats AdministeredChlorpromazineamtdAmphetamine(PositiveControlStudy)
012-058- NeurotoxicityEvaluationof PositiveControlSubstancesin Crl:CDBRVAF/PlusRats
Am
Test Substance
Dosage Information
mg/kg
Numberof mL/kg Dosages
d-amphetamine chlorpromazine
0.75,1.5,4 1,2,4
1 1
1 I
acrylamide 40 1
IDPN
200 1
caibaiyl
75 5
DDT 75 5
triadimefon 200 5
9 3 1 1 1
d-amphetamine chlorpromazine
0.5,1,4 1,2,4
1 1
l 1
acrylamide d-amphetamine
trimethyltin MK-801
45 0.75
8 10
1 1 1 1
10 1 1 1
Page 4
APPENDIX J HISTOPATHOLOGY REPORT
418-028:PAGE J-l
RESEARCH PATHOLOGY SERVICES, INC.
438 East Butler Avenue, New Britain, PA 18901 Phone: 215-345-7070 Fax: 215-345-4326
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCEENING TEST PROTOCOL 418-028 SPONSOR'S STUDY NUMBER T-7706.1 HISTOPATHOLOGY REPORT
SUBMITTED TO: Raymond G. York, Ph.D., D.A.B.T.
Argus Research 905 Sheehy Drive Horsham, PA 19044
SUBM ITTED BY:
Veterinary Pathologist July 3, 2003
418-028-.PAGE J-2
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL 418-028 S PO NSO R 'S STUDY NUMBER T-7706.1
HISTOPATHOLOGY REPORT
TABLE OF CONTENTS
REPORT
Page
M ethod....................................................................................................................................... 1
Results........................................................................................................................................ 3
Summary..................................................................................................................................... 5
Quality Assurance Unit Statem ent........................................................................................ 6
Good Laboratory Practice Compliance Statem ent............................................................ 7
TABLE
1. Incidence and Degree of Severity of Histomorphologic Observations.......................8
APPENDICES
I. Histomorphologic Observations....................................................................... 1-1 to 1-12
Key to Histomorphologic Observations........................................................................1-1
Tables
1-1. Histomorphologic Observations - Group I Male R ats.................................... I-2 I-2. Histomorphologic Observations - Group II Male R a ts ...................................I-4 I-3. Histomorphologic Observations - Group III Male R a ts ..................................I-5 I-4. Histomorphologic Observations - Group IV Male Rats..................................I-6 I-5. Histomorphologic Observations - Group V Male Rats...................................I-7 I-6. Histomorphologic Observations - Group I Female R ats............................... I-9 I-7. Histomorphologic Observations - Group V Female Rats...........................1-11
II. Individual Animal Gross and Histomorphology D ata................................. 11-1 to II-70
III. Histomorphologic Observations in the Liver - F1 Generation P u p s .......111-1 to III-2
Tables
HI-1. HI-2.
Histomorphologic Observations in the Liver - Group I F1 Generation Pups.......................................................................................... III-2 Histomorphologic Observations in the Liver - Group V F1 Generation Pups.......................................................................................... III-3
418-028 :PAGE J-3
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL 418-028 S PO N S O R 'S STUDY NUMBER T-7706.1
HISTOPATHOLOGY REPORT
METHOD
Microscopic examination was made of the specified tissues from 50 adult male and 20 adult female Crl:CD(SD)IGS BR VAF/Plus rats from five groups in an oral (gavage) combined repeated dose toxicity study of T-7706 (PFHS) with the reproduction/developmental toxicity screening test. In addition, microscopic exami nation was made of the liver of 10 pups in each of the control and high dosage groups of the F1 Generation. A brief outline of the study design showing the dose group identification, number of rats per sex per group, and dosage levels of the con trol and test substances are shown below.
DOSAGE GROUP
' II
III
NUMBER OF RATS PER SEXa
15 + 3C
15 + 3C
15 + 3C
DOSAGE (mg/kg/day)
0
0.3
1
CONCENTRATION6 (mg/mL) 0
0.03
0.1
DOSE VOLUME (mL/kg)
10
10
10
IV 15 + 3C
3
0.3
10
V 15 + 3C
10
1
10
`Ten male and ten female rats of Groups I and V were assigned for histopathologicevaluation.
The test substance was considered to be 100%activefor the purpose of dosage calculations. Three additional rats per sex per dosage group were assigned to toxicokineticsample collection.
Male rats were given the test substance once daily beginning 14 days before a cohabitation period that consisted of a maximum of 14 days. Dosing continued through the day before sacrifice, after completion of a cohabitation period, after a minimum of 42 days of administration. Female rats were given the test substance once daily beginning 14 days before a cohabitation period that consisted of a maxi mum of 14 days. Dosing continued through the day before scheduled sacrifice (Day 22 of lactation). Dosages were adjusted daily for body weight changes and were given at approximately the same time each day. The first day of dosing was desig-
Research Pathology Services, Inc.
-1
418-028:PAGE J-4
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL 418-028 S PO NSO R 'S STUDY NUMBER T-7706.1
HISTOPATHOLOGY REPORT
nated as Day 1 of the study. Pups were sacrificed and necropsied on Day 22 post partum.
All rats were necropsied and the specified tissues were collected and placed in 10% neutral buffered formalin for fixation. The testes were fixed in Bouin's solu tion for 48 to 96 hours and then retained in 10% neutral buffered formalin. The in-life portion of the study, necropsies, and recording of the gross necropsy observations were performed by the staff of Argus Research, Horsham, PA. The tissue process ing, microscopic slide preparation and histopathologic evaluation were performed by Research Pathology Services, Inc.
The tissues specified for microscopic evaluation from 10 male and 10 female rats of Groups I and V included: brain, duodenum, jejunum, ileum, cecum, colon, rectum, P eyefs patch, lung, submandibular and mediastinal lymph nodes, sciatic nerve, stomach, kidneys, spleen, thymus, trachea, urinary bladder, testes, epididy mides, seminal vesicles, coagulating gland, prostate, spinal cord (cervical, lumbar and thoracic), liver, adrenal glands, heart, thyroid, parathyroid, uterus, bone marrow (sternum), ovaries, uterus, vagina, mammary gland (female rats) and all other tis sues with gross changes. In addition, the liver and thyroid of 10 male and 10 female rats in each of the intermediate dosage groups were examined. The liver of 9 or 10 pups F1 generation pups from each of the 10 selected control and high dosage female rats were also examined. Representative samples of these tissues were routinely processed, embedded in paraffin, sectioned, and stained with hematoxylin and eosin for microscopic evaluation. In addition, sections of the testes from the control and high dosage group male rats were stained with periodic acid-Schiff (PAS) reaction and examined.
The study was initiated on June 24, 2002 and completed on July 3, 2003. Upon completion of the project, all raw data (remaining wet tissue, paraffin blocks, microscopic slides and histology records) will be returned to Argus Research for archiving.
Research Pathology Services, Inc.
-2
418-028:PAGE J-5
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL 418-028 SPO NSO R'S STUDY NUMBER T-7706.1
HISTOPATHOLOGY REPORT
RESULTS
The type, incidence and degree of severity of the histomorphologic changes in the specified tissues for the male and female rats are presented in Table 1. The microscopic observations in each rat are summarized in tabular form in Appendix I (Tables 1-1 to I-7). A key to the histomorphologic observations precedes Table 1-1. The gross necropsy observations, detailed descriptions of the microscopic observa tions, and a correlation of the microscopic findings with the gross changes in these rats, when applicable, are contained in Appendix II. The histomorphologic observa tions in the liver of the F1 Generation pups of the control and high dosage groups are summarized in tabular form in Appendix III (Tables 111-1 and III-2). A key to the histomorphologic observations is included on Tables 111-1 and III-2.
No treatment-related microscopic changes were observed in any of the male rats given 0.3 or 1 mg/kg/day of the test substance or in female rats given 10 mg/kg/day of T-7706.
Treatment-related microscopic changes were observed in the liver and thy roid gland of male rats of the 3 and 10 mg/kg/day dosage groups.
The treatment-related microscopic change in the liver consisted of minimal to moderate enlargement (hypertrophy) of centrilobular hepatocytes (Table 1). The affected hepatocytes were enlarged with an increased amount of dense eosinophilic granular cytoplasm.
The treatment-related effect in the thyroid gland consisted of an increased incidence of male rats of the 3 and 10 mg/kg/day dosage groups with hypertrophy (enlargement) of follicular cells and hyperplasia (increased follicular cells and small follicles) in male rats (Table 1). Although the incidence in Group IV was minimally increased over the controls, the hypertrophy and hyperplasia in this group of rats could have been associated with the liver-cell changes.
These microscopic changes in the liver and thyroid are consistent with the known effects of compounds that cause microsomal enzyme induction where the hepatocellular hypertrophy results in a compensatory hypertrophy and hyperplasia of
Research Pathology Services, Inc.
-3
418-028:PAGE J-6
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL 418-028 S PO NSO R 'S STUDY NUMBER T-7706.1
HISTOPATHOLOGY REPORT
the thyroid due to increased plasma turnover of thyroxine and an associated stimulation of thyroid-stimulating hormone in rats.1
There were no compound-related microscopic changes observed in the liver of the F1 generation pups from the dams given 10 mg/kg/day of the test substance.
T h e r e were a few o th e r m icro sco p ic c h a n g e s o b s e rv e d in th e v a rio u s o rg an s and tissues which were considered to have occurred spontaneously and to be inci dental and unrelated to compound administration. The type, incidence and severity of these changes were not influenced by compound administration. These changes also are listed in the attached histomorphology tables.
1 Sanders, J.E., Eigenberg, D.A., Bracht, L.J., Wang, W.R., and van Zwieten, M.J., Thyroid and Liver Trophic Changes in Rats Secondary to Liver Microsomal Enzyme Induction Caused by an Experi mental Leukotriene Antagonist (L-649,923), Toxicology and Pharmacology 95, 378-387 (1988)
Research Pathology Services, Inc.
-4
418-028 :PAGE J-7
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL 418-028 S PO NSO R 'S STUDY NUMBER T-7706.1
HISTOPATHOLOGY REPORT
SUMMARY
Microscopic examination was made of the specified tissues from five groups of male and female Crl:CD(SD)IGS BR VAF/Plus rats used in an oral (gavage) combined repeated dose toxicity study of T-7706 with the reproduction/developmental toxicity screening test. The five groups of rats had been given the vehicle (aqueous 0.5% carboxymethylcellulose), or 0.3, 1, 3 or 10 mg/kg/day of T-7706, orally by gavage, once daily for the protocol-specified number of days. In addition, the liver was examined microscopically from 9 or 10 pups of the F1 gen eration from 10 dams each of the control and high dosage groups.
No treatment-related microscopic changes were observed in female rats given 10 mg/kg/day of T-7706 or in male rats given 0.3 or 1 mg/kg/day of T-7706.
Treatment-related microscopic changes were observed in the liver and thyroid of male rats of the 3 and 10 mg/kg/day dosage groups.
The treatment-related change in the liver consisted of minimal to moderate hypertrophy of centrilobular hepatocytes and the effect in the thyroid was an in creased incidence of male rats with a compensatory hypertrophy and hyperplasia of the follicular epithelium in these groups of male rats.
No treatment-related microscopic changes were observed in the liver of the F1 generation pups from dams given 10 mg/kg/day of T-7706.
All other microscopic changes were considered to be spontaneous in origin and not treatment-related. The type, incidence or severity of these changes were not considered to be influenced by administration of the test substance.
Research Pathology Services, Inc.
-5
418-028:PAGE J-8
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL 418-028 S PO N S O R 'S STUDY NUMBER T-7706.1
HISTOPATHOLOGY REPORT
QUALITY ASSURANCE UNIT STATEMENT
All aspects of the tissue processing, microscopic slide preparation, histopathologic evaluation and report preparation for the study listed above have been performed according to the Standard Operating Pro
cedures of Research Pathology Services, Inc. and were audited in accordance with the procedures established by the Quality Assurance Unit of Research Pathology Services, Inc. in compliance with the Good Laboratory Practice regulations specified in the protocol.
OrganisationforEconomicCooperationandDevelopment(1996). OECD Guideline for Testing o f Chemicals. Section4, No. 422: CombinedRepeatedDoseToxicityStudywiththeReproduction/Developmental ToxicityScreeningTest, adopted22March1996.
OrganisationforEconomicCooperationandDevelopment(1998). TheRevisedOECDPrinciplesofGoodLaboratoryPractices [C(97)186/Final].
USFoodandDrugAdministration. GoodLaboratoryPracticeRegulations: Final Rule. 21CFRPart58.
JapaneseMinistryofHealthandWelfare(1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHWOrdinance Number21, March26,1997.
Quality assurance unit study-based inspectionswere performed as shown below. There were no devia
tions fromthe protocol, standard operating procedures and/or appropriate good laboratory practice regulations
noted during the conduct of the study. The summary report of QA inspections is included inthe final report sub
mitted to the study director on July 3,2003.
Dates of
Dates Reported to
Date Reported
Inspection
Studv Phase
Manaaement
to Studv Director
12/16/02
12/16/02 01/07/03 01/09/03
01/11/03 01/13/03
01/13/03 01/31/03 01/31/03 02/21/03 02/24/03 02/26/03 02/27/03 02/28/03 07/03/03
Master Schedule Pre-initiation Trimming Embedding
Microtomy
Staining Organization &Review
Histopathology
Data Entry Data Verification Data Processing Report Preparation
Pre-submission Audit Draft report
Final report
12/31/02 12/31/02 01/30/03 01/31/03 01/31/03
01/31/03 01/27/03
01/31/03 02/27/03 02/27/03 02/27/03
02/27/03 02/27/03 02/28/03
07/03/03
02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03 02/28/03
02128103
02/28/03 02/28/03 02/28/03 07/03/03
Research Pathology Services, Inc.
Karen W. Harkins, BS Quality Assurance Unit
oy-e-o.3
~7 Date
-6
418-028 :PAGE J-9
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL 418-028 S PO NSO R 'S STUDY NUMBER T-7706.1
HISTOPATHOLOGY REPORT
GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT
All aspects of the above-referenced study performed by Research Pathology Services, Inc. w ere conducted according to:
OrganisationforEconomicCooperationandDevelopment (1996). OECD Guideline for Testing o f Chemicals. Section4, No. 422: CombinedRepeatedDoseToxicityStudywiththeReproduction/Developmental ToxicityScreeningTest, adopted22March1996. OrganisationforEconomicCooperationandDevelopment(1998). TheRevisedOECDPrinciplesofGoodLaboratoryPractices [C(97)186/Final], USFoodandDrugAdministration. GoodLaboratoryPracticeRegulations: Final Rule. 21CFRPart58. JapaneseMinistryof HealthandWelfare(1997). Good Laboratory Practice Standard for Safety Studies on Drugs, MHWOrdinance Number21, March26,1997.
No deviations w ere noted that had any significant impact on the validity of the study.
Research Pathology Services, Inc.
-7
418-028:PAGE J-10
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1
Incidence and Degree of Severity of Histomorphologic Observations
Dose Group: Sex: Number of Animals/Group:
I II III IV V MMMMM 10 10 10 10 10
ADRENAL GLANDS: NO. EXAMINED NO. NORMAL
10 0 0 0 10 70009
-degeneration, cystic, cortex, multifocal mild
[0] [0] [0] CO] [0] 00000
-hypertrophy/vacuolation, cortex, multifocal mild
[0] [0] [0] [0] [0] 00000
-necrosis, cortex, focal mild
[0] [0] [0] [0] [0] 00000
-vacuolation, cortex, diffuse
minimal mild
[3] [0] [0] [0] [1] 20000 1000 1
-vacuolation, zona glomerulosa mild
[0] [0] [0] [0] [0] 00000
BONE MARROW (STERNUM): NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
BRAIN: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
CECUM: NO. EXAMINED NO. NORMAL
10 0 0 0 10 8 0009
-inflammation, mucosa, chronic mild moderate
[2] [0] [0] [0] [1] 0 000 1 20000
COAGULATING GLAND: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
COLON: NO. EXAMINED NO. NORMAL
10 0 0 0 10 9 0 0 0 10
-inflammation, mucosa, chronic mild
[1] [0] [0] [0] CO] 10000
DUODENUM: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
EPIDIDYMIDES: NO. EXAMINED NO. NORMAL
[ ] = Total incidence of specified lesion, all grades.
10 0 0 1 10 60009
IV FF 10 10
10 10 87 [0] [1] 01 [0] [1] 01 [0] [1] 01 [0] [0] 00 00 [2] [0] 20
10 10 10 10
10 10 10 10
10 10 8 10 [2] CO] 10 10
10 10 10 10 [0] CO] 00
10 10 10 10
-8
418-028:PAGE J -11
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1 (Continued)
Incidence and Degree of Severity of Histomorphologic Observations
Dose Group: Sex: Number of Animals/GrouD:
I II III IV V MM MM M 10 10 10 10 10
1V FF 10 10
EPIDIDYMIDES (Continued):
-exfoliated spermatogenic cells moderate
[0] [0] [0] [1] [0] 00010
-hypospermi a marked
infiltration, mononuclear-cell, focal minimal
[0] [0] [0] [1] [0] 0u010 t4] [0] [0] [0] [1] 4 0 00 1
HEART: NO. EXAMINED NO. NORMAL
-inflammation, chronic, focal minimal mild
10 0 0 0 10 80009
[2] [0] [0] [0] [1] 10001 10000
10 10 10 10
[0] [0] 00 00
ILEUM: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
10 10 10 10
JEJUNUM: NO. EXAMINED NO. NORMAL
-diverticulum
10 0 0 0 10 10 0 0 0 9
00 00 1
10 10 10 10
00
KIDNEYS: NO. EXAMINED NO. NORMAL
10 3 0 0 10 7 1 00 7
10 10 98
-basophilia/degeneration, cortical tubules, focal/multi focal minimal
-cyst(s). medulla
-dilatation, pelvis minimal mild
[0] [0] [0] [0] [1] 00001
[0] [0] 00
10002
00
[0] [2] [0] [0] [0] [0] [0]
0 1000
00
0 1000
00
-infiltration, mononuclear-cell, focal/multifocal minimal
[2] [0] [0] [0] [2] 20 00 2
[0] [0] 00
-mineralization, multifocal minimal
[0] [0] [0] [0] [0] 00000
[0] [1] 01
[ ] = Total incidence of specified lesion, all grades.
418-028:PAGEJ-12
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1 (Continued)
Incidence and Degree of Severity of Histomorphologic Observations
Dose Group: Sex:
Number of Animals /Gt o u d :
I II III IV V MMMMM
10 10 10 10 10
KIDNEYS (Continued):
-nephritis, chronic, focal minimal
[0] [0] [0] [0] [1] 00001
LIVER: NO. EXAMINED NO. NORMAL
10 10 10 10 10 23200
-hypertrophy, hepatocellular, centrilobular minimal mild moderate
[0] [0] [0] [9] [10] 0 0 08 4 000 15 00 00 1
-inflammation, chronic, focal/multifocal minimal mild
[8] [6] [7] [6] [5] 54 765 32000
-lipidosis, tension, focal
02000
-necrosis, focal minimal
[0] [0] [0] [0] [0] 00000
-vacuolation, hepatocellular, midzonal mild
[0] [0] [1] [0] [0] 00 100
-vacuolation. hepatocellular, multifocal minimal mild
[0] [1] [1] [0] [0] 01000 00100
LUNG: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
-infiltration, polymorphonuclear, perivascular/peri bronchi al
mild
[0] [0] [0] [0] [0] 00000
-inflammation, interstitial, focal minimal
[0] [0] [0] [0] [0] 00000
-macrophages, alveoli, focal minimal
[0] [0] [0] [0] [0] 00000
LYMPH NODE. MEDIASTINAL: NO. EXAMINED NO. NORMAL
8 0 0 0 10 70008
-congestion minimal
[0] [0] CO] [0] [0] 0000
IV FF 10 10
[1] [1] 11
10 10 87
[0] [0] 00 00 00
[2] [1] 21 00
00
[0] [2] 02
[0] [0] 00
[0] [0] 00 00
10 10 99
[1] [0] 10
[0] [1] 01
[0] [1] 01
10 10 7 10
[2] [0] 20
[ ] = Total incidence of specified lesion, a ll grades.
-10
418-028:PAGE J-13
ORAL CGAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPHENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1 (Continued)
Incidence and Degree of Severity of Histomorphologic Observations
Dose Group: Sex:
Number of Animals/GrouD:
I II III IV V MMMMM 10 10 10 10 10
LYMPH NODE, MEDIASTINAL (Continued):
-hyperplasia, lymphocytic/plasmacytic mild
[0] [0] [0] [0] [0] 00000
-mastocytosis minimal
LYMPH NODE. SUBMANDIBULAR: NO. EXAMINED NO. NORMAL
[1] [0] [0] [0] [2] 10002
10 0 0 0 10 50004
-hyperplasia, lymphocytic/plasmacytic minimal mild moderate
MAMMARY GLAND: NO. EXAMINED NO. NORMAL
[5] [0] [0] [0] [6] 10002
2 0000 2 0 0 04
-necrosis, focal minimal
NERVE. SCIATIC: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
OVARIES: NO. EXAMINED NO. NORMAL
-cyst(s), intraovarian
PARATHYROID: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
PEYER'S PATCH: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 9
-mineralization, focal minimal
[0] [0] [0] [0] [1] 0 0. 0 0 1
PROSTATE: NO. EXAMINED NO. NORMAL
10 0 0 0 10 60 006
IV FF 10 10
[1] [0] 10
[1] [0] 10
10 9 43
[6] t6] 10 35 21
10 10 10 9 [0] [1] 01
10 9 10 9
10 10 9 10 10
10 10 10 10
10 10 10 10
[0] [0] 00
[ ] = Total incidence of specified lesion, a ll grades.
-11
418-028-.PAGEJ-14
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1 (Continued)
Incidence and Degree of Severity of Histomorphologic Observations
Dose Group: Sex: Number of Animals/GrouD:
I II III IV V MMMMM
10 10 10 10 10
PROSTATE (Continued):
-atrophy, focal/multifocal minimal moderate
[1] [0] [0] [0] [2] 10001 0 0 00 1
-inflammation, chronic, focal/multifocal minimal
[3] [0] [0] [0] [3] 30003
RECTUM: NO. EXAMINED NO. NORMAL
10 0 0 0 10 90009
-inflammation, mucosa, chronic minimal mild
SEMINAL VESICLES: NO. EXAMINED NO. NORMAL
[1] [0] [0] [0] [1] 0 0 00 1 10000
10 0 0 0 10 10 0 0 0 10
SKIN (GROSS LESION): NO. EXAMINED NO. NORMAL
00000 00000
-dermatitis, chronic, focal minimal
mild
[0] [0] [0] [0] [0] 00000
00000
SPINAL CORD. CERVICAL: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
SPINAL CORD. LUMBAR: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
SPINAL CORD. THORACIC: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
SPLEEN: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
-atrophy mild
[0] [0] [0] [0] [0] 00000
STOMACH: Nb. Exa mined NO. NORMAL
10 0 0 0 10 80009
[ ] - Total incidence of specified lesion, a ll grades.
IV FF 10 10
10 10 10 10 [0] [0] 00 00
11 00 [1] [1] 01 10
10 10 10 10
10 10 10 10
10 10 10 10
10 10 10 9 [0] [1] 01
10 10 76
-12
418-028:PAGE J-15
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1 (Continued)
Incidence and Degree of Severity of Histomorphologic Observations
Dose Group: Sex: Number of Animals/GrouD:
I II III IV V MMMMM
10 10 10 10 10
STOMACH (Continued):
-dilatation, mucosal glands minimal
[1] [0] [0] [0] [0] 10000
-edema/inflanimation, submucosa, forestomach mild
[1] [0] [0] [0] [1] 10 00 1
-edema/inflanimation, submucosa, glandular area
minimal mild moderate
[2] [0] [0] [0] [0] 10000
00000 . 10 000
-erosion(s). glandular mucosa moderate
[0] [0] [0] [0] [0] 00000
TESTIS (H&E): NO. EXAMINED NO. NORMAL
10 0 0 1 10 10 0 0 0 10
-degeneration, multifocal mild
[0] [0] [0] [1] [0] 00010
TESTIS (PAS): NO. EXAMINED NO. NORMAL
10 0 0 1 10 10 0 0 0 10
-degeneration, multifocal mild
[0] [0] [0] [1] [0] . 00010
THYMUS: NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
-atrophy moderate marked
[0] [0] [0] [0] [0] 00000
00000
THYROID: NO. EXAMINED NO. NORMAL
10 10 10 10 10 53553
-hypertrophy/hyperplasia, follicular epithelium minimal mild moderate
[2] [3] [2] [4] [7] 0 112 0 22123 00004
-ultimobranchial body/cyst
34422
TRACHEA:
NO. EXAMINED NO. NORMAL
10 0 0 0 10 60009
[ ] = Total incidence of specified lesion, a ll grades.
IV FF 10 10
[1] [1] 11
[0] [1] 01 [2] [3] 00 13 10 [0] [1] 01
10 10 99 [1] [1] 10 01
10 10 55 [0] [0] 00 00 00 55
10 10 10 9
-13
418-028:PAGE J-16
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1 (Continued)
Incidence and Degree of Severity of Histomorphologic Observations
Dose Group: Sex:
Number of Animals/GrouD:
I II III IV V MMMMM 10 10 10 10 10
TRACHEA (Continued):
-inflammation, chronic, focal minimal mild
[4] [0] [0] [0] [1] 20000 20001
URINARY BLADDER:
NO. EXAMINED NO. NORMAL
10 0 0 0 10 10 0 0 0 10
-inflammation, chronic, focal minimal
[0] [0] [0] [0] [0] 00000
UTERUS: NO. EXAMINED NO. NORMAL
-distention, lumen mild moderate
-macrophages, pigmented minimal mild moderate marked
VAGINA: NO. EXAMINED NO. NORMAL
IV FF 10 10
[0] [1] 01 00
9 10 8 10
[1] [0] 10
10 10 01
[0] [2] 01
01
[10] 1 2
7 0
[8] 0 2
5 1
10 10 10 10
[ ] - Total incidence of specified lesion, all grades.
-14
418-028:PAGE J-17 ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL 418-028 SPO NSO R 'S STU D Y NUMBER T-7706.1
HISTOPATHOLOGY REPORT
APPENDIX I
HISTOMORPHOLOGIC OBSERVATIONS
418-028:PAGE J-18
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL 418-028 SPO NSO R 'S STUDY NUMBER T-7706.1
HISTOPATHOLOGY REPORT
KEY TO HISTOMORPHOLOGIC OBSERVATIONS - = No change (not remarkable, within normal histologic limits or indicated
change not present). * = Tissue not available (specified tissue missing, insufficient tissue
in plane of section, artifact precludes evaluation, or specified tissue not present in section). < > = Microscopic finding(s) in tissue(s) with gross observation(s). <_> = Within normal limits [no microscopic change(s) to correlate with the
gross observation(s)]. P = Indicated change or lesion present 1 = Minimal degree or amount of indicated change or lesion. 2 = Mild degree or amount of indicated change or lesion. 3 = Moderate degree or amount of indicated change or lesion. 4 = Marked degree or amount of indicated change or lesion. SS = Scheduled Sacrifice
1-1
418-028-.PAGE J-19
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1-1
Histomorphologic Observations
Dose Group: Animal Number: Sex: Death Tvoe:
IIIIIIIIII 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135
MMMMMMM MMM SS SS SS SS SS SS SS SS SS SS
ADRENAL GLANDS: -vacuolation, cortex, diffuse
-1-1-*2-
-
BONE MARROW (STERNUM):
----------
BRAIN:
----------
CECUM: -inflammation, mucosa, chronic
---3-3----
COAGULATING GLAND:
----------
COLON: -inflammation, mucosa, chronic
DUODENUM:
- -2--------------
EPIDIDYMIDES: -infiltration, mononuclear-cell, focal
-1--1- 1- 1-
HEART: -inflammation, chronic, focal
- 1---- 2 - - -
ILEUM:
--- --- -- --
JEJUNUM:
----------
KIDNEYS: -cyst(s), medulla -infiltration, mononuclear-cell,
focal/multifocal
LIVER: -inflammation, chronic, focal/multifocal
LUNG:
LYMPH NODE. MEDIASTINAL: -mastocytosis
" - <-> - - - " - P " * <-> 1 - - - - - 1
-112 112 2-1 ---------1-- -* *- --
LYMPH NODE. SUBMANDIBULAR: -hyperplasi a , 1ymphocyti c/piasmacyt1c
3 -2 - 13 2 - - *
NERVE. SCIATIC:
----------
PARATHYROID:
----------
PEYER'S PATCH:
- - - - -- - - - -
PROSTATE: -atrophy, focal/multifocal
1
1-2
418-028-.PAGE J-20
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEV ELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1-1 (Continued)
Histomorphologic Observations
Dose Group:
IIIIIIIIII
Animal Number:
19109 19115 19116 19119 19122 19125 19131 19132 19134 19135
Sex:
MMMMMMMMMM
Death Type:_________________________________ SS SS SS SS SS SS SS SS SS SS
PROSTATE (Continued): -infl armati on, chronic, focal/multi focal
1-----1--1
RECTUM: -inflammation, mucosa, chronic
SEMINAL VESICLES:
SPINAL CORD. CERVICAL:
SPINAL CORD. LUMBAR:
SPINAL CORD. THORACIC:
SPLEEN:
STOMACH:
-dilatation, mucosal glands
-edema/infiammati on, submucosa, forestomach
-edema/1nflammation, submucosa, glandular
area
- -- - - - - 3 1
TESTIS (H&E):
TESTIS (PAS):
THYMUS:
THYROID:
-hypertrophy/hyperplasia, follicular epithelium
-ultimobranchial body/cyst
2--.. - P---
-.-2 P-P-
TRACHEA: -inflammation, chronic, focal
- 2- -
1-2-1
URINARY BLADDER:
1-3
418-028:PAGE J-21
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1-2
Histomorphologic Observations
Dose Group: Animal Number:
Sex: Death Tvoe:
II II II II II II II II II II 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 MMMMMMMMMM SS SS SS SS SS SS SS SS SS SS
KIDNEYS: -dilatation, pelvis
<-> <2> <1>
LIVER: -inflammation, chronic, focal/multifocal
-lipidosis, tension, focal -vacuolation, hepatocellular, multifocal
2211-
P- -
--
--
"
11- - -
P- - - " 1-"
THYROID: -hypertrophy/hyperplasia, fol1icular
epithelium -ultimobranchial body/cyst
--"2
PP
-
12 - PP
1-4
418-028:PAGE J-22
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1-3
Histomorphologic Observations
Dose Group: Animal Number:
Sex: Death Type:_____________________________
III III III III III III III III III III 19101 19105 1910719112 19114 19121 19123 19130 19137 19146 MMMMMMMMMM
SS SS SS SS SS SS SS SS SS SS
LIVER: -inflanmation, chronic, focal/multifocal - 1 1 1 1 1 -vacuolation, hepatocellular, midzonal -vacuolation, hepatocellular, multifocal - - - - - 2
THYROID: -hypertrophy/hyperplasia, foilicular
epithelium -ultimobranchial body/cyst
1 2- - - PP P P - -
1-5
418-028:PAGE J-23
ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
' TABLE 1-4
Histomorphologic Observations
Dose Group: Animal Number: Sex: Death Type:
IV IV IV IV IV IV IV IV IV IV
19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 MMMMMMMMMM SS SS SS SS SS SS SS SS SS SS
EPIDIDYMIDES:
-exfoliated spermatogenic cells -hypospermi a
<3> <4>
LIVER:
-hypertrophy, hepatocellular, centrilobular 1
-inflammation, chronic, focal/multifocal
1
2 1111-11
1 1 -- 1 1 1-
TESTIS (H&E): -degeneration, multifocal
< 2>
TESTIS (PAS): -degeneration, multifocal
< 2>
THYROID: -hypertrophy/hyperplasia, foilicular
epithelium -ultimobranchial body/cyst
1 -
- - 1 - - - 22 - . P p - - --
1-6
418-028-.PAGE J-24
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1-5
Histomorphologic Observations
Dose Group: Animal Number:
Sex: Death Tvoe:
VVVVVVVVVV 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152
MMMMMMMMMM SS SS SS SS SS SS SS SS SS SS
ADRENAL GLANDS: -vacuolation, cortex, diffuse
----2-----
BONE MARROW (STERNUM):
----------
BRAIN:
--- --- -- --
CECUM: -inflammation, mucosa, chronic
----2----
COAGULATING GLAND:
----------
COLON: DUODENUM:
-------------------
EPIDIDYMIDES: -infiltration, mononuclear-cell, focal
--1-------
HEART: -inflammation, chronic, focal
-"-- -- -- - 1
ILEUM:
- -- - -- - - --
JEJUNUM: -diverticulum
<P> - - - - - - - - -
KIDNEYS:
-basophilia/dgnrtion, cortical tubules,
focal/multi focal -cyst(s), medulla
1 P P -- - - - - - -
-infiltration, mononuclear-cell, focal/multi focal
1. . . . . . 1. .
-nephritis, chronic, focal
--1----*-
LIVER:
-hypertrophy, hepatocellular, centrilobular 2 1 2 2 3 2 1 2 1 1
-inflammation, chronic, focal/multifocal
1-- 1-11--1
LUNG:
----------
LYMPH NODE. MEDIASTINAL: -mastocytosis
-11---"--"
LYMPH NODE. SUBMANDIBULAR: -hyperplas ia , 1ymphocyt ic/plasmacyt ic
13 " - 13 - 3 -3
NERVE. SCIATIC:
----------
PARATHYROID:
PEYER'S PATCH: -mineralization, focal
----------
1"""""
1-7
418-028:PAGE J-25
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1-5 (Continued)
Histomorphologic Observations
Dose Group: Animal Number:
Sex: Death Type:
VVVVVVVVVV 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 MMMMMMMMMM SS SS SS SS SS SS SS SS SS SS
PROSTATE:
-atrophy, focal /mult ifocal -inflammation, chronic, focal/multi focal
1
RECTUM: -inflammation, mucosa, chronic
-
SEMINAL VESICLES:
-
SPINAL CORD. CERVICAL:
-
SPINAL CORD. LUMBAR:
-
SPINAL CORD. THORACIC:
-
SPLEEN:
-
STOMACH: -edema/inflammation, submucosa, forestomach -
TESTIS (H&E):
-
TESTIS (PAS):
-
THYMUS:
-
THYROID: -hypertrophy/hyperplasia, foilicular
epithelium -ultimobranchial body/cyst
3 P
233
TRACHEA: -inflammation, chronic, focal
-
URINARY BLADDER:
1-8
418-028:PAGE J-26
ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1-6
Histomorphologic Observations
Dose Group: Animal Number: Sex: Death Tvoe:
11IIIIII1I 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065
FFFFFFFFFF SS SS SS SS SS SS SS SS SS SS
ADRENAL GLANDS: -vacuo!ation, zona glomerulosa
- - .---- 22-
BONE MARROW ISTERNUM):
----------
BRAIN:
- --- -- - ---
CECUM: -inflammation, mucosa, chronic
--------32
COLON:
----------
DUODENUM:
----------
HEART:
- - - - -- - - --
ILEUM:
----------
JEJUNUM:
----------
KIDNEYS: -nephritis, chronic, focal
------1---
LIVER: -inflanmation, chronic, focal/multi focal - - 1 - - - - - - 1
LUNG:
-infiltration, polymorphonuclear, peri vascular/peri bronchi al
___2 _
_ ..
__
LYMPH NODE. MEDIASTINAL: -congestion -hyperplasi a , 1ymphocyti c/plasmacyt ic -mastocytosis
11 - - - - - `- 2 " - " 1-"
LYMPH NODE. SUBMANDIBULAR: -hyperplasia , 1ymphocyt ic/plasmacyt ic
-2--3-3 122
MAMMARY GLAND:
- - - - - - - '- - -
NERVE, SCIATIC:
----------
OVARIES: -cyst(s), intraovarian
P- - - - -
- -- -
PARATHYROID:
----------
PEYER'S PATCH:
----------
RECTUM:
-- - -- -- ---
SKIN fGROSS LESION): -dermatitis, chronic, focal
<2>
1-9
418-028:PAGE J-27
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1-6 (Continued)
Histomorphologic Observations
Dose Group: Animal Number: Sex: Death Type:___________
II
II I I I I I I
19012 19019 19021 19023 19041 19042 19044 19050 19053 19065
FFFFFFFFFF
SS SS SS SS SS SS SS SS SS SS
SPINAL CORD. CERVICAL:
SPINAL CORD. LUMBAR:
SPINAL CORD. THORACIC:
SPLEEN:
STOMACH:
-dilatation, mucosal glands
1---------
-edema/inflammation, submucosa, glandular
area
---23-----
THYMUS: -atrophy
--------3-
THYROID; -ultimobranchial body/cyst
TRACHEA:
P-P-PP--P---------
URINARY BLADDER: -inflammation, chronic, focal
--*------
1
UTERUS: -macrophages, pigmented
3231333332
VAGINA:
----------
1-10
418-028-.PAGEJ-28
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPROOUCTION/OEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUOY NUMBER T-7706.1
TABLE 1-7
Histomorphologic Observations
Dose Group: Animal Number:
Sex: Death Tvce:
V V V V VV V V VV 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 FFFFFF FFFF SS SS SS SS SS SS SS SS SS SS
ADRENAL GLANDS: -degeneration, cystic, cortex, multifocal
"
"
<2> ~ ~ " --
--
-hypertrophy/vacuolati on, cortex,
multifocal
--
-2
--
-necrosis, cortex, focal
""2
*
"-"
BONE MARROW (STERNUM):
----------
BRAIN: CECUM: COLON: DUODENUM:
---------- - - <-> - - - - - - - - <-> - - - - - - - - <-> - - - - - -
HEART: ILEUM: JEJUNUM:
---------- - - <-> - - - - - - - - <-> - - - - - -
KIDNEYS: -mineralization, multifocal -nephritis, chronic, focal
"""
1 1
LIVER: -inflammation, chronic, focal/multifocal -necrosis, focal
LUNG: -inflammation, interstitial, focal -macrophages, alveoli, focal
*
1 1
1 1"
-*- 1
- -- - -
LYMPH NODE. MEDIASTINAL:
----------
LYMPH NODE. SUBMANDIBULAR: -hyperplasia, lymphocytic/plasmacyti c
-2-22-23*2
MAMMARY GLAND: -necrosis, focal
NERVE. SCIATIC:
OVARIES:
---- 1-- - - - - - - - - - - ----------
PARATHYROID:
----------
PEYER'S PATCH: RECTUM:
----------
- - - <->
-
"
1-11
418-028:PAGE J-29
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
TABLE 1-7 (Continued)
Histomorphologic Observations
Oose Group: Animal Number: Sex: Death TvDe:
VVVVVVVVVV
19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 FFFFFFFFFF SS SS SS SS SS SS SS SS SS SS
SKIN (GROSS LESION): -dermatitis, chronic, focal
SPINAL CORD. CERVICAL:
SPINAL CORD, LUMBAR:
SPINAL CORD. THORACIC:
--
--
--
<1> -- --
-------------------
SPLEEN: -atrophy
- - - <2>
STOMACH: -dilatation, mucosal glands -edema/inflammation, submucosa, forestomach -edema/inflammation, submucosa, glandular
area -erosion(s), glandular mucosa
-
------1 - - <2> - - - -
- <Z>
- <3>
-
-
22 --
THYMUS: -atrophy
- <4> -
--
THYROID: -ultimobranchial body/cyst
- P-PP-P-P-
TRACHEA: -inflammation, chronic, focal
URINARY BLADDER:
UTERUS: -distention, lumen -macrophages, pigmented
2 --------
3
323423-33-
VAGINA:
1-12
418-028-.PAGE 1-30
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL 418-028 S PO NSO R 'S STUDY NUMBER T-7706.1
HISTOPATHOLOGY REPORT
APPENDIX II
INDIVIDUAL ANIMAL G ROSSAND HISTOMORPHOLOGY DATA
418-028-.PAGE J-31
ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19109 SEX: M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No aross chanaes.
HISTOMORPHOLOGIC OBSERVATIONS! : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LYMPH NODE, MEDIASTINAL: LYMPH NODE, SUBMANDIBULAR: PROSTATE: THYROID:
mastocytosis (minimal) hyperplasia, lymphocytic/plasmacytic (moderate) inflammation, chronic, focal/multifocal (minimal) hypertrophy/hyperplasia, follicular epithelium (mild)
THE FOLLOWING TISSUES! WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COAGULATING GLAND
HEART LIVER PEYER'S PATCH SPINAL CORD, LUMBAR
TESTIS (H&E) URINARY BLADDER
BONE MARROW (STERNUM) COLON
ILEUM LUNG RECTUM SPINAL CORD, THORACIC TESTIS (PAS)
BRAIN DUODENUM JEJUNUM NERVE, SCIATIC SEMINAL VESICLES SPLEEN
THYMUS
End of Record- 19109
CECUM EPIDIDYMIDES KIDNEYS PARATHYROID SPINAL CORD, CERVICAL STOMACH
TRACHEA
II-l
418-028-.PAGE J-32
ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19115
SEX:
M
DOSE GROUP; DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATION!SI: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
ADRENAL GLANDS: EPIDIDYMIDES: HEART: LIVER: THYROID: TRACHEA:
vacuolation, cortex, diffuse (minimal) infiltration, mononuclear-cell, focal (minimal) inflammation, chronic, focal (minimal) inflammation, chronic, focal/multifocal (minimal) ultimobranchial body/cyst inflanmation, chronic, focal (mild)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
BONE MARROW (STERNUM) COLON KIDNEYS NERVE, SCIATIC RECTUM
SPINAL CORD, THORACIC
TESTIS (PAS)
BRAIN DUODENUM
LUNG PARATHYROID SEMINAL VESICLES SPLEEN
THYMUS
CECUM ILEUM
LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, CERVICAL STOMACH
URINARY BLADDER
COAGULATING GLAND JEJUNUM LYMPH NODE, SUBMANDIBULAR PROSTATE
SPINAL CORD, LUMBAR TESTIS (H&E)
End of Record- 19115
11-2
418-028-.PAGE J-33
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUM8ER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19116
SEX:
M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONfSl: KIDNEYS: Mottled tan and red, bilateral.
HISTOMORPHOLOGIC OBSERVATIONfSl: No microscopic change to correlate
HISTOMORPHOLOGIC OBSERVATIONS:
KIDNEYS: LIVER: LYMPH NODE, SUBMANDIBULAR:
No microscopic change to correlate inflammation, chronic, focal/multifocal (minimal)
hyperplasia, lymphocytic/plasmacytic (mild)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COAGULATING GLAND HEART
LUNG PEYER'S PATCH
SPINAL CORD, CERVICAL STOMACH
THYROID
BONE MARROW (STERNUM) COLON ILEUM
LYMPH NODE, MEDIASTINAL PROSTATE SPINAL CORD, LUMBAR TESTIS (H&E) TRACHEA
BRAIN DUODENUM JEJUNUM NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC TESTIS (PAS) URINARY BLADDER
End of Record- 19116
CECUM EPIDIDYMIDES KIDNEYS
PARATHYROID SEMINAL VESICLES SPLEEN THYMUS
11--3
418-028-.PAGEJ-34
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19119
SEX:
M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No gross changes
HISTOMORPHOLOGIC OBSERVATION'S): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
ADRENAL GLANDS: CECUM: COLON: KIDNEYS: LIVER: RECTUM:
vacuolation, cortex, diffuse (minimal) inflammation, mucosa, chronic (moderate) inflammation, mucosa, chronic (mild) infiltration, mononuclear-cell, focal/multifocal (minimal) inflammation, chronic, focal/multifocal (mild) inflammation, mucosa, chronic (mild)
THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS:
BONE MARROW (STERNUM) EPIDIDYMIDES
LUNG PARATHYROID
SPINAL CORD. CERVICAL STOMACH
THYROID
BRAIN HEART
LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD. LUMBAR TESTIS (H&E) TRACHEA
COAGULATING GLAND
DUODENUM
ILEUM
JEJUNUM
LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC
PROSTATE
SEMINAL VESICLES
SPINAL CORD, THORACIC SPLEEN
TESTIS (PAS)
THYMUS
URINARY BLADDER
End of Record- 19119
418-028`.PAGE J-35
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphol ogy Data
ANIMAL NUMBER: 19122
SEX:
M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONfSI: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONS! : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
EPIDIDYMIDES: LIVER: LYMPH NODE, SUBMANDIBULAR: TRACHEA:
infiltration, mononuclear-cell, focal (minimal) inflammation, chronic, focal/multifocal (minimal)
hyperplasia, lymphocytic/plasmacytic (minimal) inflanmation, chronic, focal (minimal)
THE FOLLOWING TISSUE!ST WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COAGULATING GLAND
ILEUM NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC TESTIS (PAS)
BONE MARROW (STERNUM) COLON JEJUNUM PARATHYROID SEMINAL VESICLES SPLEEN
THYMUS
BRAIN DUODENUM KIDNEYS PEYER'S PATCH SPINAL CORD, CERVICAL STOMACH
THYROID
CECUM HEART LUNG PROSTATE SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER
TISSUEfSl NOT AVAILABLE FOR EVALUATION:
LYMPH NODE, MEDIASTINAL
End of Record- 19122
11-5
418-028:PAGE J-36
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19125
SEX:
M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONS!: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONf ST : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
CECUM: LIVER: LYMPH NODE, SUBMANDIBULAR: PROSTATE: THYROID:
inflammation, mucosa, chronic (moderate) inflammation, chronic, focal/multifocal (minimal) hyperplasia, lymphocytic/plasmacytic (moderate) atrophy, focal/multifocal (minimal) ultimobranchial body/cyst
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS
COLON ILEUM LYMPH NODE, MEDIASTINAL RECTUM
SPINAL CORD, THORACIC TESTIS (PAS)
BONE MARROW (STERNUM)
DUODENUM JEJUNUM
NERVE, SCIATIC SEMINAL VESICLES SPLEEN THYMUS
BRAIN
EPIDIDYMIDES KIDNEYS PARATHYROID SPINAL CORD, CERVICAL STOMACH TRACHEA
End of Record- 19125
COAGULATING GLAND HEART LUNG PEYER'S PATCH SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER
11-6
418-028:PAGE J-37
i
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19131
SEX:
M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONiS): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfSl: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
ADRENAL GLANDS: EPIDIDYMIDES: HEART: LIVER: LYMPH NODE, SUBMANDIBULAR: PROSTATE: TRACHEA:
vacuolation, cortex, diffuse (mild) infiltration, mononuclear-cell, focal (minimal) inflamnation, chronic, focal (mild) inflammation, chronic, focal/multifocal (mild) hyperplasia, lymphocytic/plasmacytic (mild) inflammation, chronic, focal/multifocal (minimal) inflammation, chronic, focal (mild)
THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS:
BONE MARROW (STERNUM) COLON KIDNEYS
PARATHYROID SPINAL CORD. CERVICAL
STOMACH THYROID
BRAIN
DUODENUM LUNG
PEYER'S PATCH SPINAL CORD, LUMBAR
TESTIS (H&E) URINARY BLADDER
CECUM ILEUM LYMPH NODE, MEDIASTINAL RECTUM SPINAL CORD, THORACIC
TESTIS (PAS)
End of Record- 19131
COAGULATING GLAND JEJUNUM NERVE, SCIATIC
SEMINAL VESICLES SPLEEN
THYMUS
11--7
418-028:PAGE J-38
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19132
SEX:
M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No gross changes.
HIST0M0RPH0L06IC OBSERVATIONS! : Not applicable
HISTOM0RPH0L06IC OBSERVATIONS:
LIVER: STOMACH: THYROID:
inflammation, chronic, focal/multifocal (mild) edema/inflammation, submucosa, glandular area (moderate) ultimobranchial body/cyst
THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COAGULATING GLAND HEART
LUNG PEYER'S PATCH
SPINAL CORD, CERVICAL TESTIS (H&E) URINARY BLADDER
BONE MARROW (STERNUM) BRAIN
COLON
DUODENUM
ILEUM
JEJUNUM
LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC
PROSTATE
RECTUM
SPINAL CORD, LUMBAR
SPINAL CORD,THORACIC
TESTIS (PAS)
THYMUS
CECUM EPIDIDYMIDES KIDNEYS
PARATHYROID SEMINAL VESICLES
SPLEEN TRACHEA
TISSUEfS) NOT AVAILABLE FOR EVALUATION: LYMPH NODE. MEDIASTINAL End of Record- 19132
418-028-.PAGE J-39
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRQDUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19134
SEX:
M
GROSS OBSERVATIONf S ) : GENERAL: No gross changes.
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
HISTOMORPHOLOGIC OBSERVATIONfS): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
EPIDIDYMIDES: KIDNEYS: STOMACH:
THYROID: TRACHEA:
infiltration, mononuclear-cell, focal (minimal) cyst(s), medulla dilatation, mucosal glands (minimal) edema/infiammati on, submucosa, glandular area (minimal) edema/infiammati on, submucosa, forestomach (mild) hypertrophy/hyperplasia, follicular epithelium (mild) infiammati on, chronic, focal (minimal)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COAGULATING GLAND ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, CERVICAL TESTIS (H&E)
BONE MARROW (STERNUM)
BRAIN
COLON
DUODENUM
JEJUNUM
LIVER
LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC
PROSTATE
RECTUM
SPINAL CORD, LUMBAR
SPINAL CORD, THORACIC
TESTIS (PAS)
THYMUS
End of Record- 19134
CECUM HEART LUNG PARATHYROID SEMINAL VESICLES SPLEEN URINARY BLADDER
I I --9
418-028:PAGE J 4 0
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OP T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19135
SEX:
M
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONf Si : GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION(Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
KIDNEYS: LIVER: PROSTATE:
infiltration, mononuclear-cell, focal/multifocal (minimal) inflammation, chronic, focal/multifocal (minimal) Inflammation, chronic, focal/multifocal (minimal)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS
COAGULATING GLAND HEART LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, LUMBAR TESTIS (H&E) TRACHEA
BONE MARROW (STERNUM)
BRAIN
COLON
DUODENUM
ILEUM
JEJUNUM
LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC
RECTUM
SEMINAL VESICLES
SPINAL CORD, THORACIC SPLEEN
TESTIS (PAS)
THYMUS
URINARY BLADDER
End of Record- 19135
CECUM EPIDIDYMIDES LUNG PARATHYROID SPINAL CORD, CERVICAL STOMACH THYROID
11-10
418-028:PAGE J-41
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19102
SEX:
M
DOSE GROUP: DEATH TYPE:
II Sacrifice-Scheduled
GROSS OBSERVATIONS!: KIDNEYS: Bilateral- mottled.
HISTOMORPHOLOGIC OBSERVATIONS! : No microscopic change to correlate
HISTOMORPHOLOGIC OBSERVATIONS:
KIDNEYS: LIVER: THYROID:
No microscopic change to correlate inflammation, chronic, focal/multifocal (mild) ultimobranchial body/cyst
THF FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS KIDNEYS End of Record- 19102
11-11
418-028-.PAGE J-42
ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19106 SEX M
DOSE GROUP.: DEATH TYPE:
II Sacrifice-Scheduled
GROSS OBSERVATIONfSl: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19106
HISTOMORPHOLOGIC OBSERVATIONfSl: Not applicable
Inflammation, chronic, focal/multi focal (mild) ultimobranchial body/cyst
11-12
418-028-.PAGEJ43
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19108
SEX:
M
DOSE GROUP: DEATH TYPE:
II Sacrifice-Scheduled
GROSS OBSERVATION!Si: GENERAL: No gross changes.
HISTOMORPHOL06IC OBSERVATIONS! : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER:
lipidosis, tension, focal inflammation, chronic, focal/multifocal (minimal)
THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19108
418-028:PAGE J-44
ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19110 SEX M
DOSE GROUP: DEATH TYPE:
II Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS1: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: THYROID:
End of Record- 19110
inflammation, chronic, focal/multifocal (minimal) hypertrophy/hyperplasia, follicular epithelium (mild)
11-14
418-028-.PAGE J-45
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19113
SEX:
M
DOSE GROUP: DEATH TYPE:
II Sacrifice-Scheduled
GROSS OBSERVATIONS!: KIDNEYS: Left- pelvis, slight dilation.
HISTOMORPHOLOSIC OBSERVATIONfS1: dilatation, pelvis
HISTOMORPHOLOGIC OBSERVATIONS: KIDNEYS:
dilatation, pelvis (mild)
THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS:
LIVER
THYROID
End of Record- 19113
11-15
418-028:PAGE J 4 6
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19120
SEX:
M
DOSE GROUP: DEATH TYPE:
II Sacrifice-Scheduled
GROSS O B S E R V A T I O N S : GENERAL: No aross chanaes.
HISTOMORPHOLOGIC OBSERVATIONfS1: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER:
inflammation, chronic, focal/multi focal (minimal) lipidosis, tension, focal
THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS THYROID End of Record- 19120
11-16
418-028-.PAGEJ-47
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/OEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19129 SEX M
DOSE GROUP,: DEATH TYPE:
II Sacrifice-Scheduled
GROSS OBSERVATIONf S'): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: THYROID:
End of Record- 19129
inflammation, chronic, focal/multifocal (minimal) hypertrophy/hyperplasia, follicular epithelium (minimal)
11-17
418-028-.PAGE J-48
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRQDUCTION/DEVELQPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19136 SEX M
DOSE GROUP: DEATH TYPE:
II Sacrifice-Scheduled
GROSS OBSERVATION^!: KIDNEYS: Bilateral- mottled.
HISTOMORPHOLOGIC OBSERVATIONfSi : dilatation, pelvis
HISTOMORPHOLOGIC OBSERVATIONS:
KIDNEYS: LIVER: THYROID:
End of Record- 19136
dilatation, pelvis (minimal) vacuolation, hepatocellular, multifocal (minimal) ultimobranchial body/cyst
11-18
418-02&-.PAGE 1-49
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19138
SEX:
M
DOSE GROUP: DEATH TYPE:
II Sacrifice-Scheduled
6R0SS OBSERVATION(S): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS 1: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: THYROID:
ultimobranchial body/cyst
THE FOLLOWING TISSUEfSi WERE WITHIN NORMAL LIMITS: LIVER End of Record- 19138
11-19
418-028-.PAGE J-50
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19139 SEX M
GROSS OBSERVATION ISI: GENERAL: No gross changes.
DOSE GROUP: DEATH TYPE:
II Sacrifice-Scheduled
HISTOMORPHOLOGIC OBSERVATIONfS 1: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: THYROID:
hypertrophy/hyperplasia, follicular epithelium (mild)
THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: LIVER End of Record- 19139
11-20
418-028-.PAGE J-51
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19101
SEX:
M
DOSE GROUP: DEATH TYPE:
III Sacrifice-Scheduled
GROSS OBSERVATION(SI: GENERAL: No gross changes
HISTOMORPHOLOGIC OBSERVATIONtSl: Not applicable
THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS:
LIVER
THYROID
End of Record- 19101
11-21
418-028-.PAGE J-52
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19105
SEX:
M
DOSE 6R0UP; DEATH TYPE:
III Sacrifice-Scheduled
GROSS OBSERVATIONS): GENERAL: No aross chanaes.
HISTOMORPHOLOGIC OBSERVATIONS 1: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER:
inflammation, chronic, focal/multi focal (minimal)
THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS THYROID End of Record- 19105
11-22
418-028-.PAGEJ-53
ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19107 SEX M
DOSE GROUP: DEATH TYPE:
III Sacrifice-Scheduled
GROSS OBSERVATION(Si: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONS! : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID:
End of Record- 19107
inflammation, chronic, focal/multifocal (minimal) hypertrophy/hyperplasia, follicular epithelium (minimal) ultimobranchial body/cyst
11-23
418-028-.PAGE J-54
ORAL (GAVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPROOUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-0Z8 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19112 SEX M
DOSE GROUP: DEATH TYPE:
III Sacrifice-Scheduled
GROSS OBSERVATIONS: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION!SI : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: THYROID:
End of Record- 19112
inflanmation, chronic, focal/multifocal (minimal) ultimobranchial body/cyst
11-24
418-028:PAGE J-55
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19114 SEX M
DOSE GROUP: DEATH TYPE:
III Sacrifice-Scheduled
GROSS OBSERVATION!SI: GENERAL : No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfST : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: THYROID:
End of Record- 19114
inflammation, chronic, focal/multifocal (minimal) ultimobranchial body/cyst
11-25
418-028-.PAGE J-56
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19121 SEX M
DOSE GROUP: DEATH TYPE:
III Sacrifice-Scheduled
GROSS OBSERVATIONS: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19121
inflammation, chronic, focal/multifocal (minimal) vacuolation, hepatocellular, multifocal (mild) ultimobranchial body/cyst
11-26
418-028-.PAGEJ-57
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAl TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19123 SEX M
DOSE GROUP: DEATH TYPE:
III Sacrifice-Scheduled
GROSS OBSERVATIONfSI: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION(S): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER:
inflammation, chronic, focal/multifocal (minimal)
THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19123
11-27
418-028-.PAGE 1-58
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19130 SEX M
DOSE GROUP: DEATH TYPE:
III Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION!Si: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: THYROID:
End of Record- 19130
inflammation, chronic, focal/multifocal (minimal) hypertrophy/hyperplasia, follicular epithelium (mild)
11-28
418-028-.PAGE J-59
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19137 SEX M
DOSE GROUP: DEATH TYPE:
III Sacrifice-Scheduled
GROSS OBSERVATION(Si : GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS): Not applicable
THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS:
LIVER
THYROID
End of Record- 19137
11-29
418-028-.PAGE J-60
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19146
SEX:
M
DOSE GROUP: DEATH TYPE:
III Sacrifice-Scheduled
GROSS OBSERVATIONS!: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIDNiSl: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER:
vacuolation, hepatocellular, midzonal (mild)
THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS; THYROID End of Record- 19146
11-30
418-028`.PAGE J-61
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19100 SEX: M
DOSE GROUP: DEATH TYPE:
IV Sacrifice-Scheduled
GROSS OBSERVATION fS): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfSi : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19100
hypertrophy, hepatocellular, centrilobular (minimal) inflammation, chronic, focal/multifocal (minimal) hypertrophy/hyperplasia, follicular epithelium (minimal)
11-31
418-028:PAGE J-62
>
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19103 SEX: M
DOSE GROUP: DEATH TYPE:
IV Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No aross chanaes.
HISTOMORPHOLOGIC OBSERVATIONiSl: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER:
hypertrophy, hepatocellular, centrilobular (minimal)
THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19103
11-32
418-028:PAGE J-63
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19104
SEX:
M
DOSE GROUP: DEATH TYPE:
IV Sacrifice-Scheduled
GROSS OBSERVATIONS!: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION! S): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER:
inflarmation, chronic, focal/multi focal (minimal) hypertrophy, hepatocellular, centrilobular (mild)
THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19104
11-33
418-028:PAGE J-64
ORAL (6AVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19118 SEX: M
DOSE GROUP: DEATH TYPE:
IV Sacrifice-Scheduled
GROSS OBSERVATIONS!: GENERAL: No gross changes
HISTOMORPHOLOGIC OBSERVATION(S): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER:
inflaimiation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19118
418-028-.PAGEJ-65
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19133 SEX M
DOSE GROUP: DEATH TYPE:
IV Sacrifice-Scheduled
GROSS OBSERVATIONS!: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID:
End of Record- 19133
hypertrophy, hepatocellular, centrilobular (minimal) hypertrophy/hyperplasia, follicular epithelium (minimal) ultimobranchial body/cyst
11-35
418-028:PAGE J-66
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19141 SEX M
DOSE GROUP: DEATH TYPE:
IV Sacrifice-Scheduled
GROSS OBSERVATIONf ST : GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: THYROID:
End of Record- 19141
hypertrophy, hepatocellular, centrilobular (minimal) ultimobranchial body/cyst
11-36
418-028-.PAGE J-67
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19142
SEX:
M
DOSE GROUP.: DEATH TYPE:
IV Sacrifice-Scheduled
GROSS OBSERVATIONS:
EPIDIDYMIDES: Bilateral- small; cauda epididymis, left, small.
TESTES: Bilateral- small.
HISTOMORPHOLOGIC OBSERVATION (SI:
hypospermia exfoliated spermatogenic cells degeneration, multifocal, TESTIS (PAS) degeneration, multifocal, TESTIS (H&E)
HISTOMORPHOLOGIC OBSERVATIONS:
EPIDIDYMIDES:
LIVER:
TESTIS (H&E): TESTIS (PAS):
hypospermia (marked)
exfoliated spermatogenic cells (moderate) inflamnation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) degeneration, multifocal (mild)
degeneration, multifocal (mild)
THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19142
11-37
418-028:PAGE J-68
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENIN6 TEST PROTOCOL NUMBER 418-0Z8 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19144 SEX: M
DOSE GROUP: DEATH TYPE:
IV Sacrifice-Scheduled
GROSS OBSERVATIONfSl: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfSl: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER:
inflammation, chronic, focal/multifocal (minimal)
THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS: THYROID End of Record- 19144
11-38
418-028-.PAGE J-69
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19148
SEX:
M
DOSE GROUP: DEATH TYPE:
IV Sacrifice-Scheduled
GROSS OBSERVATION!SI: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID: End of Record- 19148
inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) hypertrophy/hyperplasia, follicular epithelium (mild)
418-028-.PAGE J-70
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENINQ TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19150 SEX M
GROSS OBSERVATION(SI : GENERAL: No gross changes.
DOSE GROUP: DEATH TYPE:
IV Sacrifice-Scheduled
HISTOMORPHOLOGIC OBSERVATIONfS1: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: THYROID:
End of Record- 19150
hypertrophy, hepatocellular, centrilobular (minimal) hypertrophy/hyperplasia, follicular epithelium (mild)
11-40
418-028-.PAGEJ-71
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19111
SEX:
M
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATIONiSi:
GASTROINTESTINAL TRACT: Jejunum- diverticulum, 1.5x0.6x0.4cm.
HISTOMORPHOLOGIC OBSERVATION!Si: diverticulum, JEJUNUM
HISTOMORPHOLOGIC OBSERVATIONS:
JEJUNUM: KIDNEYS:
LIVER:
LYMPH NODE, SUBMANDIBULAR: PEYER'S PATCH: PROSTATE: THYROID:
diverticulum
basophilia/degeneration, cortical tubules, focal/multifocal (minimal)
cyst(s), medulla infiltration, mononuclear-cell, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (mild) inflanmation, chronic, focal/multifocal (minimal) hyperplasia, lymphocytic/plasmacytic (minimal) mineralization, focal (minimal)
inflammation, chronic, focal/multifocal (minimal) ultimobranchial body/cyst
hypertrophy/hyperplasia, follicular epithelium (moderate)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS
COAGULATING GLAND HEART
NERVE, SCIATIC SPINAL CORD, CERVICAL STOMACH TRACHEA
BONE MARROW (STERNUM)
COLON ILEUM PARATHYROID SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER
BRAIN
DUODENUM LUNG RECTUM SPINAL CORD, THORACIC TESTIS (PAS)
End of Record- 19111
CECUM EPIDIDYMIDES LYMPH NODE, MEDIASTINAL
SEMINAL VESICLES SPLEEN THYMUS
11-41
418-028-.PAGE J-72
ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19117
SEX:
M
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION(S): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: LYMPH NODE, MEDIASTINAL: LYMPH NODE, SUBMANDIBULAR:: STOMACH:
hypertrophy, hepatocellular, centrilobular (minimal) mastocytosis (minimal) hyperplasia, lymphocytic/plasmacytic (moderate) edema/inflammation, submucosa, forestomach (mild)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COAGULATING GLAND
HEART LUNG PROSTATE
SPINAL CORD, LUMBAR
TESTIS (PAS) URINARY BLADDER
BONE MARROW (STERNUM) COLON ILEUM NERVE, SCIATIC RECTUM
SPINAL CORD, THORACIC
THYMUS
BRAIN DUODENUM
JEJUNUM PARATHYROID SEMINAL VESICLES SPLEEN
THYROID
End of Record- 19117
CECUM EPIDIDYMIDES KIDNEYS PEYER'S PATCH SPINAL CORD, CERVICAL TESTIS (H&E) TRACHEA
11-42
418-028:PAGE J-73
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUOY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19124
SEX:
M
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONS! : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
EPIDIDYMIDES: KIDNEYS:
LIVER: LYMPH NODE, MEDIASTINAL: THYROID:
infiltration, mononuclear-cell, focal (minimal) nephritis, chronic, focal (minimal)
cyst(s), medulla hypertrophy, hepatocellular, centrilobular (mild) mastocytosis (minimal) hypertrophy/hyperplasia, follicular epithelium (mild)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS :
ADRENAL GLANDS COAGULATING GLAND ILEUM NERVE, SCIATIC RECTUM
SPINAL CORD. THORACIC TESTIS (PAS)
BONE MARROW (STERNUM) COLON
JEJUNUM
PARATHYROID SEMINAL VESICLES SPLEEN THYMUS
BRAIN DUODENUM LUNG PEYER'S PATCH
SPINAL CORD, CERVICAL STOMACH
TRACHEA
End of Record- 19124
CECUM HEART
LYMPH NODE. SUBMANDIBULAR PROSTATE
SPINAL CORD, LUMBAR TESTIS (H&E)
URINARY BLADDER
11-43
418-028:PAGE J-74
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19126 SEX: M
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATIONfST: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION(S): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS: LIVER: PROSTATE:
inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (mild)
inflammation, chronic, focal/multifocal (minimal)
THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COAGULATING GLAND
HEART LUNG PARATHYROID SPINAL CORD, CERVICAL STOMACH
THYROID
BONE MARROW (STERNUM) COLON ILEUM
LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD. LUMBAR TESTIS (H&E) TRACHEA
BRAIN
CECUM
DUODENUM
EPIDIDYMIDES
JEJUNUM
KIDNEYS
LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC
RECTUM
SEMINAL VESICLES
SPINAL CORD. THORACIC
SPLEEN
TESTIS (PAS)
THYMUS
URINARY BLADDER
End of Record- 19126
11-44
418-028-.PAGE J-75
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19127
SEX:
M
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATIONfS1: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfSi : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
ADRENAL GLANDS: LIVER: LYMPH NODE, SUBMANDIBULAR: THYROID:
vacuolation, cortex, diffuse (mild) hypertrophy, hepatocellular, centrilobular (moderate)
hyperplasia, lymphocytic/plasmacytic (minimal) hypertrophy/hyperplasia, follicular epithelium (mild)
THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS:
BONE MARROW (STERNUM) COLON ILEUM LYMPH NODE, MEDIASTINAL PROSTATE SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER
BRAIN DUODENUM
JEJUNUM NERVE, SCIATIC RECTUM SPINAL CORD, THORACIC
TESTIS (PAS)
CECUM EPIDIDYMIDES
KIDNEYS PARATHYROID
SEMINAL VESICLES SPLEEN
THYMUS
End of Record- 19127
COAGULATING GLAND HEART
LUNG PEYER'S PATCH SPINAL CORD, CERVICAL STOMACH TRACHEA
11-45
418-028-.PAGE J-76
ORAL (6AVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAl TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19128
SEX:
M
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATION!Si: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
CECUM: LIVER:
LYMPH NODE, SUBMANDIBULAR: PROSTATE: THYROID:
inflammation, mucosa, chronic (mild) inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (mild)
hyperplasia, lymphocytic/plasmacytic (moderate) atrophy, focal/multifocal (moderate)
hypertrophy/hyperplasia, follicular epithelium (moderate)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COLON ILEUM LYMPH NODE, MEDIASTINAL RECTUM SPINAL CORD, THORACIC TESTIS (PAS)
BONE MARROW (STERNUM) DUODENUM JEJUNUM
NERVE, SCIATIC SEMINAL VESICLES SPLEEN THYMUS
BRAIN EPIDIDYMIDES KIDNEYS PARATHYROID
SPINAL CORD, CERVICAL STOMACH
TRACHEA
End of Record- 19128
COAGULATING GLAND HEART
LUNG PEYER'S PATCH
SPINAL CORD, LUMBAR TESTIS (H&E) URINARY BLADDER
11-46
418-028:PAGE J-77
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19140
SEX:
M
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATION(S): GENERAL: No aross chanaes,
HISTOMORPHOLOGIC OBSERVATION(S): Not applicable
HTSTOMORPHOLOGIC OBSERVATIONS: LIVER: THYROID:
inflammation, chronic, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (minimal) hypertrophy/hyperplasia, follicular epithelium (moderate)
THF FOI 1OWING TTSSUEfSl WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COAGULATING GLAND HEART
LUNG PARATHYROID SEMINAL VESICLES SPLEEN
THYMUS
BONE MARROW (STERNUM) COLON
ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH
SPINAL CORD, CERVICAL STOMACH
TRACHEA
BRAIN
CECUM
DUODENUM
EPIDIDYMIDES
JEJUNUM
KIDNEYS
LYMPH NODE, SUBMANDIBULAR NERVE, SCIATIC
PROSTATE
RECTUM
SPINAL CORD, LUMBAR
SPINAL CORD, THORACIC
TESTIS (H&E)
TESTIS (PAS)
URINARY BLADDER
End of Record- 19140
11-47
418-028-.PAGEJ-78
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19145
SEX:
M
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATIONfSi: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONS) : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
KIDNEYS: LIVER: LYMPH NODE, SUBMANDIBULAR: RECTUM: TRACHEA:
infiltration, mononuclear-cell, focal/multifocal (minimal) hypertrophy, hepatocellular, centrilobular (mild)
hyperplasia, lymphocytic/plasmacytic (moderate) inflammation, mucosa, chronic (minimal) inflammation, chronic, focal (mild)
THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS
COAGULATING GLAND HEART
LYMPH NODE, MEDIASTINAL PROSTATE
SPINAL CORD, THORACIC TESTIS (PAS)
BONE MARROW (STERNUM) COLON ILEUM
NERVE, SCIATIC SEMINAL VESICLES SPLEEN THYMUS
BRAIN DUODENUM JEJUNUM
PARATHYROID SPINAL CORD, CERVICAL STOMACH THYROID
End of Record- 19145
CECUM EPIDIDYMIDES LUNG
PEYER'S PATCH SPINAL CORD, LUMBAR
TESTIS (H&E) URINARY BLADDER
11-48
418-028:PAGE J-79
ORAL (6AVA6E) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL T O X IC IT Y SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19149
SEX:
M
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATIONf ST: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS1: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: THYROID:
hypertrophy, hepatocellular, centrilobular (minimal) ultimobranchial body/cyst hypertrophy/hyperplasia, follicular epithelium (moderate)
THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COAGULATING GLAND HEART LUNG PARATHYROID
SEMINAL VESICLES SPLEEN
THYMUS
BONE MARROW (STERNUM) COLON ILEUM
LYMPH NODE, MEDIASTINAL PEYER'S PATCH
SPINAL CORD, CERVICAL STOMACH
TRACHEA
BRAIN
CECUM
DUODENUM
EPIDIDYMIDES
JEJUNUM
KIDNEYS
LYMPH NODE. SUBMANDIBULAR NERVE, SCIATIC
PROSTATE
RECTUM
SPINAL CORD, LUMBAR
SPINAL CORD, THORACIC
TESTIS (H&E)
TESTIS (PAS)
URINARY BLADDER
End of Record- 19149
11-49
418-028:PAGE J-80
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19152
SEX:
M
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATIONS! : GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONSI : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
HEART: LIVER:
LYMPH NODE, SUBMANDIBULAR: PROSTATE:
THYROID:
inflammation, chronic, focal (minimal) inflammation, chronic, focal/multifocal (minimal)
hypertrophy, hepatocellular, centrilobular (minimal) hyperplasia, lymphocytic/plasmacytic (moderate) inflammation, chronic, focal/multifocal (minimal) atrophy, focal/multifocal (minimal)
hypertrophy/hyperplasia, follicular epithelium (mild)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COAGULATING GLAND ILEUM
LYMPH NODE, MEDIASTINAL RECTUM SPINAL CORD, THORACIC TESTIS (PAS)
BONE MARROW (STERNUM) COLON JEJUNUM
NERVE, SCIATIC SEMINAL VESICLES SPLEEN THYMUS
BRAIN
DUODENUM KIDNEYS
PARATHYROID SPINAL CORD, CERVICAL STOMACH TRACHEA
End of Record- 19152
CECUM EPIDIDYMIDES LUNG
PEYER'S PATCH SPINAL CORD, LUMBAR TESTIS (H8.E) URINARY BLADDER
11-50
418-028:PAGE J-81
ORAL (SAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19012
SEX:
F
DOSE GROUP: DEATH TYPE:
1 Sacrifice-Scheduled
GROSS OBSERVATION fS): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
STOMACH: THYROID: UTERUS:
dilatation, mucosal glands (minimal) ultimobranchial body/cyst macrophages, pigmented (moderate)
THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COLON JEJUNUM
LYMPH NODE, MEDIASTINAL OVARIES
SPINAL CORD, CERVICAL THYMUS
BONE MARROW (STERNUM) BRAIN
DUODENUM
HEART
KIDNEYS
LIVER
LYMPH NODE. SUBMANDIBULAR MAMMARY GLAND
PARATHYROID
PEYER'S PATCH
SPINAL CORD, LUMBAR
SPINAL CORD, THORACIC
TRACHEA
URINARY BLADDER
End of Record- 19012
CECUM ILEUM LUNG NERVE, SCIATIC RECTUM SPLEEN VAGINA
11-51
418-028-.PAGE J-82
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19019
SEX:
F
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONfST: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfSl: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LYMPH NODE, SUBMANDIBULAR: UTERUS:
hyperplasia, lymphocytic/plasmacytic (mild) macrophages, pigmented (mild)
THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COLON JEJUNUM LYMPH NODE, MEDIASTINAL
PARATHYROID SPINAL CORD, LUMBAR THYMUS VAGINA
BONE MARROW (STERNUM) DUODENUM KIDNEYS MAMMARY GLAND
PEYER'S PATCH SPINAL CORD, THORACIC THYROID
BRAIN HEART
LIVER NERVE, SCIATIC
RECTUM SPLEEN TRACHEA
End of Record- 19019
CECUM ILEUM LUNG OVARIES
SPINAL CORD, CERVICAL STOMACH URINARY BLADDER
11-52
418-028 :PAGE J-83
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19021
SEX:
F
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONf S: HEAD: Head- scab, 0.2cmx0.4cm.
HISTOMORPHOLOGIC OBSERVATIONfSi : dermatitis, chronic, focal, SKIN (GROSS LESION)
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: LYMPH NODE, MEDIASTINAL: SKIN (GROSS LESION): THYROID: UTERUS:
inflammation, chronic, focal/multifocal (minimal) congestion (minimal) dermatitis, chronic, focal (mild) ultimobranchial body/cyst macrophages, pigmented (moderate)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS
COLON JEJUNUM MAMMARY GLAND PEYER'S PATCH
SPINAL CORD, THORACIC TRACHEA
BONE MARROW (STERNUM)
DUODENUM KIDNEYS
NERVE, SCIATIC RECTUM SPLEEN VAGINA
BRAIN HEART LUNG OVARIES SPINAL CORD, CERVICAL
STOMACH
CECUM ILEUM LYMPH NODE, SUBMANDIBULAR PARATHYROID SPINAL CORO, LUMBAR THYMUS
TISSUE(S) NOT AVAILABLE FOR EVALUATION: URINARY BLADDER End of Record- 19021
11-53
418-028:PAGE J-84
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19023
SEX:
F
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONfS: GENERAL: No aross changes
HISTOMORPHOLOGIC OBSERVATION!S): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LUNG:
LYMPH NODE, MEDIASTINAL: STOMACH: UTERUS :
infiltration, polymorphonuclear, peri vascular/peri bronchial (mild)
mastocytosis (minimal) edema/inflammation, submucosa, glandular area (mild) macrophages, pigmented (minimal)
THF FOLIOWING TISSUEfSl WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COLON JEJUNUM MAMMARY GLAND PEYER'S PATCH
SPINAL CORD, THORACIC TRACHEA
BONE MARROW (STERNUM) DUODENUM KIDNEYS NERVE, SCIATIC RECTUM
SPLEEN URINARY BLADDER
BRAIN
HEART LIVER OVARIES SPINAL CORD, CERVICAL
THYMUS VAGINA
End of Record- 19023
CECUM ILEUM LYMPH NODE, SUBMANDIBULAR PARATHYROID SPINAL CORD, LUMBAR
THYROID
11-54
418-028:PAGE J-85
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19041
SEX:
F
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONS!: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONS!: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LYMPH NODE, SUBMANDIBULAR : STOMACH: THYROID: UTERUS:
hyperplasia, lymphocytic/plasmacytic (moderate) edema/inflamnation, submucosa, glandular area (moderate)
ultimobranchial body/cyst macrophages, pigmented (moderate)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COLON JEJUNUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR TRACHEA
End of Record- 19041
BONE MARROW (STERNUM) DUODENUM KIDNEYS MAMMARt GLAND PEYER'S PATCH SPINAL CORD, THORACIC URINARY BLADDER
BRAIN HEART
LIVER NERVE, SCIATIC RECTUM SPLEEN
VAGINA
CECUM ILEUM LUNG
OVARIES SPINAL CORD, CERVICAL THYMUS
11-55
418-028-.PAGEJ-86
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19042
SEX:
F
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATION!SI: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONS! : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
OVARIES: THYROID: UTERUS:
cyst(s), intraovarian ultimobranchial body/cyst macrophages, pigmented (moderate)
THE FOLLOWING TISSUEIS) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COLON JEJUNUM LYMPH NODE, MEDIASTINAL PARATHYROID
SPINAL CORD, LUMBAR THYMUS
BONE MARROW (STERNUM)
BRAIN
DUODENUM
HEART
KIDNEYS
LIVER
LYMPH NODE, SUBMANDIBULAR MAMMARY GLAND
PEYER S PATCH
RECTUM
SPINAL CORD, THORACIC
SPLEEN
TRACHEA
URINARY BLADDER
End of Record- 19042
CECUM ILEUM LUNG
NERVE, SCIATIC SPINAL CORD, CERVICAL STOMACH VAGINA
11-56
418-028:PAGE J-87
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19044
SEX:
F
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONS!: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION(S): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
KIDNEYS: LYMPH NODE, MEDIASTINAL:
LYMPH NODE, SUBMANDIBULAR: UTERUS:
nephritis, chronic, focal (minimal) congestion (minimal) hyperplasia, lymphocytic/plasmacytic (mild) hyperplasia, lymphocytic/plasmacytic (moderate) macrophages, pigmented (moderate)
THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COLON JEJUNUM
NERVE, SCIATIC RECTUM SPLEEN TRACHEA
BONE MARROW (STERNUM)
DUODENUM LIVER
OVARIES
SPINAL CORD, CERVICAL STOMACH URINARY BLADDER
BRAIN HEART
LUNG
PARATHYROID SPINAL CORD. LUMBAR THYMUS VAGINA
End of Record- 19044
CECUM ILEUM MAMMARY GLAND
PEYER'S PATCH SPINAL CORD, THORACIC THYROID
11-57 i
418-028:PAGE J-88
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19050
SEX:
F
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATION!SI: GENERAL: No aross chanaes.
HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
ADRENAL GLANDS: LYMPH NODE, SUBMANDIBULAR: UTERUS:
vacuolation, zona glomerulosa (mild) hyperplasia, lymphocytic/plasmacytic (minimal) macrophages, pigmented (moderate)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
BONE MARROW (STERNUM) DUODENUM KIDNEYS MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC THYROID
End of Record- 19050
BRAIN HEART
LIVER
NERVE, SCIATIC RECTUM SPLEEN TRACHEA
CECUM
ILEUM LUNG OVARIES SPINAL CORD, CERVICAL STOMACH URINARY BLADDER
COLON
JEJUNUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR THYMUS VAGINA
11-58
418-028:PAGE J-89
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19053
SEX:
F
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONfS): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
ADRENAL GLANDS: CECUM: LYMPH NODE, SUBMANDIBULAR: THYMUS: THYROID: UTERUS:
vacuolation, zona glomerulosa (mild) inflanmation, mucosa, chronic (moderate) hyperplasia, lymphocytic/plasmacytic (mild) atrophy (moderate)
ultimobranchial body/cyst macrophages, pigmented (moderate)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
BONE MARROW (STERNUM) HEART LIVER NERVE, SCIATIC RECTUM SPLEEN
VAGINA
BRAIN ILEUM LUNG OVARIES SPINAL CORD, CERVICAL STOMACH
COLON JEJUNUM
LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR TRACHEA
DUODENUM KIDNEYS
MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC URINARY BLADDER
End of Record- 19053
11-59
418-028:PAGE J-90
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19065
SEX:
F
DOSE GROUP: DEATH TYPE:
I Sacrifice-Scheduled
GROSS OBSERVATIONS! : GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVAT ION fS1: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
CECUM: LIVER: LYMPH NODE, SUBMANDIBULAR: URINARY BLADDER: UTERUS:
inflammation, mucosa, chronic (mild) inflammation, chronic, focal/multifocal (minimal) hyperplasia, lymphocytic/plasmacytic (mild)
inflammation, chronic, focal (minimal) macrophages, pigmented (mild)
THE FOLLOWING TISSUEfS) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS
DUODENUM KIDNEYS NERVE, SCIATIC RECTUM SPLEEN TRACHEA
BONE MARROW (STERNUM) HEART LUNG
OVARIES SPINAL CORD, CERVICAL STOMACH VAGINA
BRAIN ILEUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR THYMUS
End of Record- 19065
COLON JEJUNUM MAMMARY GLAND PEYER'S PATCH SPINAL CORD. THORACIC THYROID
11-60
418-028PAGE J-91
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19001 SEX: F
GROSS OBSERVATION(S): GENERAL: No gross changes.
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
HISTOMORPHOLOGIC OBSERVATION!Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LUNG:
TRACHEA: UTERUS:
inflammation, interstitial, focal (minimal) macrophages, alveoli, focal (minimal)
inflammation, chronic, focal (minimal) macrophages, pigmented (moderate) distention, lumen (mild)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS
BONE MARROW (STERNUM)
COLON
DUODENUM
JEJUNUM
KIDNEYS
LYMPH NODE, SUBMANDIBULAR MAMMARY GLAND
PARATHYROID
PEYER'S PATCH
SPINAL CORD, LUMBAR
SPINAL CORD, THORACIC
THYMUS
THYROID
BRAIN HEART LIVER NERVE, SCIATIC RECTUM
SPLEEN URINARY BLADDER
End of Record- 19001
CECUM ILEUM LYMPH NODE. MEDIASTINAL OVARIES SPINAL CORD, CERVICAL STOMACH VAGINA
11-61
418-028-.PAGE J-92
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19006
SEX:
F
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATIONfS): GENERAL: No gross changes.
HIST0M0RPH0L06IC OBSERVATION!Si: Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LYMPH NODE, SUBMANDIBULAR: THYROID: UTERUS:
hyperplasia, lymphocytic/plasmacytic (mild) ultimobranchial body/cyst macrophages, pigmented (mild)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COLON JEJUNUM LYMPH NODE. MEDIASTINAL PARATHYROID
SPINAL CORD. LUMBAR THYMUS
BONE MARROW (STERNUM) DUODENUM KIDNEYS MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA
BRAIN
HEART LIVER
NERVE, SCIATIC RECTUM
SPLEEN URINARY BLADDER
End of Record- 19006
CECUM ILEUM LUNG
OVARIES SPINAL CORD, CERVICAL STOMACH VAGINA
11-62
418-028;PAGE J-93
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19011
SEX:
F
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATIONfS): GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfSI : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
ADRENAL GLANDS: LIVER: UTERUS:
necrosis, cortex, focal (mild) Not remarkable macrophages, pigmented (moderate)
THE FOLLOWING TISSUES! WERE WITHIN NORMAL LIMITS:
BONE MARROW (STERNUM)
DUODENUM KIDNEYS MAMMARY GLAND PEYER'S PATCH
SPINAL CORD. THORACIC THYROID
BRAIN HEART LUNG
NERVE, SCIATIC RECTUM
SPLEEN TRACHEA
CECUM ILEUM LYMPH NODE, MEDIASTINAL OVARIES SPINAL CORD, CERVICAL STOMACH URINARY BLADDER
End of Record- 19011
COLON JEJUNUM LYMPH NODE, SUBMANDIBULAR PARATHYROID SPINAL CORD, LUMBAR
THYMUS VAGINA
11-63
418-028-.PAGE J-94
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706
WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19020
SEX:
F
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATION(S):
ADRENAL GLANDS: Bilateral- large. GASTROINTESTINAL TRACT: Abdominal distention,
large and small intestines distended with gas.
SPLEEN: Small. STOMACH: Fundic mucosa surface contains
approximately 12 black areas ranging in size from pinpoint to 0.3cm in diameter. THYMUS: Small.
HISTOMORPHOLOGIC OBSERVATION!SI :
degeneration, cystic, cortex, multifocal No microscopic change to correlate, DUODENUM No microscopic change to correlate, JEJUNUM No microscopic change to correlate, ILEUM No microscopic change to correlate, COLON No microscopic change to correlate, CECUM No microscopic change to correlate, RECTUM atrophy edema/1nflammation, submucosa, glandular area edema/inf1aumation, submucosa, forestomach eroslon(s), glandular mucosa atrophy
HISTOMORPHOLOGIC OBSERVATIONS:
ADRENAL GLANDS: CECUM: COLON: DUODENUM: ILEUM: JEJUNUM: LIVER: LYMPH NODE, SUBMANDIBULAR: RECTUM: SPLEEN: STOMACH:
THYMUS: THYROID: UTERUS:
degeneration, cystic, cortex, multifocal (mild) No microscopic change to correlate No microscopic change to correlate
No microscopic change to correlate No microscopic change to correlate
No microscopic change to correlate necrosis, focal (minimal) hyperplasia, lymphocytic/plasmacytic (mild) No microscopic change to correlate atrophy (mild) erosion(s), glandular mucosa (moderate) edema/infiammati on, submucosa, glandular area (mild) edema/inflammation, submucosa, forestomach (mild) atrophy (marked) ultimobranchial body/cyst macrophages, pigmented (marked)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
BONE MARROW (STERNUM)
DUODENUM KIDNEYS
NERVE, SCIATIC RECTUM TRACHEA
BRAIN
HEART LUNG
OVARIES SPINAL CORD. CERVICAL URINARY BLADDER
CECUM ILEUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR VAGINA
End of Record- 19020
COLON JEJUNUM MAMMARY GLAND
PEYER'S PATCH SPINAL CORD. THORACIC
11-64
418-028;PAGE J-95
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19022
SEX:
F
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
fiBOSS OBSFRVATIQNlSl : GENERAL: No gross changes.
HIST0M0RPH0L06IC OBSERVATION(S) : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: LYMPH NODE, SUBMANDIBULAR: MAMMARY GLAND: THYROID: UTERUS:
Inflaimatlon, chronic, focal/multi focal (minimal) hyperplasia, lymphocytic/plasmacytic (mild) necrosis, focal (minimal) ultimobranchial body/cyst macrophages, pigmented (mild)
THE FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COLON JEJUNUM
NERVE, SCIATIC RECTUM SPLEEN URINARY BLADDER
BONE MARROW (STERNUM)
DUODENUM KIDNEYS OVARIES SPINAL CORD, CERVICAL STOMACH VAGINA
BRAIN HEART
LUNG PARATHYROID SPINAL CORD, LUMBAR
THYMUS
End of Record- 19022
CECUM
ILEUM LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, THORACIC TRACHEA
11-65
418-028:PAGE J-96
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVEIOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19025
SEX:
F
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATIONfSI: GENERAL: No gross chanqes.
HISTOMORPHOLOGIC OBSERVATIONS! : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
ADRENAL GLANDS: KIDNEYS: STOMACH: UTERUS:
hypertrophy/vacuolation, cortex, multifocal (mild) nephritis, chronic, focal (minimal)
edema/inflammation, submucosa, glandular area (mild) macrophages, pigmented (moderate)
THF FOLLOWING TISSUEfSl WERE WITHIN NORMAL LIMITS:
BONE MARROW (STERNUM) DUODENUM
LIVER MAMMARY GLAND
PEYER'S PATCH SPINAL CORD, THORACIC
TRACHEA
BRAIN HEART LUNG NERVE, SCIATIC RECTUM SPLEEN URINARY BLADDER
CECUM ILEUM
LYMPH NODE, MEDIASTINAL OVARIES SPINAL CORD, CERVICAL THYMUS VAGINA
End of Record- 19025
COLON JEJUNUM LYMPH NODE, SUBMANDIBULAR PARATHYROID SPINAL CORD, LUMBAR THYROID
11-66
418-028:PAGE J-97
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19027
SEX:
F
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATION!SI: GENERAL: No gross changes.
HISTOMORPHOLOGIC OBSERVATIONfS): Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
KIDNEYS: LYMPH NODE, SUBMANDIBULAR:: STOMACH: THYROID:
mineralization, multifocal (minimal) hyperplasia, lymphocytic/plasmacytic (mild) edema/inflanmation, submucosa, glandular area (mild)
ultimobranchial body/cyst
THE FOLLOWING TISSUES1 WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COLON JEJUNUM MAMMARY GLAND RECTUM SPLEEN UTERUS
BONE MARROW (STERNUM) DUODENUM
LIVER OVARIES SPINAL CORD, CERVICAL THYMUS
VAGINA
BRAIN HEART
LUNG PARATHYROID SPINAL CORD, LUMBAR TRACHEA
CECUM ILEUM
LYMPH NODE, MEDIASTINAL PEYER'S PATCH SPINAL CORD, THORACIC URINARY BLADDER
TISSUE(S) NOT AVAILABLE FOR EVALUATION: NERVE, SCIATIC End of Record- 19027
418-028;PAGE J-98
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19028
SEX:
F
SSSSSSSSSSS=S53B=SSS:
GROSS OBSERVATIONf ST :
GENERAL: No gross changes.
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
HISTOMORPHOLOGIC OBSERVATION(Si : Not applicable
HISTOMORPHOLOGIC OBSERVATIONS:
LYMPH NODE, SUBMANDIBULAR: STOMACH: UTERUS:
hyperplasia, lymphocytic/plasmacytic (moderate) dilatation, mucosal glands (minimal)
macrophages, pigmented (moderate)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
ADRENAL 6LANDS
COLON JEJUNUM
LYMPH NODE, MEDIASTINAL PARATHYROID
SPINAL CORD, LUMBAR THYROID
BONE MARROW (STERNUM) DUODENUM KIDNEYS MAMMARY GLAND PEYER'S PATCH
SPINAL CORD. THORACIC TRACHEA
BRAIN HEART LIVER
NERVE, SCIATIC RECTUM
SPLEEN URINARY BLADDER
End of Record- 19028
CECUM ILEUM LUNG OVARIES SPINAL CORD, CERVICAL THYMUS VAGINA
11-68
418-028`.PAGE J-99
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19030
SEX:
F
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
GROSS OBSERVATION!S): HEAD: Head- scab, 0.3cm x 0.3cm.
HISTOMORPHOLOGIC OBSERVATION!Si : dermatitis, chronic, focal, SKIN (GROSS LESION)
HISTOMORPHOLOGIC OBSERVATIONS:
LIVER: SKIN (GROSS LESION): THYROID: UTERUS:
Not remarkable dermatitis, chronic, focal (minimal) ultimobranchial body/cyst
macrophages, pigmented (moderate)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS COLON
JEJUNUM MAMMARY GLAND PEYER'S PATCH SPINAL CORD. THORACIC TRACHEA
BONE MARROW (STERNUM) DUODENUM
KIDNEYS NERVE, SCIATIC RECTUM SPLEEN
URINARY BLADDER
BRAIN HEART LUNG OVARIES SPINAL CORD, CERVICAL STOMACH
VAGINA
CECUM ILEUM LYMPH NODE, MEDIASTINAL
PARATHYROID SPINAL CORD, LUMBAR THYMUS
TISSUEiS) NOT AVAILABLE FOR EVALUATION: LYMPH NODE, SUBMANDIBULAR End of Record- 19030
418-028:PAGE J-100
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST PROTOCOL NUMBER 418-028
SPONSOR'S STUDY NUMBER T-7706.1
Appendix II Individual Animal Gross and Histomorphology Data
ANIMAL NUMBER: 19031 SEX: F
GROSS OBSERVATION(Si: GENERAL: No gross changes
DOSE GROUP: DEATH TYPE:
V Sacrifice-Scheduled
HIST0M0RPH0L06IC OBSERVATION!S): Not applicable
HTSTOMORPHOLOGIC OBSERVATIONS:
LIVER: LYMPH NODE, SUBMANDIBULAR: UTERUS:
necrosis, focal (minimal) hyperplasia, lymphocytic/plasmacytic (mild)
distention, lumen (moderate)
THE FOLLOWING TISSUE(S) WERE WITHIN NORMAL LIMITS:
ADRENAL GLANDS
COLON JEJUNUM
MAMMARY GLAND PEYER'S PATCH SPINAL CORD, THORACIC THYROID
BONE MARROW (STERNUM)
DUODENUM KIDNEYS
NERVE, SCIATIC RECTUM SPLEEN TRACHEA
BRAIN HEART
LUNG OVARIES SPINAL CORD. CERVICAL STOMACH URINARY BLADDER
End of Record- 19031
CECUM
ILEUM LYMPH NODE, MEDIASTINAL PARATHYROID SPINAL CORD, LUMBAR
THYMUS VAGINA
11-70
418-028:PAGE J-101
ORAL (GAVAGE) CO M BINED REPEATED DOSE TO XIC ITY STUDY OF T-7706 W ITH THE REPRO DUCTIO N/DEVELO PM ENTAL TO XIC ITY SCREENING TEST
PROTOCOL 418-028 SPO NSO R 'S STU D Y NUMBER T -7706.1
HISTO PATHO LO G Y REPORT
A PPEN D IX III
HISTO M O RPHO LO G IC OBSERVATIONS IN TH E LIVER F1 GENERATION PUPS
418-028-.PAGE J-102
ORAL (GAVAGE) COMBINED REPEATED DOSE STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Table 111-1 Histomorphologic Observations inthe Liver- Group I - F1 Generation Pups
Dose Group: DamNumber:
Pud Number:____________
|I I I I I I I I I 19012 19012 19012 19012 19012 19012 19012 19012 19012 19012
1____2 3 4 5 7 8 14 15 16
LIVER:
...................................................................................................
Dose Group:
IIII IIIIII
DamNumber.
19019 19019 19019 19019 19019 19019 19019 19019 19019 19019
Pud Number_________________ 1____2____ 2____ Z____ ____ 11 12 13 14 15___
LIVER:
...................................................................................................
Dose Group: DamNumber: Pud Number:___________
LIVER:
II III IIII I 19021 19021 19021 19021 19021 19021 19021 19021 19021 19021 1 2 6 8 9 10 11 12 13 14
...................................................................................................
Dose Group: DamNumber: Pud Number____________
LIVER:
I IIIIIII II 19023 19023 19023 19023 19023 19023 19023 19023 19023 19023 1____ 2____ 3____ 6____ 7 8 9____ 10 11 12
...................................................................................................
Dose Group:
IIII IIII II
DamNumber
19041 19041 19041 19041 19041 19041 19041 19041 19041 19041
Pud Number:_________________1____ 2 3 4 5 8 9 15 16 17
LIVER:
...................................................................................................
111-1
418-028:PAGE J-103
ORAL (GAVAGE) COMBINED REPEATED DOSE STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Table 111-1 (Continued) Histomorphologic Observations inthe Liver- Group I - F1 Generation Pups
Dose Group:
III III III I
DamNumber:
19042 19042 19042 19042 19042 19042 19042 19042 19042 19042
Pud Number:________________ 1____ 2____ 4____ 5____6____ 7____ 8____ 10 12 13
LIVER:
...................................................................................................
Dose Group:
II IIII III I
DamNumber:
19044 19044 19044 19044 19044 19044 19044 19044 19044 19044
Pup Number:_________________1____ 2____ 5____ 6____ 7____ 9____ 11 12 13 14
LIVER:
...................................................................................................
Dose Group:
IIIIIIII II
DamNumber
19050 19050 19050 19050 19050 19050 19050 19050 19050 19050
Pup Number:________________ 1 2 3 4 5 6 7 8
13 14
LIVER:
...................................................................................................
Dose Group:
IIIII IIIII
DamNumber:
19053 19053 19053 19053 19053 19053 19053 19053 19053 19053
Pup Number________________ 1____ 3 4 5 6 10 11 12 13 14
LIVER:
...................................................................................................
Dose Group: DamNumber: Pud Number
LIVER:
I I I I 1I I I I I 19065 19065 19065 19065 19065 19065 19065 19065 19065 19065 3 4 5 7 8 10 11 14 15 17
-
418-028:PAGE J-104
ORAL (GAVAGE) COMBINED REPEATED DOSE STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Table III-2 Histomorphologic Observations inthe Liver- GroupV - F1 Generation Pups
Dose Group: DamNumber Pud Number:
VVVVVVVVV 19001 19001 19001 19001 19001 19001 19001 19001 19001 1 2 3 4 5 6 7 9 11
LIVER :
Dose Group: DamNumber: Pud Number
LIVER :
VVVVVVVVVV 19006 19006 19006 19006 19006 19006 19006 19006 19006 19006 1 2 3 4 5 8 10 11 13 18
Dose Group: DamNumber Pud Number:
LIVER :
VVVVVVVVVV 19011 19011 19011 19011 19011 19011 19011 19011 19011 19011 2 3 4 5 6 9 10 11 12 13
Dose Group: DamNumber Pud Number
LIVER :
VVVVVVVVVV 19020 19020 19020 19020 19020 19020 19020 19020 19020 19020 2 4 5 7 8 9 10 11 12 13
Dose Group: DamNumber: Pud Number
LIVER :
VVVVVVVVVV 19022 19022 19022 19022 19022 19022 19022 19022 19022 19022 1 4 5 7 8 11 12 13 14 15
HI-3
418-028:PAGE J-105
ORAL (GAVAGE) COMBINED REPEATED DOSE STUDY OF T-7706 WITH THE REPRODUCTION/DEVELOPMENTAL TOXICITY SCREENING TEST
PROTOCOL NUMBER 418-028 SPONSOR'S STUDY NUMBER T-7706.1
Table III-2 (Continued) Histomorphologic Observations inthe Liver- GroupV --F1 Generation Pups
Dose Group:
VVVV VVVV VV
DamNumber:
19025 19025 19025 19025 19025 19025 19025 19025 19025 19025
Pud Number_________________1____ 2____ 7____8____ 13 14 15 18 19 20
LIVER :
...................................................................................................
DoseGroup:
VVVVVVVVV
DamNumber:
19027 19027 19027 19027 19027 19027 19027 19027 19027
Pud Number:_____________ _________ 1 2 3 4 5 6 7 13 14
LIVER :
........................................................................................
DoseGroup:
VVVVVVVVVV
DamNumber:
19028 19028 19028 19028 19028 19028 19028 19028 19028 19028
Pud Number:_________________1 2 3 4 5 6 7 10 11 12
LIVER :
...................................................................................................
DoseGroup:
VVVVVVVVVV
DamNumber
19030 19030 19030 19030 19030 19030 19030 19030 19030 19030
Pud Number_________________1 2 4 5 6 8 9 11 12 13
LIVER :
...................................................................................................
Dose Group: DamNumber Pud Number
LIVER :
VVVVVVVVVV 19031 19031 19031 19031 19031 19031 19031 19031 19031 19031 1 2 3 5 6 9 11 12 14 15
-
III-4
APPENDIX K HEMATOLOGY AND CLINICAL CHEMISTRY REPORTS
Study Report for Hematology
IN D IV ID U A L ANIM AL REPORT BY GROUP PER IO D : TERMINAL
418-028:PAGE K-l
STUDY ID: ARGUS 418-028 STUDY NO: 060 -0 6 9
A n ia a l ID
WBC
RBC
THSH/CU KB KILL/CU KM
GROUP: 1-K 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167
MEAN
SD N
13.5 15.9 15.1 12.7 16.4 17.6 17.7 14.9 15.0 14.3
-- -- -- -- --
15.3 1.63
10
7.10 8.58 6.95 7.16 6.77 7.61 7.37 7.45 7.43 8.71
-- -- -- -- --
7.51 0.648
10
HGB GRAKS/DL
15.4 19.0 16.3 16.2 15.7 16.2 16.3 16.3 15.6 18.2
-- -- -- --
16.5 1.16
10
SEX: MALE
HCT MCV MCH X CU MICRONS PICO GRAMS
KCHC
PLT
X THSN/CU MM
40.6 50.0 42.6 42.1 40.6 41.4 41.6 43.3 42.7 49.7
-- -- -- -- --
43.5 3.48
10
57.2 58.3 61.3 58.8 59.9 54.4 56.5 58.1 57.5 57.1
-- -- -- -- --
57.9 1.89
10
21.7 22.1 23.5 22.6 23.2 21.3 22.1 21.9 21.0 20.9
-- -- -- -- --
'
37.9 38.0 38.3 38.5 38.7 39.1 39.2 37.6 36.5 36.6
-- -- -- -- --
22.0 38.0 0.87 0.93
10 10
1219 1072 964 1354 1074 1322 1049 1264 1269 1203
-- -- -- -- --
1179 130.9
10
<-- ) - Data Unavailable LABCAT HEA.43
27-JUN-2002
Study Report for Hematology
IN D IV ID U A L ANIMAL REPORT BY GROUP PER IO D : TERMINAL
418-028:PAGEK-2
STUDY ID: ARGUS 418 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A nial ID
UBC
RBC
THSN/CU HK HILL/CU UN
GROUP: 2-M 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
1 0 .9 1 7 .0 1 2 .7 f 13.1 1 5 .7 1 8 .4 14.7 10.5 1 7 .2 1 9 .0
-- -- -- -- --
MEAN SD N
1 4 .9 3 .0 3
10
7 .5 5 6 .9 3 7 .0 2 8 .2 0 6 .8 0 7 .4 2 7 .2 9 7 .3 2 7 .5 3 7 .2 0
--
--
--
--
7 .3 3 0.396
10
HGB GRAHS/DL
16.2 15.2 16.1 1 5 .9 16.1 16.4 1 5 .9 1 5 .4 16.4 15.5
--
--
--
-
1 5 .9 0 .4 2
10
HCT HCV MCH Z CU MICRONS PICO GRAHS
4 3 .6 3 9 .6 4 0 .3 4 3 .9 4 2 .0 4 4 .4 4 3 .2 4 1 .3 4 2 .2 4 1 .7
--
-- --
~
4 2 .2 1 .5 7
10
5 7 .7 57.1 5 7 .4 53.5 6 1 .8 5 9 .8 5 9 .3 5 6 .4 5 6 .0 5 7 .9
--
-- -- --
-
57.7 2 .2 7
10
21.5 2 1 .9 2 2 .9 19.4 2 3 .7 22.1 2 1 .8 2 1 .0 2 1 .a 2 1 .5
--
--
-- --
~
2 1 .8 1.13
10
SEX: MALE
HCHC
PLT
% THSN/CU UH
3 7 .2 3 8 .4 4 0 .0 3 6 .2 3 8 .3 3 6 .9 3 6 .8 3 7 .3 3 8 .9 3 7 .2
--
-- --
--
926 970 959 1468 1170 1382 1184 1183 1069 994
--
--
-- --
3 7 .7 1.15
10
1131 183.7
10
( -- ) - Data Unava i Leble LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
IN D IV ID U A L ANIMAL REPORT BY GROUP PE R IO D : TERMINAL
418-028:PAGE K-3
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
WBC
THSN/CU MM
RBC MILL/CU MM
HGB GRAMS/DL
HCT MCV HCH X CU MICRONS PICO GRAMS
SEX: MALE
MCHC X
PLT THSN/CU MM
GROUP: 3-M 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174
MEAN SD N
13.1 11.0 12.5 13.3 11.2 20.9 14.1 13.9 12.2 15.4
-- -- -- --
--
13.8 2.84
10
7.38 7.28 7.59 7.20 7.72 7.23 6.69 7.96 7.60 6.54
-- -- -- -- --
7.32 0.441
10
16.0 16.3 16.1 15.4 15.7 15.4 15.0 16.4 16.3 14.7
-- -- -- -- ----
15.7 0.59
10
42.4 43.2 44.4 40.1 42.6 40.5 39.1 43.8 45.0 38.8
-- -- -- -- ---
42.0 2.22
10
57.4 59.3 58.5 55.7 55.2 56.0 58.4 55.0 59.2 59.4
-- -- -- -- --
57.4 1.78
10
21.7 22.4 21.2 21.4 20.3 21.3 22.4 20.6 21.4 22.5
-- -- -- --
--
21.5 0.75
10
37.7 37.7 36.3 38.4 36.9 38.0 38.4 37.4 36.2 37.9
-- -- -- -- --
'
958 960 993 1002 1253 1340 1143 1123 1046 1336
-- -- -- -- --
37.5 0.79
10
1115 149.2
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-20Q2
418-028:PAGE K-4
Study Report for Hematology
IN D IV ID U A L ANIMAL REPORT BY GROUP PE R IO D : TERMINAL
STUDY ID: ARGUS 413-028 STUDY NO: 060-069
Animal ID
WBC
THSN/CU MM
RBC MILL/CU HH
HGB GRAMS/DL
HCT MCV MCH % CU MICRONS PICO GRAMS
SEX: MALE
MCHC X
PLT THSN/CU MM
GROUP: 4-M 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166
MEAN SD N
12.6 21.0 18.1 12.0 22.0 17.4 12.8 19.6 15.6 11.1
-- -- -- -- --
16.2 3.97
10
6.59 6.73 6.75 6.83 7.50 7.07 6.87 7.37 6.97 6.62
--- -- -- --
6.93 0.305
10
14.6 15.0 15.6 14.8 16.8 15.5 15.0 16.1 15.6 15.0
-- -- -- -- ----
15.4 0.67
10
38.2 39.0 39.3 38.4 45.5 40.3 39.9 42.4 40.6 38.1
-- -- -- --
"
40.2 2.29
10
57.9 58.0 58.2 56.2 60.7 57.0 58.1 57.5 58.2 57.6
-- -- -- -- ""
57.9 1.15
10
22.2 22.3 23.1 21.7 22.4 21.9 21.8 21.8 22.4 22.7
-- -- -- -- ""
22.2 0.45
10
38.2 38.5 39.7 38.5 36.9 38.5 37.6 38.0 38.4 39.4
-- -- -- -- ----
38.4 0.80
10
1072 1144 1029 1274 1124 1125 998
962 1155 1161
-- -- -- --
1104 91.4
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Aniaal ID
UBC
THSN/CU MM
RBC KILL/CU MM
GROUP: 5-M 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170
MEAN SD N
15.7 14.3 10.8 12.5 11.0 14.2 15.2 20.7 18.3 13.9
-- --
--
-- --
14.7 3.07
10
7.20 6.72 6.68 8.07 6.61 7.09 7.05 7.13 6.66 6.68
--
-- --
--
--
6.99 0.442
10
HGB GRAMS/DL
16.1 15.7 15.0 17.3 14.7 15.5 16.2 15.7 14.8 14.8
--
-- -- --
15.6 0.81
10
HCT HCV HCH % CU MICRONS PICO GRAMS
41.7 39.8 39.0 44.4 38.1 41.1 41.9 41.4 39.8 39.5
--
--
--
--
40.7 1.81
10
57.9 59.2 58.4 55.0 57.6 58.0 59.5 58.1 59.8 59.2
-- -- -- --
_
58.3 1.37
10
22.4 23.4 22.5 21.4 22.2 21.9 23.0 22.0 22.2 22.2
--
-- -- --
22.3 0.56
10
418-028:PAGE K-5
SEX: MALE
MCHC
PLT THSN/CU MM
38.6 39.4 38.5 39.0 38.6 37.7 38.7 37.9 37.2 37.5
--
--* -- -- ----
38.3 0.70
10
1013 1181 1249 1142 1040 1001 1059 1523 1234 1041
-- -- ----
1148 159.9
10
(-- ) - Data Unavaitable LABCAT HEA.43
27-JUN-2002
418-028-.PAGE K-6
Study Report for Hematology
IN D IV ID U A L ANIMAL REPORT BY GROUP PE R IO D : TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
UBC
THSN/CU MM
RBC MILL/CU MM
GROUP: 1 -F 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
15.9 6.6 7.4 7.3 8.0 6.8 10.6 8.2 6.6 12.5 -- -- -- --
5.60 6.95 7.10 6.62 6.86 6.45 6.09 6.64 6.08 6.67
--
--
--
MEAN SD N
9.0 3.09
10
6.51 0.461
10
HGB GRAMS/DL
14.0 16.4 16.7 16.3 16.2 15.1 14.3 16.0 14.7 15.7
--
--
-- --
15.5 0.95
10
HCT MCV MCH % CU MICRONS PICO GRAMS
35.2 42.5 44.7 42.4 42.4 40.2 37.6 42.2 37.5 40.2
--
--
--
40.5 2.93
10
62.9 61.1 63.0 64.1 61.8 62.3 61.7 63.6 61.6 60.2
-- -- -- --
62.2 1.19
10
25.0 23.6 23.5 24.6 23.6 23.4 23.5 24.1 24.2 23.5
-- -- -- --
23.9 0.55
10
SEX: FEMALE
MCHC 2
PLT THSN/CU MM
39.8 38.6 37.4 38.4 38.2 37.6 38.0 37.9 39.2 39.1
-- -- --
--
38.4 0.76
10
1421 1344 1199 1352 1529 1225 1343 1629 1524 1623
-- -- -- --
1419 153.0
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028-.PAGE K-7
Study Report for Hematology
IN D IV ID U A L ANIMAL REPORT BY GROUP PER IO D : TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Aninat ID
UBC
THSN/cu m m
RBC MILL/CU HM
HGB GRAMS/DL
HCT MCV MCH % CU MICRONS PICO GRANS
SEX: FEHALE
HCHC X
PLT THSN/CU MU
GROUP: 2- F 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
MEAN SD N
7.8 14.6 17.0 13.3
9.1 18.0 26.3 13.5 11.1
7.1 -- --
--
--
--
13.8 5.73
10
7.07 5.90 6.32 5.61 6.36 6.30 6.23 5.83 5.93 6.60
--
--
--
--
6.22 0.423
10
16.6 14.8 14.9 14.1 15.5 14.5 14.8 14.7 14.5 16.0
-- -- -- --
15.0 0.77
10
43.8 38.3 38.5 35.3 41.6 38.9 37.8 38.3 37.5 43.4
-- --
-- "
39.3 2.72
10
62.0 64.9 60.9 63.0 65.4 61.7 60.6 65.7 63.3 65.8
--
--
--
--
~
63.3 2.01
10
23.5 25.1 23.6 25.1 24.4 23.0 23.8 25.2 24.5 24.2
-- -- -- --
24.2 0.76
10
37.9 38.6 38.7 39.9 37.3 37.3 39.2 38.4 38.7 36.9
-- ""
--
38.3 0.94
10
1540 1157 1529 1057 1443 1166 1257
942 1041 1264
-- --
--
~
1240 208.1
10
(-- > - Data Unavai table LABCAT HE4.43
27-JUH-2002
418-028-.PAGE K-8
Study Report for Hematology
IN D IV ID U A L ANIMAL REPORT BY GROUP PE R IO D : TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
WBC
THSN/CU MM
RBC MILL/CU MM
GROUP: 3-F 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
MEAN SD N
11.1 7.9 7.0 16.6 -- 7.4 12.9 10.5 12.5 12.1 -- 12.7 --- --
11.1 2.98
10
6.43 6.31 6.71 5.53
-- 6.41 6.03 6.93 5.69 6.54
-- 7.38
-- -- --
6.40 0.554
10
HGB GRAMS/DL
15.7 15.4 15.7 13.8
-- 15.1 14.4 15.6 14.0 16.1
-- 16.6
-- --
15.2 0.91
10
HCT MCV MCH X CU MICRONS PICO GRAMS
40.0 39.9 40.5 33.1
-- 39.8 38.0 42.1 35.6 41.9
--
44.2 -- --
39.5 3.24
10
62.2 63.3 60.3 59.9
-- 62.1 63.0 60.8 62.6 64.1
-- 59.9
-- --
61.8 1.50
10
24:4 24.4 23.4 25.0
--
23.6 23.9 22.5 24.6 24.6
-- 22.5
-- --
~
23.9 0.88
10
SEX: FEMALE
MCHC X
PLT THSN/CU MM
39.3 38.6 38.8 41.7
--
37.9 37.9 37.1 39.3 38.4
-- 37.6
-- --
"
38.7 1.29
10
1165 1450 1319 1167
-- 1671
866 1424 1062 1231
--
1380 -- --
1274 226.3
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-9
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
UBC
THSN/CU MM
RBC MILL/CU MM
GROUP: 4-F 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
MEAN SD N
9.5 9.6 12.8 10.0 9.7
--
-14.9 15.7
6.2 12.9
7.1 -- --
10.8 3.15
10
6.51 6.81 6.48 6.48 5.77
-- -- 7.33 5.94 6.86 5.68 6.01
--
6.39 0.532
10
HGB GRAMS/DL
15.8 16.2 14.8 15.8 13.7
-- -- 15.7 14.2 15.7 14.0 15.7 --
15.2 0.90
10
HCT MCV MCH % CU MICRONS PICO GRAMS
42.0 42.4 38.9 41.3 36.7
-- -- 44.1 37.2 43.3 35.2 40.3 --
40.1 3.02
10
64.5 62.3 60.1 63.8 63.6
-- -- 60.2 62.6 63.1 61.9 67.0 --
62.9 2.04
10
_
24.3 23.8 22.8 24.4 23.7
-- -- 21.4 23.9 22.9 24.6 26.1 --
"
23.8 1.25
10
SEX: FEMALE
MCHC %
PLT THSN/CU MM
37.6 38.2 38.0 38.3 37.3
-- -- 35.6 38.2 36.3 39.8 39.0 --
37.8 1.22
10
1479 1527 1066 1333 1148
-- -- 1497 1094 1399 999 1506 --
1305 207.2
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028-.PAGH K-10
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
WBC
THSN/cu rm
RBC MILL/CU MM
GROUP: 5-F 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
MEAN SD N
15.1 7.6 6.4 4.2 5.4 7.3 12.3 10.2 8.1 12.3 -- -- -- -- --
8.9 3.48
10
5.90 6.33 6.46 7.49 6.79 6.47 6.69 5.76 6.62 5.72
--
--
--
-- --
6.42 0.538
10
HGB GRAMS/DL
14.3 15.4 15.7 16.1 16.0 15.1 15.9 13.8 15.6 14.7
-- --
--
--
--
15.3 0.77
10
HCT MCV MCH X CU MICRONS PICO GRAMS
37.3 39.0 40.5 46.8 43.0 39.7 42.2 35.8 41.4 38.4
-- -- -- --
40.4 3.15
10
63.2 61.6 62.7 62.5 63.4 61.3 63.1 62.2 62.6 67.1
-- --
--
--
"
63.0 1.60
10
24.2 24.3 24.3 21.5 23.6 23.3 23.8 24.0 23.6 25.7
-- -- -- --
"
23.8 1.05
10
SEX: FEMALE
MCHC X
PLT THSN/CU MM
38.3 39.5 38.8 34.4 37.2 38.0 37.7 38.5 37.7 38.3
-- -- -- --
37.8 1.37
10
1131 1312 1254 1549 1448 1391 1667 1286 1417 1099
-- -- -- --
1355 176.8
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K -11
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
MPV
CU MICRON
PT seconds
GROUP: 1-H 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167
8.0 8.0 7.2 7.5 8.2 8.9 8.2 8.0 8.4 8.8
--
--
-- --
--
13.2 13.3 13.7 13.6 13.1 13.6 13.2 13.7 13.2 13.2
-- -- -- --
--
MEAN SD N
8.1 0.52
10
13.4 0.24
10
APTT seconds
13.2 21.5 22.4 23.0 19.8 20.8 19.8 21.8 23.9 23.6
-- -- -- --
21.0 3.09
10
. SEX: MALE
NRBC COUNT
Lymphocyte THSN/CU MM
Segmented THSN/CU MM
Bands THSN/CU MM
Monocytes THSN/CU MM
0 9.7 0 11.4 0 11.6 0 9.1 0 14.1 0 14.3 0 13.1 0 12.7 0 11.0 0 12.2 ---- ---- ---- ---- ----
2.0 2.7 3.0 2.2 1.5 1.4 2.7 1.5 3.5 1.6
-- -- -- -- --
0 11.9
2.2
0.0 1.72 0.73
10 10 10
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
-- -- -- -- --
0.0 0.00
10
1.1 1.6 0.3 1.3 0.2 1.1 1.6 0.4 0.5 0.3 -- -- --
--
.--
0.8 0.56
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028-.PAGE K -12
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
MPV
CU MICRON
PT seconds
GROUP: 2-M 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
MEAN SD N
7.5 7.6 8.4 8.4 7.2 7.6 7.2 8.8 8.1 7.8
-- --- -- --
7.9 0.54
10
14.0 14.0 14.6 14.2 14.4 14.4 14.3 14.2 13.7 14.5
-- --
--
--
14.2 0.27
10
APTT seconds
22.1 22.0 24.6 26.2 20.0 17.5 20.8 19.3 16.6 31.4
'' --
--
22.1 4.41
10
SEX: MALE
NRBC COUNT
Lymphocyte THSN/CU MM
Segmented THSN/CU MM
Bands THSN/CU MM
Monocytes THSN/CU MM
0 6.5 2.7
0 12.1
2.9
0 10.9
1.4
0 10.0
2.0
0 11.1
3.6
0 13.4
3.1
0 9.4 4.0
0 8.6 1.4
0 11.4
5.2
0 16.3
2.5
-- ----
-- ----
-- -- .-
----
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
--
-- --
--
1.0 1.4 0.1 0.7 0.8 1.5 0.7 0.3 0.2 0.2
-- -- -- --
0 11.0 2.9 0.0 0.7 0.0 2.68 1.18 0.00 0.50
10 10 10 10 10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-13
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
MPV
CU MICRON
PT seconds
APTT seconds
SEX: MALE
NRBC COUNT
Lymphocyte THSN/CU MM
Segmented THSN/CU MM
Bands THSN/CU MM
Monocytes THSN/CU MM
GROUP: 3-M 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174
MEAN SD N
8.0 7.4 8.0 9.9 8.3 8.3 8.1 8.9 7.8 7.6
--- -- -- --
8.2 0.72
10
13.9 13.7 13.6 13.6 13.5 13.2 13.7 13.7 13.4 14.0
-- -- -- --
13.6 0.23
10
18.3 24.6 22.0 22.1 19.8 21.2 18.1 22.3 20.6 16.7
-- -- --
20.6 2.38
10
0 10.1 0 8.8 0 9.8 0 11.0 0 7.8 0 14.8 0 10.4 0 11.7
0 10.6
0 13.1 --
2.1 0.0 1.9 0.0
0.6 0.1 1.3 0.0 2.7 0.0 4.0 0.0 3.4 0.0 1.7 0.0 1.1 0.0 1.4 0.0
0.5 0.2 1.5 0.5 0.6 1.5 0.1 0.4 0.2 0.3
0 10.8 2.0 0.0 0.6 0.0 2.02 1.06 0.03 0.51
10 10 10 10 10
(-- ) - Data Unavai table LABCAT HE4.43
27-JUN-2002
418-028-.PAGE K-14
Study Report for Hematology
IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
MPV
CU MICRON
PT seconds
APTT seconds
SEX: MALE
NRBC COUNT
Lymphocyte THSN/CU MM
Segmented THSN/CU MM
Bands THSN/CU MM
Monocytes THSN/CU MM
GROUP: 4-M 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166
MEAN SD N
7.1 8.2 7.9 8.3 7.4 8.4 7.5 9.3 8.7 9.3
-- -- -- -- --
8.2 0.76
10
13.5 14.6 14.0 13.9 14.0 13.6 13.5 13.9 13.8 13.1
-- -- --
--
"""
13.8 0.40
10
19.8 26.3 23.0 21.4 19.1 21.5 20.8 21.5 19.7 18.6
-- --
--
--
21.2 2.24
10
0 7.7 0 16.4 0 12.1 0 9.4 0 17.4 0 12.7 0 8.6 0 15.9 0 12.3 0 8.3 ---- ---- ---- ----
-
0 12.1 0.0 3.57
10 10
4.0 2.3 3.1 1.4 2.9 3.7 2.8 2.7 3.1 2.4
-- -- --
--
__
2.8 0.73
10
0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0
-- -- --
--
0.0 0.03
10
0.6 1.7 2.2 0.5 0.7 0.5 1.0 0.6 0.0 0.2
-- -- --
--
--
0.8 0.67
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-20Q2
Study Report for Hematology
418-028:PAGE K-15
IN D IV ID U A L ANIMAL REPORT BY GROUP PE R IO D : TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
HPV
CU MICRON
PT seconds
GROUP: 5-M 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170
MEAN SD N
7.7 7.5 7.3 9.0 8.8 8.6 8.0 7.5 7.8 8.2
-- -- -- -- --
8.0 0.59
10
13.9 15.1 13.8 13.7 14.1 13.5 13.9 14.3 13.5 13.7
-- -- -- --
--
14.0 0.47
10
APTT seconds
23.6 23.3 20.8 21.8 20.7 21.6 19.6 21.9 19.5 20.0
--
-- -- -- --
21.3 1.43
10
SEX: HALE
NRBC COUNT
Lymphocyte THSN/CU HR
Segmented THSN/CU NM
Bands THSN/CU MM
Monocytes THSN/CU MM
0 13.0 0 11.3 0 10.2 0 10.1 0 8.0 0 12.4 0 12.2 0 17.2 0 16.1 0 13.1 ---- ---- ---- ---- ----
0 12.4 0.0 2.75
10 10
1.4 1.7 0.3 1.1 2.4 1.4 2.1 2.5 2.2 0.4
-- --
--
--
--
1.6 0.78
10
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
-- -- -- -- ' --
0.0 0.00
10
0.6 0.9 0.2 0.9 0.2 0.3 0.2 0.8 0.0 0.4
-- -- ---
--
0.5 0.33
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-16
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
MPV
CU MICRON
PT seconds
APTT seconds
SEX: FEMALE
NRBC COUNT
Lymphocyte THSN/CU HN
Segmented THSN/CU MM
Bands THSN/CU MM
Monocytes THSN/CU MM
GROUP: 1-F 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
KEAN SD N
7.7 8.9 7.8 7.9 9.1 8.4 8.4 8.2 8.1 8.9
-- -- -- --
8.3 0.49
10
13.9 13.0 13.8 12.9 13.4 12.8 12.8 13.1 13.3 12.8
--
--
-- --
13.2 0.41
10
26.6 20.4 24.2 21.9 19.3 21.8 18.5 20.5 22.5 21.6
--
--
-- --
21.7 2.36
10
_ ..
0 12.6 0 4.4 0 5.7 0 6.1 0 5.0 0 5.3 0 7.3 0 6.1 0 4.7 0 8.4
----
----
---- ----
0 6.6 0.0 2.44
10 10
2.7 2.0 1.4 0.9 2.9 1.5 3.1 1.8 1.8 3.8
--
-- --
2.2 0.90
10
_
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
--
--
--
--
0.0 0.00
10
0.5 0.2 0.0 0.1 0.1 0.0 0.1 0.2 0.0 0.1
-- -- --
--
0.1 0.15
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-20Q2
418-028:PAGE K-17
Study Report for Hematology
IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 0 6 0 -0 6 9
A nim al ID
MPV
CU MICRON
PT seconds
APTT seconds
SEX: FEMALE
NRBC Lym phocyte Segm ented
Bands M onocytes
COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM
GROUP: 2 - F 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
MEAN SD N
9 .6 7 .2 8 .8 8 .2 8 .4 7 .8 8.1 8 .0 6 .9 7 .0
--
--
-- -- --
8 .0 0.84
10
13.3 1 3 .8 1 3 .3 1 3 .7 1 2 .8 13.5 1 3 .3 1 3 .2 13.5 13.1
-- -- --
--
--
13.4 0 .2 9
10
2 7 .5 2 1 .3 2 9 .2 2 2 .6 2 0 .3 2 4 .3 2 0 .0 2 6 .8 2 5 .3 22.1
--
--
-- --
2 3 .9 3 .1 9
10
0 5.8 2 .0
0 12.7
1.6
0 13.6
3.1
0 10.9
2 .3
0 7.7
1.4
0 15.1
2 .2
0 11.0
1 3 .7
0 9.6 3.5
0 6.2
4.6
0 5.4
1.6
-- ----
-- ----
-- ----
----
--
0 9.8
3 .6
0.0 3.44 3.69
10 10 10
0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0
--
--
--
--
0 .0 0 .0 0
10
0.1 0.1 0 .0 0 .0 0 .0 0 .4 1 .6 0 .3 0 .2 0 .0
-- --
-- --
0 .3 0 .4 9
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028-.PAGE K -IB
Study Report for Hematology
IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A nim al ID
MPV
CU MICRON
PT seconds
GROUP: 3-F 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
MEAN SD N
7 .2 7 .3 9 .3 8.5
-- 9 .0 7 .8 8 .8 7 .4 8.1
-- 9 .3
-- -- --
8 .3 0 .8 2
10
1 2 .9 1 2 .9 1 2 .8 1 3 .7
--
1 3 .6 13.3 1 2 .9 13.3 1 2 .7
-- 1 3 .6
--
--
--
1 3 .2 0 .3 7
10
APTT seconds
22.7 21.7 22.6 22.7
-- 27.6 21.9 22.1 24.4 21.2
--
27.6
--
--
23.5 2.35
10
SEX: FEMALE
NRBC Lym phocyte Segm ented
Bands Monocytes
COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM
0 0 0 0 -- 0 0 0 0 0 -- 0
--
----
0 0 .0
10
6 .5 5 .7 5 .0 12.3
-- 5 .7 9 .8 7 .4 10.3 10.9
-- 10.2
--
--
8 .4 2 .6 0
10
4 .0 2 .0 1 .9 3 .8
-- 1.6 2 .6 2 .6 2.1 1 .0
-- 2 .2
-- --
----
2 .4 0 .9 3
10
0 .0 0.0 0 .0 0 .0
--
0 .0 0 .0 0 .0 0 .0 0 .0
-- 0 .0
--
--
0 .0 0 .0 0
10
0 .3 0 .2 0 .0 0 .3
--
0.1 0.1 0 .2 0 .0 0.1
-- 0 .4
--
--
0 .2 0 .1 3
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K -19
Study Report for Hematology
IN D IV ID U A L ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
Anim al ID
MPV
CU MICRON
PT seconds
GROUP: 4 - F 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
MEAN SD N
7 .8 9 .0 7 .8 8.1 7 .6
-- -- 7 .5 7 .5 9.1 8 .5 7 .4 -- --
8 .0 0 .6 3
10
13.1 1 3 .4 1 3 .4 1 2 .9 1 3 .0
-- -- 14.1 13.5 1 3 .9 1 4 .0 1 3 .5 --
13.5 0 .4 2
10
APTT seconds
2 1 .4 24.5 2 3 .7 2 7 .9 2 1 .9
-- -- 27.1 2 5 .7 25.2 2 6 .2 2 8 .9 --
"
25.3 2.45
10
SEX: FEMALE
NRBC Lymphocyte Segm ented
Bands Monocytes
COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM
__
0 7.7 0 7.1 0 9.6 0 7.7 0 5.4 ---- ---- 0 12.2 0 11.5 0 4.8 0 9.8 0 6.0 ----
_
1 .6 2 .3 2 .8 2.2 3 .8
-- --
1 .9 3 .9 1.4 2 .6 1 .0
--
----
0 .0 0.0 0 .0 0 .0 0 .3
-- --
0 .0 0 .0 0 .0 0 .0 0 .0
--
~
0.1 0.1 0 .3 0.1 0.2
--
-- 0 .4 0 .2 0.1 0 .3 0.1
--
0 8.2 2 .4 0 .0 0.2 0 .0 2.52 0.96 0 .0 9 0.11
10 10 10 10 10
(-- ) - Data Unavai table LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-20
Study Report for Hematology
IN D IV ID U A L ANIMAL REPORT BY GROUP PER IO D : TERMINAL
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 060 -0 6 9
A nim al ID
MPV
CU MICRON
PT seconds
APTT seconds
SEX: FEMALE
NRBC Lymphocyte Segm ented
Bands M onocytes
COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM
GROUP: 5-F 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
MEAN SD N
6 .9 9 .2 7 .4 7 .0 7 .6 8 .3 7 .3 8.1 7 .9 6 .8
-- -- --
--
--
7 .7 0 .7 4
10
1 3 .8 1 2 .8 1 2 .9 1 6 .8 1 3 .7 13.5 1 3 .2 1 3 .6 1 3 .7 13.5
--
--
-- -- --
1 3 .8 1 .1 2
10
3 0 .4 22.1 22.3 2 7 .6 2 1 .6 25.3 27.5 22.2 31.5 2 1 .6
--
--
--
-- --
2 5 .2 3.81
10
0 10.1 0 4.6 0 4.4 2 2.2 0 3.1 0 5.2 0 10.2 0 7.1 0 5.2 0 8.2 ----
----
---- ---- ----
0 6.0 0 .6 2.77
10 10
4 .2 2 .7 1.8 1 .9 2 .0 2 .0 2 .0 2 .8 2 .8 3 .7
--
--
--
--
--
2 .6 0 .8 2
10
0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0
-- -- --
--
--
0 .0 0 .0 0
10
0 .5 0 .2 0.1 0.1 0 .2 0.1 0.1 0 .3 0.1 0 .0
--
--
-- --
--
0 .2 0 .1 4
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028 :PAGE K-21
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 0 6 0 -0 6 9
Animal. ID E o s in o p h il B a s o p h iI s THSN/CU HH THSN/CU m
Abnormal L
O ther
THSN/CU MM THSN/CU PI
GROUP: 1-M 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167
MEAN SD N
0 .7 0.2 0 .2 0.1 0 .2 0 .5 0 .2 0.0 0 .2 0 .3
-- -- -- --
--
0 .3 0 .2 0
10
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
-- -- -- -- --
0.0 0 .0 0
10
0.0 0.0 0.0 0.0 0.5 0 .4 0.2 0.3 0.0 0.0
-- -- -- -- --
0.1 0 .2 0
10
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
-- -- -- --
0.0 0 .0 0
10
SEX: MALE
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028 :PAGE K-22
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID E o s in o p h il B a s o p h iIs Abnorm al L
O th er
THSN/CU HK THSN/CU HK THSN/CU HK THSN/CU KK
GROUP: 2-H 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
KEAN SD N
0 .3 0 .5 0.0 0.3 0 .2 0 .4 0 .6 0 .2 0.5 0.0
-- -- -- --
--
0 .3 0.21
10
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
-- -- -- -- --
0 .0 0 .0 0
10
0.3 0 .2 0.3 0.3 0.0 0.0 0.0 0.0 0.0 0.0
-- -- -- -- --
0.1 0.14
10
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
-- -- -- -- --
0.0 0.00
10
SEX: KALE
(-- ) - Data Unavai table LABCAT HE4.43
27-JUN-20Q2
418-028:PAGE K-23
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060 -0 6 9
A n in al 10 E o sin o p h il B a so p h ils Abnormal L
O ther
THSN/CU KM THSN/CU MM THSN/CU MM THSN/CU MM
SEX: MALE
GROUP: 3-M 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174
MEAN SD N
0.3 0 .0 0.5 0.3 0.1 0 .4 0 .0 0.1 0 .2 0 .6
-- -- -- -- --
0 .3 0.21
10
0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0
-- -- --- --
0 .0 0 .0 0
10
0.1 0.1 0 .0 0.1 0 .0 0 .2 0.1 0 .0 0 .0 0 .0
-- -- -- -- --
0.1 0 .0 7
10
0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0
-- -- -- -- --
0 .0 0 .0 0
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-24
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 060 -0 6 9
Anim al ID E o s in o p h il THSN/CU
B aso p h iIs Abnormal L
O th er
THSN/CU PI THSN/CU HM THSN/CU
GROUP: 4-M 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166
MEAN SD N
0.1 0.0 0 .4 0 .2 0 .9 0 .3 0.1 0 .4 0 .2 0.1
-- -- -- --
--
0 .3 0 .2 6
10
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
-- -- -- --
--
0.0 0 .0 0
10
0.1 0.6 0 .4 0.5 0.2 0.2 0.1 0.0 0.0 0.0
-- -- -- -- --
0 .2 0 .2 2
10
0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
-- -- -- -- --
0.0 0 .0 0
10
SEX: MALE
(-- ) _ Data Unavailable LABCAT HE4.43
2 7 - JUN-2002
418-028:PAGE K-25
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A n ia a l ID E o s in o p h il
B a so p h ils Abnormal L
O ther
THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM
GROUP: 5-M 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170
HEAN SD N
0 .2 0 .4 0.1 0 .4 0.1 0.1 0 .3 0 .2 0 .0 0 .0
--- -- -- --
0 .2 0 .1 5
10
0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0
-- -- -- -- --
0 .0 0 .0 0
10
0.5 0.0 0.0 0.0 0.2 0 .0 0.5 0 .0 0 .0 0 .0
-- -- -- -- --
0.1 0.21
10
0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0
-- -- -- -- --
0 .0 0 .0 0
10
SEX: HALE
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-20Q2
418-028:PAGE K-26
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 0 6 0 -0 6 9
Anim al ID E o s in o p h il
B asophiIs Abnormal L
O ther
THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM
GROUP: 1-F 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
MEAN SD N
0 .2 0 .0 0 .3 0.1 0 .0 0 .0 0.1 0.1 0 .0 0.1
-- -- -- --
0.1 0 .1 0
10
0 .0 0 .0 0.0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0
-- -- --
0 .0 0 .0 0
10
_
0 .0 0 .0 0 .0 0.1 0 .0 0 .0 0 .0 0 .0 0.1 0.1
-- -- -- --
0 .0 0.05
10
_
0 .0 0 .0 0 .0 0 .0 0.0 0 .0 0 .0 0 .0 0 .0 0 .0
-- -- --
0 .0 0.00
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-20Q2
418-028:PAGE K-27
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
Ani n a l ID E o s in o p h il B a s o p h iIs Abnorm al L
O ther
THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM
SEX: FEMALE
GROUP: 2-F 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
MEAN SD N
0 .0 0.1 0 .3 0.1 0 .0 0 .4 0 .0 0.1 0.1 0.1
-- -- -- --
--
0.1 0 .1 3
10
0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0
-- -- -- -- --
0 .0 0 .0 0
10
0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0
-- -- -- -- --
0 .0 0 .0 0
10
0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0 0 .0
-- --
--
-- --
0 .0 0 .0 0
10
.
(-- ) - Oata Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-28
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A nim al ID E o s in o p h il B a s o p h ils Abnorm al L
O ther
THSN/CU MM THSN/CU HH THSN/CU MM THSN/CU MM
SEX: FEMALE
GROUP: 3-F 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
MEAN SD N
0.1 0 .0 0 .0 0 .0
-- 0 .0 0.4 0.2 0.1 0.1
-- 0 .0
-- -- --
0.1 0.13
10
0 .0 0 .0 0 .0 0 .0
-- 0 .0 0 .0 0 .0 0 .0 0 .0
-- 0 .0
-- -- --
0 .0 0 .0 0
10
0.1 0.1 0.1 0 .2
-- 0 .0 0 .0 0.1 0 .0 0 .0
-- 0 .0
-- -- --
0.1 0 .0 7
10
0 .0 0 .0 0 .0 0 .0
-- 0 .0 0 .0 0 .0 0 .0 0 .0
-- 0 .0
-- -- --
0 .0 0 .0 0
10
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-29
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 060 -0 6 9
Anim al ID E o s in o p h il B a s o p h iIs Abnormal L
O ther
THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM
GROUP: 4-F 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
KEAN SD N
0.1 0.0 0.1 0.0 0.0
-- -- 0.0 0 .2 0.0 0 .3 0.0 -- --
0.1 0.11
10
0.0 0.0 0.0 0.0 0.0
-- -- 0.0 0.0 0.0 0.0 0.0 -- --
0.0 0 .0 0
10
0.0 0.1 0.0 0.0 0.0
-- -- 0.3 0.0 0.0 0.0 0.1 -- --
0.1 0 .1 0
10
0.0 0.0 0.0 0.0 0.0
-- -- 0.0 0.0 0.0 0.0 0.0 -- --
0.0 0 .0 0
10
SEX: FEMALE
(-- ) - Data Unavailable LABCAT HE4.43
2 7 -Jim-2002
418-028:PAGE K-30
Study Report for Hematology
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID Eosinophil BasophiIs Abnormal L
Other
THSN/CU FIM THSN/CU MM THSN/CU MM THSN/CU MM
GROUP: 5-F
19001
0.3 0.0 0.0 0.0
19006
0.0 0.0 0.0 0.0
19011
0.0 0.0 0.1 0.0
19020
0.0 0.0 0.0 0.0
19022
0.1 0.0 0.0 0.0
19025
0.0 0.0 0.1 0.0
19027
0.0 0.0 0.0 0.0
19028
0.0 0.0 0.0 0.0
19030
0.0 0.0 0.1 Q.O
19031
0.4 0.0 0.0 0.0
19032
-- --
----
19033 -- -- -- --
19049 -- -- -- --
19059 -- -- -- --
19070 -- -- -- -
MEAN SD N
0.1 0.15
10
0.0 0.00
10
0.0 0.05
10
0.0 0.00
10
SEX: FEMALE '
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028:PAGE K-31
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: HALE
TEST(s) : UNITS:
UBC RBC THSN/CU MM MILL/CU MM
HGB GRAMS/DL
HCT HCV MCH
x cu MICRONS PICO GRAMS
MCHC PLT MPV % THSN/CU MM CU MICRON
Group: 1-M MEAN
SD N
15.3 1.63
10
7.51 0.648
10
16.5 1.16
10
43.5 3.48
10
57.9 1.89
10
22.0 0.87
10
38.0 0.93
10
1179 130.9
10
8.1 0.52
10
Group: 2-M MEAN
SD N
Group: 3-M MEAN
SD N
14.9 3.03
10
7.33 0.396
10
13.8 2.84
10
7.32 0.441
10
15.9 0.42
10
42.2 1.57
10
57.7 2.27
10
15.7 0.59
10
42.0 2.22
10
57.4 1.78
10
21.8 1.13
10
37.7 1.15
10
1131 183.7
10
21.5 0.75
10
37.5 0.79
10
1115 149.2
10
7.9 0.54
10
8.2 0.72
10
Group: 4-M MEAN
SD N
16.2 3.97
10
6.93* 0.305
10
15.4** 0.67
10
40.2* 2.29
10
57.9 1.15
10
22.2 0.45
10
38.4 0.80
10
1104 91.4
10
8.2 0.76
10
Group: 5-H MEAN
SD N
14.7 3.07
10
6.99* 0.442
10
15.6* 0.81
10
40.7* 1.81
10
58.3 1.37
10
22.3 0.56
10
38.3 0.70
10
1148 159.9
10
8.0 0.59
10
-Significant Difference fro Control P < .05 LABCAT HE4.43
**-Significant Difference fro* Control P < .01 27-JUN-2002
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028:PAGE K-32
STUDY 10: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS 0F VARIANCE F0LL0VED BY OUNNETT'S PROCEDURE
SEX: HALE
TEST(s): UNITS:
PT seconds
APTT seconds
Group: 1-H MEAN
SD N
13.4 0.24
10
21.0 3.09
10
Group: 2-H MEAN
SD N
14.2** 0.27
10
22.1 4.41
10
Group: 3-M MEAN
SD N
13.6 0.23
10
20.6 2.38
10
Group: 4-H HEAN
SD N
13.8* 0.40
10
21.2 2.24
10
Group: 5-H MEAN
SD N
14.0** 0.47
10
21.3 1.43
10
NRBC Lymphocyte Segmented
Bands Honocytes Eosinophil Basophils
COUNT THSN/CU HM THSN/CU HH THSN/CU HH THSN/CU HH THSN/CU HM THSN/CU HH
0 11.9 2.2 0.0 0.8 0.3 0.0 0.0 1.72 0.73 0.00 0.56 0.20 0.00
10 10 10 10 10 10 10
0 11.0 2.9 0.0 0.7 0.3 0.0
0.0 2.63
1.18
0.00
0.50
0.21
0.00
10 10 10 10 10 10 10
0 10.8 2.0 0.0 0.6 0.3 0.0
0.0 2.02
1.06
0.03
0.51
0.21
0.00
10 10 10 10 10 10 10
0 12.1 2.8 0.0 0.8 0.3 0.0 0.0 3.57 0.73 0.03 0.67 0.26 0.00
10 10 10 10 10 10 10
0 12.4 1.6 0.0 0.5 0.2 0.0 0.0 2.75 0.78 0.00 0.33 0.15 0.00
10 10 10 10 10 10 10
-Significant Difference from Control P < .05 LABCAT HE4.43
**-Significant Difference from Control P < .01 27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028:PAGE K-33
ANALYSIS 0F VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: HALE
TEST(s): Abnornal L
Other
UNITS:
THSN/CU HH THSN/CU MM
Group: 1--M MEAN
SD N
0.1 0.20
10
0.0 0.00
10
Group: 2-M MEAN
SD N
0.1 0.14
10
0.0 0.00
10
Group: 3-M MEAN
SD N
0.1 0.07
10
0.0 0.00
10
Group: 4-H MEAN
SD N
0.2 0.22
10
0.0 0.00
10
Group: 5-M MEAN
SD N
0.1 0.21
10
0.0 0.00
10
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028:PAGE K-34
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: MALE
White Blood Count
Std.
Group
N Total
Mean
Dev.
DUNNETT'S t'
1-M
10 153.1
15.3
1.63
2-M
10 149.2
14.9
3.03 0.29
3-M
10 137.6
13.8
2.84 1.15
4-M
10 162.2
16.2
3.97 0.68
5-M
10 146.6
14.7
3.07 0.48
DUNNETT'S RANGES
L0 -95X- HI
L0 -99X- HI
Degree Source Fdm
Sum of Squares
11.9 11.9 11.9 11.9
18.7 18.7 18.7 18.7
11.1
11.1 11.1 11.1
TREATMENTS 4
19.5
ERROR 45
1 9 . 5 ------------------
19.5
TOTAL 49
19.5
32.41 406.23
438.64
Mean Square
8.10
9.03
F Ratio = Coeff. Var. % =
0.90 20.065
F* table values Dunnett's 'T' table values
Red Blood Count
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
1-M
10 75.13
7.51
0.648
TREATMENTS 4
2.44
0.61
2-M
10 73.26
7.33
0.396 0.91
7.00 8.03
6.87 8.16
ERROR 45
9.54
0.21
3-M
10 73.19
7.32
0.441 0.94
7.00 8.03
6.87 8 . 1 6 ------------------
4-M
10 69.30
6.93
0.305 2.83
7.00 8.03* 6.87 8.16
TOTAL 49
11.98
5-M
10 69.89
6.99
0.442 2.54
7.00 8.03* 6.87 8.16
F Ratio = Coeff. Var. X =
2.88 6.381
Hemoglobin
'F ' table values Dunnett's 'T* table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
1-M
10 165.2
16.5
1.16
TREATMENTS 4
7.40
1.85
2-M
10 159.1
15.9
0.42 1.77
15.7 17.4
15.4 1716
ERROR 45
26.78
0.60
3-M
10 157.3
15.7
0.59 2.29
15.7 17.4
15.4 17.6
4-M
10 154.0
15.4
0.67 3.25
15.7 17.4* 15.4 17.6**
TOTAL 49
34.18
5-M
10 155.8
15.6
0.81 2.72
15.7 17.4* 15.4 17.6
F Ratio = Coeff. Var. % =
3.11 4.874
'F ` table values Dunnett's 'T' table values
F.01 P.01
3.78 3.12
F .05 P.05
2.58 2.51
-Significant Difference from Control P < .05 -Significant Difference from Control P < .01 Error-within groups
LABCAT HE4.43
Source-Source of Variation Treatments-between groups
27-JUW-20Q2
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028:PAGE K-35
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: KALE
Hematocrit
Group
N Total
Mean
Std. DUNNETT'S
Dev.
't1
DUNNETT'i! RANGES
LO -957.- HI
L0 -997.- HI
Degree Source Fdm
1-M
10 434.6
43.5
3.48
TREATMENTS
4
2--PI
10 422.2
42.2
1.57 1.17
40.8 46.1
40.2 46.8
ERROR 45
3-M
10 419.9
42.0
2.22 1.39
40.8 46.1
40.2 46.8 -
4-M
10 401.7
40.2
2.29 3.11
40.8 46.1* 40.2 46.8
TOTAL 49
5-M
10 406.7
40.7
1.81 2.64
40.8 46.1* 40.2 46.8
F Ratio = Coeff. Var. % =
3.06 5.676
1F 1 table values Dunnett's `T 1 table values
Mean Corpuscular Volume
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2. 58 2. 51
Sum of Squares
68.54 252.15
320.69
Mean Square
17.13 5.60
1-M
10 579.1
57.9
1.89
2-M
10 576.9
57.7
2.27 0.28
56.0 59.9
3-M
10 574.1
57.4
1.78 0.64
56.0 59.9
4-M
10 579.4
57.9
1.15 0.04
56.0 59.9
5-M
10 582.7
58.3
1.37 0.46
56.0 59.9
F Ratio = Coeff., Var. X =
0.34 3.006
*F' table values Dunnett's 'T' table values
F.01 = P.01 =
Mean Corpuscular Hemoglobin
55.5 55.5 55.5 55.5
TREATMENTS 4
60.3
ERROR 45
6 0 . 3 -------------------
60.3
TOTAL 49
60.3
4.07 136.05
140.12
3.78 3.12
F.05 = P.05 =
2.58 2.51
1.02 3.02
1-M
10 220.3
22.0
0.87
TREATMENTS 4
4.40
1.10
2-M
10 217.6
21.8
1.13 0.76
21.1 22.9
20.9 23.1
ERROR 45
28.04
0.62
3-M
10 215.2
21.5
0.75 1.44
21.1 22.9
20.9 23.1
4-M
10 222.3
22.2
0.45 0.57
21.1 22.9
20.9 23.1
TOTAL 49
32.44
5-M
10 223.2
22.3
0.56 0.82
21.1 22.9
20.9 23.1
F Ratio = Coeff. Var. X =
1.77 3.593
'F' table values Dunnett's 'T' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
-Significant Difference fro Control P < .05 Error-within groups
LABCAT HE4.43
Source-Source of Variation Treatments-between groups
27-JUN-2002
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028:PAGE K-36
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: HALE
Mean Corpuscular Hem. Cone.
Std. DUNNETT'S
Group
N Total
Mean
Dev.
't'
DUNNETT' S RANGES
L0 -95Z- HI
L0 -99Z- HI
Degree Source Fdm
Sum of Squares
Mean Square
1-M
10 380.4
38.0
0.93
2-H
10 377.2
37.7
1.15 0.80
37.0 39.0
3-H
10 374.9
37.5
0.79 1.38
37.0 39.0
4-H
10 383.7
38.4
0.80 0.83
37.0 39.0
5-H
10 383.1
38.3
0.70 0.68
37.0 39.0
F Ratio = Coeff. Var. % =
1.81 2.343
1F ' table values Dunnett's *'P table values
F.01 = P.01 =
Platelets
36.8 36.8 36.8 36.8
39.3 39.3 39.3 39.3
TREATMENTS ERROR
TOTAL
4 45
49
3.78 3.12
F.05 = P.05 =
2. 58 2. 51
5.72 35.64
41.36
1.43 0.79
1-N
10 11790
1179
130.9
TREATMENTS 4
34523
8631
2-H
10 11305
1131
183.7 0.74
1015 1343
975 1383
ERROR 45
963815
21418
3-M
10 11154
1115
149.2 0.97
1015 1343
975 1383 -------------------
4-M
10 11044
1104
91.4 1.14
1015 1343
975 1383
TOTAL 49
998339
5-H
10 11483
1148
159.9 0.47
1015 1343
975 1383
F Ratio = Coeff.. Var. % =
0.40 12.888
'F * table values Dunnett's 'T' table values
MEAN PLATELET VOLUME
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
1-M 10 81.2 8.1 0.52
TREATMENTS 4
0.90
0.23
2-M
10 78.6 7.9 0.54 0.92
7.4 8.8
7.2 9.0
ERROR 45
18.03
0.40
3-M
10 82.3 8.2 0.72 0.39
7.4 8.8
7.2 9.0 -------------------
4-M
10 82.1
8.2 0.76 0.32
7.4 8.8
7.2 9.0
TOTAL 49
18.94
5-H
10 80.4 8.0 0.59 0.28
7.4 8.8
7.2 9.0
F Ratio = Coeff. Var. % =
0.56 7.823
'F' table values Dunnett's 'T' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
Error-within groups Source-Source of Variation
LABCAT HE4.43
Treatments-between groups
27-JUN-2002
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028:PAGE K-37
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY OUNNETT'S PROCEDURE
SEX: KALE
Prothrombin
Group
N Total
Kean
Std. DUNNETT'S
Dev.
't '
DUNNETT'S> RANGES
L0 -957.- HI
L0 -99X- HI
Degree Source Fdm
1-M
10 133.8
13.4
0.24
TREATMENTS 4
2-M
10 142.3
14.2
0.27 5.63
13.0 13.8* 12.9 13.9**
ERROR 45
3-H
10 136.3
13.6
0.23 1.66
13.0 13.8
12.9 13.9
4-M
10 137.9
13.8
0.40 2.71
13.0 13.8* 12.9 13.9
TOTAL 49
5-H
10 139.5
14.0
0.47 3.77
13.0 13.8* 12.9 13.9**
F Ratio = Coeff. Var. % =
9.05 2.448
'F ' table values Dunnett's 'T* table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2. 58 2. 51
Act. Part. Thromboplastin Time
Sum of Squares
4.13 5.13
9.26
Mean Square
1.03 0.11
1-M
10 209.8
21.0
3.09
2-M
10 220.5
22.1
4.41 0.83
17.7 24.2
3-M
10 205.7
20.6
2.38 0.32
17.7 24.2
4-M
10 211.7
21.2
2.24 0.15
17.7 24.2
5-M
10 212.8
21.3
1.43 0.23
17.7 24.2
F Ratio = Coeff., Var. % =
0.35 13.609
F' table values Dunnett's 'T' table values
F.01 = P.01 =
Nucleated Red Cells
17.0 17.0 17.0 17.0
TREATMENTS 4
25.0
ERROR 45
2 5 . 0 ------------------
25.0
TOTAL 49
25.0
11.75 374.92
386.66
3.78 3.12
F.05 = P.05 =
2.58 2.51
2.94 8.33
1-M 10 2-M 10 3-M 10 4-M 10 5-M 10
F Ratio = Coeff., Var. % =
0 0 0 0 0
0.00 0.000
0 0.0 0 0.0 0.00 0 0.0 0.00 0 0.0 0.00 0 0.0 0.00
00 00 00 00
F' table values Dunnett's 'T* table values
F.01 = P.01 =
0 0 0 0
3.78 3.12
TREATMENTS 4
0.00000
0
ERROR 45
0.00000
0 ------------------
0
TOTAL 49
0.00000
0
0.00000 0.00000
F.05 = P.05 =
2.58 2.51
-Significant Difference from Control P < .05 -Significant Difference from Control P < .01 Error-within groups
LABCAT HE4.43
Source-Source of Variation Treatments-between groups
27-JUN-2002
418-028 :PAGE K-38
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE F0LL0WED BY DUNNETT1S PROCEDURE
SEX: MALE
Lymphocytes
Group
N Total
Mean
Std. DUNNETT'S
Dev.
t`
DUNNETT'S RANGES
LO -95X- HI
LO -99X- HI
Degree Source Fda
1-M
10 119.2
11.9
1.72
TREATMENTS 4
2-M
10 109.7
11.0
2.68 0.81
9.0 14.9
8.3 15.6
ERROR 45
3-M
10 108.1
10.8
2.02 0.94
9.0 14.9
8.3 15.6 -
4-M
10 120.8
12.1
3.57 0.14
9.0 14.9
8.3 15.6
TOTAL 49
5-M
10 123.6
12.4
2.75 0.37
9.0 14.9
8.3 15.6
F Ratio = Coeff. Var. % =
0. 70 22.619
'F' table values Dunnett's 'T* table values
Segmented Neutrophils
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2. 58 2. 51
Su b of Squares
19.27 311.29
330.56
Mean Square
4.82 6.92
1-M 10 22.1 2.2 0.73
2-M
10 28.8 2.9 1.18 1.63
1.2 3.2
3-M
10 20.2 2.0 1.06 0.46
1.2 3.2
4-M
10 28.4 2.8 0.73 1.54
1.2 3.2
5-M
10 15.5 1.6 0.78 1.61
1.2 3.2
F Ratio = Coeff. Var. % =
3.79 39.885
' F` table values Dunnett's `T ` table values
F.01 = P.01 =
Bands
TREATMENTS 4
12.77
0.9 3.5
ERROR 45
37.87
0.9 3.5 -------------------
0.9 3.5
TOTAL 49
50.64
0.9 3.5
3.78 3.12
F.05 = P.05 =
2.58 2.51
3.19 0.84
1-M 10 0.0 0.0 0.00
TREATMENTS 4
0.0012
0.0003
2-M
10 0.0 0.0 0.00 0.00
0.0 0.0
0.0 0.0
ERROR 45
0.0180
0.0004
3-M
10 0.1 0.0 0.03 1.12
0.0 0.0
0.0 0.0
4-M
10 0.1 0.0 0.03 1.12
0.0 0.0
0.Q 0.0
TOTAL 49
0.0192
5-M
10 0.0 0.0 0.00 0.00
0.0 0.0
0.0 0.0
F Ratio = Coeff. Var. X =
0.75 500.000
'F' table values Dunnett's 'T' table values
F.01 P.01
3.78 3.12
F.05 = P.05 =
2.58 2.51
Error-within groups Source-Source of Variation
LABCAT HE4.43
Treatiaents-between groups
27-JUN-2002
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028:PAGE K-39
STIIDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: MALE
Monocytes
Group
N Total
Mean
Std. DUNNETT'S
Dev.
t'
DUNNETT'S RANGES
LO -952- HI
LO -99X- HI
Degree Source Fdm
Sum of Squares
Mean Square
1-M 10 8.4 0.8 0.56
2-M 10 6.9 0.7 0.50 0.64
5.8
0.6
0.51
1.11
4-K 10 8.0 0.8 0.67 0.17 5-M 10 4.5 0.5 0.33 1.66
0.2 1.4 n o 1.4
0.2 1.4 0.2 1.4
F Ratio = Coeff. Var. % =
0.93 78.222
'F' table values Dunnett's 'T' table values
F.01 = P.01 =
Eosinophils
1-M
2-M
3"K
4-M 5-M
10 2.6 0.3 0.20
10 3.0 0.3 0.21 0.43 2.5 0.3 0.21 0.11
10 2.7 0.3 0.26 0.11 10 1.8 0.2 0.15 0.86
0.0 0.5 0.0 0*5 0.0 0.5 0.0 0.5
F Ratio = Coeff. Var. % =
0.46 82.096
'F' table values Dunnett's 'T' table values
F.01 P.01
Basophils
TREATMENTS 4
0.1 1.6
ERROR 45
0.1 1.6
0.1 1.6
TOTAL 49
0.1 1.6
3.78 3.12
F. 05 = P..05 =
2. 58 2..51
TREATMENTS 4
0.0 0.5
ERROR 45
0 0 0.5
0.0 0.5
TOTAL 49
0.0 0.5
3.78 3.12
F.05 = P.05 =
2.58 2.51
1.03 12.43 13.46
0.08 1.93 2.00
0.26 0.28
0.02 0.04
1-M 10 0.0 0.0 0.00
TREATMENTS 4
0.00000 0.00000
2-M
10 0.0 0.0 0.00 0.00
0.0 0.0
0.0 olo
ERROR 45
0.00000 0.00000
0.0 0.0 0.00 0.00
0.0 n n
0.0 0.0 -
4-M
10 0.0 0.0 0.00 0.00
0.0 0.0
0.0 0.0
TOTAL 49
0.00000
5-M
10 0.0 0.0 0.00 0.00
0.0 0.0
0.0 0.0
F Ratio = Coeff. Var. % =
0.00 0.000
F* table values Dunnett's 'T' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
Error-within groups Source-Source of Variation
LABCAT HE4.43
Treatments-between groups
27-JUN-20Q2
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028-.PAGE K-40
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS 0F VARIANCE FOLLOUED BY DUNNETT'S PROCEDURE
SEX: MALE
Abnormal Lymphocytes
Std. DUNNETT'S
Group
N Total
Mean
Dev.
t '
DUNNETT' S RANGES
L0 -95Z- HI
L0 -99X- HI
Degree Source Fdm
Sum of Squares
Mean Square
1-M 10 1.4 0.1 0.20
TREATMENTS 4
0.12
0.03
2-M
10 1.1 0.1 0.14 0.38
-.1 0.3
-.1 0.4
ERROR 45
1.40
0.03
3-M
10 0.6 0.1 0.07 1.01
-.1 0.3
-.1 0.4
4-M
10 2.1 0.2 0.22 0.89
-.1 0.3
-.1 0.4
TOTAL 49
1.52
5-M
10 1.2 0.1 0.21 0.25
-.1 0.3
-.1 0.4
F Ratio = Coeff. Var. % =
0.95 137.898
'F' table values
Dunnett's ''r* table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
Other
1-M 10 0.0 0.0 0.00
TREATMENTS 4
0.00000 0.00000
2-M
10 0.0 0.0 0.00 0.00
0.0 0.0
0.0 0.0
ERROR 45
0.00000 0.00000
3-M
0.0 0.00 0.00
o o 0.0 0.0 0.0
4-M
10 0.0 0.0 0.00 0.00
0.0 0.0
0.0 0.0
TOTAL 49
0.00000
5-M
10 0.0 0.0 0.00 0.00
0.0 0.0
0.0 0.0
F Ratio = Coeff. Var. X =
0.00 0.000
F' table values Dunnett's 'T' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
Error-within groups Source-Source of Variation
LABCAT HE4.43
Treatments-between groups
27-JUN-2002
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028:PAGE K-41
STUDY ID: ARGUS AI8-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOUED BY DUNNETT'S PROCEDURE
SEX: FEMALE
TEST(s) * UNITS:
UBC RBC THSN/CU MM HILL/CU MM
HGB GRAMS/DL
Group: 1-F MEAN
SD N
9.0 3.09
10
6.51 0.A61
10
15.5 0.95
10
Group: 2-F MEAN
SD N
13.8* 5.73
10
6.22 0.A23
10
15.0 0.77
10
Group: 3-F MEAN
SD N
11.1 2.98
10
6. AO 0.55A
10
15.2 0.91
10
Group: A-F MEAN
SD N
10.8 3.15
10
6.39 0.532
10
15.2 0.90
10
Group: 5-F MEAN
SD N
8.9 3.A8
10
6.A2 0.538
10
15.3 0.77
10
HCT MCV MCH X CU MICRONS PICO GRAMS
AO. 5 2.93
10
62.2 1.19
10
23.9 0.55
10
39.3 2.72
10
63.3 2.01
10
2A.2 0.76
10
39.5 3.2A
10
61.8 1.50
10
23.9 0.88
10
A0.1 3.02
10
62.9 2.0A
10
23.8 1.25
10
AO.A 3.15
10
63.0 1.60
10
23.8 1.05
10
MCHC PLT MPV X THSN/CU MM CU MICRON
38. A 0.76
10
1A19 153.0
10
8.3 0.A9
10
38.3 0.9A
10
12AO 208.1
10
8.0 0.8A
10
38.7 1.29
10
127A 226.3
10
37.8 1.22
10
1305 207.2
10
8.3 0.82
10
8.0 0.63
10
37.8 1.37
10
1355 176.8
10
7.7 0.7A
10
-Significant Difference from Control P < .05 LABCAT HEA.A3
27-JUN-2002
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028 :PAGE K-42
STUDY 1D: ARGUS 418-028 STUDY N0: 060-069
ANALYSIS 0F VARIANCE FOLLOUED BY DUNNETT'S PROCEDURE
SEX: FEMALE
TEST(s): UNITS:
PT seconds
APTT seconds
NRBC Lymphocyte Segmented
Bands Monocytes Eosinophil Basophils
COUNT THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM THSN/CU MM
Group: 1-F MEAN
SD N
Group: 2-F MEAN
SD N
Group: 3-F MEAN
SD N
Group: 4-F MEAN
SD N
Group: 5-F MEAN
SD N
13.2 0.41
10
13.4 0.29
10
13.2 0.37
10
13.5 0.42
10
13.8 1.12
10
21.7 2.36
10
23.9 3.19
10
23.5 2.35
10
25.3 2.45
10
25.2 3.81
10
0 6.6 2.2 0.0 0.1 0.1 0.0
0.0
2.44
0.90
0.00
0.15
0.10
0.00
10 10 10 10 10 10 10
0
9.8*
3.6
0.0
0.3
0.1
0.0
0.0
3.44
3.69
0.00
0.49
0.13
0.00
10 10 10 10 10 10 10
0 8.4 2.4 0.0 0.2 0.1 0.0 0.0 2.60 0.93 0.00 0.13 0.13 0.00
10 10 10 10 10 10 10
0 8.2 2.4 0.0 0.2 0.1 0.0
0.0
2.52
0.96
0.09
0.11
0.11
0.00
10 10 10 10 10 10 10
0 6.0 2.6 0.0 0.2 0.1 0.0
0.6
2.77
0.82
0.00
0.14
0.15
0.00
10 10 10 10 10 10 10
-Significant Difference from Control P < .05 LABCAT HE4.43
27-JUN-20Q2
STUDY ID: ARGUS 418-028 STUDY N0: 060-069
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
ANALYSIS OF VARIANCE FOLLOWED BY OUNNETT1S PROCEDURE
TESTCs): Abnormal L
Other
UNITS:
THSN/CU NM THSN/CU MM
Group: 1-F MEAN
SD N
0.0 0.05
10
0.0 0.00
10
Group: 2-F MEAN
SD N
0.0 0.00
10
0.0 0.00
10
Group: 3-F MEAN
SD N
0.1 0.07
10
0.0 0.00
10
Group: 4-F MEAN
SD N
0.1 0.10
10
0.0 0.00
10
Group: 5-F MEAN
SD N
0.0 0.05
10
0.0 0.00
10
418-028:PAGE K-43
SEX: FEMALE
LABCAT HE4.43
27-JUN-20Q2
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028:PAGE K-44
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: FEMALE
White Blood Count
Std.
Group
N Total
Bean
Dev.
DUNNETT'S t'
1-- F 10 89.9 9.0 3.09
2-F
10 137.8
13.8
5.73 2.80
3-F
10 110.7
11.1
2.98 1.22
4-F
10 108.4
10.8
3.15 1.08
5-F 10 88.9 8.9 3.48 0.06
DUNNETT1S RANGES
L0 -95X- HI
LO -99X- HI
Degree Source Fdm
4.7 13.3* 4.7 13.3 4.7 13.3 4.7 13.3
TREATMENTS 4
3.6 14.3
ERROR 45
3.6 14.3
3.6 14.3
TOTAL 49
3.6 14.3
Sum of Squares
158.42 659.12
817.54
Bean Square
39.61 14.65
1: Ratio =: Coeff . Var. % =:
2.70 35.721
F' table values Dunnett's ''T' table values
Red Blood Count
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2. 58 2. 51
1-F
10 65.06
6.51
0.461
2-F
10 62.15
6.22
0.423 1.29
5.94 7.07
3-F 10 63.96
0.554 0.49
5.94 7.07
4-F
10 63.87
6.39
0.532 0.53
5.94 7.07
5-F
10 64.23
6.42
0.538 0.37
5.94 7.07
F Ratio = Coeff., Var. X =
0.44 7.896
'F' table values Dunnett's 'T' table values
F.01 = P.01 =
Hemoglobin
5.80 5.80 5.80 5.80
7.21 7 pi
7.21 7.21
TREATMENTS ERROR
,,
TOTAL
4 45
49
3.78 3.12
F.05 = P.05 =
2.58 2.51
0.45 11.44
11.89
0.11 0.25
1-F
10 155.4
15.5
0.95
2-F
10 150.4
15.0
0.77 1.29
14.6 16.5
3-F
10 152.4
15.2
0.91 0.78
14.6 16.5
4-F
10 151.6
15.2
0.90 0.98
14.6 16.5
5-F
10 152.6
15.3
0.77 0.72
14.6 16.5
F Ratio = Coeff,. Var. % =
0.46 5.669
'F' table values Dunnett's 'T' table values
F.01 = P . 01 =
14.3 14.3 14.3 14.3
16:7 16.7 16.7 16.7
TREATMENTS ERROR
--TOTAL
4 45
49
3.78 3.12
F.05 = P .05 =
2.58 2.51
1.36 33.62
34.98
0.34 0.75
-Significant Difference from Control P < .05 Error-vithin groups
LABCAT HE4.43
Source-Source of Variation Treataents-between groups
27-JUN-20Q2
418-028:PAGE K-45
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX : FEMALE
Hematocrit
G roup
N T otal
Mean
S td . DUNNETT'S
Dev.
't '
DUNNETT' S RANGES
L0 -95% - HI
L0 -99% - HI
D egree S ource Fdm
Sum o f Squares
Mean Square
1-F
10 404.9
40.5
2 .9 3
2-F
10 393.4
3 9 .3
2 .72 0.85
37.1
4 3 .9
3-F
10 395.1
39.5
3.24 0.73
37.1
4 3 .9
4-F
10 401.4
40.1
3.02 0.26
37.1
4 3 .9
5-F
10 404.1
4 0 .4
3.15 0.06
37.1
4 3 .9
F R atio = C oeff. Var. X -
0 .3 0 7 .5 4 8
`F' ta b le v alu es D u n n e tt's *T1 t a b l e v a lu e s
Mean Corpuscular Volume
F.01 = P.01 =
36.3 36.3 36.3 36.3
4 4 .7 4 4 .7 4 4 .7 4 4 .7
TREATMENTS ERROR
-----TOTAL
4 45
49
3 .7 8 3.12
F.05 = P.05 =
2 .5 8 2.51
11.01 4 0 9 .8 0
420.81
2 .7 5 9.11
1-F
10 622.3
6 2 .2
1 .1 9
2-F
10 633.3
63.3
2.01
1.45
60.3 64.1
3-F
10 618.2
6 1 .8
1.50 0.54
60.3 64.1
4-F
10 629.1
6 2 .9
2.04 0.90
60.3 64.1
5-F
10 629.7
6 3 .0
1.60 0.97
60.3 64.1
F R atio = C oeff. Var. X -
1 .3 0 2 .7 0 9
'F 1 ta b le values D u n n e t t's 1T* t a b l e v a lu e s
F.01 = P.01 =
Mean Corpuscular Hemoglobin
59.9 5 9 .9 59.9 5 9 .9
TREATMENTS
6 4 .6
ERROR
6 4 . 6 ------
6 4 .6
TOTAL
6 4 .6
4 45
49
3 .7 8 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
14.98 129.67
144.64
3 .7 4 2 .8 8
1-F
10 239.0
2 3 .9
0 .5 5
TREATMENTS 4
1 .2 8
0 .3 2
2-F
10 242.4
24.2
0.76 0.82
22.9 24.9
22.6 25.2
ERROR 45
3 8 .9 2
0 .8 6
3-F
10 238.9
2 3 .9
0.88 0.02
22.9 24.9
2 2 .6 2 5 .2 -----
4-F
10 237.9
2 3 .8
1.25 0.26
22.9 24.9
22.6 25.2
TOTAL 49
40.21
5-F
10 238.3
2 3 .8
1.05 0.17
22.9 24.9
22.6 25.2
F R atio = C oeff. Var. X =
0 .3 7 3 .8 8 6
' F' ta b le values D u n n ett's 'T ' ta b le v alu es
F.01 = P.01 =
3 .7 8 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
E rro r-w ith in groups Source-Source of V ariation
LABCAT HE4.43
Treatm ents-betw een groups
27-JUN-2002
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028 :PAGE K-46
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 060 -0 6 9
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: FEMALE
Mean Corpuscular Hem. Cone.
S td . DUNNETT'S
Group
N T otal
Mean
Dev.
`t*
OUNNETT' S RANGES
LO - '95%- HI
L0 -99% - HI
D eg ree S o u rc e Fdm
Sum o f Squares
Mean Square
1-F
10 384.2
3 8 .4
0 .7 6
2-F
10 382.9
3 8 .3
0.94 0.26
37.1 39.7
3-F
10 386.6
3 8 .7
1.29 0.47
37.1
3 9 .7
4 -F
10 378.3
3 7 .8
1.22 1.16
37.1
3 9 .7
5-F
10 378.4
3 7 .8
1.37 1.14
37.1
3 9 .7
oW T1
F R a tio =: C o e f f . V a r. X =:
1. 2 .9 7 8
Platelets
ta b le values D u n n e tt's 'T ' ta b le valu es
F.01 = P.01 =
3 6 .8 3 6 .8 3 6 .8 3 6 .8
4 0 .0 4 0 .0 4 0 .0 4 0 .0
TREATMENTS ERROR
TOTAL
4 45
49
3 .7 8 3 .1 2
F.05 = P.05 =
2. 58 2.51
5 .3 4 58.25
63.60
1 .3 4 1 .2 9
1-F
10 14189
1419
153.0
TREATMENTS 4
198797
49699
2-F
10 12396
1240
208.1
2 .0 5
1199 1639
1145 1692
ERROR 45
1729216
38427
3-F
10 12735
1274
226.3 1.66
1199 1639
1145 1692 ------
4-F
10 13048
1305
207.2 1.30
1199 1639
1145 1692
TOTAL 4 9
1928012
5-F
10 13554
1355
176.8 0.72
1199 1639
1145 1692
F R atio = C oeff. Var. X -
1 .2 9 14.868
F* t a b l e v a lu e s D u n n ett's 'T ' ta b le valu es
MEAN PLATELET VOLUME
F.01 = P.01 =
3 .7 8 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
1-F 10 83.4 8 .3 0.49
TREATMENTS 4
2 .9 5
0 .7 4
2-F
10 80.0 8 .0 0.84 1.06
7 .5 9.1
7.3 9.3
ERROR 45
23.11
0.51
3-F
10 82.7 8 .3 0.82 0.2 2
7 .5 9.1
7 .3 9 .3 -----
4-F
10 80.3 8 .0 0.63 0.9 7
7.5 9.1
7.3 9.3
TOTAL 49
26.06
5-F
10 76.5 7 .7 0.74 2.15
7.5 9.1
7.3 9.3
F R atio = C oeff. Var. % =
1 .4 4 8 .8 9 4
' F* t a b l e v a lu e s D u n n ett's T ta b le values
F.01 = P.01 =
3 .7 8 3 .1 2
F.05 = P.05 =
2.58 2.51
Error-within groups Source-Source of Variation
LABCAT HE4.43
Treatments-between groups
27-JUN-2002
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028:PAGE K 47
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: FEMALE
Prothrombin
Group
N T otal
Mean
S td . DUNNETT'S
Dev.
't `
DUNNETT'S RANGES
LO -95% - HI
L0 -99% - HI
D egree S o u rc e Fdm
Sum o f Squares
Mean Square
1-F
10 131.8
1 3 .2
0.41
2 -F
10 133.5
1 3 .4
0.29 0.63
12.5 13.9
3-F
10 131.7
1 3 .2
0.37 0.04
1 2 .5
1 3 .9
4-F
10 134.8
13.5
0.42 1.11
12.5 13.9
5-F
10 137.5
1 3 .8
1.12 2.11
12.5
1 3 .9
F R a tio =: C o e f f . V ar. % =:
1 .5 8 4.521
F' t a b l e v a lu e s D u n n e tt's 'T ' ta b le v a lu e s
Act. Part. Thromboplastin Time
F.01 = P.01 =
12.3 12.3 12.3 12.3
1 4 .0 1 4 .0 1 4 .0 1 4 .0
TREATMENTS ERROR
TOTAL
4 45
49
3 .7 8 3 .1 2
F .05 <= P .0 5 =
2 .5 8 2.51
2.32
0 .5 8
16.48
0 .3 7
--
18.80
1-F
10 217.3
2 1 .7
2 .3 6
2-F
10 239.4
2 3 .9
3.1 9 1.71
18.5 25.0
3-F
10 234.5
2 3 .5
2.35 1.33
18.5 25.0
4-F
10 252.5
2 5 .3
2.45 2.72
18.5 25.0*
5-F
10 252.1
2 5 .2
3.81 2.6 9
18.5 25.0*
F R a tio := C o e f f . V a r. X ==
2 .5 3 12.081
1F ' t a b l e v a lu e s D u n n e tt's *T' t a b l e v a lu e s
F.01 = P.01 =
Nucleated Red Cells
17.7 17.7 17.7 1 7 .7
2 5 .8 2 5 .8 2 5 .8 2 5 .8
TREATMENTS ERROR
TOTAL
4 45
49
3 .7 8 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
84.50 375.66
460.17
2 1 .1 3 8 .3 5
1-F
10 0
0 0.0
TREATMENTS 4
0 .3 2
0 .0 8
2-F
10 0 0 0 .0 0.00
00
00
ERROR 45
3 .6 0
0 .0 8
3-F
10 0 0 0 .0 0.00
00
0 0-
4-F
10 0 0 0 .0 0.00
00
00
TOTAL 49
3.92
5-F
10 2 0 0 .6 1.58
00
00
F R a tio = C o e f f . V a r. X =
1 .0 0 707.107
*F ' t a b l e v a lu e s D u n n e t t's *T' t a b l e v a lu e s
F.01 = P.01 =
3 .7 8 3.12
F.05 = P.05 =
2 .5 8 2.51
-Significant Difference fro Control P < .05 Error-within groups
LABCAT HE4.43
Source-Source of Variation Treatments-between groups
27-JUN-2002
418-028:PAGE K-48
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: FEMALE
Lymphocytes
Group
N T otal
Mean
S td . DUNNETT'S
Dev.
t*
DUNNETT' S RANGES
L0 -95% - HI
L0 -99/- HI
D egree S o u rc e Fd a
-F 10 65.6 6 .6 2.44
!-F
10 98.0 9 .8 3.44 2.61
3 .4 9.7*
i-F
10 83.8 8 .4 2.60 1.46
3.4 9 .7
>-F
10 81.8 8 .2 2.52 1.30
3 .4 9.7
i-F
10 60.3 6 .0 2.77 0.43
3.4 9.7
F R atio = C oeff. V ar. X =
2 .9 6 35.677
*F * t a b l e v a lu e s
D u n n e tt's ''r* t a b l e v a lu e s
F.01 = P.01 =
Segmented Neutrophils
TREATMENTS 4
2 .7 10.4
ERROR 45
2 .7 10.4
2 .7 10.4
TOTAL 49
2 .7 10.4
3 .7 8 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
Sua of Squares
91.51 347.60
439.11
Mean Square
2 2 .8 8 7 .7 2
1-F 10 21.9 2 .2 0.90
2-F
10 36.0 3 .6 3.69 1.72
0.1 4 .3
3-F
10 23.8 2 .4 0.93 0.23
0.1 4 .3
4-F
10 23.5 2 .4 0.96 0.19
0.1 4 .3
5-F
10 25.9 2 .6 0.82 0.49
0.1 4 .3
F R atio = C oeff.. Var. % =
0.95 70.025
F' ta b le vaLues D u n n ett's 'T' ta b le values
F.01 = P.01 =
Bands
TREATMENTS 4
- .4 4.8
ERROR 45
- .4 4.8 -
- .4 4.8
TOTAL 49
-.4 4.8
3 .7 8 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
12.77 151.70
164.47
3 .1 9 3 .3 7
1-F 10 0 .0 0 .0 0.00
TREATMENTS 4
0.0072
0.0018
2-F
10 0 .0 0 .0 0.00 0.00
0.0 0 .0
-.1 0.1
ERROR 45
0.0810
0 .0 0 1 8
3-F
10 0 .0 0 .0 0.00 0 .0 0
0 .0 0 .0
- . 1 0 .1 -------------------------------
4-F
10 0.3 0 .0 0.09 1 .5 8
0.0 0 .0
-.1 0.1
TOTAL 49
0.0882
5-F
10 0 .0 0 .0 0.00 0.00
0.0 0 .0
-.1 0.1
F R atio = C oeff. V ar. X -
1.00 707.107
F' ta b le values D u n n e tt's 'T ' ta b le v alu es
F.01 = P.01 =
3 .7 8 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
-Significant Difference fro Control P < .05 Error-within groups
LABCAT HE4.43
Source-Source of Variation Treataents-between groups
27-JUN-2002
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY N0: 060 -0 6 9
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028:PAGE K-49
ANALYSIS OF VARIANCE FOLLOUED BY DUNNETT'S PROCEDURE
SEX: FEMALE
Group
N T otal
Mean
S td . DUNNETT' S
Dev.
f
DUNNETT' S RANGES
LO -9 5 Z - HI
L0 -99X - HI
D egree S o u rc e Fdm
1-F 10 1.3 0.1 0.15
TREATMENTS 4
2-F
10 2 .7 0 .3 0.49 1.26
- . 1 0 .4
- .2 0.5
ERROR 45
3-F
10 1.7 0 .2 0.13 0.36
-.1 0.4
-.2 0.5 -
4 -F
10 1 .9
0 .2
0.11
0 .5 4
-.1 0 .4
-.2 0.5
TOTAL 49
5-F
10 1.7 0 .2 0.14 0.36
-.1 0 .4
-.2 0.5
-n b
II
F R atio = C oeff. Var. X =
0 .4 3 133.942
'F ' ta b le values D u n n e t t's 'T' t a b l e v a lu e s
P.01 =
3 .7 8 3 .1 2
F.05 = P.05 =
2. 58 2 . 51
Eosinophils
Sun of Squares
0.11 2 .7 9
2 .9 0
Mean Square
0 .0 3 0 .0 6
1-F 10 0.9 0.1 0.10
2-F
10 1.2 0.1 0.13 0.54
0 .0 0.2
3-F 10
0.1 0.13 0.00
0 .0 0 .2
4-F
10 0 .7 0.1
0.11 0.36
0 .0 0 .2
5-F
10 0.8 0.1 0.15 0.18
0 .0 0 .2
F R atio = C oeff. Var. X =
0 .2 3 137.686
'F' ta b le values D u n n e tt's 'T ' ta b le v alu es
F.01 = P.01 =
Basophils
TREATMENTS 4
-.1 0.3
ERROR 45
-.1 n 1 -
-.1 0.3
TOTAL 49
-.1 0.3
3 .7 8 3.12
F.05 = P.05 =
2 .5 8 2.51
0.014 0.691
0.705
0 .0 0 4 0 .0 1 5
1-F 10 0 .0 0 .0 0.00
TREATMENTS 4
0.00000 0.00000
2-F
10 0.0 0 .0 0.00 0.00
0 .0 0 .0
0.0 0.0
ERROR 45
0.00000 0.00000
3-F
10 0.0 0 .0 0.00 0.00
0 .0 0 .0
0 .0 0 .0 -------------------------------
4-F
10 0.0 0 .0 0.00 0.00
0 .0 0 .0
0.0 0 .0
TOTAL 49
0.00000
5-F
10 0.0 0 .0 0.00 0.00
0 .0 0 .0
0.0 0.0
F R atio = C oeff.. Var. Z =
0 .0 0 0.000
' F` ta b le values D u n n e tt's T ta b le values
F.01 = P.01 =
3 .7 8 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
Error-within groups Source-Source of Variation
LABCAT HE4.43
Treatments--between groups
27-JUN-2002
Study Report for Hematology
SUMMARY REPORT PERIOD: TERMINAL
418-028:PAGE K-50
STUDY ID: ARGUS 418 -0 2 8 STUDY N0: 060 -0 6 9
ANALYSIS 0F VARIANCE FOLLOUED BY DUNNETT'S PROCEDURE
SEX: FEMALE
Abnormal Lymphocytes
S td . DUNNETT'S
Group
N T otal
Mean
Dev.
't '
DUNNETT' S RANGES
L0 -95X - HI
L0 -99X - HI
D egree S o u rc e Fdm
Sun o f Squares
Mean Square
1-F 10 0.3 0 .0 0.05
TREATMENTS 4
0.021
0.005
0.0042 - F
10
0 .0
0 .0
0 .0 0
1.09
0 .0 0.1
-.1 0.1
ERROR 45
0.171
3-F
10 0 .6 0.1
0.07 1.09
0 .0 0.1
-.1 0.1 -
--
4 -F
10 0.5 0.1 0 .1 0 0 .7 3
0 .0 0.1
-.1 0.1
TOTAL 49
0 .1 9 2
5-F
10 0.3 0 .0 0.05 0.00
0 .0 0.1
-.1 0.1
F R atio = C oeff. Var. X =
1 .3 9 181.306
Other
F' t a b l e v a lu e s D u n n e tt's 'T 1 ta b le v alu es
F .01 = P .01 =
3 .7 8 3 .1 2
F .05 = P .05 =
2 .5 8 2.51
1-F 10 0 .0 0 .0 0.0 0
TREATMENTS 4
0.00000 0.00000
2-F
10 0 .0 0 .0 0 .0 0 0 .0 0
0.0 0 .0
0 .0 0.0
ERROR 45
0.00000 0.00000
3-F
10 0.0 0 .0 0.00 0.00
0 .0 0 .0
0 .0 0 .0
4 -F
10 0 .0 0 .0 0 .0 0 0.00
0.0 0.0
0.0 0.0
TOTAL 49
0.00000
5-F
10 0 .0 0 .0 0 .0 0 0.0 0
0.0 0.0
0.0 0.0
F R atio = C oeff. Var. X =
0 .0 0 0.000
F' ta b le v alues D u n n e tt's 'T 1 ta b le valu es
F .01 =
P .01 =
3 .7 8 3 .1 2
F .05 =
P .05 =
2 .5 8 2.51
Error-within groups Source-Source of Variation
LABCAT HE4.43
Treatments-between groups
27-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-51
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
Anim al ID
GROUP: 1-M
19109 19115 19116
N u c le a te d Red C e lls L y m phocytes Segmented N e u tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther UBC
N u c lea ted Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E osinophils B asophils Abnormal Lymphocytes O ther UBC
N u c le a te d Red C e lls
L y m phocytes
Segmented N e u tro p h ils
Bands
M onocytes
'
E osinophiIs
B asophiIs
Abnormal Lymphocytes
O ther
UBC
TERMINAL CNT ABS
0 72 9.7 15 2 .0
0 0.0 6 1.1 5 0.7 0 0.0 0 0.0 0 0.0
13.5
0 72 11.4 17 2 .7
0 0.0 10 1 .6
1 0.2 0 0.0 0 0.0 0 0.0
1 5 .9
0 77 11.6 20 3 .0
0 0.0 2 0.3 1 0.2 0 0 .0 0 0.0 0 0.0
15.1
SEX: MALE
LABCAT HEA.43
27-JUH-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-52
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
GROUP: 1-M
SEX: HALE
A nim al ID
19119 19122 19125
N u cleated Red C e lls Lymphocytes Segmented N e u tro p h iIs Bands M onocytes E o sin o p h iIs B asophils Abnormal Lymphocytes O ther WBC
N u cleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes E osinophils B asophils Abnormal Lymphocytes O th er UBC
N u cleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O th er WBC
TERHINAL CNT ABS
0 72 9.1 17 2.2
0 0.0 10 1.3
1 0.1 0 0.0 0 0.0 0 0.0
12.7
0 86 14.1
9 1.5 0 0.0 1 0.2 1 0.2 0 0.0 3 0.5 0 0.0
16.4
0 81 1 4 .3
8 1.4 0 0.0 6 1.1 3 0.5 0 0.0 2 0.4 0 0.0
17.6
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-53
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A nim al ID
GROUP: 1-H
19131 19132 19134
N u c lea te d Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
N u c lea te d Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
N u c lea te d Red C e lls L y m phocytes Segmented N e u tro p h ils Bands M onocytes Eosinophi Is B asophils Abnormal Lymphocytes O ther UBC
TERMINAL CNT ABS
0 74 13.1 15 2 .7
0 0.0 9 1.6 1 0.2 0 0.0 1 0.2 0 0 .0
1 7 .7
0 85 1 2 .7 10 1.5
0 0.0 3 0.4 0 0 .0 0 0 .0 2 0 .3 0 0.0
1 4 .9
0 73 1 1 .0 23 3 .5
0 0 .0 3 0.5 1 0.2 0 0 .0 0 0 .0 0 0.0
1 5 .0
SEX: MALE
LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-54
Study Report for Hematology
WHITE D IFFERENTIA L DATA
STUDY ID: ARGUS 418-028 STUDY NO: 0 6 0 -0 6 9
Anim al ID
GROUP: 1-M
19135 19143 19151
N u c lea ted Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther UBC
N u c lea ted Red C e lls L y m phocytes Segmented N eu tro p h iIs Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
N u cleated Red C e lls Lymphocytes Segmented N eu tro p h iIs Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther UBC
TERMINAL CNT ABS
0 85 1 2 .2 11 1 .6
0 0.0 2 0.3 2 0.3 0 0.0 0 0 .0 0 0 .0
14.3
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
SEX: MALE
(-- ) - Data U navailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
WHITE DIFFERENTIAL DATA
418-028:PAGE K-55
STUDY ID: ARGUS 418-028 STUDY NO: 0 6 0 -0 6 9
A nnual ID
GROUP: 1-M
19157 19161 19167
N u c le a te d Red C e lls L ym phocytes Segmented N eu tro p h iIs Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther WBC
N u c le a te d Red C e lls L ym phocytes Segmented N eu tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther WBC
N u c lea te d Red C e lls L ym phocytes Segmented N eu tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther WBC
TERMINAL CNT ABS
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0 -0-- 0-- 0--
SEX: MALE
(-- ) - Data U navailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
WHITE DIFFERENTIAL DATA
418-028:PAGEK-56
STUDY ID: ARGUS 41 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A nim al ID
GROUP: 2-M
19102 19106 19108
N u cleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O th er WBC
N u cleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes Eosinophi Is B asophils Abnormal Lymphocytes O ther WBC
N u cleated Red C e lls L ym phocytes Segmented N eu tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther WBC
TERMINAL CNT ABS
0 60 6.5 25 2 .7
0 0.0 9 1.0 3 0.3 0 0.0 3 0.3 0 0 .0
10.9
0 71 1 2 .1 17 2 .9
0 0 .0 8 1.4 3 0.5 0 0 .0 1 0.2 0 0.0
1 7 .0
0 86 10.9 11 1 .4
0 0.0 1 0.1 0 0.0 0 0.0 2 0.3 0 0.0
1 2 .7
SEX: MALE
LABCAT HE4.43
Z7-JUN-20Q2
Study Report for Hematology
WHITE DIFFERENTIAL DATA
418-028:PAGE K-57
STUDY ID: ARGUS A 18-028 STUDY MO: 0 6 0 -0 6 9
GROUP: 2-M
SEX: MALE
A nim al ID
TERMINAL CNT ABS
19110
N u c lea te d Red C e lls Lymphocytes Segmented N e u tro p h iIs Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O th er UBC
19113
N u c lea te d Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
19120 '
N u cleated Red C e lts
Lymphocytes
Segmented N e u tro p h ils
Bands
M onocytes
'
E osinophils
Basophi ts
Abnormal Lymphocytes
O th er
UBC
0 76 10.0 15 2 .0
0 0 .0 5 0.7 2 0.3 0 0.0 2 0.3 0 0.0
13.1
0 71 1 1 .1 23 3 .6
0 0.0 5 0.8 1 0 .2 0 0.0 0 0.0 0 0.0
1 5 .7
0 73 1 3 .A 17 3.1
0 0 .0 8 1.5 2 0. A 0 0 .0 0 0 .0 0 0 .0
1 8 .A
LABCAT HEA.A3
27-JUM-2002
418-028:PAGEK-58
Study Report for Hematology
WHITE D IFFER EN TIA L DATA
--------
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A n i m i ID
GROUP: 2-M
TERMINAL CNT ABS
SEX: MALE
19129 19136 19138
N u c lea ted Red C e lls L y m phocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther WBC
N u c lea te d Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes Eosinophi Is B asophiIs Abnormal Lymphocytes O ther WBC
N u c lea ted Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophils Abnormal Lymphocytes O ther WBC
0 64 9.4 27 4 .0
0 0.0 5 0.7 4 0.6 0 0.0 0 0.0 0 0.0
14.7
0 82 8 .6 13 1 .4
0 0.0 3 0.3 2 0.2 0 0.0 0 0.0 0 0.0
10.5
0 66 11.4 30 5.2
0 0.0 1 0.2 3 0.5 0 0.0 0 0.0 0 0.0
17.2
LABCAT HEA.43
27-JUN-20Q2
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-59
STUDY ID: ARGUS 418-028 STUDY NO: 0 6 0 -0 6 9
GROUP: 2-M
A nim al ID
19139 19147 19153
N u c lea te d Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther UBC
N u cleated Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
N u c lea te d Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
TERMINAL CNT ABS
0 86 16.3 13 2 .5
0 0.0 1 0.2 0 0.0 0 0.0 0 0.0 0 0.0
19.0
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
_
(-- ) - Data U n av ailab le LABCAT HE4.43
27-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-60
STUDY ID: ARGUS 418 -0 2 8 STUDY NO: 0 6 0 -0 6 9
Anim al ID
GROUP: 2-M
19164 19165 19171
N u c lea te d Red C e lls L y m phocytes Segmented N eu tro p h iIs Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
N u c lea ted Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther UBC
N u c le a te d Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther UBC
TERMINAL CNT ABS
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0 -0-- 0-- 0-- 0-- 0-- 0-- 0--
SEX: MALE
(-- ) - Data U n av ailab le LABCAT HE4.43
27-JUN-2002
418-028-.PAGEK-61
Study Report for Hematology WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 0 6 0 -0 6 9
Ani n a i ID
GROUP: 3-M
19101 19105 19107
N u c lea te d Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther UBC
N u c lea ted Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O th er UBC
N u c lea te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes Eosinophi Is B asophiIs Abnormal Lymphocytes O th er UBC
TERMINAL
CNT ABS
0 77 10.1 16 2.1
0 0.0 4 0.5 2 0.3 0 0.0 1 0.1 0 0.0
13.1
0 80 8 .8 17 1 .9
0 0.0 2 0.2 0 0.0 0 0 .0 1 0.1 0 0.0
1 1 .0
0 78 9.8
5 0.6 1 0.1 12 1.5 4 0.5 0 0.0 0 0.0 0 0.0
12.5
SEX: MALE
LABCAT HE4.43
27-JUH-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028 :PAGE K-62
STUDY ID: ARGUS A18-0 2 8 STUDY NO: 0 6 0 -0 6 9
A nim al ID
GROUP: 3-M
TERMINAL CNT ABS
SEX: MALE
19112 1911A 19121
N u c le a te d Red C e lls L ym phocytes Segmented N eu tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
N u cleated Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
N u c lea te d Red C e lls L ym phocytes Segmented N eu tro p h ils Bands M onocytes E osinophils B asophils Abnormal Lymphocytes O ther UBC
0 83 11.0 10 1.3
0 0.0 A 0.5 2 0.3 0 0.0 1 0.1 0 0.0
13.3
0 70 7.8 2A 2 .7
0 0.0 5 0.6 1 0.1 0 0.0 0 0.0 0 0.0
11.2
0 71 1A.8 19 A.O
0 0.0 7 1.5 2 0.A 0 0.0 1 0.2 0 0.0
2 0 .9
LABCAT HEA.A3
27-JUN-20Q2
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-63
STUDY ID: ARGUS A18 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A nim ai ID
GROUP: 3-M
19123 19130 19137
N u c lea ted Red C e lls Lymphocytes Segmented N eu tro p h iIs Bands M onocytes E osinophils B asophils Abnormal Lymphocytes O ther UBC
N u c lea ted Red C e lls L y m phocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
N u cleated Red C e lls
Lymphocytes
Segmented N e u tro p h ils
Bands
M onocytes
'
E osinophils
B asophiIs
Abnormal Lymphocytes
O ther
UBC
TERMINAL CNT ABS
0 7A 1 0 .A 2A 3 . A
0 0.0 1 0.1 0 0.0 0 0.0 1 0.1 0 0 .0
1A.1
0 8A 1 1 .7 12 1 .7
0 0.0 3 0.A 1 0.1 0 0.0 0 0.0 0 0.0
1 3 .9
0 87 10.6
9 1.1 0 0 .0 2 0.2 2 0.2 0 0.0 0 0.0 0 0.0
12.2
SEX: MALE
LABCAT HEA.A3
27-JUN-20Q2
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-64
STUDY ID: ARGUS 418-028 STUDY NO: 0 6 0 -0 6 9
GROUP: 3-M
SEX: MALE
Anim al ID
TERMINAL CNT ABS
19146
N u c le a te d Red C e lls L y m phocytes Segmented N e u tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther WBC
0 85 13.1
9 1.4 0 0.0 2 0.3 4 0.6 0 0.0 0 0.0 0 0.0
15.4
19155
N u c lea te d Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E o sin o p h i Ls B asophiIs Abnormal Lymphocytes O ther UBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
19159
N u c le a te d Red C e lls L ym phocytes Segmented N eu tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther WBC
0 0-- 0-- 0-- 0 '-- 0-- 0-- 0-- 0--
C-- ) - D ata U n a v a ila b le LABCAT HE4.43
27-JUH-20Q2
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-65
STUDY ID: ARGUS 418-028 STUDY NO: 0 6 0 -0 6 9
A nim al ID
GROUP: 3-M
19172 19173 19174
N u c lea te d Red C e lls L y m phocytes Segmented N eu tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
N u c lea te d Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O th er UBC
N u c le a te d Red C e lls Lymphocytes Segmented N eu tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther UBC
TERMINAL CNT ABS
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
SEX: MALE
<-- ) - D ata U n a v a ila b le LABCAT HE4.43
27-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028'.PAGE K-66
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A nim al ID
GROUP: 4-M
19100 19103 19104
N u cleated Red C e lls L y m phocytes Segmented N eu tro p h iIs Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
N u c lea te d Red C e lls L ym phocytes Segmented N eu tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther UBC
N u cleated Red C e lls L ym phocytes Segmented N eu tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O th er UBC
TERMINAL CNT ABS
0 61 7 .7 32 4.0
0 0.0 5 0.6 1 0.1 0 0.0 1 0.1 0 0.0
1 2 .6
0 78 16.4 11 2 .3
0 0.0 8 1.7 0 0 .0 0 0.0 3 0.6 0 0.0
2 1 .0
0 67 12.1 17 3.1
0 0.0 12 2 .2
2 0.4 0 0.0 2 0.4 0 0.0
18.1
SEX: MALE
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-67
STUDY ID: ARSUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A nim al ID
GROUP: 4-M
19118 19133 19141
N u c lea te d Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes E o sin o p h i Ls B asophiIs Abnormal Lymphocytes O ther UBC
N u c lea ted Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes E osinophils B asophils Abnormal Lymphocytes O ther UBC
N u c lea te d Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
TERMINAL CNT ABS
0 78 9 .4
12 1.4
0 0.0
4 0.5
2 0.2 0 0.0 4 0.5 0 0.0
12.0
0
79 17.4
13 2 .9 0 0.0 3 0.7 4 0.9 0 0.0 1 0.2 0 0.0 2 2 .0
0 73 12.7 21 3 .7
0 0.0 3 0.5 2 0.3 0 0.0 1 0.2 0 0.0
17.4
SEX: MALE
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-68
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
Anim al ID
GROUP: 4-M
19142 19144 19148
N ucleated Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
N u c lea ted Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
N u c leated Red C e lls L y m phocytes Segmented N e u tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther UBC
TERMINAL CNT ABS
0 67 8 .6 22 2 .8
1 0.1 8 1.0 1 0.1 0 0.0 1 0.1 0 0 .0
12.8
0 81 1 5 .9 14 2 .7
0 0.0 3 0.6 2 0.4 0 0 .0 0 0 .0 0 0.0
1 9 .6
0 79 12.3 20 3.1
0 0.0 0 0.0 1 0.2 0 0.0 0 0.0 0 0.0
1 5 .6
SEX: MALE
LABCAT HE4.43
27-JUN-20Q2
Study Report for Hematology
418-028:PAGE K-69
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 0 6 0 -0 6 9
Anim al ID
GROUP: 4-M
TERMINAL CNT ABS
SEX: MALE
19150 19156 19160
N u c le a te d Red C e lls L y m phocytes Segmented N e u tro p h ils Bands M onocytes E osinophils B asophiIs Abnormal Lymphocytes O ther UBC
N u c le a te d Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
N u c le a te d Red C e lls L y m phocytes Segmented N eu tro p h iIs Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
0 75 8 .3 22 2 .4
0 0.0 2 0.2 1 0.1 0 0.0 0 0.0 0 0.0
11.1
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0 -- 0-- 0-- 0-- 0--
m
(-- ) - Data U navailable LABCAT HE4.43
27-JUH-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-70
STUDY ID: ARGUS 418-028 STUDY NO: 0 6 0 -0 6 9
A nim al ID
GROUP: 4-M
19162 19163 19166
N u c lea te d Red C e lls L ym phocytes Segmented N eu tro p h iIs Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther WBC
N u c lea ted Red C e lls L y m phocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophils Abnormal Lymphocytes O th er WBC
N u cleated Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther WBC
TERMINAL CNT ABS
0 0-- 0-- 0-- 0-- 0 -0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
SEX: MALE
(-- ) - Data U navailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
418-028'.PAGE K-71
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418 -0 2 8 STUDY NO: 0 6 0 -0 6 9
GROUP: 5 -
SEX: MALE
A nim al ID
TERMINAL CNT ABS
19111
N u cleated Red C e lls L y m phocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lym phocytes O th er WBC
0 83 13.0
9 1.4 0 0.0 4 0.6 1 0.2 0 0.0 3 0.5 0 0.0
15.7
19117
N u cleated Red C e lls L ym phocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lym phocytes O th er UBC
0 79 11.3 12 1 .7
0 0.0 6 0.9 3 0.4 0 0.0 0 0.0 0 0.0
14.3
19124
N u c lea ted Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O th er UBC
0 94 10.2
3 0.3 0 0.0 2 0.2 1 0.1 0 0.0 0 0.0 0 0.0
10.8
LABCAT HE4.43
27-JUN-20Q2
Study Report for Hematology
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418 -0 2 8 STUDY NO: 0 6 0 -0 6 9
GROUP: 5-M
A nim aL ID
19126 19127 19128
N u cleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O th er UBC
N u cleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes E o sin o p h i Ls B asophiIs Abnormal Lymphocytes O ther UBC
N u cleated Red C e lls Lymphocytes Segmented N e u tro p h ils Bands M onocytes E osinophiIs B asophiIs Abnormal Lymphocytes O ther UBC
TERMINAL CNT ABS
0 81 1 0.1
9 1.1 0 0.0 7 0.9 3 0.4 0 0.0 0 0.0 0 0.0
12.5
0 73 8 .0 22 2 .4
0 0.0 2 0.2 1 0.1 0 0.0 2 0.2 0 0.0
11.0
0 87 12.4 10 1 .4
0 0.0 2 0.3 1 0.1 0 0.0 0 0.0 0 0.0
14.2
418-028:PAGE K-72
" -~ SEX: MALE
LABCAT HE4.43
27-JUH-2002
Study Report for Hematology
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 5-M
Animal ID
TERHINAL CNT ABS
19140 19145 19149
Nucleated Red CeLls Lymphocytes Segmented Neutrophils Bands Honocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes Eosinophils Basophi Is Abnormal Lymphocytes Other WBC
0
80 12.2 14 2.1
0 0.0
1 0.2 2 0.3
0 0.0
3 0.5
0 0.0
15.2
0
83 17.2 12 2.5
0 0.0
4 0.8
1 0.2 0 0.0 0 0.0 0 0.0
20.7
0 88 16.1 12 2.2
0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0
18.3
418-028:PAGE K-73
SEX: HALE
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
418-028:PAGE K-74
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 5-M
SEX: MALE
Animal ID
TERMINAL CT ABS
19152
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
0 94 13.1
3 0.4 0 0.0 3 0.4 0 0.0 0 0.0 0 0.0 0 0.0
13.9
19154
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
19158
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-75
Study Report for Hematology
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 41B-028 STUDY NO: 060-069
Aninal ID
GROUP: 5-M
19168 19169 19170
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other UBC
Nucleated Red Cells
Lymphocytes
Segmented Neutrophils
Bands
Monocytes
'
Eosinophils
BasophiIs
Abnormal Lymphocytes
Other
UBC
TERMINAL CNT ABS
0 0--
0-- 0-- 0-- 0--
0-- 0--
0--
--
0
0-- 0-- 0-- 0--
0--
0--
0-- 0--
--
0 0-- 0--
0-- 0-- 0-- 0-- 0--
0--
SEX: MALE
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
WHITE D IFFE R E N T IA L DATA
418-028-.PAGEK-76
STUDY ID: ARGUS 418-028 STUDY HO: 060-069
Animal ID
GROUP: 1-F
19010 19012 19019
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
TERMINAL CNT ABS
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0
79 12.6 17 2.7
0 0.0
3 0.5 1 0.2
0 0.0 0 0.0 0 0.0
15.9
0
66 4.4 31 2.0
0 0.0
3 0.2
0 0.0 0 0.0 0 0.0 0 0.0
6.6
SEX: FEMALE
LABCAT HE4.43
27-JUN-2002
418-028-.PAGE K-77
Study Report for Hematology
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 1-F
Animal ID
19021 19023 19041
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
TERMINAL CNT ABS
0
77 5.7 19 1.4
0 0.0 0 0.0
4 0.3
0 0.0 0 0.0 0 0.0
7.4
0 83 6.1 12 0.9
0 0.0
2 0.1 2 0.1
0 0.0
1 0.1
0 0.0
7.3
0
63 5.0 36 2.9
0 0.0
1 0.1
0 0.0 0 0.0 0 0.0 0 0.0
8.0
~~""-- SEX: FEMALE
LABCAT HE4.43
27-JUN-2002
418-028:PAGE K-78
Study Report for Hematology
WHITE D IFFERENTIA L DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 1-F
19042 19044 19050
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs Basophils Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
TERMINAL CNT ABS
0
78 5.3 22 1.5
0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0
6.8
0
69 7.3 29 3.1
0 0.0 1 0.1
1 0.1
0 0.0 0 0.0 0 0.0
10.6
0
74 6.1 22 1.8
0 0.0
3 0.2 1 0.1
0 0.0 0 0.0 0 0.0
8.2
SEX: FEMALE
LABCAT HE4.43
27-JUN-20Q2
418-028:PAGE K-79
Study Report for Hematology
WHITE DIFFERENTIA L DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Aninal ID
GROUP: 1-F
19053 19065 19068
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes Eosinophils Basophils Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes Eosinophils Basophi Is Abnormal Lymphocytes Other UBC
TERH1NAL CNT ABS
0
71 4.7 28 1.8
0 0.0 0 0.0 0 0.0 0 0.0
1 0.1
0 0.0
6.6
0
67 8.4 30 3.8
0 0.0
1 0.1 1 0.1
0 0.0
1 0.1
0 0.0
12.5
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
SEX: FEHALE
(-- > - Data Unavailable LABCAT HE4.43
27-JUN-2002
418-028-.PAGEK-80
Study Report for Hematology
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 1-F
TERMINAL CNT ABS
19072 19074 19075
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0--
0--
0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
SEX: FEMALE
(-- ) - Data Unavailable LA8CAT HE4.43
27-JUN-2002
Study Report for Hematology
WHITE D IFFERENTIA L DATA
418-028:PAGE K-81
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 2-F
19004 19009 19016
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other
use
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs Basophils Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other UBC
TERMINAL CNT ABS
0 74 5.8 25 2.0
0 0.0
1 0.1
0 0.0 0 0.0 0 0.0 0 0.0
7.8
0 87 12.7 11 1.6
0 0.0
1 0.1 1 0.1
0 0.0 0 0.0 0 0.0
14.6
0
80 13.6 18 3.1
0 0.0 0 0.0
2 0.3
0 0.0 0 0.0 0 0.0
17.0
SEX: FEMALE
LABCAT HEA.43
27-JUN-2002
418-028-.PAGEK-82
Study Report for Hematology
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Ani M l ID
GROUP: 2-F
19018 19026 19036
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs Basophils Abnormal Lymphocytes Other UBC
TERMINAL CNT ABS
0 82 10.9 17 2.3
0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0
13.3
0 85 7.7 15 1.4
0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0
9.1
0 84 15.1 12 2.2
0 0.0 2 0.4 2 0.4 0 0.0 0 0.0 0 0.0
18.0
SEX: FEMALE
LABCAT HE4.43
27-JUN-20Q2
418-028-.PAGEK-83
Study Report for Hematology
WHITE D IFFERENTIA L DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
A n i m i ID
GROUP: 2-F
19037 19043 19047
Nucleated Red Cells Lynphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lynphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophi Is BasophiIs Abnormal Lynphocytes Other UBC
Nucleated Red Cells Lynphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other UBC
TERMINAL CNT ABS
0 42 11.0 52 13.7
0 0.0 6 1.6 0 0.0 0 0.0 0 0.0 0 0.0
26.3
0 71 9.6 26 3.5
0 0.0 2 0.3 1 0.1 0 0.0 0 0.0 0 0.0
13.5
0 56 6.2 41 4.6
0 0.0 2 0.2 1 0.1 0 0.0 0 0.0 0 0.0
11.1
SEX: FEMALE
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
418-028-.PAGEK-84
WHITE D IFF E R E N T IA L DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 2-F
TERMINAL CNT ABS
SEX: FEMALE
19048
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
0 76 5.4 23 1.6
0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0
7.1
19052 19055
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs Basophils Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
(-- ) - Data Unavailable LABCAT HEA.43
27-JUN-2002
418-028-.PAGE K-85
Study Report for Hematology
WHITE D IFFER E N T IA L DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Aniaal ID
GROUP: 2-F
19061 19067 19071
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs Basophi Is Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophi Is Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
TERMINAL CNT ABS
0 0-- 0-- 0--
0--
0--
0-- 0--
0--
0
0--
0-- 0--
0--
0-- 0-- 0-- 0--
--
0 0-- 0-- 0--
0-- 0--
0 '-- 0--
0--
SEX: FEMALE
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 3-F
Anisal ID
TERMINAL CNT ABS
19003
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
0 59 6.5 36 4.0
0 0.0 3 0.3 1 0.1 0 0.0 1 0.1 0 0.0
11.1
19007
Nucleated Red CelLs Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
0 72 5.7 25 2.0
0 0.0 2 0.2 0 0.0 0 0.0 1 0.1 0 0.0
7.9
19008
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
0 72 5.0 27 1.9
0 0.0 0 0.0 0 0.0 0 0.0 1 0.1 0 0.0
7.0
418-028:PAGE*K-86
SEX: FEMALE
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 3-F
Aninai ID
TERMINAL CNT ABS
19013 19014 19015
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC
Nucleated Red Cells
Lymphocytes
Segmented Neutrophils Bands
Monocytes
'
Eosinophils BasophiIs
Abnormal Lymphocytes Other
WBC
0 74 12.3 23 3.8
0 0.0 2 0.3 0 0.0 0 0.0 1 0.2 0 0.0
16.6
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 77 5.7 22 1.6
0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0
7.4
418-028:PAGE K-87
SEX: FEMALE
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
418-028:PAGE K-88
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
GROUP: 3-F
SEX: FEMALE
Animal ID
TERMINAL CNT ABS
19017
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
0 76 9.8 20 2.6
0 0.0 1 0.1 3 0.4 0 0.0 0 0.0 0 0.0
12.9
19024
Nucleated Red Cells
Lymphocytes
Segmented Neutrophils
Bands
-
Monocytes
EosinophiIs
Basophils
Abnormal Lymphocytes
Other
WBC
0 70 7.4 25 2.6
0 0.0 2 0.2 2 0.2 0 0.0 1 0.1 0 0.0
10.5
19029
Nucleated Red Cells
Lymphocytes
Segmented Neutrophils
Bands
Monocytes
'
EosinophiIs
BasophiIs
Abnormal Lymphocytes
Other
WBC
0 82 10.3 17 2.1
0 0.0 0 0.0 1 0.1 0 0.0 0 0.0 0 0.0
12.5
LABCAT HE4.43
27-JUN-20Q2
418-028:PAGE K-89
Study Report for Hematology WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 3-F
TERMINAL CNT ABS
SEX: FEMALE
19034 19038 19056
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
0 90 10.9
8 1.0 0 0.0 1 0.1 1 0.1 0 0.0 0 0.0 0 0.0
12.1
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 80 10.2 17 2.2
0 0.0 3 0.4 0 0.0 0 0.0 0 0.0 0 0.0
12.7
(-- > - Data Unavailable LABCAT HE4.43
27-JUN-20Q2
Study Report for Hematology
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS A18-028 STUDY NO: 060-069
GROUP: 3-F
Animal ID
TERMINAL CNT ABS
19057 19060
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes Eosinophils Basophi Is Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
1906A
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
418-028-.PAGEK-90
SEX: FEMALE
(-- ) - Data Unavailable LABCAT HEA.A3
27-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGEK-91
STUDY ID: ARGUS A18-028 STUDY NO: 060-069
Animal ID
GROUP: A-F
19002 19005 19035
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs Basophils Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
TERMINAL CNT ABS
0 0 -0-- 0 -0-- 0-- 0-- 0-- 0--
--
0 81 7.7 17 1.6
0 0.0 1 0.1 1 0.1 0 0.0 0 0.0 0 0.0
9.5
0 7A 7.1 2A 2.3
0 0.0 1 0.1 0 0.0 0 0.0 1 0.1 0 0.0
9.6
SEX: FEMALE
LABCAT HEA.A3
27-JUN-2002
Study Report for Hematology
418-028:PAGE K-92
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Anisal ID
GROUP: 4-F
TERMINAL CNT ABS
SEX: FEMALE
19039 19040 19045
Nucleated Red Cells Lynphocytes Segmented Neutrophils Bands Monocytes EoslnophlIs BasophlIs AbnorMl Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophl Is AbnorMl Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EoslnophlIs BasophlIs AbnorMl Lymphocytes Other UBC
0 75 9.6 22 2.8
0 0.0 2 0.3 1 0.1 0 0.0 0 0.0 0 0.0
12.8
0 77 7.7 22 2.2
0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0
10.0
0 56 5.4 39 3.8 3 0.3 2 0.2 0 0.0 0 0.0 0 0.0 0 0.0
9.7
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
418-028:PAGE R-93
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS A18-028 STUDY NO: 060-069
Animal ID
GROUP: A-F
TERHINAL CNT ABS
SEX: FEMALE
190A6 19051 1905A
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes EosinophiIs Basophils Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0 --
--
0 82 12.2 13 1.9
0 0.0 3 O.A 0 0.0 0 0.0 2 0.3 0 0.0
1A.9
(-- ) - Data Unavailable LABCAT HEA.A3
27-JUN-20Q2
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-94
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 4-F
19058 19062 19063
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs Basophils Abnormal Lymphocytes Other WBC
Nucleated Red Cells
Lymphocytes
Segmented Neutrophils
Bands
Monocytes
'
Eosinophils
BasophiIs
Abnormal Lymphocytes
Other
UBC
TERMINAL CNT ABS
0 73 11.5 25 3.9
0 0.0 1 0.2 1 0.2 0 0.0 0 0.0 0 0.0
15.7
0 77 4.8 22 1.4
0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0
6.2
0 76 9.8 20 2.6
0 0.0 2 0.3 2 0.3 0 0.0 0 0.0 0 0.0
12.9
SEX: FEMALE
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-95
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 4-F
19066 19069 19073
Nucleated Red Cells Lyaphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
TERMINAL CNT ABS
0 84 6.0 14 1.0
0 0.0 1 0.1 0 0.0 0 0.0 1 0.1 0 0.0
7.1
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
SEX: FEMALE
(-- ) - Data Unavailable LABCAT HEA.43
27-JUN-2002
Study Report for Hematology
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 413-028 STUDY NO: 060-069
GROUP: 5-F
Aninel ID
TERMINAL CNT ABS
19001 19006 19011
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC
0 67 10.1 28 4.2
0 0.0 3 0.5 2 0.3 0 0.0 0 0.0 0 0.0
15.1
0 61 4.6 36 2.7
0 0.0 3 0.2 0 0.0 0 0.0 0 0.0 0 0.0
7.6
0 69 4.4 28 1.8
0 0.0 2 0.1 0 0.0 0 0.0 1 0.1 0 0.0
6.4
418-028:PAGE K-96
SEX: FEMALE
LABCAT HEA.43
2/-JUN-2002
418-028'.PAGE K-97
Study Report for Hematology WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 5-F
TERMINAL CNT ABS
SEX: FEMALE
19020 19022 19025
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other UBC
2 52 2.2 46 1.9
0 0.0 2 0.1 0 0.0 0 0.0 0 0.0 0 0.0
4.2
0 58 3.1 37 2.0
0 0.0 3 0.2 2 0.1 0 0.0 0 0.0 0 0.0
5.4
0 71 5.2 27 2.0
0 0.0 1 0.1 0 0.0 0 0.0 1 0.1 0 0.0
7.3
LABCAT HEA.43
27-JUH-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028 :PAGE K-98
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 5-F
19027 19028 19030
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Honocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils Basophils Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes Eosinophils BasophiIs Abnormal Lymphocytes Other WBC
TERMINAL CNT ABS
0 83 10.2 16 2.0
0 0.0 1 0.1 0 0.0 0 0.0 0 0.0 0 0.0
12.3
0 70 7.1 27 2.8
0 0.0 3 0.3 0 0.0 0 0.0 0 0.0 0 0.0
10.2
0 64 5.2 34 2.8
0 0.0 1 0.1 0 0.0 0 0.0 1 0.1 0 0.0
8.1
SEX: FEMALE
LABCAT HE4.43
27-JUN-2002
Study Report for Hematology
418-028:PAGE K-99
WHITE DIFFERENTIAL DATA
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 5-F
19031 19032 19033
Nucleated Red Cells Lymphocytes Segmented NeutrophiIs Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs Basophils Abnormal Lymphocytes Other UBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other UBC
TERMINAL CNT ABS
0 67 8.2 30 3.7
0 0.0 0 0.0 3 0.4 0 0.0 0 0.0 0 0.0
12.3
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
SEX: FEMALE
(-- ) - Data Unavailable LABCAT HEA.43
27-JUH-2002
Study Report for Hematology WHITE DIFFERENTIAL DATA
418-028:PAGE K-100
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
GROUP: 5-F
19049 19059 19070
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
Nucleated Red Cells Lymphocytes Segmented Neutrophils Bands Monocytes EosinophiIs BasophiIs Abnormal Lymphocytes Other WBC
Nucleated Red Cells
Lymphocytes
Segmented Neutrophils
Bands
Monocytes
'
EosinophiIs
Basophils
Abnormal Lymphocytes
Other
WBC
TERMINAL CNT ABS
0 0 .0 0 0 0 0 0 0
-- -- -- -- -- -- -- -- --
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
--
0 0-- 0-- 0-- 0-- 0-- 0-- 0-- 0--
SEX: FEMALE
(-- ) - Data Unavailable LABCAT HE4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Anim al ID
TP g/dL
GROUP: 1-M 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167
5 .9 6.5 5 .8 6 .0 6 .2 6 .5 6 .5 6.1 6 .3 7 .0
-- -- -- -- --
MEAN SD N
6 .3 0 .3 6
10
418-028-.PAGEK-101 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: ALE
ALB g/dL
GLU mg/dL
CHOL mg/dL
T-BIL mg/dL
BUN mg/dL
CREAT mg/dL
CK U/L
3 .9 4.4 4 .0 4.1 4 .3 4.3 4 .2 4 .3 4 .3 4 .7
-- --
--
-- --
4 .3 0 .2 2
10
164 165 119 134 140 169 128 141 140 153
-- -- -- -- --
145 1 6 .8
10
46 0.1 62 0 .2 61 0 .2 44 0.1 62 0.1 56 0 .3 59 0.1 51 0 .1 56 0.2 72 0 .2 ---- ----
----
---- ----
57 0 .2 8.3 0.07
10 10
16 0 .3 19 0 .4 16 0 .3 14 0 .3 15 0 .3 15 0 . 4 18 0 .3 15 0 .3 15 0 .3 15 0 .3 ---- ---- ---- ---- ----
263 164 330 105 177 260 385 250 722 221
-- -- -- -- --
16 0 .3
288
1.5
0 .0 4
172.6
10 10 10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 060 -0 6 9
A nim al ID
TP g/dL
GROUP: 2-M 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
MEAN
SD
N
6.1 6 .2 5 .8 6.1 5 .6 6 .5 5 .7 6 .2 6 .3 6.1
-- -- -- -- --
6.1 0 .2 8
10
418-028:PAGE K-102
Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: HALE
ALB g/dL
GLU mg/dL
CHOL mg/dL
T-BIL mg/dL
BUN mg/dL
CREAT mg/dL
CK U/L
4.1 4 .0 3 .9 4.1 3 .9 4 .3 3 .9 4 .3 4 .4 4 .2
--
-- -- --
4 .1 0 .1 9
10
172 166 152 104 157 115 149 123 108 165
-- --
-- --
141 2 6 .0
10
40 44 38 33 30 28 33 52 60 55
--
-- -- --
41 11.1
10
0 .2 0.1 0.1 0.1 0.1 0 .2 0.1 0.1 0.2 0 .2
--
-- -- --*
0.1 0.05
10
16 0 .3 17 0 .3 15 0 .3 16 0 .3 16 0 .3 17 0 .4 17 0 .3 17 0 .3 15 0 .4 16 0 .4 ----
---- ----
----
169 151 235 307 133 350 292 134 478 213
---
--
--
. "**
16 0 .3
246
0 .8
0.05
111.5
10 10 10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
418-028:PAGE K-103 Study Report for Clinical Chemistry
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
A nim al ID
GROUP: 3-H 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174
MEAN SD N
TP g/dL
6.2 H 6.1 5 .8 6.3 6 .3 6 .6 6 .2 5 .7 6 .7 6 .6
-- -- -- --.
--
6 .3 0.33
10
ALB g/dL
4 .0 H 4 .3 4.1 4.3 4 .3 4 .4 4 .4 4.1 4 .4 4 .4
-- -- -- -- --
4 .3 0.15
10
GLU g/dL
304 H 254 198 137 142 121 156 149 158 204
-- -- -- -- --
182 58.2
10
CHOL mg/dL
27 H 52 50 46 65 45 46 34 59 35
-- --
-- --
--
46 1 1 .6
10
T-BIL g/dL
0.3 H 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
-- --
-- -- --
0.1 0 .0 6
10
BUN g/dL
CREAT mg/dL
CK U/L
18 H 16 15 12 16 18 17 17 17 16
_ _
--
--
--
16 1 .8
10
0 .4 H 0 .3 0.3 0.3 0 .3 0 .4 0 .2 0 .3 0 .3 0.3
. .. _ _
--
0 .3 0 .0 6
10
129 H 118 132 286 250 289 329 480 200 175
--
239 1 1 2 .9
10
(-- ) - Data Unavailable LABCAT CC4.43
H - Henolyzed
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Anim al ID
TP ' g/dL
GROUP: 4-M 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166
HEAN SD N
6 .0 5 .7 5 .9 6 .0 6 .3 6 .2 6 .6 6 .2 6 .5 6 .4
-- -- -- --
--
6 .2 0 .2 8
10
418-028-.PAGE K-104 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: HALE
ALB g/dL
GLU g/dL
CHOL ng/dL
T-BIL g/dL
BUN mg/dL
CREAT g/dL
CK U/L
4 .0 4 .0 4.1 4 .2 4 .4 4.3 4 .4 4.1 4 .4 4 .4
-- -- -- -- --
4 .2 0 .1 7
10
175 202 167 131 179 147 132 130 175 181
--
--
-- --
162 2 5 .2
10
42 28 42 39 49 70 56 29 42 30 -- -- -- --
43 13.1
10
0.1 0.1 0.1 0.1 0.1 0 .2 0 .2 0.1 0.1 0.2
--
-- -- --
0.1 0.05
10
16 0 .3
111
20 0 .3 16 0 .3
145 196
20 0 .4 17 0 .3 16 0 .3 17 0 .3
187 146 182 270
18 0 .3
242
16 0 .3
267
18 0.3
218
---- --
----
--
----
--
----
--
-- ----
17 0 .3
196
1.6 0.03 53.5
10 10 10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A n ia a l ID
TP g/dL
GROUP: 5-M 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170
MEAN SO N
6.6 H 6.1 H 6 .6 6 .4 6 .6 6.5 6.0 6 .4 6 .3 5.8
-- -- -- --
--
6 .3 0 .2 8
10
418-028:PAGE K-105
Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: ALE
ALB g/dL
GLU g/dL
CHOL g/dL
T-BIL g/dL
BUN mg/dL
CREAT mg/dL
CK U/L
4 .6 H 4 .3 H 4 .8 4 .6 4 .6 4 .8 4 .3 4 .5 4.5 4 .2
-- -- -- --
173 H 177 H 226 165 156 181 110 134 195 132
-- -- --
--
4 .5 0 .2 0
10
165 3 3 .7
10
38 H 37 H 25 29 47 35 24 27 38 31 -- -- -- --
0.2 H 0.3 H 0.1 0.1 0 .2 0.2 0 .2 0 .2 0.2 0.2
-- -- -- --
33 0 .2 7.2 0.06
10 10
26 H 23 H 20 20 22 21 18 19 19 19 -- -- -- -- --
21 2 .4
10
0 .4 H 0.3 H 0 .4 0 .3 0 .3 0 .4 0 .3 0 .3 0 .3 0 .3
-- -- -- -- --
211 1 269 1
94 156 379 472 304 239 175 128
-- -- -- -- --
0 .3 0.05
10
243 117.4 10
(-- ) - Data Unavailable LABCAT CC4.43
H - Henolyzed
27-JUN-2002
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY MO: 0 6 0 -0 6 9
A nim al ID
TP g/dL
GROUP: 1-F 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
5 .4 6.3 7.1 6.1 5.9 6.3 6 .6 5 .8 5.5 5.7
-- -- -- --
MEAN SD N
6.1 0.52
10
418-028:PAGE K-106 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: FEMALE
ALB g/dL
3 .7 4 .3 4 .9 4 .3 4 .3 4 .3 4 .4 3 .9 3 .7 3.5
-- -- -- --
4.1 0 .4 2
10
GLU g/dL
_
149 139 157 156 165 155 144 184 108 163
-- -- -- --
152 1 9 .8
10
CHOL g/dL
63 92 136 85 62 77 93 78 43 40 -- -- -- --
77 2 7 .8
10
T-BIL g/dL
0.2 0.1 0.1 0.2 0.2 0.1 0.3 0.2 0.1 0.1
-- -- -- --
0 .2 0.07
10
BUN g/dL
32 29 33 26 28 25 27 34 28 19 -- -- --
--
28 4 .4
10
CREAT mg/dL
CK U/L
0 .4 0.3 0 .4 0 .4 0.3 0 .4 0 .4 0.3 0 .3 0.3
-- -- --
--
0 .4 0.05
10
166 212 210 222 201 178 332 198 123 175
--
-- -- --
202 54.1
10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A nim ai ID
TP g/dL
GROUP: 2-F 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
5.9 5 .7 5.5 5.6 5.5 5 .9 5 .0 5 .7 4 .3 5 .9
-- -- -- -- --
MEAN SO N
5.5 0 .5 0
10
418-028:PAGE K-107
Study Report for Clinical Chemistry INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: FEMALE
ALB g/dL
GLU mg/dL
CHOL g /d L
T-BIL g/dL
BUN g/dL
CREAT mg/dL
CK U/L
4 .3 3 .9 4 .2 4 .2 3 .9 4 .2 3.5 3 .8 3 .3 4 .2
--
--
-- -- --
4 .0 0 .3 4
10
178 166 173 152 170 203 153 149 135 142
--
--
-- -- --
162 2 0 .0
10
56 62 83 77 85 84 54 92 57 73
--
-- -- -- --
72 1 4 .0
10
0 .2 0 .2 0.2 0.2 0.1 0.2 0.2 0.2 0.2 0.2
-- -- -- -- --
0.2 0.03
10
20 0.3
144
26 0.4
311
26 0.3
237
27 0 .4
151
32 0.3 208
22 0 .4 228
22 0 .3 369
21 0 .4 269
16 0 .3 392
29 0 .4
186
-- ----
-- ----
------
------
---- --
24 0 .4 250 4 .7 0.05 85.6
10 10 10
(-- ) - Data Unavailable LABCAT CC4.43.
27-JUN-2002
418-028:PAGE K-108 . Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418 -0 2 8 STUDY NO: 0 6 0 -0 6 9
SEX: FEMALE
A nim al ID
GROUP: 3-F 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
MEAN
SD
N
TP
g/dL
5 .6 5.3 5 .7 5 .8
--
5 .6 5 .8 6 .7 5 .8 6 .4
--
6.1
-- -- --
5 .9 0.41
10
ALB g/dL
3 .9 3 .8 4 .0 4.1
--
3 .7 4.1 4.5 4 .0 4.3
--
4 .2
--
-- --
4.1 0 .2 4
10
GLU 9/dL
179 121 171 146
--
155 164 140 142 151
--
179
-- -- --
155 18.7
10
CHOL g/dL
54 45 56 59
--
61 87 96 79 105
--
63
-- -- --
71 2 0 .0
10
T-BIL g/dL
0.1 0.1 0.1 0 .2
--
0 .2 0 .2 0 .2 0 .2 0.1
--
0.1
-- -- --
0 .2 0 .0 5
10
BUN g/dL
CREAT g/dL
36 0 .3 41 0 .3 20 0.3 24 0 .4
__ _ _
28 0 .3 22 0 .4 33 0 .4 26 0 .3 23 0 .4
--
28 0.3
-- ___
-- ___
----
28 0 .3 6 .7 0.05
10 10
CK U/L
199 159 206 160
212 190 215 212 169
_
197
__
_ ..
.--
192 2 1 .7
10
(-- ) - Data Unavailable LABCAT CCA.43
27-JUN-2002
STUDY ID: ARGUS 418 -0 2 8 STUDY NO: 060 -0 6 9
A nim al ID
TP g/dL
GROUP: 4 - F 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
MEAN SD N
6.1 5 .7 5 .5 5.8 5.6
--
--
6.3 5 .6 6 .0 5 .2 5 .9
--
--
5.8 0.32
10
418-028-.PAGE K-109 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: FEMALE
ALB g/dL
GLU g/dL
CHOL 9/dL
T-BIL ag/dL
BUN g/dL
CREAT g/dL
CK U/L
4 .3 4 .0 4 .0 3 .9 3 .7
-- -- 4 .5 3 .9 4 .4 3 .6 4.1
--
4 .0 0 .2 9
10
167 161 163 127 160
-- --
129 150 127 145 132
--
146 16.2
10
70 47 71 63 91 -- -- 41 64 49 62 63
--
62 1 4 .2
10
0.2 0.1 0.2 0.1 0 .2
-- --
0.1 0.1 0.1 0.1 0.1
--
0.1 0.05
10
30 0 .4 27 0 .4 26 0 .4 20 0.3 25 0 .5 ---- ---- 25 0 .4 20 0.3 34 0.3 23 0 .4 22 0 .2 ----
--
259 193 160 233 398
--
--
124 267 176 172 147
--
--
25 0 .4
213
4.4 0.08 80.4
10 10 10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A n ia a l ID
TP g/dL
GROUP: 5 - F 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
MEAN SO N
5.5 5 .7 5 .8 5 .6 5 .8 5 .8 5.5 5 .9 6 .3 6 .3
-- -- --
--
--
5 .8 0 .2 9
10
418-028:PAGE K -l 10 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: FEMALE
ALB g/dL
GLU ag/dL
CHOL mg/dL
T-BIL ag/dL
BUN ag/dL
CREAT ag/dL
CK U/L
4 .0 4 .0 4 .3 3 .5 4.1 3 .7 3 .8 4 .0 4 .5 4 .4
-- -- --
--
--
4 .0 0.31
10
165 119 154
53 132 133 152 159 180 157
-- --
--
--
140 3 5 .5
10
55 58 48 33 60 49 71 70 58 108
--
--
--
--
61 1 9 .8
10
0.1 0.1 0.1 0 .2 0.1 0.1 0.1 0.2 0.1 0.2
--
-- -- --
0.1 0.05
10
23 19 29 73 25 28 27 23 26 25 -- --
--
--
30 1 5 .4
10
0 .3 0 .3 0 .4 0 .2 0 .3 0 .4 0 .3 0 .3 0 .3 0 .3
-- --
--
--
0 .3 0 .0 6
10
341 373 149 438 186 143 252 261 168 210
-- -- -- -- --
252 101.6
10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A n ia a l ID
ALT U/L
GROUP: 1-M 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167
MEAN SD N
36 38 40 33 51 49 39 42 49 43 -- -- -- -- --
42 6 .0
10
418-028:PAGEKM11 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD; TERMINAL
SEX: MALE
AST ALP
CA PHOS TRIG
NA
K
U/L
U/L
g/dL
g/dL
g/dL
ninol/L
nm ol/L
78 77 93 83 86 113 116 80 146 85 -- -- -- -- --
96 2 2 .4
10
91 77 102 112 103 115 107 98 126 119 -- -- --
--
105 14.3
10
10.6 11.8 10.3 1 0 .8 11.3 1 0 .6 11.1 11.1 1 0 .4 11.4
-- -- -- --
10.9 0 .4 8
10
12.0 11.6
9.7 7 .9 9 .4
8.7
7 .9 9 .8 8.5 9 .2
-- -- -- --
9 .5 1 .4 0
10
23 48 59 43 28 65 93 45 36 76 -- -- -- --
52 2 1 .8
10
143 10.3 146 10.5 145 6 .6 147 4 .6 146 5 .9 145 5 .5 146 4 .9 146 6 .2 147 5 .7 148 5.5
---- ---- ---- ---- ----
146 6 .6 1 .4 2.10
10 10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A nim al ID
ALT U/L
GROUP: 2-M 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
37 38 37 57 40 46 48 34 261 33 -- -- -- -- --
MEAN SD N
63 6 9 .9
10
418-028:PAGE K-112 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: MALE
AST ALP
CA PROS TRIG
NA
K
U/L
U/L
g/dL
mg/dL
g/dL
ranol/L
m ol/L
84 77 81 116 91 111 104 80 382 87 -- -- -- -- --
121 9 2 .6
10
101 70 99
141 130
91 99 88 199 95
111 3 6 .9
10
10.5 1 1 .6 10.3 1 0 .3 1 1 .2 1 0 .7 1 0 .6 10.7 10.3 11.1
1 0 .7 0 .4 4
10
10.3 12.0
9.1 8.9 8 .9 9.3 9.3 8 .8 7 .8 9.3
9 .4 1.11
10
26 60 62 44 43 29 27 78 57 43 -- -- -- --
47 1 7 .2
10
145 6 .8 144 8 .0 145 6 .0 146 5 .4 147 5 .2 146 5 .5 145 6 .2 144 6 .9 147 5.5 148 5.5
---- ---- -- .-- ----
146 6.1 1.3 0.89
10 10
(-- ) - Data U navailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A nim al ID
ALT U/L
GROUP: 3-M 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174
MEAN SD N
60 H 35 35 45 141 42 101 55 44 42 -- -- -- --
60 3 4 .4
10
418-028:PAGE K -l 13 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: HALE
AST ALP
CA PHOS TRIG
NA
K
U/L
U/L g/dL
g/dL
g/dL
mmol/L
m o l/L
124 H 70 82 99
197 92
171 140 102
94
--
-- --
--
117 4 0 .9
10
101 H 107
97 92 108 88 80 124 108 96
--
-- --
--
11.5 H 11.5 11.5 1 0 .2 1 0 .8 1 0 .7 11.2 10.7 11.3 11.3
--
-- -- --
10.4 H 9.5
1 5 .6 8 .8 9 .9 9 .0 9 .4 9 .4 8 .3 8 .8
--
-- -- --
100 1 2 .4
10
11.1 0 .4 4
10
9 .9 2 .0 9
10
20 H 56 34 51 35 56 21 34 22 35 -- -- -- --
36 13.8
10
143 H 147 148 147 145 147 146 148 146 148
-- -- --
--
147 1 .6
10
8 .9 H 5 .6 8 .4 6 .5 7 .0 5 .5 6.1 5 .4 5 .7 5 .4
-- -- --
--
--
6 .5 1 .2 7
10
(-- ) - Data Unavailable LABCAT CC4.43
H - Hemolyzed
27-JUN-20Q2
418-028-.PAGEK-114
Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
A nim al ID
ALT U/L
AST U/L
GROUP: 4-H 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166
HEAN SD
N
51 37 50 439 54 46 45 48 138 46 -- -- -- -- --
95 124.1
10
91 83 107 887 106 91 108 119 277 107 -- -- --
--
--
198 2 4 8 .7
10
ALP U/L
122 76 98
154 152
93 98 124 112 123 --
--
-- --
115 25.1
10
CA mg/dL
1 0 .9 1 1 .0 11.5 1 0 .8 1 1 .7 1 0 .7 1 0 .7 1 1 .2 1 1 .2 11.3
--
--
-- --
11.1 0 .3 4
10
PHOS mg/dL
8.3 13.3
8.6 9.B 9.3 10.7 8 .8 9 .8 9 .2 9.3
-- -- -- --
9 .7 1.43
10
SEX: HALE
T R IG
mg/dL
NA mmol/L
X mmol/L
14 19 35 23 32 113 35 30 28 32 -- -- -- --
36 2 7 .9
10
146 5 .5 147 6 .6 148 5 .6 148 6 .9 147 5 .3 145 6 .4 148 5 .3 147 5.5 147 6.1 146 6 .5
---- ---- ----
----
--
147 6 .0 1 .0 0.60
10 10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
418-028:PAGE K-115
Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
ALT U/L
GROUP: 5-M 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170
38 H 49 H 33 52 49 50 40 54 40 42 -- -- -- -- --
MEAN SD N
45 7.0
10
AST U/L
86 H 114 H
76 88 104 112 95 125 87 87 -- -- -- -- --
97 15.6
10
ALP U/L
115 H 153 H 204 159 182
83 169 137 140
99 -- -- -- -- --
144 37.5
10
SEX: MALE
CA mg/dL
PKOS mg/dL
TRIG mg/dL
NA mmol/L
K mmol/L
11.7 H 11.0 H 11.9 11.3 11.8 11.6 10.9 11.3 12.0 11.8
-- -- -- -- --
11.5 0.38
10
12.9 H 9.2 H 9.8 9.6
11.1 8.4 9.0
10.8 10.2 11.3
-- -- -- -- *--
10.2 1.33
10
7H 18 H
2 17 21 17 23 16 16 31 -- -- -- -- --
17 8.0
10
142 H 144 H 147 146 147 148 148 143 147 148
-- -- -- -- --
146 2.2
10
10.7 H 6.6 H 5.5 6.8 7.1 6 .0 5.5 7 .9 7.1 5.8 -- -- -- -- --
6 .9 1.55
10
(-- ) - Data Unavailable LABCAT CC4.43
H - Heaolyzed
27-JUN-20Q2
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
AniaaL ID
ALT U/L
GROUP: 1-F 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
MEAN SD N
144 136 177 115 142 104 153 156
87 80 -- -- -- --
129 31.7
10
418-028:PAGE K-l 16 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: FEMALE
AST ALP
CA PHOS TRIG
NA
K
U/L
U/L
ag/dL
ag/dL
ag/dL
amoL/L
aaoL/L
123 182 167 114 154 121 149 157 123 133
-- -- -- --
142 22.8
10
217 77
345 89
171 82
100 202
92 73 -- --
--
--
145 88.7
10
10.5 10.9 11.8 10.3
9.9 10.2 11.7 10.5
9.6 10.1
-- -- --
--
10.6 0.72
10
6.8 11.4
8.3 8.6 9.2 8.7 8.3 10.4 7.6 8.2
-- -- -- --
8.8 1.33
10
70 65 47 91 46 44 70 51 40 20 -- -- -- --
54 19.9
10
143 6 .0 142 5 .8 159 5 .4 140 5.5 140 6.2 138 5 .7 149 4 .8 140 7 .4 140 5 .7 143 5 .6
---- ---- ---- ----
143 5 .8 6.3 0.67
10 10
(-- ) - Data Unavai LabLe LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
A n iaal ID
ALT U/L
GROUP: 2-F 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
97 116 150 136 145 176 115 150 117 132
-- -- -- --
--
MEAN SD N
133 23.0
10
418-028-.PAGEK-117 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: FEMALE
AST ALP
CA PHOS TRIG
NA
K
U/L
U/L
mg/dL
ag/dL
mg/dL
aaol/L
amol/L
133 110 141 102 142 125 181 139 131 147
-- -- -- -- --
135 21.6
10
80 193 242 240 183 200
48 252
46 102
--
-- --
--
--
159 81.7
10
11.3 11.7 11.6 11.6 10.7 11.9 10.9 11.5 10.0 10.4
--
-- -- -- --
11.2 0.63
10
8.4 7.6 7.8 6.7 9.6 8.5 5.3 8.3 5.3 11.8
" --
--
-- --
7.9 1.94
10
45 60 68 45 45 47 43 55 55 32 -- --- -- --
50 10.2
10
139 5.3 144 5 .9 147 5.4 144 5.0 141 5 .0 145 5 .4 143 5 .2 142 6.1 142 5 .6 140 6 .9
---- ---- ---- ---- ----
143 5 .6 2.4 0.58
10 10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Animal ID
ALT U/L
GROUP: 3 - F 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
MEAN SD N
182 90
107 137
-- 178 166 121 189 124
-- 130
--
-- --
142 34.2
10
418-028-.PAGEK-118 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: FEMALE
AST ALP
CA PHOS TRIG
NA
K
U/L
U/L
mg/dL
g/dL
ag/dL
amol/L
m o l/L
134 113 143 125
-- 137 153 139 151 140
-- 133
-- --
--
137 11.8
10
101 60 64
154
--
97 418
60 190 108
-- 111
-- --
136 107.3
10
9.6 9.3 9.7 10.6
-- 9.3 11.3 11.3 11.5 11.0
-- 10.7
--
--
--
10.4 0.87
10
9.7 9.2 7.3 5.6
-- 14.3
5.9 11.5
6.1 10.5
-- 9.9
--
--
--
9.0 2.80
10
26 17 28 65 -- 116 33 46 53 72 -- 34
--
--
--
49 29.4
10
142 5 .5 139 5 .8 139 5 .7 144 5 .4
---- 141 4 .9 145 5 .4 142 6 .0 147 5 .4 141 5 .5
---- 142 5 .9
-- -- ---- ----
142 5 .6 2.5 0.32
10 10
(-- > - Data Unavailable LABCAT CC4.43
27-JUH-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Anin a l ID
ALT U/L
GROUP: 4 - F 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
MEAN SD N
134 115 174 134 157
-- -- 94 124 98 119 116 --
--
127 24.7
10
418-028:PAGE K-l 19 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: FEMALE
AST ALP
CA PHOS TRIG
NA
K
U/L
U/L
mg/dL
ng/dL
ng/dL
anol/L
maol/L
127 128 125 132 149
-- -- 107 117 129 114 112 --
124 12.1
10
108 107 228
90 432
-- -- 70 171 102 388 88 --
178 131.0
10
10.6 10.0 11.0
9 .7 11.1
-- -- 10.0 10.7 10.3 10.7 10.3 --
10.4 0.46
10
9.6 9.2 4.4 10.8 8.6
-- -- 10.1 5.4 10.7 5.0 13.2
--
""
8.7 2.88
10
49 67 62 77 55 -- -- 28 30 18 34 33 --
45 19.5
10
142 6 .2 142 5.5 147 5 .8 138 7 .0 145 5 .9
---- ---- 139 6 .5 142 5 .3 144 7.1 143 5.1 142 6 .6 ---- ----
142 6.1 2.6 0.70
10 10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
418-028:PAGE K -120
Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
Ania a l ID
ALT U/L
AST U/L
SEX: FEMALE
ALP CA PHOS TRIG NA
1C
U/L
g/dL
ag/dL
9/dL
amol/L
aaol/L
GROUP: 5-F 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
MEAN SD N
116 133 160 149 132 131 151 263 143 167 113 141 149 138 179 127 156 177 148 138
---- ---- -- -- -- . ----'
145 20.0
10
156 40.7
10
135 71
131 138 101 142
58 122 171 211
--
--
-- -- ""
128 44.7
10
10.1 10.1 10.3
9.8 10.3
9 .6 9 .6 12.0 10.9 11.6
--
--
-- --1
10.4 0.82
10
10.7 9.0 8.2
13.7 10.0
9.4 10.6
9.2 11.6
8.6
--
-- -- --
10.1 1.64
10
37 49 53
7 38 30 44 45 77 57 -- -- -- --
44 18.3
10
141 6 .8 138 6 .8 142 5 .2 143 6 .9 145 6 .4 142 5 .4 141 7 .6 147 5.1 139 6 .3 143 5.1
---- ---- ---- ---- -- .--
142 6 .2 2.6 0.90
10 10
(-- ) - Data Unavailable LABCAT CC4.43
2 7-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028:PAGE K-121
Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: HALE
A niaal ID
CL M M l/L
GROUP: 1-M 19109 19115 19116 19119 19122 19125 19131 19132 19134 19135 19143 19151 19157 19161 19167
103 100
98 100
97 96 98 99 98 93 -- -- -- -- --
MEAN SD N
98 2 .7
10
GLOB g/dL
2.0 2.1 1.8 1.9 1.9 2.2 2.3 1.8 2.0 2.3
--
--
-- -- --
2.0 0.19
10
A/G none
2.0 2.1 2.2 2.2 2.3 2.0 1.8 2.4 2.2 2.0
-- -- -- -- --
2.1 0.18
10
(-- ) - Data Unavailable LABCAT CCA.43
27-JUW-20Q2
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028:PAGE K-122 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: HALE
A n im i ID
CL anol/L
GROUP: 2-M 19102 19106 19108 19110 19113 19120 19129 19136 19138 19139 19147 19153 19164 19165 19171
98 99 101 101 98 96 99 99 99 98 -- -- -- -- --
MEAN SD N
99 1.5
10
GLOB g/dL
2.0 2.2 1.9 2 .0 1.7 2.2 1.8 1.9 1.9 1.9
-- -- -- -- --
2 .0 0.16
10
A/G none
2.1 1.8 2.1 2.1 2.3 2.0 2.2 2.3 2.3 2.2
-- -- -- -- --
2.1 0.16
10
(-- ) - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028:PAGE K-123 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: MALE
A n im i ID
CL m o l/L
GROUP: 3-M 19101 19105 19107 19112 19114 19121 19123 19130 19137 19146 19155 19159 19172 19173 19174
101 H 96
105 100
99 99 100 100 98 99 -- -- -- --
--
MEAN SD N
100 2 .3
10
GL08 g/dL
2.2 H 1.8 1.7 2 .0 2 .0 2.2 1.8 1.6 2.3 2 .2
-- -- -- --
--
2 .0 0.24
10
A/G none
1.8 H 2 .4 2 .4 2.2 2 .2 2 .0 2 .4 2 .6 1.9 2 .0
-- -- -- --
--
2.2 0.26
10
(-- ) - Data Unavailable LABCAT CC4.43
H - Henolyzed
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028:PAGE K-124 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: HALE
Animal ID
CL mmol/L
GROUP: 4-H 19100 19103 19104 19118 19133 19141 19142 19144 19148 19150 19156 19160 19162 19163 19166
104 104 100 103
98 99 96 99 98 99 -- -- -- --
--
HEAN SD N
100 2.7
10
GLOB g/dL
2 .0 1 .7 1.8 1.8 1.9 1.9 2.2 2.1 2.1 2 .0
--
--
-- --
--
2.0 0.16
10
A/G none
2.0 2.4 2.3 2.3 2.3 2.3 2.0 2.0 2.1 2.2
-- --
--
--
--
2.2 0.15
10
C-- ) - Data Unavailable LABCAT CC4.43
2 7 -JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028:PAGE K-125 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: HALE
Animal ID
CL maol/L
GROUP: 5-H 19111 19117 19124 19126 19127 19128 19140 19145 19149 19152 19154 19158 19168 19169 19170
101 H 101 H
99 100 101
98 101
98 100
99 -- -- -- -- --
MEAN SD N
100 1.2
10
GLOB g/dL
2.0 H 1.8 H 1.8 1.8 2.0 1.7 1.7 1.9 1.8 1.6
-- -- -- --
--
1.8 0.13
10
A/G none
2.3 H 2.4 H 2.7 2.6 2.3 2.8 2.5 2.4 2.5 2.6
-- -- -- -- --
2.5 0.17
10
(-- ) - Data Unavailable LABCAT CC4.43
H - Heaolyzed
27-JUN-20Q2
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028'.PAGE K-126 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: FEMALE
Aniaal ID
CL amol/L
GROUP: 1-F 19010 19012 19019 19021 19023 19041 19042 19044 19050 19053 19065 19068 19072 19074 19075
96 92 100 91 93 92 96 99 99 98 --
--
-- --
MEAN SD N
96 3.4
10
GLOB g/dL
1.7 2.0 2.2 1.8 1.6 2.0 2.2 1.9 1.8 2.2
-- -- --
--
1.9 0.22
10
A/G none
2.2 2.2 2.2 2.4 2.7 2.2 2.0 2.1 2.1 1.6
_ _
--
2.2 0.28
10
(-- > - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028-.PAGE K-127 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: FERALE
Animal ID
CL mmol/L
GROUP: 2 - F 19004 19009 19016 19018 19026 19036 19037 19043 19047 19048 19052 19055 19061 19067 19071
89 93 98 97 94 95 96 91 93 95 -- -- -- --
--
MEAN SD N
94 2 .7
10
GLOB g/dL
1.6 1.8 1 .3 1.4 1.6 1.7 1.5 1.9 1.0 1 .7
-- -- -- --
--
1.6 0.26
10
A/G none
2.7 2.2 3.2 3.0 2.4 2.5 2.3 2.0 3.3 2.5
-- -- --
--
--
2 .6 0.43
10
<-- > - Data Unavailable LABCAT CC4.43
27-JUN-2002
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028:PAGE K-128 Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
SEX: FEMALE
Animal ID
CL mmol/L
GROUP: 3--F 19003 19007 19008 19013 19014 19015 19017 19024 19029 19034 19038 19056 19057 19060 19064
92 97 96 97 -- 92 99 94 101 88 -- 93 -- -- --
MEAN SD N
95 3.8
10
GLOB g/dL
1.7 1.5 1.7 1.7
-- 1.9 1.7 2.2 1.8 2.1
-- 1.9
-- --
--
1.8 0.21
10
A/e none
2.3 2.5 2.4 2.4
-- 1.9 2.4 2.0 2.2 2.0
-- 2.2
-- --
--
2.2 0.21
10
(-- ) - Oats Unavailable LABCAT CC4.43
2 7 -JUN-2002
418-028-.PAGE K-129
Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
SEX: FEMALE
Aninal ID
CL PMOl/L
GLOB g/dL
A/G none
GROUP: 4-F 19002 19005 19035 19039 19040 19045 19046 19051 19054 19058 19062 19063 19066 19069 19073
MEAN SD N
90 96
101
91 97 -- -- 94 97 98 97 93 -- --
95 3.4
10
1.8
1.7 1.5 1.9 1.9
--
--
1.8
1.7
1.6 1.6 1.8
-- --
1.7 0.13
10
2.4 2.4 2.7
2 .1
1.9
--
--
2.5 2.3
2.8
2.3 2.3
--
--
2.4 0.26
10
(-- ) - Data Unavailable
LABCAT CC4.43
27-JUN-2002
418-028:PAGE K-130
Study Report for Clinical Chemistry
INDIVIDUAL ANIMAL REPORT BY GROUP PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
SEX: FEMALE
Anisal ID
CL bsoL/L
GLOB g/dL
A/G none
GROUP: 5-F 19001 19006 19011 19020 19022 19025 19027 19028 19030 19031 19032 19033 19049 19059 19070
MEAN SD N
91 . 93 92 91
100
94 96 95 95 89 -- -- -- -- --
94 3.1
10
1.5 1.7 1.5
2 .1
1.7
2 .1
1.7 1.9
1.8
1.9 -- -- -- --
--
1.8 0 .2 1
10
2.7 2.4 2.9 1.7 2.4
1.8 2 .2 2 .1
2.5 2.3 -- --
-- -- --
2.3 0.37
10
(-- > - Data Unavailable
LABCAT CC4.43
27-JUN-2002
418-028:PAGE K-131
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOUED BY DUNNETT'S PROCEDURE
SEX: MALE
TEST(s): UNITS:
Group: 1-M MEAN
SD N
Group: 2-M MEAN
SD N
Group: 3-M MEAN
SD N
Group: 4-M MEAN
SD N
Group: 5--M MEAN
SD N
TP g/dL
6.3 0.36
10
6.1
0.28
10
6.3 0.33
10
6.2
0.28
10
6.3 0.28
10
ALB GLU CHOL T-BIL BUN CREAT
CK ALT
g/dL
mg/dL
g/dL
g/dL
mg/dL
mg/dL
U/L
U/L
4.3
0 .2 2 10
145 16.8
10
57 0 .2 8.3 0.07
10 10
16 0.3 288 1.5 0.04 172.6
10 10 10
42
6.0 10
4.1 0.19
10
141 26.0
10
41**
11.1 10
0 .1
0.05
10
16 0.3 246 0 .8 0.05 111.5
10 10 10
63 69.9
10
4.3 0.15
10
182 58.2
10
46
11.6 10
0 .1
0.06
10
16 0.3 239
60
1 .8 0.06 112.9 34.4
10 10 10 10
4.2 0.17
10
162 25.2
10
43* 13.1
10
0 .1
0.05
10
17 0.3 196
95
1 .6 0.03 53.5 124.1
10 10 10 10
4.5**
0.20 10
165 33.7
10
33** 7.2
10
0 .2
0.06
10
2 1** 2.4
10
0.3 0.05
10
243 117.4
10
45 7.0
10
-Significant Difference froa Control P < .05 LABCAT CC4.43
**-Significant Difference fro Control P < .01 27-JUN-2002
418-028:PAGE K -132
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: HALE
TEST(s): UNITS:
AST ALP
CA PHOS TRIG
NA
K CL GLOB
U/L U/L g/dL ng/dL g/dL mol/L MOl/L m o I /L g/dL
Group: 1-H HEAN
SD N
Group: 2-M HEAN
SD N
Group: 3-H HEAN
SD N
96 22.4
10
121
92.6
10
117 40.9
10
105 14.3
10
111
36.9
10
100
12.4
10
10.9 0.48
10
10.7 0.44
10
11.1
0.44
10
9.5 1.40
10
9.4
1.11 10
9.9 2.09
10
52
2 1.8 10
47 17.2
10
36 13.8
10
146 6.6 1.4 2 .1 0
10 10
146 6 .1 1.3 0.89
10 10
147 6.5 1 .6 1.27
10 10
98 2 .0 2.7 0.19
10 10
99 2 .0 1.5 0.16
10 10
100 2 .0
2.3 0.24
10 10
Group: 4-H HEAN
SD N
Group: 5-H HEAN
SD
N
198 248.7
10
97 15.6
10
115 25.1
10
11.1
0.34
10
9.7 1.43
10
144** 37.5
10
11.5** 0.38
10
10 .2
1.33
10
36 27.9
10
147
1.0 10
17**
8.0 10
146
2 .2 10
6.0
0.60
10
6.9 1.55
10
100 2 .0
2.7 0.16
10 10
100 1 .8
1 . 2 0.13
10 10
**-Significant Difference fro* Control P < .01
LABCAT CC4.43
27-JUN-20Q2
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
418-028:PAGE K-133
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
SEX:
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
TEST(s): UNITS:
A/G none
Group: 1-H MEAN
SD N
2 .1
0.18
10
Group: 2-H MEAN
SD N
Group: 3-M MEAN
SD N
Group: 4-M MEAN
SD N
2 .1
0.16
10
2 .2
0.26
10
2 .2
0.15
10
Group: 5-M MEAN
SD N
2.5** 0.17
10
**-Signifieant Difference from Control P < .01 LABCAT CC4.43
27-JUN-2002
418-028:PAGE K-134
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE F0LL0WED BY DUNNETT1S PROCEDURE
SEX: HALE
Total Protein
Group N Total Mean
Std. DUNNETT'S
DUNNETT'S RANGES
Dev. 't1
LO -95X- HI L0 -99X- HI
Degree Sum of
Mean
Source Fdo Squares Square
1-H 10 62.8 6.3 0.36
TREATMENTS 4
0.44
0 .11
2 -M
10 60.6
6 .1
0.28 1.60
5.9 6.6
5.9 6.7
ERROR 45
4.26
0.09
3-M
10 62.5 6.3 0.33 0 .22
5.9 6.6
5.9 6.7 -------------
4-M
10 61.B
6 .2
0.28 0.73
5.9 6 .6
5.9 6.7
TOTAL 49
4.70
5--M
10 63.3 6.3 0.28 0.36
5.9 6.6
5.9 6.7
F Ratio = Coeff. Var. X =
1.16 F* table values 4.948 Dunnett's 'T' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
Albumin
1 -M 10 42.5 4.3 0 .22
2-M
10 41.1 4.1 0.19 1.6 6
4.0 4.5
3-M
10 42.7 4.3 0.15 0.24
4.0 4.5
4-M
10 42.3 4.2 0.17 0.24
4.0 4.5
5-M
10 45.2 4.5 0.20 3.21
4.0 4.5*
F Ratio = Coeff. Var. % =
6.35 F' table values 4.399 Dunnett's 'T' table values
F.01 = P.01 =
Glucose
1-H 10 1453 145 16.8
2-M
10 1411 141 26.0 0.27
106 185
3-M
10 1823 182 58.2 2.37
106 185
4-M
10 1619 162 25.2 1.06
106 185
5-M
10 1649 165 33.7 1.25
106 185
F Ratio = Coeff. Var. % =
2.24 F1 table values 21.988 Dunnett's 'T* table values
F.01 = P.01 =
TREATMENTS 4
4.0 4.5
ERROR 45
4.0 4 . 5 -------------
4.0 4.5
TOTAL 49
4.0 4.5**
3.78 3.12
F.05 = P.05 =
2.58 2.51
TREATMENTS 4
96 194
ERROR 45
96 1 9 4 -------------
96 194
TOTAL 49
96 194
3.78 F.05 = 3.12 P.05 =
2.58 2.51
0.90 1.59
2.49
0 .2 2
0.04
10942 55071
66013
--
2735 1224
-Significant Difference from Control P < .05 -Significant Difference from Control P < .01 Error-within groups
LABCAT CC4.43
Source-Source of Variation Treatments-between groups
27-JUN-2002
418-028:PAGE K-135
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY D: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOVED BY DUNNETT'S PROCEDURE
sEX: MALE
Cholesterol
Group N Total Mean
1 -H
10 569
57
2-N
10 413
41
3-H
10 459
46
4-M
10 427
43
5-M
10 331
33
Std. DUNNETT'S
DUNNETT'S RANGES
Dev. 't'
LO -95X- HI L0 -99X- HI
Degree Sum of
Mean
Source Fdm Squares Square
8.3
11.1 11.6
13.1 7.2
3.32 2.34 3.03 5.07
TREATMENTS 4 2978.08 744.52
45 69* 42 72** ERROR 45 4954.90 1 1 0 .1 1
45 69
42 7 2 --------- -- _
45 69* 42 72
TOTAL 49 7932.98
45 69* 42 72**
F Ratio = Coeff. Var. % =
6.76 F' table values 23.859 Dunnett's T table values
Total Bilirubin
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
1-M 10 1 .6 0 .2 0.07
TREATMENTS 4
0.031
0.008
2-M
10
1.4 0 .1
0.05 0.76
0 .1 0.2
0 .1 0.2
ERROR 45
0.154 0.003
3-H 10 1 . 2 0 .1 0.06 1.53 0 .1 0 .2 0 .1 0 . 2 -------------
4-M
10
1.3 0 .1
0.05 1.15
0.1 0.2
0 .1 0.2
TOTAL 49
0.185
5-M
10
1.9 0 .2
0.06 1.15
0 .1 0.2
0.1 0.2
F Ratio = Coeff. Var. X =
2.25 'F' table values 39.527 Dunnett1s *T' table values
Blood Urea Nitrogen
F.01 = P.01 =
3.78 F.05 = 3.12 P.05 =
2.58 2.51
1-M 10 158 16 1.5
TREATMENTS 4
162.32
40.58
2-M
10 162 16 0.8 0.53
14 18
13 18
ERROR 45
129.30
2.87
3-M
10 162 16 1 .8 0.53
14 18
13 1 8 -------------
4-M
10 174 17 1 .6 2 .1 1
14 18
13 18
TOTAL 49
291.62
5-M
10 207
21
2.4 6.46
14 18* 13 18**
F Ratio = Coeff. Var. % =
14.12 F' table values 9.821 Dunnett's 'T` table values
F.01 = P.01 =
3.78 F.05 = 3.12 P.05 =
2.58 2.51
-Significant Difference fro* Control P < .05 -Significant Difference froa Control P < .01 Error-within groups
LABCAT CC4.43
Source-Source of Variation Treataents-between groups
27-JUN-2002
418-028:PAGE K-136 Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: MALE
Creatinine
Group N Total Mean
Std. DUNNETT'S
DUNNETT'S RANGES
Dev. 't'
LO -95X- HI L0 -99X- HI
Degree Sun of
Mean
Source Fdn Squares Square
1 -N 10 3.2 0.3 0.04
TREATMENTS 4
0.0040 0.0010
2-H
10 3.3 0.3 0.05 0.48 0.3 0.4 0.3 0.4
ERROR 45
0.0960 0.0021
3-M
10 3.1 0.3 0.06 0.48
0.3 0.4 0.3 0.4 --
4-M
10 3.1 0.3 0.03 0.48
0.3 0.4 0.3 0.4
TOTAL 49
0.1000
5-H
10 3.3 0.3 0.05 0.48
0.3 0.4
0.3 0.4
F Ratio = Coeff. Var. X -
0.47 1F` table values
14.434 Dunnett's 'T1 table values
F.01 =
P.01 =
3.78 F.05 =
3.12 P.05 =
2.58 2.51
Creatine Kinase
1-M
10 2877
288 172.6
TREATMENTS 4
41956
10489
2-M
10 2462
246 111.5 0.78
153 422
12 1 455
ERROR 45
644538
14323
3-M
10 2388
239 112.9 0.91
153 422
12 1 4 5 5 -------------
4-M
10 1964 196 53.5 1.71
153 422
12 1 455
TOTAL 49
686494
5-M
10 2427
243 117.4 0.84
153 422 121 455
F Ratio = Coeff.. Var. X =
0.73 F' table values 49.381 Dunnett's 'T* table values
F.01 = P.01 =
3.78 F.05 = 3.12 P.05 =
2.58 2.51
Alanine Aminotransferase
1-M 10 420 42 6.0
TREATMENTS 4
18155
4539
2-M
10 631
63 69.9 0.72
-32 116 -50 134
ERROR 45 194111
4314
3-M
10 600
60 34.4 0.61
-32 116 -50 134 --
4-M
10 954
95 124.1 1.82
-32 116 -50 134
TOTAL 49
212266
5-M
10 447
45 7.0 0.09
-32 116 -50 134
F Ratio =
1.05 'F' table values
Coeff.. Var. X = 107.598 Dunnett's 'T* table values
F.01 = P.01 =
3.78 F.05 = 3.12 P.05 =
2.58 2.51
Error-within groups Source-Source of Variation
LABCAT CCA.43
Treataents-between groups
27-JN-2002
418-028:PAGEK-137
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY 1D: ARGUS 41B-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOVED BY DUNNETT'S PROCEDURE
SEX: HALE
Aspartate Aminotransferase
Std. DUNNETT'S
Group N Total Hean
Dev. t'
DUNNETT' S RANGES LO -95Z- HI LO -99X- HI
Degree Sun of
Mean
Source Fdm Squares Square
1 -M 10 957 96 22.4
TREATMENTS 4
69637
17409
2-H
10 1213 12 1
92.6 0.47
-40 231
-73 264
ERROR 45
655378
14564
3-M
10 1171 117 40.9 0.40
-40 231
-73 264
4-H
10 1976 198 248.7 1.89
-40 231
-73 264
TOTAL 49
725015
5-H
10 974
97 15.6 0.03
-40 231
-73 264
F Ratio = Coeff. Var. X =
1.2 0 F' table values 95.916 Dunnett's ''r table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
Alkaline Phosphatase
1-M 10 1050 105 14.3
TREATMENTS 4
11825
2956
2 -M
10 1113
111
36.9 0.51
74 136
67 143
ERROR 45
33780
751
3-M
10 1001 100 12.4 0.40
74 136
67 143
4-H
10 1152 115 25.1 0.83
74 136
67 143
TOTAL 49
45604
5-M
10 1441 144 37.5 3.19
74 136*
67 143**
F Ratio = Coeff.. Var. X =
3.94 F* table values 23.795 Dunnett's 'T' table values
F.01 = P.01 =
3.78 F.05 = 3.12 P.05 =
2.58 2.51
Calcium
1-M
10 109.4 10.9
0.48
TREATMENTS 4
3.45
0.86
2-M
10 107.3 10.7
0.44 1 . 1 2
10.5 11.4 10.4 11.5
ERROR 45
7.97 0.18
3-M
10 110.7 1 1 . 1
0.44 0.69 10.5 11.4 10.4 1 1 . 5 --------------
4-M
10 111.0
11.1
0.34 0.85
10.5 11.4 10.4 11.5
TOTAL 49
11.42
5-M
10 115.3 11.5
0.38 3.14
10.5 11.4* 10.4 11.5**
F Ratio = Coeff. Var. X -
4.87 'F' table values 3.800 Dunnett's 'T' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
-Significant Difference froa Control P < .05 -Significant Difference fro Control P < .01 Error-within groups
LABCAT CC4.43
Source-Source of Variation Treataents-between groups
27-JUN-2002
418-028-.PAGE K-138 Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY N0: 060-069
ANALYSIS 0F VARIANCE F0LL0WED BY OUNNETT'S PROCEDURE
SEX: MALE
Phosphorus
Group N Total Mean
Std. OUNNETT'S
OUNNETT'S RANGES
Dev. t'
LO -955- HI LO -99Z- HI
Degree Source Fda
1-M 10 94.7 9.5 1.40
TREATMENTS 4
2-M
10 93.7 9.4 1 . 1 1 0.15
7.8 1 1 . 2
7.4 11.6
ERROR 45
3-M
10 99.1 9.9 2.09 0.65
7.8 1 1 . 2
7.4 11.6 -
4-M
10 97.1 9.7 1.43 0.36
7.8 1 1 . 2
7.4 11.6
TOTAL 49
5-M
1 102.3 1 0 .2
1.33 1.13
7.8 1 1 . 2
7.4 11.6
F Ratio = Coeff. Var. X =
0.53 'F' table values 15.485 Dunnett's *T" table values
F.01 = P.01 =
3.78 F.05 = 3.12 P.05 =
2 .58 2 .51
Triglycerides
Sun of Squares Square
4.80
1.2 0
102.32
2.27
------
107.12
1-M
10 516
52 2 1 .8
2-M
10 469
47 17.2 0.55
30 73
3-M
10 364
36 13.8 1.79
30 73
4-M
10 361
36 27.9 1.82
30 73
5-M
10 168 17 8 .0 4.10
30 73*
F Ratio = Coeff. Var. X -
4.98 F' table values 50.584 Dunnett's 'T' table values
F.01 = P.01 =
Sodium
1-M
10 1459
146
1.4
2-M
10 1457
146
1.3 0.29
144 148
3-M
10 1465
147
1 .6 0.86
144 148
4-M
10 1469 147
1 .0 1.44
144 148
5-M
10 1460
146
2 .2 0.14
144 148
F Ratio = Coeff. Ver. % =
1.00 'F' table values 1.062 Dunnett1s 'T' table values
F.01 P.01
TREATMENTS 4
25 78
ERROR 45
25 78
25 78
TOTAL 49
25 78**
3.78 F.05 = 3.12 P.05 =
2 .58 2.51
TREATMENTS 4
144 148
ERROR 45
144 148
144 148
TOTAL 49
144 148
3.78 F.05 = 3.12 P.05 =
2.58 2.51
7188 16244 23432
9.60 108.40 118.00
1797 361
2.40 2.41
-Significant Difference fron Control P < .05 -Significant Difference fron Control P < .01 Error-vithin groups
LABCAT CC4.43
Source-Source of Variation Treatnents-betveen groups
27-JUN-2002
418-028:PAGE K-139 Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: MALE
Potassium
Group N Total Mean
Std. DUNNETT'S
DUNNETT'S RANGES
Dev. f
LO -95X- HI LO -99X- HI
Degree Sun of
Mean
Source Fdn Squares Square
1 -M
10 65.7 6 .6
2 .10
TREATMENTS 4
5.56 1.39
2-M
10 61.0
6 .1
0.89 0.76
5.0 8 .1
4.6 8.5
ERROR 45
86.21
1.92
3-H
10 64.5 6.5 1.27 0.19
5.0 8 .1
4.6 8.5
4-M
10 59.7
6.0
0.60 0.97
5.0 8 .1
4.6 8.5
TOTAL 49
91.77
5-M
10 69.0 6.9 1.55 0.53
5.0 8 .1
4.6 8.5
F Ratio = Coeff. Var. X =
0.73 'F' table values 21.633 Dunnett's 'T' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 =
2.58 2.51
Chloride
1-M 10 982 98 2.7
TREATMENTS 4
23.60
5.90
2-M
10 988 99 1.5 0.62
96 10 1
95 101
ERROR 45
212.90
4.73
3-M
10 997 100
2.3 1.54
96 101
95 101
4-M
10 1000
100
2.7 1.85
96 101
95 101
TOTAL 49
236.50
5-M
10 998 100
1 . 2 1.64
96 101
95 101
F Ratio = Coeff. Var. X =
1.25 'F' table values 2.190 Dunnett's 'T' table values
F.01 = P.01 =
3.78 F.05 = 3.12 P.05 =
2.58 2.51
Globulin
1-M
10 20.3
2 .0
0.19
2-M
10 19.5
2 .0
0.16 0.99
1.8 2.2
3-M
10 19.8
2 .0
0.24 0.62
1.8 2.2
4-M
10 19.5
2 .0
0.16 0.99
1.8 2.2
5-M
10 18.1
1.8
0.13 2.73
1 .8 2 .2*
F Ratio = Coeff., Var. X ~
2.06 F* table values 9.253 Dunnett's 'T' table values
F.01 = P.01 =
TREATMENTS 4
1 .8 2.3
ERROR 45
1 .8 2.3 --------------
1 .8 2.3
TOTAL 49
1 .8 2.3
3.78 3.12
F.05 = P.05 =
2.58 2.51
0.27 1.46
1.72
0.07 0.03
*-Significant Difference fro Control P < .05 Error--within groups
LABCAT CCA.43
Source-Source of Variation Treatnents-between groups
27-JUN-2Q2
418-028-.PAGE K -140
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT1S PROCEDURE
sEX: HALE
Albumin/Globulin Ratio
Std. DUNNETT'S
Group N Total Mean
Dev. t'
DUNNETT'S RANGES L0 -95X- HI L0 -99Z- HI
Degree Sue of
Mean
Source Fda Squares Square
1 -H 10 2 1 .2 2 .1 0.18
TREATMENTS 4
1.0 2 0.25
2-M
10 21.4
2 .1
0.16 0.24
1.9 2.3
1.9 2.4
ERROR 45
1.57 0.03
3-M
10 21.9
2 .2
0.26 0.84
1.9 2.3
1.9 2.4 -
4-M
10 21.9
2 .2
0.15 0.84
1.9 2.3
1.9 2.4
TOTAL 49
2.59
5-M
10 25.1 2.5 0.17 4.67
1.9 2.3* 1.9 2.4**
F Ratio = Coeff. Var. X =
7.31 *F* table values 8.368 Dunnett's 'T' table values
F.01 = P.01 =
3.78 3.12
F.05 = P.05 *
2.58 2 .51
-Significant Difference fro Control P < .05 -Significant Difference fro Control P < .01 Error-within groups
LABCAT CC4.43
Source-Source of Variation Treataents-between groups
27-JUN-2002
418-028:PAGE K-141 Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY 10: ARGUS 418-028 STUDY N0: 060-069
ANALYSIS 0F VARIANCE F0LL0VED BY DUNNETT1S PROCEDURE
SEX: FEHALE
TEST(s): UNITS:
Group: 1-F MEAN
SD N
Group: 2-F MEAN
SD N
Group: 3-F MEAN
SD N
Group: 4-F MEAN
SD N
Group: 5-F MEAN
SD N
TP g/dL
6 .1
0.52
10
5.5 0.50
10
5.9 0.41
10
5.8 0.32
10
5.8 0.29
10
ALB GLU CHOL T-BIL BUN CREAT g/dL g/dL mg/dL g/dL g/dL g/dL
CK U/L
4.1 0.42
10
152 19.8
10
77 27.8
10
0 .2
0.07
10
28 0.4 202 4.4 0.05 54.1
10 10 10
4.0 0.34
10
162
20.0 10
72 14.0
10
0.2
0.03
10
24 0.4 250 4.7 0.05 85.6
10 10 10
4.1 0.24
10
155 18.7
10
71
20.0 10
0 .2
0.05
10
28 0.3 192 6.7 0.05 21.7
10 10 10
4.0 0.29
10
146 16.2
10
62 14.2
10
0 .1
0.05
10
25 0.4 213 4.4 0.08 80.4
10 10 10
4.0 0.31
10
140 35.5
10
61 19.8
10
0 .1
0.05
10
30 15.4
10
0.3 0.06
10
252
10 1.6 10
ALT U/L
129 31.7
10
133 23.0
10
142 34.2
10
127 24.7
10
145
20.0 10
LABCAT CC4.43
27-JUN-2002
418-028:PAGE K-142
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 418-028 STUDY NO: 060-069
TEST(s): UNITS:
Group: 1-F MEAN
SD N
Group: 2-F MEAN
SD N
Group: 3-F MEAN
SD N
Group: 4-F MEAN
SD N
Group: 5-F MEAN
SD N
AST U/L
142
22.8 10
135
21.6 10
137
11.8 10
124
12.1 10
156 40.7
10
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
ALP CA PHOS TRIG NA
K
U/L g/dL g/dL g/dL naol/L nol/L
SEX: FEMALE
CL atmol/L
GLOB g/dL
145 88.7
10
10.6
0.72
10
8 .8
1.33
10
54 19.9
10
143 5.8 6.3 0.67
10 10
96 1.9 3.4 0.22
10 10
159 81.7
10
11.2
0.63
10
7.9 1.94
10
50
10.2 10
143 5.6 2.4 0.58
10 10
94 1.6** 2.7 0.26
10 10
136 107.3
10
10.4 0.87
10
9.0 2.80
10
49 29.4
10
142 5.6 2.5 0.32
10 10
95 1 .8 3.8 0.21
10 10
178 131.0
10
10.4 0.46
10
8.7
2.88 10
45 19.5
10
142 6.1 2 .6 0.70
10 10
95 1.7 3.4 0.13
10 10
128 44.7
10
10.4 0.82
10
10.1
1.64
10
44 18.3
10
142 6 .2 2 .6 0.90
10 10
94' 3.1
10
1.8 0.21
10
**-Significant Difference fro Control P < .01
LABCAT CC4.43
27-JUN-20Q2
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
418-028:PAGE K-143
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
SEX: FEMALE
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
TEST(s): UNITS:
Group: 1-F MEAN
SD N
Group: 2-F MEAN
SD N
Group: 3-F MEAN
SD N
Group: 4-F MEAN
SD N
Group: 5-F NEAN
SD N
A/G none
2 .2 0 .2 8
10
2 .6 * 0 .4 3
10
2 .2 0.21
10
2 .4 0.26
10
2.3 0 .3 7
10
-S ig n ific a n t D iffere n c e from C ontrol P < .05
LABCAT CC4.43
27-JUN-202
418-028:PAGE K -144
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY 10: ARGUS 4 1 8 -0 2 8 STUDY N0: 0 6 0 -0 6 9
ANALYSIS OF VARIANCE F0LL0WED BY DUNNETT'S PROCEDURE
SEX: FEMALE
Total Protein
Group
N T otal
Nean
S td . DUNNETT'S
Dev.
t '
DUNNETT'S RANGES
LO -95% - HI
LO -99X - HI
D egree S o u rc e Fdm
Sun of Squares
Mean Square
1-F
10 60.7
6.1
0 .5 2
TREATMENTS 4
1 .7 0
0 .4 3
2-F
10 55.0 5.5 0.50 3.04
5.6 6.5* 5.5 6 .7
ERROR 45
7.91
0 .1 8
3-F
10 58.8
5 .9
0.41
1.01
5 .6 6.5
5.5 6 .7
4-F
10 57.7
5 .8
0 .3 2
1 .6 0
5.6 6.5
5.5 6 .7
TOTAL 49
9 .6 2
5-F
10 58.2
5 .8
0 .2 9
1 .3 3
5.6 6.5
5.5 6 .7
F R atio = C oeff. Var. X =
2 .4 2 7 .2 2 0
Albumin
'F ' ta b le values D u n n e tt's ''P ta b le v alu es
F.01 = P.01 =
3 .7 8 3 .1 2
F.05 = P.05 =
2. 58 2 . 51
1-F 10 41.3 4.1 0.42
TREATMENTS 4
0 .1 7
0 .0 4
2-F
10 39.5
4 .0
0 .3 4
1.24
3.8 4.5
3.7 4 .6
ERROR 45
4 .7 8
0.11
3-F 10
0.24 0.48
3.8 4.5
3.7 4 6 -
4-F
10 40.4 4 .0 0.29 0.62
3 .8 4.5
3.7 4 .6
TOTAL 49
4 .9 4
5-F
10 40.3
4 .0
0.31
0 .6 9
3.8 4.5
3.7 4 .6
F R atio = Coeff.. Var. % =
0 .3 9 8 .0 5 9
Glucose
' F' ta b le v alu es D u n n e t t's *T* t a b l e v a lu e s
F.01 = P.01 =
3 .7 8 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
1-F 10 1520 152 19 .8
TREATMENTS 4
2750
687
2-F
10 1621 162 2 0 .0 0 .9 8
126 178
120 184
ERROR 45
24006
533
3-F
10 1548 155 1 8 .7 0 .27
126 178
120 1 8 4 --------------------------------
4-F
10 1461 146 1 6 .2 0 .5 7
126 178
120 184
TOTAL 49
26756
5-F
10 1404
140
35.5
1.12
126 178
120 184
F R atio = C oeff.. Var. X -
1 .2 9 15.288
F' ta b le values D u n n e tt's 'T ' ta b le values
F.01 = P.01 =
3 .7 8 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
-S ig n ific an t D ifferen ce fro * C ontrol P < .05 E rro r-w ith in groups
LABCAT CC4.43
Source-Source of V ariatio n T reatm ents-betveen groups
27-JUN-20Q2
418-028:PAGE K-145
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: FEMALE
Cholesterol
Group
N T otal
Mean
S td . DUNNETT' S
Dev.
t '
DUNNETT' S RANGES
L0 -9 5 X - HI
LO -99% - HI
D egree S o u rc e Feta
Sua of Squares
Mean Square
1-f
10 769
77 27.8
TREATMENTS 4
1862
465
2-F
10 723
72 14.0 0.52
55 99
49 105
ERROR 45
17702
393
3-F
10 705
71 2 0 .0 0 .7 2
55 99
49 105 --------------------------------
--
4-F
10 621
62 14.2 1.67
55 99
49 105
TOTAL 49
19564
5-F
10 610
61 1 9 .8 1 .7 9
55 99
49 105
F R atio = C oeff. Var. X =
1 .1 8 2 8 .9 2 9
*F* t a b l e v a lu e s D u n n e t t 's 'T* t a b l e v a lu e s
Total Bilirubin
F.01 = P.01 =
3 .7 8 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
1-F 10 1 .6 0 .2 0 .0 7
2-F
10 1 .9 0 .2 0.03 1.30
0.1 0 .2
3-F
10 1 .5 0 .2 0.05 0.43
0.1 0.2
A-F
10 1.3 0.1 0.05 1.30
0.1 0 .2
5-F
10 1 .3 0.1 0.05 1.30
0.1 0 .2
F R atio = C o eff. Var. X =
2 .3 3 33.97A
*F ' t a b l e v a lu e s D u n n e tt's 'T ' ta b le values
F.01 = P.01 =
Blood Urea Nitrogen
TREATMENTS 4
0.025
0.1 0 .2
ERROR 45
0.120
0 .1 0 . 2 --------------------------------
0.1 0 .2
TOTAL 4 9
0.145
0.1 0.2
3 .7 8 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
0.006 0.003
1-F 10 281 28 4 .4
TREATMENTS 4
218.92
54.73
2-F
10 2A1 2 4 4 .7 1 .0 8
19 37
17 40
ERROR 45
3099.90
68.89
3-F
10 281 28 6 .7 0 .0 0
19 37
17 40 -------------------------------
A-F
10 252 25 4 .4 0.78
19 37
17 40
TOTAL 49
3318.82
5-F
10 298
30 15.4 0.46
19 37
17 40
F R atio = C oeff. Var. X =
0 .7 9 3 0 .6 7 2
'F ' ta b le values D u n n e t t's 'T* t a b l e v a lu e s
F.01 = P.01 =
3 .7 8 3 .1 2
F.05 = P.05 *
2 .5 8 2.51
Error-within groups Source-Source of Variation
LABCAT CCA.43
Treatnents-betveen groups
27-JUN-202
418-028:PAGE K-146
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: FEMALE
Creatinine
Group
N T otal
Mean
1--F
10 3.5
0 .4
2 -F
10 3.5
0 .4
3 - F 10 3 .4 0 .3
4-F
10 3 .6
0 .4
5 -F
10 3.1
0 .3
S td . DUNNETT'S
Dev.
`f
0.05 0.05 0.05 0 .0 8 0 .0 6
0 .0 0 0 .3 7 0 .3 7 1 .4 7
DUNNETT' S RANGES
L0 -9 5 X - HI
L0 -99% - HI
D egree Source Fda
0.3 0.4 0.3 0.4 0.3 0.4 0.3 0.4
TREATMENTS 4
0.3 0.4
ERROR 45
0.3 0 .4 -
0.3 0 .4
TOTAL 49
0.3 0.4
Sua of Squares
0.015 0.167
0.182
Mean Square
0.004 0.004
__
F R atio = C oeff. Var. X =
1 .0 0 17.813
'F* t a b l e v a lu e s
D u n n e t t's '1r1 t a b l e v a lu e s
Creatine Kinase
F.01 = P.01 =
3 .7 8 3.12
F.05 = P .05 =
2 .5 8 2.51
1-F 10 2017 202 54.1
2 -F
10 2495 250 85.6 1.44
118 285
3-F
10 1919 192 21.7 0.3 0
118 285
4-F
10 2129 213 80.4 0 .3 4
118 285
5 -F
10 2521
252 101.6 1.52
118 285
F R atio = C oeff. Var. % =
1 .3 9 33.472
'F ' ta b le values D u n n ett's 'T ' ta b le v alu es
F.01 = P.01 =
Alanine Aminotransferase
TREATMENTS 4
98 305
ERROR 45
98 305
98 305
TOTAL 49
98 305
3 .7 8 3 .1 2
F. 05 = P .05 =
2 .5 8 2.51
30624 247619
278244
7656 5503
--
1-F 10 1294 129 31 .7
TREATMENTS 4
2546
637
2 -F
10 1334 133 2 3.0 0.33
99 160
91 167
ERROR 45
33396
742
3-F
10 1424 142 34.2 1.07
99 160
91 167
.... -- . . .
4-F
10 1265 127 2 4.7 0 .2 4
99 160
91 167
TOTAL 49
35942
5-F
10 1447 145 2 0 .0 1.26
99 160
91 167
F R atio = C oeff. Var. X =
0 .8 6 2 0 .1 3 8
'F ' ta b le values D unnett`s 'T` ta b le values
F.01 P.01
3 .7 8 3 .1 2
F.05 P.05
2 .5 8 2.51
Error-within groups Source-Source of Variation
LABCAT CC4.43
Treatments-between groups
2 7 -JUN-2002
418-028:PAGE K-147
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 060 -0 6 9
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
SEX: FEMALE
Aspartate Aminotransferase
S td . DUNNETT' S
Group
N T otal
Mean
Dev.
t '
DUNNETT' S RANGES
LO -95% - HI
LO -99% - HI
D egree S o u rc e Feta
Sun of Squares
Mean Square
1-F 10 1423 142 22 .8
TREATMENTS 4
5587
1397
2-F
10 1351 135 2 1 .6 0 .6 7
115 169
109 176
ERROR 45
26359
586
3 -F
10 1368 137 11.8 0.51
115 169
109 176
4-F
10 1240
124
12.1
1 .6 9
115 169
109 176
TOTAL 49
31946
5 -F
10 1564 156 4 0 .7 1 .3 0
115 169
109 176
F R atio = C o eff. Var. X =
2 .3 8 17.422
F' t a b l e v a lu e s D u n n e t t's 'T* t a b l e v a lu e s
Alkaline Phosphatase
F.01 = P.01 =
3 .7 8 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
1-F 10 1448 145 8 8 .7
2-F
10 1586 159 81 .7 0.32
38 252
3-F
10 1363
136 107.3 0.20
38 252
4-F
10 1784
178 131.0 0.79
38 252
5-F
10 1280 128 44.7 0 .4 0
38 252
F R atio = C o eff. Var. X =
0 .4 4 63.733
'F ' ta b le values D u n n e tt's 'T ` ta b le valu es
F.01 = P.01 *
Calcium
TREATMENTS 4
12 277
ERROR 45
12 277
12 277
TOTAL 49
12 277
3 .7 8 3.12
F.05 = P.05 =
2 .5 8 2.51
15762 406995
422757
3941 9044
1-F
10 105.5
1 0 .6
0 .7 2
TREATMENTS 4
3 .9 9
1 .0 0
2-F
10 111.6
11.2
0.63 1.90
9 .7 11.4
9.5 11.6
ERROR 45
23.11
0.51
3-F
10 104.3
1 0 .4
0.87 0.37
9 .7 11.4
9 .5 1 1 . 6 ------
4-F
10 104.4
1 0 .4
0.46 0.34
9 .7 11.4
9.5 11.6
TOTAL 49
27.11
5-F
10 104.3
1 0 .4
0.82 0.37
9.7 11.4
9.5 11.6
F R atio = C oeff.. Var. X =
1 .9 4 6 .7 6 0
F' t a b l e v a lu e s D u n n e tt's ' T' ta b le v alu es
F.01 = P.01 =
3 .7 8 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
Error--within groups Source-Source of Variation
LABCAT CC4.43
Treatnents-between groups
27-JUM-2002
418-028:PAGE K-148
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 4 1 8 -0 2 8 STUDY NO: 0 6 0 -0 6 9
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT' S PROCEDURE
SEX: FEMALE
Phosphorus
Group
N T otal
Mean
1-F
10 87.5
8 .8
2 -F
10 79.3
7 .9
3-F
10 90 .0
9 .0
4-F
10 87.0
8 .7
5-F
10 101.0
10.1
S td . DUNNETT'S
Dev.
t'
DUNNETV S RANGES
L0 -9 5 X - HI
LO -9 9 2 - HI
D egree S o u rc e Fdm
1 .3 3 1 .9 4 2 .8 0 2 .8 8 1 .6 4
0 .8 3 0 .2 5 0 .0 5 1 .3 7
6.3 11.2 6 .3 11.2 6.3 11.2 6.3 11.2
TREATMENTS 4
5.7 11.8
ERROR 45
5.7 11.8
5 .7 11.8
TOTAL 49
5.7 11.8
Sub o f Squares
24.53 219.09
243.62
Mean Square
6 .1 3 4 .8 7
F R atio = C o eff. Var. X =
1 .2 6 24.803
'F' ta b le values D u n n e tt's " r' ta b le v a lu es
Triglycerides
F.01 = P.01 =
3 .7 8 3.12
F.05 = P.05 =
2 .5 8 2.51
1-F
10 544
54 19.9
2-F
10 495
50 10.2 0 .54
32 77
3-F
10 490
49 29.4 0 .59
32 77
4-F
10 453
45 19.5 1.00
32 77
5-F
10 437
44 18.3 1.17
32 77
F R atio = C o eff. Var. X =
0 .4 2 4 2 .1 4 8
*F ' t a b l e v a lu e s D u n n e tt' s *T' t a b l e v a lu e s
F.01 = P.01 =
Sodium
TREATMENTS 4
26 83
ERROR 45
26 83 ------
26 83
TOTAL 49
26 83
3.78 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
693 18711
19404
173 416
1-F
10 1434
143
6 .3
TREATMENTS 4
10.92
2 .7 3
2-F
10 1427
143
2 .4 0.43
139 147
138 148
ERROR 45
587.40
13.05
3-F
10 1422
142
2 .5 0.74
139 147
138 148 ------
4-F
10 1424
142
2 .6 0.62
139 147
138 148
TOTAL 49
598.32
5-F
10 1421
142
2.6 0.80
139 147
138 148
F R atio = Coeff.. V ar. X =
0.21 2 .5 3 4
' F* t a b l e v a lu e s D u n n e tt's 'T' ta b le v a lu e s
F.01 = P.01 =
3.78 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
Error-within groups Source-Source of Variation
LABCAT CC4.43
Treataents-between groups
27-JUN-2002
418-028:PAGE K-149 Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS A18-028 STUDY NO: 0 6 0 -0 6 9
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
Potassium
Group
N T otal
Mean
S t d . DUNNETT'S
Dev.
t '
DUNNETT'S RANGES
L0 - '952- HI
L0 -9 9 2 - HI
D egree S o u rc e Fdm
1-F 10 58.1 5 .8 0 .67
TREATMENTS A
2-F
10 55. B
5 .6
0.58 0.78
5.1 6 .6
A.9 6 .7
ERROR AS
3-F
10 55.5 5 .6 0.3 2 0 .8 8
5.1 6 .6
A.9 6 .7 --
A-F
10 61.0
6.1
0.70 0.98
5.1 6 .6
A.9 6 .7
TOTAL A9
5-F
10 61.6 6 .2 0.90 1.18
5.1 6 .6
A.9 6 .7
F R atio = C oeff. Var. X =
1.8A 11.322
Chloride
'F ' ta b le values D u n n e tt's 'T ' ta b le values
F.01 = P.01 =
3 .7 8 3.12
F.05 = P.05 =
2 .5 8 2.51
1-F 10 956 96 3 .A
TREATMENTS A
2-F
10 9A1 9A 2 . 7 1 .0 1
92 99
91 100
ERROR A5
3-F
10 9A9
95
3 .8 0.A7
92 99
91 100
A-F
10 95A
95
3 .A 0.1A
92 99
91 100
TOTAL A9
5-F
10 936 9A 3 .1 1 .3 5
92 99
91 100
F R atio = C oeff. Var. X =
0 .6 6 3.A9A
Globulin
*F' t a b l e v a l u e s D u n n e tt's 'T ' ta b le values
F.01 = P.01 =
3 .7 8 3.12
F.05 = P.05 =
2 .5 8 2.51
1-F
10 19 .A
1 .9
0 .2 2
TREATMENTS A
2-F
10 15.5 1 .6 0 .2 6 A .12
1 .7 2.2* 1 .6 2.2**
ERROR A5
3-F
10 18.2
1 .8
0.21
1 .2 7
1.7 2.2
1 .6 2 .2 ------
4-F
10 17.3 1 .7 0.13 2.22
1.7 2.2
1.6 2.2
TOTAL A9
5-F
10 17.9
1 .8
0.21
1 .5 9
1.7 2.2
1.6 2.2
F R atio = Coeff. Var. 2 =
A. 56 11.982
' F' ta b le values D u n n e t t 's ' T* t a b l e v a lu e s
F.01 = P.01 *
3 .7 8 3.12
F.05 = P.05 =
2 .5 8 2.51
SEX : FEMALE
Sum o f Squares
3.23 19.67
22.90
Mean Square
0.81 0.AA
29.08 A93.00
522.08
7 .2 7 10.96
0.82 2.02
2.83
0 .2 0 O.OA
-S ig n ific a n t D ifferen ce fro a C ontrol P < .05 -S ig n ific a n t D iffere n c e fr o a C o n tro l P < .01 E rro r-w ith in groups
LABCAT CCA.A3
Source-Source of V ariation T reataents-betw een groups
27-JUN-20Q2
418-02B-.PAGE K-150
Study Report for Clinical Chemistry
SUMMARY REPORT PERIOD: TERMINAL
STUDY ID: ARGUS 418 -0 2 8 STUDY NO: 0 6 0 -0 6 9
ANALYSIS OF VARIANCE FOLLOWED BY DUNNETT'S PROCEDURE
Albumin/Globulin Ratio
S t d . DUNNETT'S
G roup
N T otal
Mean
Dev.
t'
DUNNETT'S RANGES
L0 -9 5 X - HI
LO -99% - HI
D egree S o u rc e Feist
1-F 10 21.7 2 .2 0 .2 8
TREATMENTS 4
2-F
10 26.1 2 .6 0 .4 3 3 .07
1.8 2.5* 1.7 2 .6
ERROR 45
3-F
10 22.3
2 .2
0.21
0 .4 2
1.8 2.5
1.7 2 .6
4 -F
10 23.7 2 .4 0 .2 6 1.39
1.8 2.5
1.7 2 .6
TOTAL 49
5-F
10 23.0 2 .3 0 .3 7 0.91
1.8 2.5
1.7 2.6
F R atio = C oeff. Var. X =
2 .8 3 13.734
'F ' ta b le values D u n n e t t 's ' ' r* t a b l e v a lu e s
F.01 = P.01 =
3 .7 8 3 .1 2
F.05 = P.05 =
2 .5 8 2.51
SEX: FEMALE
Su of Squares
Mean Square
1 .1 6 4 .6 3
0 .2 9 0 .1 0
5.80
* -S ig n ifie a n t D iffere n c e fro C o n tro l P < .05 E rro r-w ith in groups
LABCAT CC4.43
Source-Source of V ariatio n T reataents-betueen groups
27-JUN-2002
APPENDIX L STATEMENT OF THE STUDY DIRECTOR
90S Sheehy Drive, Bldg. A Horsham, PA 19044 Telephone: (215) 443-8710 Telefax: (215)443-8587
418-028:PAGE L-l
ARGUS RESEARCH Chartes R iver Laboratories Discovery and Development Services
PROTOCOL 418-028:
ORAL (GAVAGE) COMBINED REPEATED DOSE TOXICITY STUDY OF T-7706 WITH THE REPRODUCTION/ DEVELOPMENTAL TOXICITY SCREENING TEST
SPONSOR'S STUDY NUMBER: T-7706.1
STATEMENT OF THE STUDY DIRECTOR
This final report accurately reflects the raw data obtained during the performance of the study. No deviations from the U.S. Food and Drug Administration (FDA) Good Laboratory Practice Regulations; Final Rule3, the Japanese Ministry o f Health and Welfare (MHW) Good Laboratory Practice Standardfo r Safety Studies on Drugsb, the Organisation for Economic Co-operation and Development (OECD). The Revised OECD Principles of Good Laboratory Practices0and the Organisation for Economic Co-operation and Development (OECD), The OECD Guideline for Testing of Chemicals'1occurred that affected the quality or integrity of the study.
Argus Research
a. U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58.
b. Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard fo r Safety Studies on Drugs, MHW Ordinance No. 21, March 26,1997.
c. Organisation for Economic Co-operation and Development (1998). The Revised OECD Principles o f Good Laboratory Practices [C(97)186/Final].
d. Organisation for Economic Co-operation and Development (1996). OECD Guideline fo r Testing o f Chemicals. Section 4, No. 422: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, adopted 22 March 1996.
APPENDIX M QUALITY ASSURANCE STATEMENT
418-028: PAGE M -l
90S Sheehy Drive, Bldg. A Horsham. PA 19044 Telephone: (215) 443-8710 Telefax: (2 IS) 443-8587
ARGUS RESEARCH Charles River Laboratories
Discovery and D evelopm ent Services
QUALITY ASSURANCE STATEMENT
Argus Protocol: 418-028 Sponsor's Study Number: T-7706.1 Study Director: Raymond G. York, Ph.D., DABT
The protocol, critical phases, raw data and draft final report were inspected by the Quality Assurance Unit (QAU), to assure conformance with:
Organisation for Economic Co-operation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final].
U.S. Food and Drug Administration. Good Laboratory Practice Regulations; Final Rule. 21 CFR Part 58.
Japanese Ministry of Health and Welfare (1997). Good Laboratory Practice Standard fo r Safety Studies on Drugs, MHW Ordinance Number 21, March 26,1997.
The undersigned indicate that the report is an accurate representation of the raw data. Data provided by the Sponsor or a subcontractor were not audited by the Argus Research Quality Assurance Unit.
418-028:PAGE M-2
The QAU inspection and report audit dates are listed below:
Date(s) Findings
Submitted to Study
Inspection Phase
Inspection Datefs)
Director
Protocol
22 MAR 02
22 MAR 02
Test Substance
Administration
04 APR 02
05 APR 02
Test Substance
Preparation
05 APR 02
06 APR 02
Motor Activity
08 MAY 02
16 MAY 02
Blood Collection
09 MAY 02
10 MAY 02
Fetal Blood Collection 09 MAY 02
13 MAY 02
Fetal Liver Collection
09 MAY 02
13 MAY 02
Satellite Caesarean-
Sectioning
09 MAY 02
13 MAY 02
Male Sacrifice
14 MAY 02
14 MAY 02
Male Blood Collection 14 MAY 02
14 MAY 02
Sperm Evaluation
14 MAY 02
14 MAY 02
Litter Observations
17 MAY 02
17 MAY 02
Functional Observational
Battery
24 MAY 02
24 MAY 02
Blood Collection
30 MAY 02
04 JUN 02
Dam/Litter Sacrifice
30 MAY 02
04 JUN 02
In-Life Data
11-20 SEP 02
23 SEP 02
Necropsy Data
13-20 SEP 02
20 SEP 02
Formulation Data
17 SEP 02
17 SEP 02
Report Tables
16-23 SEP 02
23 SEP 02
24 SEP 02
24 SEP 02
Report Text
19,22-23 SEP 02 23 SEP 02
25 SEP 02
25 SEP 02
Revised Report
06 NOV 02
06 NOV 02
Date(s) Findings Submitted to Management 22 MAR 02
05 APR 02
06 APR 02 16 MAY 02 10 MAY 02 13 MAY 02 13 MAY 02
13 MAY 02 14 MAY 02 14 MAY 02 14 MAY 02 17 MAY 02
24 MAY 02 04 JUN 02 04 JUN 02 23 SEP 02 20 SEP 02 17 SEP 02 23 SEP 02 24 SEP 02 23 SEP 02 25 SEP 02 06 NOV 02
-- % d U l?
Matthew J. Vaneman, B.S.
Date
Manager of Regulatory Compliance
